Person with diabetes testing blood glucose levels

Diabetes and Glucose Control

Diabetes and Glucose Control

Last Section Update: 05/2022

Contributor(s): Robert Iafelice, MS/RD/LDN; Maureen Williams, ND; Shayna Sandhaus, PhD; Stephen Tapanes, PhD; Carrie Decker, ND, MS

1 Overview

Summary and Quick Facts for Diabetes and Glucose Control

  • When diagnosed in middle age, diabetes reduces life expectancy by roughly 10 years. Worldwide, one person dies every seven seconds from diabetes-related causes.
  • This protocol will explain the difference between type 1 and type 2 diabetes, and how elevated blood sugar, even within the conventional normal range, can damage tissues throughout the body. You will read about the dangers of insulin resistance and excess insulin, and how some of the drugs that mainstream medicine uses to treat diabetes increase insulin levels without regard to ambient glucose levels, potentially contributing to problems in the long term.
  • A self-management and self-care program that includes an understanding of home glucose monitoring, lifestyle changes and medication is critical. The goal is to bring blood sugar under control and control blood sugar- and insulin-derived damage to the heart, small and large blood vessels and other tissues.

Diabetes mellitus is characterized by high levels of glucose in the blood. Type 2 diabetes is far more common than type 1 diabetes and is mainly caused by resistance to the effects of the hormone insulin, which facilitates removal of glucose from the blood. Type 1 diabetes is primarily caused by destruction of insulin-producing pancreatic beta cells.

Chronically elevated fasting blood glucose levels—or recurrent, excessive spikes in glucose levels after meals—can lead to devastating long-term consequences such as heart disease, blindness, kidney failure, liver disease, and cancer.

Several natural products, such as white mulberry leaf extract, brown seaweed extract, cinnamon extract, and sorghum bran extract, may promote optimal glucose metabolism and help facilitate healthy glycemic control.

Diagnosis

  • Conventional diagnostic criteria for diabetes include:
    • Fasting plasma glucose 126 mg/dL or greater,
    • Non-fasting plasma glucose level 200 mg/dL or greater with diabetes symptoms,
    • Plasma glucose level 200 mg/dL or greater 2 hours after a 75-g oral glucose tolerance test, or
    • HbA1C 6.5% or greater

Note: Life Extension suggests targeting a fasting glucose level of 80 – 86 mg/dL and a HbA1C level of 5 – 5.4%.

Treatment of Type 2 Diabetes

Dietary and Lifestyle Considerations

  • Blood sugar control (as assessed by the HbA1C test) is the primary goal of diabetes treatment.
    • Note: The risk-benefit equation of intensive glycemic control may progressively shift in favor of less-intensive control as diabetes progresses.
  • Control blood pressure and lipids (see Life Extension’s High Blood Pressure and Atherosclerosis and Cardiovascular Disease protocols).
  • Eat a low-glycemic-load diet, such as the Mediterranean diet.
  • In adults with diabetes, 150 minutes per week of moderate-intensity aerobic exercise is generally recommended.

Conventional Treatment

  • Metformin is considered the first-line drug for type 2 diabetes. Metformin has also been shown to promote weight loss and protect against some cancers, cardiovascular disease, and Alzheimer disease.
  • Acarbose is a drug that lowers glucose by blocking breakdown of starches and slowing absorption of sugar and carbohydrates.
  • Other oral glucose-lowering agents or injectable drugs such as insulin may be necessary depending on individual glycemic control and diabetes severity.

Novel and Emerging Strategies

  • Stem cell therapy is aimed at replacing damaged or destroyed insulin-producing pancreatic beta cells in diabetics with new beta cells derived from human stem cells.
  • Glucokinase activators have been shown to lower glucose levels and stimulate proliferation of pancreatic beta cells in animal models of type 2 diabetes.
  • Two anti-obesity agents, lorcaserin and the combination of phentermine and topiramate, have been shown to improve glycemic control in obese individuals with type 2 diabetes.

Integrative Interventions

  • White mulberry leaf: A component of white mulberry slows carbohydrate absorption and may lessen post-meal blood sugar spikes.
  • Brown seaweed: In a randomized controlled trial, brown seaweed extract caused a 48.3% decrease in post-meal blood sugar spikes. Significant reductions in post-meal insulin concentrations and improved insulin sensitivity were also observed.
  • Cinnamon: Studies that supplemented type 2 diabetics and healthy individuals with cinnamon reported lower levels of fasting glucose, HbA1C, and after-meal glucose and insulin concentrations, as well as improvements in insulin sensitivity. These effects have been demonstrated even in those already taking glucose-lowering medication.
  • Sorghum bran: In a randomized trial in healthy men, muffins made with sorghum were shown to reduce average after-meal glucose and insulin responses.
  • Benfotiamine: In a clinical trial, type 2 diabetics consumed a high-AGE (advanced glycation end product) meal before and after a 3-day course of benfotiamine. The subjects’ vascular function was assessed after both high-AGE meals. Benfotiamine administration reduced vascular dysfunction.

Note: Under no circumstances should people suddenly stop taking antidiabetic drugs, especially insulin. Individuals with diabetes should work closely with their healthcare provider before initiating a supplement regimen due to the potential risk of hypoglycemia.

2 Introduction

Note: This protocol will focus on type 2, and to a lesser extent type 1 diabetes; readers seeking information about gestational diabetes should consult their physician.

Diabetes mellitus is characterized by high levels of glucose in the blood. Types of diabetes include type 1, type 2, and gestational. Type 2 diabetes is far more common than type 1 and is mainly caused by acquired resistance to the effects of the hormone insulin, which facilitates removal of glucose from the blood. Type 1 diabetes is primarily caused by destruction of insulin-producing pancreatic beta cells by autoimmune disease or rarely other causes such as trauma; type 1 diabetes generally necessitates lifelong insulin therapy (ADA 2015e; Kishore 2014; CDC 2015a; NIDDK 2014a; Mayo Clinic 2014; Norman 2016). Gestational diabetes is a reversible form of diabetes that occurs during pregnancy (NIDDK 2014b).

Chronically elevated fasting blood glucose levels—or recurrent, excessive spikes in glucose levels after meals—can lead to devastating long-term consequences such as heart disease and stroke, blindness, kidney failure, neuropathy, liver disease, and even cancer (Ahmadieh 2014; Kishore 2014; Szablewski 2014; Del Bene 2015; Huang 2014; Kim 2013; Fowler 2008; CDC 2015a). Abnormal glucose and insulin metabolism has been implicated in Alzheimer disease as well. In fact, this link is so compelling that many researchers have referred to Alzheimer disease as type 3 diabetes (Ahmed 2015; Halmos 2016; Mittal 2016).

When diagnosed in middle age, diabetes reduces life expectancy by roughly 10 years, and worldwide one person dies every seven seconds from diabetes-related causes (Shahbazian 2013; Gregg 2012; IDF 2014).

What is alarming, though, is that diabetes is not formally diagnosed until fasting blood glucose reaches 126 mg/dL, and levels up to 100 mg/dL are considered “normal” by mainstream medicine (NIDDK 2014c; Bjornholt 1999; Tirosh 2005).

This is regrettable—as readers of Life Extension publications have long known—because the adverse consequences of impaired glucose metabolism begin to emerge as fasting glucose surpasses about 86 mg/dL (Bjornholt 1999; Kato 2009; Muti 2002; Simons 2000; Meigs 1998).

In contrast to the conventional dogma that fasting glucose levels up to 100 mg/dL are acceptable, an upper limit for fasting glucose of 86 mg/dL is far better for longevity and health (Bjornholt 1999; Gerstein 1999). Also, maintaining a hemoglobin A1C level between 5% and 5.4% appears to be associated with several measures of health status (Cheng 2011).

In contrast to the conventional dogma that fasting glucose levels up to 100 mg/dL are acceptable, an upper limit for fasting glucose of 85 mg/dL is far better for longevity and health (Bjornholt 1999; Gerstein 1999). Also, maintaining a hemoglobin A1C level of less than 5% is likely optimal for enhanced longevity (Cheng 2011).

Type 2 diabetes can usually be significantly improved with diet and lifestyle changes, especially in the early stages (Lagger 2015; Jain 2008; Cho 2014; Lim 2011; Steven 2013). Adopting eating habits modeled after the Mediterranean dietary pattern is a proven strategy to improve cardiometabolic risk and glucose metabolism. The Mediterranean diet is rich in fresh vegetables and fruits, whole grains, nuts and seeds, and olive oil, and contains moderate amounts of fish, dairy, and red wine or other alcoholic beverages. Sweets, highly processed foods, and meat are eaten in small amounts only (Tognon 2014). Regular exercise is also important (Inzucchi 2012b; Fonseca 2013; O'Connor 2015; Whitlatch 2015).

The antidiabetic drugs metformin and acarbose lower fasting glucose with little risk of hypoglycemia, in contrast to drugs like sulfonylureas that directly stimulate insulin secretion. They can often help control glucose levels and improve insulin sensitivity in people who cannot accomplish their blood sugar goals with diet and lifestyle alone (Delgado 2002; Meneilly 2000; Gold Standard 2015c; Gold Standard 2015a). Several natural products, such as sorghum bran extract, white mulberry leaf extract, brown seaweed extract, and cinnamon extract, may also promote optimal glucose metabolism and help users attain healthy glycemic control (Andallu 2001; Hoehn 2012; Poquette 2014; Paradis 2011).

This protocol will explain the difference between type 1 and type 2 diabetes, and how elevated blood sugar, even within the conventional “normal” range, can damage tissues throughout the body. You will read about the dangers of insulin resistance and excess insulin, and how some of the drugs that mainstream medicine uses to treat diabetes increase insulin levels without regard to ambient glucose levels, potentially contributing to problems in the long term. Several novel and emerging glucose control strategies will be described, and evidence for the benefits of many natural agents that support optimal glycemic control will be reviewed.

Since diabetes greatly increases cardiovascular risk, readers of this protocol should also review these other Life Extension protocols:

3 The Difference Between Type 1 And Type 2 Diabetes

Type 1 diabetes is usually an autoimmune disorder in which the insulin-producing beta cells of the pancreas are destroyed by the body’s immune system. As a result, little or no insulin is produced, and lifelong insulin therapy is essential (Malik 2014; CDC 2015a; Kishore 2014).

Although type 1 diabetes usually appears during childhood or adolescence, it can occur at any age. It accounts for roughly 5% of diagnosed cases of diabetes (CDC 2015b; Kishore 2014; Cohen 2013). Insulin therapy should begin as soon as possible after diagnosis (Whitlatch 2015; Vimalananda 2014). Type 1 diabetes may arise due to genetic predisposition, with a potential role for viral infections and other environmental or dietary factors such as inadequate vitamin D intake (Dong 2013; Cohen 2013; Inzucchi 2012a).

Type 2 diabetes accounts for up to 95% of diabetes cases; its onset is typically after age 45, and it is more common with advancing age. Unlike the relatively rapid onset of type 1 diabetes, type 2 diabetes usually develops slowly, unnoticed by the patient until routine blood testing reveals elevated glucose (Fonseca 2013; CDC 2015b; Kishore 2014; CDC 2014; UMMC 2014).

In early type 2 diabetes, the pancreas remains capable of secreting insulin. However, as muscle, fat, and liver tissues become more insulin resistant, they may eventually become unable to respond effectively to insulin’s signal. Insulin resistance contributes to poor blood glucose control and diabetes (Wilcox 2005; DeFronzo 2009). As diabetes progressively worsens, pancreatic beta cells begin to “burn out,” and exogenous insulin is often necessary in late-stage disease (Prentki 2006; White 2003).

4 Understanding Blood Glucose Regulation And How Diabetes Develops

Glucose is a chief energy source for cells. You can obtain sugars that can be broken down into glucose from food, and the liver can manufacture glucose. In order for cells to extract energy from glucose, they must first take up glucose from the bloodstream. The hormone insulin facilitates this cellular glucose uptake and utilization (Mayo Clinic 2014).

In the simplest of terms, diabetes is the result of insufficient insulin signaling. In type 1 diabetes, the pancreas does not produce enough insulin to move glucose out of the bloodstream. In early type 2 diabetes, cells become resistant to the effects of insulin; in late-stage type 2 diabetes, pancreatic beta cell dysfunction may necessitate exogenous insulin administration (Mayo Clinic 2014; White 2003; Prentki 2006). This leads to uncontrolled blood glucose in both cases.

Glucose Levels within Conventional "Normal" Ranges Still Cause Damage

The devastating consequences of high blood sugar, both fasting and after meals, are not unique to diabetics and prediabetics. Glucose toxicity begins long before blood levels reach 126 mg/dL, the conventional diagnostic threshold for diabetes, and even before they reach 100 mg/dL, the point at which conventional medicine diagnoses “prediabetes” (Nichols 2008; Lin 2009; Levitan 2004; Pai 2013).

Glucose levels above 85 mg/dL may increase cardiovascular risk over time. This was shown in a 22-year study of nearly 2000 men. Men with fasting glucose over 85 mg/dL had a 40% increased risk of death from cardiovascular disease. The researchers stated “Fasting blood glucose in the upper normal range appears to be an important independent predictor of cardiovascular death in nondiabetic apparently healthy middle-aged men” (Bjornholt 1999).

Elevated after-meal blood sugar levels, even in the “normal” range, also predict risk of cardiovascular disease. In post-menopausal women with normal blood sugar metabolism, those with the highest post-meal blood sugar levels—though still in what conventional medicine considers to be the normal range—had increased thickness of the carotid artery wall, a marker of atherosclerosis (Alssema 2008). In an observational study of 400 nondiabetic men who were followed-up for over 15 years, higher blood sugar after an oral glucose tolerance test was associated with significantly greater risk of ischemic heart disease and fatal ischemic heart disease (Feskens 1992).

Life Extension has long advocated that fasting glucose levels should not exceed 86 mg/dL for optimal health and longevity, and 2-hour post-meal glucose levels ideally should not exceed 125 mg/dL.

Factors that Influence Blood Glucose Levels

Diet (especially processed carbohydrates). Dietary refined carbohydrates, such as processed sugars and starches, have the greatest impact on blood glucose, especially in the postprandial (after-meal) period (UIE 2014; Wheeler 2008). Life Extension has long recommended that 2-hour postprandial glucose levels be kept below 125 mg/dL. This is because acute surges in blood glucose and insulin that follow meals (postprandial period) are important contributors to the overall adverse effects caused by excessive glucose and insulin levels. Compelling evidence indicates that postprandial hyperglycemia—not just elevated fasting blood glucose—is an independent risk factor for cardiovascular disease in type 2 diabetes and prediabetes (glucose levels above 100 mg/dL but below 126 mg/dL) (Singh 2012; Zeymer 2006; Ceriello 2010; Cavalot 2006).

Body weight and adiposity. Being overweight or obese can impair glucose and insulin metabolism. Fat (adipose) tissue can release cytokines (cell-signaling molecules) such as tumor necrosis factor-alpha (TNF-α) that interfere with the action of insulin (in this context, these cytokines are referred to as “adipokines”). Immune cells called macrophages can infiltrate adipose tissue and drive further inflammatory processes that contribute to insulin resistance. This macrophage infiltration can be lessened through weight loss, and losing weight can even improve the expression profile of inflammatory genes in adipose tissue. Obesity also downregulates expression of adiponectin, which promotes insulin sensitivity under healthy conditions (Bastard 2006; Rabe 2008; Kammoun 2014; Krogh-Madsen 2006). Leptin is another key hormonal metabolic regulator that is perturbed in obesity. Leptin normally increases energy expenditure and reduces food intake. However, obesity causes resistance to the beneficial effects of leptin (Galic 2010). For more information about how excessive body weight negatively impacts health and ways to lose weight healthily, refer to Life Extension’s Weight Loss protocol.

Glycogenolysis. The liver is a critical regulator of blood glucose. One way the liver maintains normal blood glucose is by breaking down glycogen (stored carbohydrate) into glucose and releasing it into the bloodstream. This process is called glycogenolysis and provides a short-term source of glucose when blood glucose levels are low, such as during an overnight fast or a bout of intense exercise (Matsui 2012; Sprague 2011; Edgerton 2002; Roden 2008).

Normally, when blood glucose levels rise after eating, the hormone insulin suppresses glycogenolysis in the liver. However, in prediabetes and diabetes, this signal is blunted by insulin resistance in the liver. The liver then continues to release glucose in spite of already high blood levels (Edgerton 2002; Basu 2005; Nathan 2007).

Gluconeogenesis. Another way the liver regulates blood sugar is by creating new glucose from protein and other non-carbohydrate sources. This process is called gluconeogenesis. Gluconeogenesis is the cause of high fasting blood glucose after an overnight fast in type 2 diabetics (Chung 2015; Toft 2005; Magnusson 1992; Boden 2004). Insulin resistance in the liver blunts insulin’s signal to turn off gluconeogenesis (Basu 2005; Bock 2007). Metformin, the first-line drug treatment for type 2 diabetes, lowers elevated blood glucose in part by suppressing gluconeogenesis in the liver (McIntosh 2011; Nasri 2014; Gold Standard 2015c).

Increased activity of an enzyme called glucose-6-phosphatase contributes to excessive gluconeogenesis (and glycogenolysis) in diabetics. Glucose-6-phosphatase completes the final step in the creation and release of glucose in the liver (Clore 2000; Arion 1997). Chlorogenic acid, a natural compound concentrated in green coffee bean extract and specially roasted coffee, helps lower blood sugar levels by inhibiting glucose-6-phosphatase (Meng, Cao 2013).

Major Hormones Involved in Blood Glucose Regulation

Insulin. When blood glucose rises after a meal, insulin is released into the bloodstream by pancreatic beta cells. Insulin helps move glucose into cells, particularly muscle, fat, and liver cells. This process begins when insulin binds to insulin receptors embedded in cell membranes, signaling the cell to “unlock” and allow glucose to enter. Insulin also lowers high blood sugar by suppressing glucose production in the liver (NDIC 2014).

Insulin resistance is decreased responsiveness to insulin signaling. In insulin resistance, muscle, liver, and fat cells lose their sensitivity to insulin, making insulin less able to promote the movement of glucose from the bloodstream into cells. Glucose levels in the blood rise as a result. To compensate, the pancreas secretes more insulin in an effort to move sugar into the cells and maintain normal blood glucose levels. This worsens insulin resistance and increases risk of diabetes, cardiovascular disease, liver disease, and even some cancers (See “The Dangers of Excess Insulin”) (Wolpin 2013; Capasso 2013; NDIC 2014; Lopez-Alarcon 2014; DeFronzo 2009).

Excess body fat stored in and around the abdominal organs, under the muscle layer of the abdominal wall, is called visceral fat and is strongly associated with insulin resistance. Excess visceral fat and insulin resistance are strongly associated with chronic, low-grade inflammation, which may cause some of the health consequences of obesity (Hocking 2013; Hamdy 2006; Indulekha 2011; Kaess 2012; McLaughlin 2011).

Insulin resistance is the hallmark of metabolic syndrome—an increasingly common disorder diagnosed by the presence of three of five metabolic abnormalities: high blood pressure, elevated fasting triglycerides, low levels of beneficial HDL cholesterol, increased abdominal circumference, and high fasting blood glucose (Bassi 2014; Ruderman 2013; Adiels 2008). Metabolic syndrome is strongly associated with increased risk of type 2 diabetes; cardiovascular disease, including heart attack and stroke; death from any cause; non-alcoholic fatty liver disease; poor surgical outcomes; and many other conditions (Kaur 2014; Azzam 2015; Tzimas 2015; Wong 2015; Drager 2013; Kelly 2014).

The Dangers of Excess Insulin

Insulin resistance causes the pancreas to oversecrete insulin in order to reduce elevated blood glucose levels. Over time, excessive blood insulin (hyperinsulinemia) causes the body’s cells to become even more resistant to the actions of insulin (DeFronzo 2009). Eventually, if insulin resistance goes unchecked, the insulin-producing pancreatic beta cells can "burn out," becoming incapable of sustaining high insulin levels. This can lead to chronic high blood glucose and diabetic complications (NDIC 2014; Pories 2012; Madonna 2012).

(Karhapaa 1994; Hansen 2013; Feueres 2000; Raven 2011; Reaven 1988; Wang 2014; Godsland 2010; Mussig 2011; Park, Kim 2014; Dankner 2012)

High concentrations of insulin trigger pro-inflammatory signals that promote atherosclerosis. Specifically, insulin activates triglyceride formation and blood clotting pathways, and promotes proliferation of vascular smooth muscle cells, leading to thickening of artery walls. Hyperinsulinemia also contributes to endothelial dysfunction (Madonna 2012; Muntoni 2008; Wang 2014). In fact, elevated fasting insulin levels independently predict heart disease in men (Despres 1996; Reaven 1988).

The body’s own secretion of insulin is not the only potential source of dangerous excess insulin. Prescription insulin and medications that stimulate insulin release, such as sulfonylureas, carry a substantial risk of inducing severe hypoglycemia (low blood sugar) (Whitlatch 2015). Some researchers suggest using insulin injections to treat type 2 diabetes may result in excessive insulin levels, possibly worsening problems associated with diabetes (Wang 2014; Lee, Berglund 2014; Kelly 2014).

Excess blood insulin levels are thought to play a key role in the increased risk of some cancers observed in patients with type 2 diabetes (Ryu 2014; Balkau 2001; Nilsen 2001; Muntoni 2008). Insulin can stimulate cancer cell growth. Some cancer cells have an overabundance of insulin receptors, making them particularly responsive to high insulin levels. High levels of insulin may even interfere with the efficacy of anticancer therapy (Cowey 2006; Orgel 2013; Djiogue 2013; Belfiore 2011). Cancer risk increases in diabetics taking insulin or agents that stimulate insulin release. Conversely, metformin—a drug that improves insulin sensitivity—has been repeatedly shown to reduce the risk of cancer (Soranna 2012; Orgel 2013; Currie 2009; Bowker 2006; Thakkar 2013).

Glucagon. The hormone glucagon, which is produced by alpha cells in the pancreas, partners with insulin to regulate blood glucose levels. When blood glucose falls too low, glucagon is released to raise blood sugar levels to supply energy for the body. Glucagon does this by prompting the liver to break down stored carbohydrate (glycogen) into glucose. When glycogen stores become depleted, glucagon stimulates the liver to make glucose from amino acids and other noncarbohydrate molecules (Roden 2008; NDIC 2014).

Cortisol. Cortisol is a steroid hormone made by the adrenal glands that plays a critical role in the response to stress. Among other functions, cortisol raises blood glucose by activating the enzyme glucose-6-phosphatase, which stimulates gluconeogenesis in the liver. Cortisol also makes muscle and fat cells resistant to the actions of insulin (Lehrke 2008; Nussey 2001; Smith 2006).

Over the long term, elevated cortisol from chronic physical or psychological stress compromises health, in part by promoting insulin resistance and accumulation of visceral fat (Lehrke 2008; Innes 2007).

Catecholamines. The catecholamines—epinephrine (adrenalin), norepinephrine, and dopamine—are hormones released into the blood in response to physical or emotional stress (Dimsdale 1980; Goldberg 1996; Kjaer 1987). In addition to increasing heart rate and blood pressure, catecholamines increase blood glucose levels to provide energy for the “fight-or-flight” response. Catecholamines raise blood glucose by stimulating glycogenolysis and gluconeogenesis in the liver, and by inhibiting insulin-stimulated glycogen synthesis (Barth 2007). Life Extension’s Stress Management protocol describes methods to reduce the burden of chronic stress.

Incretins. Incretins are hormones secreted by cells within the gastrointestinal tract directly into the bloodstream within minutes after food intake. They stimulate insulin secretion from the pancreas. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are very important incretin hormones. Together, they account for 70% of after-meal glucose-stimulated insulin secretion (Kim, Egan 2008; Tasyurek 2014).

In addition, GLP-1 delays stomach emptying, suppresses appetite, inhibits glucagon secretion, and slows glucose production in the liver. The risk of hypoglycemia is low with GLP-1-mimetic drugs (eg, exenatide [Byetta], liraglutide [Victoza]) because their effects are dependent on high levels of glucose in the bloodstream. GLP-1 also protects insulin-producing beta cells from apoptosis (programmed cell death) and promotes their proliferation (Jellinger 2011; Kim, Egan 2008; Tasyurek 2014; Meloni 2013).

Other drugs that affect incretin function are the DPP-IV inhibitors (eg, sitagliptin [Januvia]). These compounds block the action of an enzyme, dipeptidyl peptidase-IV, which normally rapidly degrades GLP-1. As a result, more of the incretin hormones are left in circulation (Kim, Egan 2008).

Adiponectin and leptin. Adiponectin and leptin are hormones secreted from adipose tissue (fat cells) (Yadav 2013; Zuo 2013; Aleidi 2015).

Adiponectin increases glucose absorption and fat burning in muscle and liver cells, and decreases glucose production in the liver (Yadav 2013). It does this in part by activating an enzyme called AMPK—a critical cellular energy sensor—and a protein called PPAR-alpha, which turns on fat-burning genes (Coughlan 2014; Yamauchi 2003; Yamauchi 2002; Yadav 2013). Several studies show long-lived people—over the age of 100—have high concentrations of adiponectin, and suggest this may contribute to their longevity (Bik 2013; Arai 2011; Atzmon 2008; Bik 2006).

Leptin acts on the hypothalamus (control center) in the brain, causing reduced food intake and burning of fat stores for energy (Meister 2000; Zuo 2013; Zoico 2004). Leptin resistance is a condition in which the body fails to respond adequately to leptin’s satiety-inducing, fat-burning signal. Leptin resistance is a major contributor to obesity and hinders weight loss. Insulin resistant and obese individuals generally have elevated leptin levels, but are resistant to its effects (Zhou 2013; Sainz 2015; Zuo 2013; Kraegen 2008; Considine 1996). The inflammatory marker C-reactive protein (CRP) contributes to leptin resistance and weight gain by binding to leptin and reducing its signaling ability (Chen 2006; Zeki Al Hazzouri 2013).

An extract of Irvingia gabonensis, also called African mango, has been shown to produce weight loss in humans, and to lower leptin and CRP levels (Ngondi 2009; Oben, Ngondi, Blum 2008).

Type 3 Diabetes

People with type 2 diabetes also have increased risk of Alzheimer disease (Kim 2013; Park 2011). Excess insulin reduces the brain’s ability to degrade and clear away toxic proteins, such as beta-amyloid, which build up to form the plaques characteristic of Alzheimer (Barbagallo 2014; Dineley 2014; Li 2015; De Felice 2014). In fact, it has been suggested Alzheimer disease be termed “type 3 diabetes” (de la Monte 2008).

Indeed, type 2 diabetes and Alzheimer disease share some striking features. Insulin resistance is a prominent characteristic of both diseases, and autopsy studies of type 2 diabetics have shown amyloid beta—the same toxic protein that builds up in the brains of Alzheimer patients—accumulates in pancreatic endocrine cells including beta cells (Miklossy 2010).

In the brain, normal, healthy insulin signaling plays an important role in learning and memory. In fact, spatial memory training in rats has been shown to upregulate insulin receptors in the hippocampus, a region of the brain important for cognitive function and which is damaged in Alzheimer disease. Thus, resistance to the effects of insulin in the brain may contribute to cognitive deterioration by disrupting normal neuro-metabolic activity (Sandhir 2015).

Interestingly, intranasal insulin therapy has shown promise in treating cognitive dysfunction or symptoms of Alzheimer disease, as have common diabetes medications like metformin and thiazolidinediones (Halmos 2016).

Recently, intriguing research has suggested inhibiting an enzyme called glycogen synthase kinase-3 (GSK-3) may combat metabolic derangements common to both Alzheimer disease and diabetes (Eldar-Finkelman 2011; Morris 2016; Gonzalez-Reyes 2016). GSK-3 contributes to the formation of plaques and tangles, which disrupt normal cellular machinery and cause dysfunction in the brain. Blocking GSK-3 has been shown to suppress tau hyperphosphorylation and amyloid beta, which are underlying contributors to plaques and tangles. Moreover, inhibiting GSK-3 appears to promote neurogenesis, or the formation of new neurons, in the hippocampus (Maqbool 2016; Beurel 2015).

One compound rapidly gaining attention in the diabetes and Alzheimer disease research communities is lithium. GSK-3 inhibition by physiologically relevant concentrations of lithium has been noted in many studies, and lithium treatment has been shown to mitigate cognitive impairment associated with diabetes in animal models (King 2014; Beurel 2015).

Lithium’s ability to modulate brain activity is not a new discovery. The metal has been in use as psychiatric drug for more than 65 years, particularly in the treatment of bipolar disorder. More recently, studies have revealed some of the mechanisms that underlie lithium’s remarkable effects on the brain. Research has now shown that lithium increases the proliferation of neuronal progenitor cells and enhances the ability of specialized neuro-protective cells called Schwann cells to divide (Ferensztajn-Rochowiak 2016).

These effects are thought to contribute to increased synaptic plasticity. This elegant process allows the brain to adapt to new stimuli and is an important aspect of learning and memory (Rybakowski 2016; Costemale-Lacoste 2016). Lithium also appears to have several neuroprotective properties (Chiu 2010).

5 How High Blood Sugar Damages Tissues And Promotes Aging

Glucose toxicity is mediated primarily by three tissue-damaging processes: glycation, inflammation, and free radical damage. These interrelated processes contribute to complications of diabetes including endothelial dysfunction, atherosclerosis, diabetic nephropathy, and other chronic diseases (Yamagishi 2011; Yan 2014; de Carvalho Vidigal 2012; Wada 2013; de Vries 2014; Lontchi-Yimagou 2013).

Glycation and AGEs

Glycation is a process whereby sugars such as glucose bond to proteins, fats, and nucleic acids in an uncontrolled fashion. This results in the formation of toxic compounds called advanced glycation end products, or AGEs. The accumulation of AGEs in the body irreversibly modifies the structure and function of proteins such as collagen and elastin. These damaged proteins can become joined together through a mechanism called crosslinking, which causes increased stiffness and loss of elasticity in several tissues throughout the body (Nawale 2006; Simm 2013). Glycation and AGEs contribute to the aging process and age-related diseases as well as diabetic complications (Semba 2010; van Heijst 2005; Simm 2013; Nawale 2006).

One study showed plasma levels of AGEs were significantly higher in type 2 diabetic patients compared with nondiabetics. In addition, patients with diabetic complications had significantly higher levels of AGEs compared with complication-free patients. This study also showed a strong correlation between high levels of AGEs and elevated glycated hemoglobin, or hemoglobin A1C—a blood test that reflects average blood sugar levels over a 60- to 90-day period by measuring the amount of hemoglobin that has undergone glycation (Jakus 2014; Bozkaya 2010; ADA 2014a). A study in patients with type 2 diabetes followed over 10 years found that higher levels of blood AGEs predicted cardiovascular events (Hanssen 2015).

This same glycation process that “ages” our body is responsible for the browning reaction that occurs when foods are cooked at high temperatures. When meat is seared or potatoes are fried, AGEs are created (Uribarri 2010). These dietary AGEs can be absorbed into the circulation and remain in the body long enough to cause tissue damage (Vlassara 2014; Luevano-Contreras 2013). Food preparation methods that utilize high heat, such as frying, grilling, and broiling, lead to the formation of more AGEs, while cooking at lower temperatures, shorter cooking times, steaming, boiling, and the use of acids like lemon juice or vinegar in cooking minimize AGE formation (Uribarri 2010). A detailed examination of dietary AGEs and ways to avoid them is available in the Life Extension Magazine article “Are You Cooking Yourself to Death?”.

The antidiabetic drug metformin, amino acid derivative carnosine, and B-vitamin derivatives benfotiamine and pyridoxal-5’-phosphate are examples of agents that mitigate glycation- and AGE-related tissue damage (Ceriello 2009; Schurman 2008; Miyazawa 2012; Nagai 2014; Hipkiss 2005).

Inflammation

Acute inflammation is necessary to fight infections and repair damaged tissue. However, long-term, unabated inflammation can lead to chronic disease. Chronic, low-grade inflammation is a major feature of diabetes and its complications, particularly cardiovascular disease. Persistent high blood sugar, excess abdominal fat, and insulin resistance cause chronic inflammation. Acute, excessive postprandial blood sugar surges can also induce inflammation; foods high in AGEs can aggravate postprandial inflammation (Dandona 2004; Ota 2014; Agrawal 2014; Lontchi-Yimagou 2013; Nowlin 2012; Calder 2011).

Concentrations of proinflammatory cytokines including TNF-α, C-reactive protein (CRP), and interleukin-6 (IL-6) are increased in diabetes (Nguyen 2012; Lontchi-Yimagou 2013). These cytokines impair beta cell function, lowering insulin secretion (Lontchi-Yimagou 2013; Agrawal 2014).

Proinflammatory cytokines induce negative effects throughout the body. Increased levels of these cytokines “switch on” pathways that cause muscle and bone breakdown and neuronal degeneration, accelerate atherosclerosis, and damage DNA, increasing the risk of death (Kabagambe 2011; Michaud 2013; Kiraly 2015; Xu 2015).

Numerous strategies for combatting inflammation are described in the Chronic Inflammation protocol.

Free Radical Damage

Free radicals are highly reactive, unstable molecules produced in the body as byproducts of normal metabolic processes. They can also be created by environmental factors such as X-rays, ozone, tobacco smoke, and air pollution. If excessive free radicals chronically overwhelm the body’s ability to neutralize them, free radical damage can occur within cells, triggering destructive changes that can lead to degenerative disease and aging (Guo 1999; Venkataraman 2013; Lobo 2010; Ortuno-Sahagun 2014; Masters 1995; Gilgun-Sherki 2004).

Several harmful processes induced by hyperglycemia, including AGE formation, are associated with overproduction of a free radical called superoxide. While reactive oxygen species such as superoxide are a normal byproduct of energy production in mitochondria, superoxide radicals generated by glucose overload may cause diabetic complications (Giacco 2010; Ceriello 2011; Rahman 2007; Sasaki 2012).

6 Diagnosis Of Type 2 Diabetes

Conventional Diagnostic Approach

Conventional diagnostic criteria for diabetes include:

  • Fasting plasma glucose 126 mg/dL or greater (fasting glucose between 100 mg/dL and 125 mg/dL is considered “impaired fasting glucose” or “prediabetes”).
  • Non-fasting plasma glucose level 200 mg/dL or greater with diabetes symptoms.
  • Plasma glucose level 200 mg/dL or greater 2 hours after a 75-g oral glucose tolerance test.
  • Glycated hemoglobin (HbA1C) 6.5% or greater. An HbA1C of 5.7–6.4% is considered prediabetes.

Confirmation with a repeat or second test is necessary. A repeat of the same diagnostic test is preferred, though abnormal results on two different tests are also acceptable for diagnosis (O’Connor 2015; Inzucchi 2012b; Bansal 2015).

Life Extension’s Approach

A shocking number of people unknowingly suffer from chronic high blood sugar or frequent post-meal glucose surges. The longer or more frequently your blood sugar is elevated, the more time it has to cause cellular and tissue damage and promote insulin resistance, predisposing you to degenerative disease and accelerated aging. In fact, the toxic effects of excess blood sugar may be a leading cause of premature death (Nwaneri 2013; Seshasai 2011; Ding 2014; Kalyani 2013; De Tata 2014; Huang 2015).

Life Extension believes everyone should strive for optimal glucose control, regardless of whether or not they are diabetic. This means taking action to improve your glycemic control if your fasting glucose is over 86 mg/dL or your HbA1C is higher than 5.4%. Studies have shown the incidence of age-related disease begins to increase as fasting blood sugar levels climb above 85 mg/dL—a level currently accepted as normal by conventional medicine (Kato 2009; Muti 2002; Nichols 2008; Bjornholt 1999; Simons 2000; Meigs 1998; Tirosh 2005; Gerstein 1999; Coutinho 1999).

7 Type 2 Diabetes Treatment: Overview & Goals

Overview of Type 2 Diabetes Treatment

Dietary & Lifestyle Changes. For people newly diagnosed with diabetes, as well as those with pre-diabetes, comprehensive dietary and lifestyle changes are cornerstones of the initial treatment approach. Three to six months of concerted effort to make the following changes should be initiated as soon as you become aware that you have, or are at risk for, diabetes:

  1. 1) lose weight (if overweight or obese),
  2. 2) shift to a healthy, Mediterranean-style or other plant-based diet,
  3. 3) increase physical activity and exercise, and
  4. 4) incorporate an evidence-based regimen of targeted nutrient supplementation to promote healthy glucose metabolism (see section 14 of this Protocol).

Medications. If genuine efforts to improve blood sugar control using these dietary and lifestyle strategies are not successful, medications may be indicated for those with diabetes and should be initiated under the supervision of a physician. Individuals with very high HbA1C may need to begin drug therapy immediately upon diagnosis (in addition to implementing the aforementioned dietary and lifestyle changes).

Metformin has long been a top choice for the first drug to be tried if dietary and lifestyle changes are not sufficient to regain glucose control and metabolic health. The starting dosage of metformin is typically 500 mg – 850 mg once or twice daily. The dosage is generally increased over several weeks to 1,000 mg twice daily as long as gastrointestinal tolerability does not become an issue.

Other, newer drugs, such as SGLT2 inhibitors and GLP-1 receptor agonists are now also favored as first-line therapies in some cases, particularly for people who have cardiovascular and/or kidney health concerns in addition to diabetes. In some cases, drug therapy may begin with a combination of medications, such as metformin plus an SGLT2 inhibitor (which is available in a single pill for improved convenience).

Your drug regimen may be adjusted over time, possibly to include a third drug and/or insulin, depending on how you respond to initial therapy.

Determining your ideal drug treatment regimen is your physician’s responsibility. Many variables such as baseline glycemic control, comorbidities, liver and kidney function, and hypoglycemia risk influence the selection of drug therapy. A successful treatment regimen for one person with diabetes may not be appropriate for another, so working closely with your physician to plan and initiate a drug regimen is essential.

Goals of Treatment

Achieve blood sugar goals. Blood sugar control (as assessed by the HbA1C test) is a primary goal of diabetes treatment (Delamater 2006; ADA 2014c; Inzucchi 2012b; Whitlatch 2015; Fonseca 2013). The HbA1C test measures glycated hemoglobin and reflects average blood sugar over two to three months. Hemoglobin is the oxygen-carrying component of red blood cells; glycated hemoglobin is irreversibly bound to glucose, forming an advanced glycation end product (AGE). Once you are diagnosed with diabetes and begin treatment, HbA1C testing should be performed routinely to monitor how well you blood glucose is being controlled (Bozkaya 2010; ADA 2014a).

  • Target A1C Levels
    • The American Diabetes Association (ADA) recommends most diabetic patients attempt to achieve an HbA1C level of about 7% or less (ADA 2021a).
    • The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) recommend an A1C level of 6.5% or less for diabetics without concurrent serious illness and low hypoglycemia risk, and a level of about 6.5% - 7% for those with concurrent illnesses or increased hypoglycemia risk (Garber 2020).
    • A less stringent target of 8% or less may be appropriate for diabetics in whom the harms of treatment are expected to outweigh the benefits of further A1C lowering.
    • On the other hand, more aggressive treatment to goal A1C levels closer to 6% may be beneficial in diabetics with long life expectancy and in whom the benefits of more intensive treatment are expected to outweigh the risks.
  • Target fasting glucose levels
    • The ADA suggests a target fasting glucose level of 80 – 130 mg/dL for many (non-pregnant) adults with diabetes (ADA 2021a).
    • The AACE/ACE suggest a fasting glucose target of less than 110 mg/dL (Garber 2020).
    • Fasting glucose levels are not generally relied upon to independently monitor blood sugar control and should be interpreted in conjunction with A1C.
  • Target two-hour after-meal (postprandial) glucose levels
    • For people with diabetes whose A1C levels are not at goal despite fasting glucose levels being within the targeted range (80 – 130 mg/dL), the ADA suggests assessment of two-hour after-meal (postprandial) glucose levels, with a targeted level of less than 180 mg/dL (ADA 2021a).
    • The AACE/ACE suggests intensifying treatment for people with diabetes whose postprandial glucose levels are not at the target level of less than 140 mg/dL.
  • Life Extension’s suggested optimal goals for health and longevity. The following are suggested target levels for variables related to glycemic control. Note: it may be very difficult for patients with long-standing type 2 diabetes to achieve these goals. Risks of hypoglycemia should be discussed with a healthcare provider, especially among individuals who attempt intensive glucose control using drugs that stimulate insulin secretion (eg, sulfonylureas) or insulin itself.
    • Hemoglobin A1C: 5 – 5.4% (Adams 2009; Jorgensen 2004)
    • Fasting glucose: 80 ‒ 86 mg/dL (Bjornholt 1999; Kato 2009; Muti 2002; Nichols 2008; Simons 2000; Meigs 1998; Tirosh 2005; Gerstein 1999; Coutinho 1999)
    • Glucose: 125 mg/dL or less 2 hours after a meal (or no more than 40 mg/dL above baseline fasting level) (Gerstein 1999)

Risks of Intensive Glucose Control in Long-Standing Diabetes and the Need for Individualized Targets

The risk-benefit equation for intensive glycemic control may progressively shift in favor of less-intensive control as diabetes progresses. This is because the risk of hypoglycemia and associated complications inherently increases with the medications and dosages needed to maintain lower glucose and HbA1C levels in late-stage type 2 diabetes (Unger 2011).

During healthy metabolic conditions, the body regulates insulin secretion in response to blood glucose levels, avoiding hypoglycemia risk. However, as glucose metabolism becomes increasingly perturbed with advancing diabetes, tight glucose and HbA1C control may require treatment intensification by adding or increasing the doses of insulin or insulinogenic drugs such as sulfonylureas. These drugs increase insulin levels independently of glucose levels, thus posing serious risk of hypoglycemia if dosage is excessive or if glucose levels are not frequently monitored (Unger 2011).

Intensive glycemic management in patients with long-standing and advanced type 2 diabetes not only increases hypoglycemia risk, but has also been associated with increased risk of death from any cause and no reduction in cardiovascular risk in studies (ACCORD Study Group 2008; Gerstein 2011; Duckworth 2009; Inzucchi 2012d; Chokrungvaranon 2011; Mendez 2019). Although the reasons for these findings remain unclear, weight gain triggered by the use of these medications, complex medication regimes, and hypoglycemia itself are suspected contributors to the increased risk of death and lack of cardiovascular benefit (Inzucchi 2012d). In addition, sulfonylureas, which are frequently used as part of intensive glycemic control regimens, do not reduce, and may even increase, cardiovascular risk (Shimoda 2016).

The glycemic targets described as optimal in this protocol may not be suitable for individuals with long-standing diabetes. Individuals with long-standing diabetes should work closely with their healthcare provider to optimize their treatment plan and closely monitor their glucose levels to avoid hypoglycemia. Patients with late-stage type 2 diabetes may be able to significantly improve their glycemic control through motivated dietary and lifestyle changes coupled with diligent medication usage, but a brute force approach via treatment intensification with insulin or insulin secretagogues (eg, sulfonylureas) aimed at achieving the glycemic goals described in this protocol may pose greater risk than benefit. A comprehensive glycemic management plan for diabetes must take into account several variables including age, cardiovascular health, duration of diabetes, kidney function, hypoglycemia risk, and potential for medication interactions (Inzucchi 2012d; Chokrungvaranon 2011).

Reduce cardiovascular complications. Controlling blood pressure and lipids is an important part of diabetes treatment (Fonseca 2013; Whitlatch 2015; Inzucchi 2012b; O'Connor 2015). Recommendations for blood pressure targets in diabetes range from less than 130/80 mm Hg to less than 140/90 mm Hg. Statin medications are typically used as first-line cholesterol-lowering treatment (unless contraindicated) based on individualized cardiovascular risk assessment and LDL cholesterol levels (Whitlatch 2015; O'Connor 2015; Garber 2020).

Strategies for reducing cardiovascular risk are reviewed in the Atherosclerosis and Cardiovascular Disease protocol.

8 Dietary & Lifestyle Changes for Type 2 Diabetes

Dietary changes are an essential aspect of type 2 diabetes treatment. Increasing consumption of vegetables, nuts and seeds, whole grains, legumes, and fruit, as reflected in the Mediterranean dietary pattern, is an effective approach. Avoiding highly processed foods, fast food, and junk food can help reduce “empty calories” in the diet. Avoiding high-heat cooking methods can reduce exposure to dietary AGEs. Sugar-sweetened beverages, including sodas and drinks made with high-fructose corn syrup, should be eliminated. Also, eating a balanced diet can help prevent blood sugar surges, as protein, fat, and fiber may help slow glucose absorption (AHA 2014; ADA 2015a; JDC 2011; Moghaddam 2006). Typical recommendations are that low-glycemic, high-fiber carbohydrates should comprise about 45–60% of total caloric intake, fats should provide about 20–35%, and protein about 15–20% (Dworatzek 2013; Hung 1989; Bazzano 2008; Vlassara 2014; Xi 2014; ADA 2015a; Esposito 2014; Takahashi 2012; Carter 2013; Odegaard 2012). Some of the most thoroughly studied dietary considerations in the context of type 2 diabetes are briefly described below.

  • Mediterranean diet. Mediterranean-type diets are primarily characterized by abundant quantities of legumes, whole grains, vegetables, fruits, and nuts, and light-to-moderate alcohol consumption, with olive oil as a primary dietary fat (Tognon 2014). The Mediterranean diet includes moderate amounts of fish and dairy products, and low amounts of poultry, meat, highly processed foods, and refined sugars. A rigorous analysis of 10 studies involving over 136 000 participants found highest (versus lowest) compliance with the Mediterranean dietary pattern was associated with a 23% reduction in type 2 diabetes risk (Koloverou 2014). The Mediterranean diet is associated with improved glycemic control and lower risk of multiple degenerative conditions associated with advancing age and diabetes, including cardiovascular disease, cancer, obesity, lung disease, and cognitive decline (Gotsis 2015; Milenkovic 2021).
  • Caloric restriction. Caloric restriction, which has multiple health benefits, is an effective strategy in diabetes prevention and treatment. Calorie restriction has been shown to significantly improve several measures of glucose metabolism and diabetic complication risk (Colman 2009; Wing 1994; Soare 2014; Lefevre 2009; Bales 2013; Rizza 2014). The benefits of caloric restriction, and how to approach this dietary regimen, are presented in the Caloric Restriction protocol.
  • Low-glycemic-index and low-glycemic-load diet. Glycemic index and glycemic load are estimates of the impact foods have on postprandial blood sugar. Glycemic index is a numerical value that reflects the blood sugar response to a given food in comparison with the response to a specific amount of a pure glucose solution and of white bread (Sheard 2004; Barclay 2008; Juanola-Falgarona 2014; Derdemezis 2014; Afaghi 2012; Higdon 2009). Glycemic load is determined by both glycemic index as well as the total amount of carbohydrate in a food. A low glycemic load denotes a smaller expected postprandial glucose elevation than a high glycemic load (Bhupathiraju 2014; Venn 2007).

Beans, fruits, vegetables, and unsweetened dairy products are generally low-glycemic-index foods, while rice and grains (whole and refined), breads, and breakfast cereals can be high- or low-glycemic index foods, depending in part on how they are prepared. Fiber-containing foods usually have a lower glycemic index and load (Atkinson 2008; Sheard 2004; ADA 2014b; AHA 2014).

A comprehensive analysis of observational studies found that, compared with the lowest glycemic index and glycemic load diets, the highest glycemic index and glycemic load diets were associated with significantly higher risk of developing type 2 diabetes, heart disease, gallbladder disease, and other diseases. Intervention trials using low glycemic index and glycemic load diets have shown improved metabolic parameters in diabetics and overweight or obese subjects. The American Diabetes Association endorses the use of glycemic index and glycemic load as an adjunct to counting carbohydrates for controlling blood glucose (ADA 2014b; Sheard 2004; Atkinson 2008; Barclay 2008; Juanola-Falgarona 2014; Afaghi 2012).

  • Diet rich in prebiotic fibers. Consuming a diet high in fiber (especially cereal-derived whole-grain fiber) is perhaps the most well-documented dietary strategy for reducing risk of developing diabetes and helping control existing diabetes (McRae 2018; Silva 2013; Weickert 2018). Certain kinds of dietary fiber, often referred to as “prebiotics,” support healthy microbiota growth in the gut. There are many sources and types of prebiotic fibers, but some more common examples include psyllium, whole grain wheat, bananas, acacia gum, and various oligosaccharides. Upon metabolizing prebiotic fibers, the gut bacteria generate short-chain fatty acids (SCFAs) that can be used as an energy source by both bacteria and people, and which may help mitigate inflammation (Slavin 2013; Davani-Davari 2019). Type 2 diabetes is associated with deficiency in SCFA production. In a 12-week clinical study, 43 patients with type 2 diabetes were randomized to receive either standard dietary recommendations or a high-fiber diet that consisted of whole grains, traditional Chinese medicinal foods, and prebiotics. Both groups were also given acarbose. While both groups experienced improvements in HbA1c, fasting glucose, and postprandial glucose, participants in the high-fiber group experienced better glycemic control (89% achieved HbA1c < 7% vs. only 50% in the control group) and faster improvements in glucose levels. Part of this improvement was attributed to increased GLP-1 production. Those in the high-fiber group also had better reductions in body weight and blood lipid profiles. The researchers determined that the high-fiber diet promoted SCFA-producing bacterial strains, which helped improve glycemic control (Zhao 2018). Probiotic supplementation, which may also promote SCFA-producing strains, has been shown to be beneficial in type 2 diabetes as well (Perraudeau 2020; Kocsis 2020).

Diets High in Animal Protein and Fat—Potential Long-term Risks

Low-carbohydrate, high-protein diets containing relatively large amounts of animal products, protein, and fat are sometimes suggested for diabetics (Klonoff 2009; Bolla 2019). In short-term studies, lower-carbohydrate diets have shown some beneficial effects (Masharani 2015; Jonsson 2009; Boers 2014; Gower 2015). Their long-term effects on health, however, may be negative. Low-carbohydrate diets have been associated with decreased insulin sensitivity and increased risk of death from all causes, and are usually considered inadvisable in diabetes (Noto 2013; Li, Flint 2014; Fung 2010; Sheard 2004; Handa 2014). Higher intake of animal protein may account for a portion of the risk associated with this type of diet. Two large population studies found that a high-vegetable, low-carbohydrate diet was associated with lower overall mortality, whereas a low-carbohydrate diet high in animal products increased risk of death from any cause, cardiovascular death, and cancer death (Li, Flint 2014; Fung 2010).

Importantly, the concepts of “low-glycemic-index” and “low-carbohydrate” do not mean the same thing, nor do they necessarily call for reliance on proteins and fats (Mayo 2016). A whole-food, plant-based diet low in animal products, such as the Mediterranean diet, is well-known to help control blood sugar metabolism, but is not necessarily low in carbohydrates (Esposito 2014). Unrefined plant-based carbohydrates are typically paired naturally with fiber, and thus whole plant foods (eg, whole grains, vegetables, fruits, and beans) generally have less impact on glucose levels than refined, processed plant-based foods (eg, white bread, white rice) (UOS 2015).

Self-monitoring. Self-monitoring of blood glucose levels with a glucose meter is an important part of diabetes management (Benjamin 2002). Keeping a log of blood glucose readings can help patients recognize patterns and fluctuations in their blood sugar levels in relation to diet, lifestyle, and medications (Kishore 2014; Benjamin 2002; ADA 2015b). Effective self-monitoring, as part of a comprehensive treatment plan, has been shown to reduce complications of diabetes; and greater frequency of self-monitoring is associated with lower HbA1C levels (ADA 2015f).

Finger-stick glucose meters are available for purchase over the counter, and even people who are not diabetic should consider obtaining a glucose meter and periodically monitoring their fasting as well as postprandial glucose levels.

Weight loss. For individuals with diabetes who are overweight, even relatively modest weight loss has been shown to improve glycemic control and cardiovascular risk markers (Wing 1987; Wing 2011). Potential benefits include improvements in HbA1C, increased HDL cholesterol, decreased triglycerides, and lower blood pressure (ADA 2015a). Moreover, for those who are not diabetic but are overweight, losing 7% of body weight, or 15 lbs. for individuals weighing 200 lbs. or more, reduces the risk of developing type 2 diabetes by 58% (Diabetes Prevention Program (DPP) Research Group 2002; NIDDK 2012). In obese individuals with diabetes, weight loss of about 15 kg (33 lbs.), achieved by a regimen involving calorie restriction, can lead to remission of type 2 diabetes in about 80% of individuals (Magkos 2020). Several strategies to promote healthy weight loss are reviewed in the Weight Loss protocol.

Physical activity. Regular exercise improves blood glucose control, lowers risk of cardiovascular disease, aids in weight loss, and improves overall health. It may also prevent development of diabetes in those at high risk. In adults with diabetes, a minimum of 150 minutes per week of moderate-intensity aerobic exercise (to 50‒70% max heart rate) or vigorous aerobic exercise (to >70% max heart rate) is generally recommended. Seventy-five minutes of vigorous-intensity activity may suffice for younger and physically fit individuals. Additional strength training is also beneficial at least twice weekly. Adults over 65 or those with disabilities for whom this level of activity is not possible should be as physically active as possible. Sedentary time should be minimized and prolonged sitting should be interrupted every 30 minutes for blood glucose benefits (ADA 2021b). Moderate exercise, such as rapid walking for 30 minutes per day, five days per week, has been shown to substantially lower the risk of type 2 diabetes (Colberg 2010). Methods to maximize the benefits of exercise are described in Life Extension’s Exercise Enhancement protocol.

Comprehensive Lifestyle Changes for Diabetes Control

Dietary and lifestyle changes work best when used together.

In a randomized controlled trial of 147 overweight adults with type 2 diabetes, an intensive lifestyle intervention program (which included changes to diet and physical activity, and structured lifestyle support) was more effective than usual medical care at reducing body weight, improving glycemic control, and inducing remission of type 2 diabetes. The lifestyle intervention program included low-calorie meal replacements in the first phase followed by a gradual reintroduction of food, plus exercise and lifestyle support. Participants in the intervention group lost over three times as much weight as those in the control group during the 12-month study. In addition, 61% of participants in the intervention group experienced remission of their diabetes, compared with only 12% in the control group. The intervention group also had better glucose control (Taheri 2020). This study reinforces the standard of care for people with diabetes and prediabetes to include both dietary changes and a physical activity regimen, with the help of their doctor, in order to take a comprehensive approach to diabetes and glucose control (ADA 2021b).

9 Starting Drug Therapy for Type 2 Diabetes: What to Expect

When you are newly diagnosed with diabetes, your doctor will assess your current health status (particularly your cardiovascular and kidney health), blood sugar control, and overall risk for further health problems before selecting the treatment strategy best suited to your needs. Depending on your baseline assessment, your doctor may start you on a single drug (monotherapy) or more than one drug with different mechanisms of action (combination therapy).

Chart showing the benefits of blood sugar balance Figure 1: Sites of action of Pharmacological Therapies for the Treatment of Type 2 Diabetes. Adapted with permission from Endotext (Feingold 2000).

What follows is a general overview of some common approaches to drug treatment of type 2 diabetes based upon initial blood sugar control and health status. These approaches will not be suitable for everyone and are presented here only to help you generally understand what to expect when beginning drug therapy.

Monotherapy versus Combination Therapy

The decision to initiate drug therapy with metformin alone or in combination with another agent is influenced by HbA1C level and health status when diabetes is newly diagnosed. The presence and severity of symptoms as well as health status and comorbidities will influence the selection drugs for combination therapy.

First-line medication (if not contraindicated) is typically metformin; additional medication selection is based on age, life expectancy, and comorbidities such as heart or kidney disease (Feingold 2000; Wexler 2021a). The dosage of most hypoglycemic medications is gradually increased, if needed, according to a prescribed dosing schedule and therapeutic glycemic targets or until maximal dosage is reached. However, dosage may be limited by kidney (or liver) function, as well as side effects of treatment.

For patients with cardiovascular or kidney disease, SGLT2 inhibitors or GLP-1 receptor agonists (oral or injectable) may be considered as part of first-line therapy for their cardiorenal benefits. A review and analysis of trials of GLP-1 receptor agonists found that they reduce the risk of cardiovascular and all-cause mortality and stroke; this review also found that these drugs appear to reduce the risk of decline in kidney function. The same analysis found that SGLT2 inhibitors also reduce the risk of cardiovascular and all-cause mortality, protect kidney function, and reduce the risk of hospitalization for heart failure (Htike 2017; Kanie 2021; Liu 2015; Rehman 2017).

Although weight loss is an important consideration for a considerable proportion of type 2 diabetics, medication is not first-line therapy for weight loss, at least in part due to medication side effects (Wexler 2021a). However, among the glycemia-lowering agents used in diabetes care, liraglutide 3 mg (a GLP-1 receptor agonist) is the most clearly indicated for weight loss (Garber 2020). The treatment selected must consider the additional potential benefits, contraindications, and side effects (some of which are described above) on a case-by-case basis. Beyond this, selection may be guided by cost and the availability of generic alternatives, although safety and efficacy should be higher priorities.

Your doctor will follow-up with you regularly to evaluate your progress and watch for medication-associated adverse events. If target goals are not being achieved at maximum medication dosage, a medication from another category may be added. However, keep in mind that if a medication is added as a third agent, it is typically less effective in lowering glucose than if it was used as a first- or second-line agent.5

Chart for new type 2 diabetes diagnosis Figure 2: Example of Pharmacological Treatment Approaches to Newly Diagnosed Type 2 Diabetes.

Initial HbA1C Levels and Therapeutic Selection

HbA1C < 7.5%. Metformin is the preferred first-line pharmacologic agent for the treatment of type 2 diabetes in those for whom it is not contraindicated due to its efficacy, favorable side effect profile, and affordability (Garber 2020). In the absence of cardiovascular or renal disease, newly diagnosed diabetics with HbA1C levels below 7.5% are typically started on metformin plus dietary and lifestyle changes. An SGLT2 inhibitor or GLP-1 receptor agonist may be started as an alternate first-line agent in people with pre-existing cardiovascular or renal disease. Diet and lifestyle changes, including weight loss for those who are overweight, are key parts of treating diabetes at all stages, and are a very important cornerstone of treatment.

Simplified approach to monotherapy Figure 1: Simplified approach to monotherapy for patients with baseline HbA1C < 7.5%. *Additional drugs that may be considered: DPP4i, TZD, AGi, SU/GLN. This algorithm will not be appropriate for all patients. Treatment regimens should be individualized based upon patient health status and risk profile (Garber 2020).

HbA1C ≥ 7.5% and < 9%. For newly diagnosed diabetics with an HbA1C of ≥ 7.5% to < 9%, a combination of metformin and one or two additional pharmacologic agents, in addition to intensive and comprehensive diet and lifestyle changes, is indicated to most effectively control blood sugar. Data support the use of combination therapies at the time of diagnosis for more rapid glucose lowering effects, particularly if HbA1C levels are 1.5–2.0% above the target goal (Garber 2020; ADA 2021c). Therapies used in combination should have complementary mechanisms of action (and not be within the same category) so they act simultaneously by different pathways to achieve treatment goals (Garber 2020). Because antidiabetic medications are often used in combination, single-pill options with fixed doses are available, which may improve compliance. Available combinations of oral medications include metformin and/or SGLT2 inhibitors, DPP4 inhibitors, thiazolidinediones, and sulfonylureas.

Simplified approach to dual and triple therapy Figure 2: Simplified approach to dual and triple therapy for patients with baseline HbA1C ≥ 7.5%‒9.0%. †Additional drugs that may be considered: DPP4i, TZD, Agi, SU/GLN, basal insulin, colesevelam, bromocriptine QR, AGi. ‡Additional drugs that may be considered: TZD, SU/GLN, basal insulin, DPP4i, colesevelam, bromocriptine QR, AGi. This algorithm will not be appropriate for all patients. Treatment regimens should be individualized based upon patient health status and risk profile (Garber 2020).

A1C > 9%. If HbA1C levels are 9.0% or higher, initial treatment may comprise two or three medications at maximal dosages. Insulin may be added if there are symptoms of hyperglycemia (excessive thirst, hunger, or urination or unintentional weight loss). A 2021 analysis of three-year follow-up data from the EDICT (Efficacy and Durability of Initial Combination Therapy) randomized controlled trial found that initiation of triple therapy with metformin, pioglitazone, and exenatide at the time of diagnosis not only led to greater improvements in HbA1C values at six months, it also significantly reduced HbA1C levels by 0.5% more than sequential initiation of metformin followed by glipizide and insulin in diabetics with a HbA1C value of approximately 9% (Abdul-Ghani 2021). Furthermore, triple therapy increased insulin sensitivity three-fold and beta-cell function 30-fold while sequential treatment did not improve insulin sensitivity and led to a more modest 34% increase in beta-cell function.

10 Overview of Type 2 Diabetes Drugs

Oral Type 2 Diabetes Drugs

There are 10 classes of oral drugs used to treat type 2 diabetes (Feingold 2000; Lexicomp 2022). These drugs may be used alone (monotherapy) or in combinations of two or more medications from different classes. Also, several branded products that combine two drugs from different classes into a single pill are available.

  • Biguanide (metformin)
    • Primary mechanism(s) of action
      • Reduces glucose production in the liver and improves liver insulin sensitivity. Metformin also alters the intestinal microbiome (Vallianou 2019), increases intestinal glucose utilization, and stimulates GLP-1 secretion.
    • Examples
      • Metformin
        • Dosage
          • Immediate release
            • Initial: 500 mg once or twice daily OR 850 mg once daily
            • Maximum: 2,550 mg daily (dosages above 2,000 mg daily are typically administered in three divided doses)
          • Extended release
            • Initial: 500–1,000 mg once daily
            • Maximum: 2,000 mg daily
    • Possible side effects include:
      • Gastrointestinal: diarrhea, nausea, and/or abdominal discomfort
      • Vitamin B12 deficiency (and elevated homocysteine)
      • Testosterone reduction (blood tests can measure this and natural testosterone prescription creams may be considered)
  • Oral glucagon-like peptide-1 (GLP-1) receptor agonist
    • Primary mechanism(s) of action
      • Enhance incretin signaling to increase glucose-dependent insulin secretion, reduce post-prandial glucagon, and delay gastric emptying (resulting in reduced after-meal glucose levels and increased satiety)
    • Examples
      • Semaglutide (Rybelsus) is the only approved medication in this class as of early 2022.
        • Dosage:
          • Initial: 3 mg once daily for 30 days. It may then be increased, if indicated, to 7 mg once daily.
          • Maximum: 14 mg once daily, if 7 mg dose is insufficient
    • Possible side effects include:
      • Gastrointestinal: nausea, vomiting, diarrhea
      • The long-term safety of GLP-1 receptor agonists has not yet been established.
  • Sodium-glucose transport protein 2 (SGLT2) inhibitors
    • Primary mechanism(s) of action
      • Reduce reabsorption of glucose in the kidneys (renal tubules) by inhibiting sodium-glucose transport protein 2 (SGLT2). This leads to increased urinary glucose excretion.
    • Examples
      • Canagliflozin (Invokana)
        • Dosage
          • Initial: 100 mg once daily before the first meal of the day
          • Maximum: 300 mg once daily
      • Dapagliflozin (Farxiga)
        • Dosage
          • Initial: 5‒10 mg once daily
          • Maximum: 10 mg once daily
      • Empagliflozin (Jardiance)
        • Dosage
          • Initial: 10 mg once daily
          • Maximum: 25 mg once daily
    • Possible side effects include:
      • Urinary tract infections
      • Genital fungal (mycotic) infections (ie, Candida infection)
      • Hypovolemia (low extracellular fluid) and hypotension (low blood pressure)
      • Acute kidney injury, possibly as a result of volume depletion (limited and contradictory evidence)
      • Diabetic ketoacidosis (rare)
      • Osteoporosis and bone fractures
  • Dipeptidyl peptidase-IV (DPP-4) inhibitors
    • Primary mechanism(s) of action
      • Enhance incretin signaling via inhibition of the enzyme dipeptidyl peptidase-IV (DPP-4), which breaks down GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). This results in increased concentrations of GLP-1 and GIP (incretin hormones), both of which stimulate insulin secretion, while GLP-1 also promotes satiety.
    • Examples
      • Sitagliptin (Januvia)
        • Dosage
          • Initial: 25–100 mg once daily (depending on kidney function)
          • Maximum: 100 mg once daily
      • Saxagliptin (Onglyza)
        • Dosage
          • Initial: 2.5–5 mg once daily
          • Maximum: 5 mg once daily
      • Linagliptin (Tradjenta)
        • Dosage
          • Initial: 5 mg once daily
          • Maximum: 5 mg once daily
      • Alogliptin (Nesina)
        • Dosage
          • Initial: 6.25–25 mg once daily (depending on kidney function)
          • Maximum: 25 mg once daily
    • Possible side effects include:
      • Acute pancreatitis (this appears to be rare)
      • Severe joint pain
  • Thiazolidinediones (TZDs)
    • Primary mechanism(s) of action
      • Modulation of glucose and lipid metabolism via activation of the PPAR-gamma nuclear hormone receptor. This leads to reduction of insulin resistance/improved insulin sensitivity and decreased fat accumulation in the liver, muscle, and pancreas.
    • Examples
      • Pioglitazone (Actos)
        • Dosage
          • Initial: 15–30 mg once daily
          • Maximum: 45 mg daily
      • Rosiglitazone (Avandia)
        • Dosage
          • Initial: 4 mg daily as a single dose or in two divided doses
          • Maximum: 8 mg daily as a single dose or in two divided doses
    • Possible side effects include:
      • Weight gain
      • Fluid retention (edema), including macular edema
      • Increased risk of heart failure (related to fluid retention)
      • Osteoporosis and bone fracture
      • Possible increased risk of bladder cancer with pioglitazone
  • Alpha-glucosidase inhibitors
    • Primary mechanism(s) of action
      • Inhibition of intestinal α-glucosidase and pancreatic α-amylase, which reduces carbohydrate absorption.
    • Examples
      • Acarbose (Precose)
        • Dosage
          • Initial: 25 mg three times daily with first bite of each meal
          • Maximum: Generally 300 mg, with meals, per day
      • Miglitol (Glyset)
        • Dosage
          • Initial: 25 mg three times daily at the start of each meal
          • Maximum: 50 mg three times daily
      • Possible side effects include:
        • Gastrointestinal: flatulence (gas), abdominal discomfort, diarrhea
          • High-carbohydrate diet may worsen these side effects
          • Gastrointestinal side effects usually become less pronounced with continued use
        • Liver enzyme (transaminases) elevation
  • Sulfonylureas
    • Primary mechanism(s) of action
      • Sulfonylureas stimulate insulin release by pancreatic beta cells. Their effect is independent of blood glucose levels.
    • Examples
      • Glyburide [glybenclamide] (Glynase)
        • Dosage
          • Micronized
            • Initial: 0.75–3 mg once daily with the first main meal
            • Maximum: 12 mg daily
          • Conventional:
            • Initial: 1.25–5 mg once daily with the first main meal
            • Maximum: 20 mg daily
      • Glipizide (Glucotrol, Glucotrol XL)
        • Dosage
          • Immediate release
            • Initial: 2.5–5 mg daily 30 minutes before first meal. Higher doses may necessitate divided dose (twice/day) administration.
            • Maximum: 20 mg daily
          • Extended release
            • Initial: 2.5–5 mg once daily with first main meal
            • Maximum: 20 mg daily
      • Glimepiride (Amaryl)
        • Dosage
          • Initial: 1–2 mg once daily with first main meal
          • Maximum: 8 mg daily
    • Possible side effects include:
      • Hypoglycemia
      • Weight gain
  • Meglitinides (glinides)
    • Primary mechanism(s) of action
      • Meglitinides stimulate insulin release by pancreatic beta cells. Their effect is dependent on glucose levels. Their effects have a rapid onset but do not last long.
    • Examples
      • Repaglinide (Prandin)
        • Dosage
          • Initial: 0.5–2 mg before each meal, up to four times daily
          • Maximum: 16 mg daily, 4 mg per dose
      • Nateglinide (Starlix)
        • Dosage
          • Initial: 60–120 mg before meals, up to three times daily
          • Maximum: 360 mg daily, 120 mg per dose
    • Possible side effects include:
      • Hypoglycemia (lower risk than sulfonylureas)
      • Weight gain
  • Bile acid sequestrants
    • Primary mechanism(s) of action
      • Bile acid sequestrants were originally developed and approved to lower LDL-cholesterol. The mechanism(s) by which they lower glucose are unclear, although an increase in GLP-1 and GIP may be involved.
    • Example
      • Colesevelam (Welchol)
        • Dosage
          • Initial: 3,750 mg daily, either in one dose or divided into two doses (available as pills or packets of powder)
          • Maximum: 3,750 mg in one or two doses
  • Bromocriptine-QR [Cycloset] (a dopamine agonist)
    • Primary mechanism(s) of action
      • Acts on the central nervous system, particularly the hypothalamus, as a dopamine D2 receptor agonist, increasing insulin sensitivity in liver, muscle, and fat (adipose tissue)
    • Dosage
      • Initial: 0.8 mg once daily, within two hours of waking
      • Maximum: 4.8 mg daily
    • Possible side effects include:
      • Nausea and vomiting (usually improves with continued use)
      • Low blood pressure (hypotension)

Injectable (Non-Insulin) Type 2 Diabetes Drugs

There are three classes of injectable drugs approved to treat type 2 diabetes. Insulin also may be included in combination with other therapies if glucose or HbA1C levels are particularly high for a faster glucose lowering effect. If the individual is experiencing symptoms of hyperglycemia such as increased urination or thirst or unintentional weight loss along with very high blood sugar, insulin is typically indicated (Feingold 2000; ADA 2021c; Lexicomp 2022).

  • GLP-1 receptor agonists
    • Primary mechanism(s) of action
      • Increase glucose-dependent insulin secretion, reduce post-prandial glucagon, and delay gastric emptying (resulting in reduced after meal glucose levels and increased satiety)
    • Examples
      • Exenatide (Byetta 10 mcg Pen, Byetta 5 mcg Pen, Bydureon BCise 2 mcg Pen)
        • Dosage
          • Immediate release (Byetta)
            • Initial: 5 mcg subcutaneous injection twice daily a maximum of 60 minutes before morning and evening meals, or before the two main meals of the day
            • Maximum: 10 mcg subcutaneous injection twice daily a maximum of 60 minutes before morning and evening meals, or before the two main meals of the day
          • Extended release (Bydureon BCise)
            • Initial: 2 mg subcutaneous injection once weekly
            • Maximum: 2 mg subcutaneous injection weekly
      • Lixisenatide (Adlyxin) – Short-acting
        • Dosage
          • Initial: 10 mcg subcutaneous injection once daily, up to one hour before the first meal of the day, for 14 days; then increase to 20 mcg once daily on day 15
          • Maximum: 20 mcg subcutaneous injection once daily
      • Liraglutide (Victoza) – Long-acting
          • Dosage
            • Initial: 0.6 mg subcutaneous injection once daily for one week, then increase to 1.2 mg once daily
            • Maximum: 1.8 mg subcutaneous injection once daily
      • Dulaglutide (Trulicity) – Long-acting
        • Dosage
          • Initial: 0.75 mg subcutaneous injection once weekly, then may increase to 1.5 mg once weekly after four to eight weeks if needed to achieve blood sugar goals
          • Maximum: 4.5 mg subcutaneous injection once weekly. Dosage increased only after a minimum of four weeks at the prior dose.
      • Semaglutide (Ozempic) – Long-acting
        • Dosage
          • Initial: 0.25 mg subcutaneous injection once weekly for four weeks. This dosage is intended for treatment initiation only, not for glycemic control. Then, increase to 0.5 mg once weekly.
          • Maximum: 1 mg subcutaneous injection once weekly, only after a minimum of four weeks at the 0.5 mg dose does not sufficiently control glycemia.
    • Possible side effects include:
      • The long-term safety of GLP-1 receptor agonists has not yet been established.
      • Gastrointestinal: nausea, vomiting, diarrhea. Nausea may decrease over time and may respond to dose titration.
      • Gall bladder/bile duct disease
      • Acute pancreatitis and other pancreatic disorders have been reported, though the relationship to treatment is unclear
      • Injection-site reactions
  • Dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist
    • Primary mechanism(s) of action
      • Selectively binds and activates both GIP and GLP-1 receptors
    • Example
      • Tirzepatide (Mounjaro)
        • Dosage
          • Initial: 2.5 mg subcutaneous injection once weekly, titrated up to 5 mg weekly after 4 weeks
            • If additional glycemic control is needed, dosage can be increased in 2.5 mg increments after at least 4 weeks on the current dosage.
          • Maximum: 15 mg subcutaneous injection once weekly
    • Possible side effects include:
      • Gastrointestinal (eg, nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, abdominal pain)
      • Pancreatitis
      • Acute gallbladder disease
      • Hypoglycemia (when used with insulin or insulin secretagogues)
      • Changes in vision (people with a history of diabetic retinopathy should be monitored closely)
      • Acute kidney injury (primarily in people with pre-existing kidney problems who experience gastrointestinal side effects)
      • Allergic reactions (eg, swelling, rash, dizziness)
  • Amylin mimetic
    • Primary mechanism(s) of action
      • Reduces glucagon secretion, slows gastric emptying, suppresses appetite
    • Example
      • Pramlintide (SymlinPen 60, SymlinPen 120)
        • Dosage
          • Initial: 60 mcg subcutaneous injection immediately before each major meal, then increase to 120 mcg subcutaneous injection before each major meal if no significant nausea occurs after three days
          • Maximum: 120 mcg subcutaneous injection before each major meal
    • Possible side effects include:
      • Nausea

11 Type 2 Diabetes Drugs – Additional Details

Oral Drugs

Metformin has long been the preferred first-line pharmacologic agent for the treatment of type 2 diabetes in those for whom it is not contraindicated (namely those with significant kidney dysfunction, alcohol abuse, liver disease, unstable or acute heart failure, or elevated risk of lactic acidosis) (ADA 2021c; Wexler 2021a). It is well-tolerated, inexpensive, and does not increase risk of hypoglycemia or weight gain. However, with the more recently introduced SGLT2 inhibitors and GLP-1 receptor agonists having shown impressive cardiovascular risk reduction in addition to glycemic control efficacy, these newer agents may also be considered as first-line therapies in patients with pre-existing cardiovascular or renal disease (Garber 2020). Nevertheless, metformin remains the typical first-line choice because of its well-established safety profile, efficacy, low cost, and wide accessibility (Wexler 2021b).

Life Extension has reported on the myriad potential health and longevity benefits of metformin for many years. In addition to its glucose-lowering benefits, metformin has been clinically demonstrated to have anti-cancer effects, especially as regards pancreatic, colorectal, and liver cancers (Yu 2019; Kasznicki 2014). There has also been considerable interest in metformin’s ability to protect cardiovascular health, and it has been shown to protect the heart and prolong life in patients with heart failure (Monami 2021; Halabi 2020). The potential of metformin as a more general anti-aging drug is being actively investigated (Glossmann 2019).

Gastrointestinal side effects are common upon initiation of metformin therapy but can also begin anew in patients who have taken metformin for many years. These side effects can often be managed by taking the medication with food, taking a drug holiday, switching to an extended-release formulation, or starting with a low dosage and gradually increasing over time (Wexler 2021b). However, if metformin is still not tolerated, the presence (or absence) of comorbidities helps inform the choice of alternative medications.

Chemically, metformin resembles naturally occurring biguanide molecules in the French lilac, a plant used in traditional medicine for hundreds of years (Witters 2001). Metformin, the only biguanide medication currently available for the treatment of diabetes, is considered the first-line drug for type 2 diabetes (Misbin 2004; Kajbaf 2016). The primary reason is that the glucose-lowering action of metformin, when used alone, is at least as effective as that of any other oral glucose-lowering drug, without promoting weight gain and only rarely causing excessively low blood sugar. Also, metformin can be safely used with other drugs, including insulin. According to the American Diabetes Association and the European Association for the Study of Diabetes, metformin therapy, together with lifestyle intervention, should be initiated at the time of diagnosis of type 2 diabetes. Metformin was selected as first-line treatment because of its record of safety and efficacy, as well as its low cost (Gold Standard 2015). Worldwide, metformin is prescribed to over 100 million patients annually (Inzucchi 2012c; Rena 2013; Scheen 2013).

Metformin lowers blood glucose by several different mechanisms (Viollet 2012; LaMoia 2021). Its main modes of action are suppressing glucose production in the liver, mostly through inhibition of gluconeogenesis, and opposing the activity of the hormone glucagon (Kishore 2014; Pernicova 2014; LaMoia 2021). Metformin also functions as an insulin sensitizer, and it decreases intestinal glucose absorption (Gold Standard 2015). Unlike other antidiabetic drugs that cause the pancreas to secrete more insulin, metformin makes the body’s tissues more sensitive to insulin, thus reducing insulin resistance (Nasri 2014). Side effects of metformin may include gastrointestinal distress or a slight taste disturbance, usually a metallic taste. Rarely, metformin may cause potentially serious lactic acidosis, a buildup of lactic acid in the blood (Diabetes.co.uk 2016).

The health benefits of metformin extend beyond diabetes. In particular, abundant evidence indicates metformin has significant anti-cancer activity. In a large, rigorous review of over 50 studies involving more than one million patients, metformin use in patients with type 2 diabetes was associated with a 35% reduction in risk of death from cancer, and a 27% reduction in risk of any cancer (Franciosi 2013). In a study of over 1000 breast cancer patients with diabetes, those taking metformin had an almost 24% lower mortality risk compared with controls, whereas those not taking metformin had an almost 71% higher mortality risk (Hou 2013). Numerous epidemiologic and observational studies have also found metformin use is associated with dramatically reduced risk of developing cancer (Morales 2015). Clinical trials are investigating metformin as an anti-cancer therapy in breast, prostate, endometrial, and pancreatic cancers (Dowling 2011). In addition to its benefits in diabetes and cancer, metformin has been shown to promote weight loss and protect against cardiovascular disease, Alzheimer disease, and non-alcoholic fatty liver disease (Forouzandeh 2014; Blagosklonny 2009; Gupta 2011; Mazza 2012; Berstein 2012; Miles 2014; LaMoia 2021).

In fact, metformin shows such great promise as an anti-aging drug (Martin-Montalvo 2013; Anisimov 2013; Violett 2012; Blagosklonny 2009; Greer 2007) that the US Food and Drug Administration (FDA) approved a large-scale clinical trial—the Targeting Aging with Metformin (TAME) trial—to test its effects on biological aging (AFAR 2016).

One underlying reason for metformin’s many benefits is thought to be its ability to activate AMPK—a critical enzyme that functions as a key regulator of energy balance in the body (Coughlan 2014; Boyle 2010; Trefts 2021). AMPK (adenosine monophosphate-activated protein kinase) is a major hub for a network of cell signaling that, when activated, keeps the metabolism running smoothly (Ruderman 2013). Activation of AMPK, for example, signals cells to burn glucose and fatty acids for energy rather than store them as body fat. Exercise and calorie restriction are proven methods to boost AMPK activity. However, the body’s response to AMPK signaling becomes blunted with age. Disturbances in AMPK signaling and overall energy balance lead to chronic inflammation, obesity, and the development of age-related diseases (Lee 2013; Lee 2006; Rana 2015). AMPK even helps control the aging process itself by inducing several known longevity factors (such as SIRT1) that have been shown to extend lifespan in many organisms (Salminen 2011).

Since metformin is a prescription medication, people without diabetes may have difficulty accessing it. Fortunately, medicinal plants, such as Gynostemma pentaphyllum, may activate AMPK and provide some of the same metabolic benefits as metformin (Yoo 2016).

Another explanation for metformin’s wide-ranging benefits has more recently gained recognition: its ability to impact the gut and the intestinal microbial community (microbiome) (McCreight 2016; Pryor 2015). The intestinal microbiome is increasingly thought to be a crucial factor in the development of obesity and diabetes (Palau-Rodriguez 2015; Hur 2015), and a growing body of laboratory, animal, and human research indicates metformin may normalize the disturbed microbial balance associated with abnormal glucose metabolism (Pryor 2015; Forslund 2015; McCreight 2016).

In a pilot study, 12 diabetic subjects being treated with metformin were examined as they discontinued and then re-started their metformin treatment. Tests showed that, within one week of stopping metformin, bile acid metabolism was altered such that total bile acid levels were increased, and levels of GLP-1, which is derived from intestinal cells, were decreased. Both of these changes point to alterations in digestive system functioning. In addition, significant individual changes in the composition of the intestinal microbiome were seen. These effects were reversed when metformin was reintroduced (Napolitano 2014).

Findings from a two-part study add to evidence that the gut is an important site of metformin’s action. In the first phase, 20 overweight but otherwise healthy individuals were treated with four distinct metformin preparations, each for one day. Metformin (immediate release, extended release, and two doses of delayed release) were used. The delayed-release preparations, designed to deliver metformin to the lower small intestine, were found to be poorly absorbed, resulting in lower metformin blood levels than the other preparations. In the second phase, 240 subjects with type 2 diabetes were treated with a placebo; delayed-release metformin with breakfast at doses of 600 mg, 800 mg, or 1000 mg; or extended-release metformin with evening meals at doses of 1000 or 2000 mg for 12 weeks. At all doses, the delayed-release metformin preparation had a significant effect on blood glucose and HbA1C levels versus placebo. Delayed-release metformin was about half as bioavailable as immediate-release or extended-release metformin, but was about 40% more potent than extended-release metformin in reducing fasting plasma glucose. Based on this research, it appears a significant proportion of metformin’s action could be attributed to its effect on the lower digestive tract (Buse 2016).

Metformin and Vitamin B12

Metformin is the preferred first-line drug for type 2 diabetes. It is one of the few antidiabetic agents associated with reduced risk of cardiovascular disease and cancer, and does not cause weight gain or hypoglycemia. Metformin, however, does interfere with absorption of vitamin B12, increasing the risk of vitamin B12 deficiency. Low B12 levels, in turn, may contribute to elevated concentrations of homocysteine—an independent risk factor for cardiovascular disease (Strack 2008; Davidson 1997; Kasznicki 2014; de Jager 2010). In a 2015 review, 15 of 22 studies showed a significant decrease in serum vitamin B12 in people taking metformin (Niafar 2015). Duration of metformin usage has been tied to risk of B12 deficiency, with risk rising about 13% for each additional year of usage (Aroda 2016).

Regular testing of serum B12 and plasma homocysteine levels in patients on long-term metformin therapy is advised, and those taking metformin should supplement with vitamin B12 (de Jager 2010; Mahajan 2010).

Acarbose. Acarbose belongs to a class of drugs called alpha-glucosidase inhibitors, commonly referred to as “starch blockers.” These drugs lower glucose by blocking breakdown of starches and slowing absorption of sugar and carbohydrates (ADA 2015d).

Acarbose is the most researched and widely used of the alpha-glucosidase inhibitors (Josse 2006). In China, the country with the largest diabetic population, acarbose is one of the most commonly prescribed oral glucose-lowering medications (Standl 2014; Gu 2015). Like metformin, acarbose is effective as a first-line drug for type 2 diabetes insufficiently controlled by diet alone, and does not stimulate insulin secretion or cause hypoglycemia or weight gain. Acarbose blocks the intestinal enzyme alpha-glucosidase needed to digest complex carbohydrates (eg, starches) into simple sugars such as glucose that can be easily absorbed into the bloodstream. As a result, acarbose helps reduce after-meal blood sugar levels (Campbell 1996; Hanefeld 1998; Gu 2015; Joshi 2014; Derosa 2012).

In a rigorous review of 19 randomized controlled trials that enrolled type 2 diabetics, acarbose was found to significantly reduce HbA1C levels when given alone or as add-on treatment with other antidiabetic drugs (Derosa 2012). In an international trial involving over 500 patients with impaired glucose tolerance, treatment with acarbose significantly improved glucose tolerance, and reduced the risk of progression to diabetes by 25% over 3.3 years (Chiasson 2002). The Acarbose Cardiovascular Evaluation (ACE) trial, which enrolled 7,500 Chinese subjects (of which 6,522 completed the trial) with coronary heart disease and impaired glucose tolerance, found acarbose treatment for four months reduced the incidence of diabetes and promoted regression to normoglycemia (Gerstein 2020).

The mechanism of action of acarbose is complementary to that of metformin. While metformin primarily controls fasting blood sugar, acarbose regulates postprandial glucose levels. Combination therapy with acarbose and metformin has been demonstrated, in multiple studies, to be more effective for the control of blood glucose than treatment with either drug alone (Mooradian 1999; Johnson 1993; Joshi 2014; Jayaram 2010; Wang 2013).

In a study in diet-treated diabetic patients, even a single mixed meal of 450 Calories caused immediate and significant impairment in endothelial function, a key early step in the development of atherosclerosis. Prior treatment with acarbose markedly reduced the postprandial rise in blood glucose and associated endothelial dysfunction (Steyers 2014; Shimabukuro 2006).

In a review of seven long-term placebo-controlled studies in type 2 diabetics, acarbose reduced the risk of any cardiovascular event by 35% and the incidence of heart attack by 64% (Hanefeld 2004). The aforementioned ACE trial tested whether acarbose treatment can prevent heart attacks, strokes, or death from these events. Results suggest acarbose did not reduce the risk of major adverse cardiovascular events, but it did reduce the incidence of diabetes (Wamil 2020).

Side effects of acarbose treatment are generally mild, and tend to be short-lived. Gastrointestinal effects such as flatulence and diarrhea are most common (Coniff 1995; Joshi 2014; Derosa 2012; Standl 2014).

Since acarbose is a prescription medication, some individuals who wish to use it to control post-meal glucose elevations but are not diabetic may have difficulty obtaining the drug. Fortunately, natural products such as white mulberry leaf extract, green tea extract, and brown seaweed extract also inhibit the alpha-glucosidase enzyme and help reduce postprandial hyperglycemia (Lordan 2013; Zhang 2007; Yatsunami 2008; Hansawasdi 2006). Other bioactive compounds from plant-based foods such as mangos and jackfruit have displayed inhibitory effects against alpha-glucosidase (Assefa 2019).

SGLT2 inhibitors. The sodium-glucose cotransporter 2 (SGLT2) is responsible for reabsorption of glucose from the kidneys’ filtration system back into the blood (Sano 2020). SGLT2 inhibitors are a class of prescription drugs that modestly lower blood sugar levels by preventing glucose reabsorption in the kidneys. This results in increased urinary glucose excertion (Tat 2018). SGLT2 inhibitors are generally combined with other treatments in type 2 diabetes. For instance, SGLT2 inhibitors may be added if first-line therapies such as diet and lifestyle changes plus metformin are insufficient. These drugs may also be used to more specifically target and prevent kidney and cardiac complications in certain patient populations (Garber 2020; ADA 2019). SGLT2 inhibitors such as dapagliflozin (Farxiga), canagliflozin (Invokana), and empagliflozin (Jardiance) have been shown to reduce HbA1C levels, promote weight loss, and lower blood glucose levels. A growing body of research is establishing that SGLT2 inhibitors improve cardiovascular and renal outcomes in both diabetics and non-diabetics (Tat 2018).

A systematic review and meta-analysis of 58 randomized controlled trials involving over 16,400 participants with diabetes found that SGLT2 inhibitors reduced Hb1AC levels, promoted reductions in body weight, and decreased systolic blood pressure (Vasilakou 2013). Several meta-analyses in various diabetic populations have found that SGLT2 inhibitor treatment is associated with reduced risk of dying from any cause (Garber 2020).

In a meta-analysis of 10 placebo-controlled trials including over 71,000 subjects with or without diabetes at recruitment, treatment with SGLT2 inhibitors reduced the risk of heart failure hospitalization or cardiovascular death by 24% and lowered the risk of poor renal outcomes by 32% (Barbarawi 2021). Another meta-analysis, published in 2021, examined the results of six SGLT2 inhibitor trials that included nearly 47,000 subjects with type 2 diabetes, about 31,000 of whom had atherosclerotic cardiovascular disease. The meta-analysis found that SGLT2 inhibitors were associated with a 10% reduced risk of major adverse cardiovascular events, a 22% reduced risk of heart failure or cardiovascular death, and a 38% risk reduction in a composite of adverse kidney outcomes (Inzucchi 2021). Results of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, which compared dapagliflozin (10 mg once daily) to placebo, found that dapagliflozin was associated with a 44% reduction in a composite of adverse kidney outcomes and a 29% reduction in death from cardiovascular causes or hospitalization for heart failure; this trial was ended early due to overwhelming efficacy (Heerspink 2020). The SGLT2 inhibitor dapagliflozin has been shown to decrease the risk of developing type 2 diabetes. In a clinical trial including 2,605 people with heart failure but no prior history of diabetes, dapagliflozin (10 mg daily) led to a 32% reduction in new diabetes incidence over a median follow-up of 18 months (Barbarawi 2021; Silverii 2021; Neuen 2021; Koh 2021).

Blood pressure medications are also commonly prescribed to people who have diabetes, since diabetes and high blood pressure tend to co-occur. A meta-analysis of seven studies including 1,757 participants with type 2 diabetes found that SGLT2 inhibitor therapy in combination with blood pressure medications (known as renin-angiotensin system blockers) was well-tolerated and resulted in greater improvement in blood pressure, glucose control, body weight, and indices of kidney function compared with the blood pressure drugs alone (Tian 2021).

Although typically considered second-line therapy, SGLT2 inhibitors may have a role as initial pharmacological treatment in type 2 diabetes in conjunction with metformin in appropriately selected patients (Donnan 2019; Chen 2020). In a systematic review and meta-analysis of four randomized controlled trials including over 3,700 subjects, combination therapy with an SGLT2 inhibitor and metformin beginning at diabetes diagnosis resulted in greater weight loss and reduction of HbA1C levels compared with either drug alone. Adverse effects of combination therapy included an increased risk of genital infections and diarrhea (Milder 2019). As of late 2021, available evidence suggests first-line therapy with SGLT2 inhibitors may improve some outcomes, particularly in individuals with newly diagnosed diabetes and comorbid heart and kidney health concerns; however, increased ischemic stroke risk in this context has been observed as well (Chen 2020; Milder 2019). Additional randomized controlled trials are needed to clarify the efficacy and safety of SGLT2 inhibitors in the first-line treatment of type 2 diabetes.

SGLT2 inhibitors have limited glucose-lowering efficacy in individuals with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 because these drugs’ ability to lower glucose is a function of kidney filtration rate. Nevertheless, individuals with diabetes and eGFR in the range of 30–90 mL/min/1.73 m2 have been shown to derive kidney health benefits from SGLT2 inhibitor therapy in the clinical trial setting (Garber 2020; Perkovic 2019).

Although SGLT2 inhibitors have a strong safety profile, it is important to consider the risks that may arise from treatment. These risks include urinary tract infections and genital mycotic (fungal) infections; diabetic ketoacidosis (particularly when used in combination with insulin or sulfonylureas); hypoglycemia when used in combination with other type 2 diabetes medications; and hypovolemia (Vasilakou 2013; Wilding 2019; Scheen 2019; Sarafidis 2020; Engelhardt 2021; Wang 2020; Horii 2020; Menne 2019). They also carry a risk of dehydration and hypotension due to increased urinary output, especially in the elderly and those being treated with blood pressure-lowering drugs (Garber 2020). Canagliflozin has been shown to increase the risk of amputation and bone fractures (ADA 2019). Careful monitoring for adverse effects is important, particularly in older individuals and those using diuretics or non-steroidal anti-inflammatory drugs (NSAIDs). It is important for those taking SGLT2 inhibitors to be compliant with their treatment regimen and remain mindful of their own signs and symptoms to reduce the risk of adverse effects.

Sulfonylureas. As both insulin and most GLP-1 agonists are injections, high doses of sulfonylureas may be considered for those who are injection averse, as treatment adherence is critical to therapeutic success. Sulfonylureas may also be used in combination with metformin and other medications with complementary mechanisms of action. The risk of hypoglycemia is also high with sulfonylureas and may be further increased through their combined use with other medications such as SGLT2 inhibitors (Jiang 2021).

Sulfonylureas are an older medication class with side effects of weight gain and additional concerns of cardiovascular safety. They have increasingly fallen out of favor as metformin has proven to be optimal first-line therapy, and as the evidence basis grows for the glycemic and cardiorenal benefits of newer drug classes.

Injectable Drugs (Excluding Insulin)

Glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 receptor agonists (eg, exenatide, liraglutide) increase insulin secretion while inhibiting glucagon release, but only when blood glucose is high, thus reducing the risk of hypoglycemia. They reduce body weight and lower systolic blood pressure in type 2 diabetics, and increase after-meal satiety. These drugs are administered by subcutaneous injection. Adverse effects associated with GLP-1 agonists include nausea, diarrhea, and vomiting; development of antibodies against the drug; and reactions at the injection site (Garber 2011; Trujillo 2015). Some evidence suggests GLP-1 receptor agonists may be associated with a small increase in risk of pancreatitis or pancreatic cancer, but research thus far has been inconclusive and proven cardiovascular benefits likely outweigh the risks (Drucker 2006; Vilsbøll 2012; Ryder 2013; Nauck 2013; Peng 2016; Cao 2019).

Tirzepatide

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (Bailey 2021). The FDA approved tirzepatide as a type 2 diabetes treatment in May 2022 (FDA 2022).

GIP was long ignored as a treatment target in type 2 diabetes because it was believed to have low effectiveness in stimulating insulin secretion. However, newer studies have now revealed that—when hyperglycemia is first sufficiently controlled by another agent such as insulin—GIP effectively stimulates insulin secretion in type 2 diabetics (Bailey 2021). Multiple randomized controlled clinical trials have demonstrated that tirzepatide is superior for glycemic control and weight management in type 2 diabetics, compared to semaglutide 1 mg/week; titrated insulin degludec; or placebo (Ludvik 2021; Frias 2020; Frias 2021; Rosenstock 2021).

SURPASS-4 was a randomized controlled trial that compared the once-weekly tirzepatide (5 mg, 10 mg, or 15 mg) to titrated insulin glargine in nearly 2,000 subjects (Del Prato 2021). This trial followed patients for a minimum of 52 weeks and was designed to establish the safety and efficacy of tirzepatide in patients at high cardiovascular risk, and in whom glycemic management with one or more of three oral diabetes medications (metformin, a sulfonylurea, or an SGLT-2 inhibitor) had failed. All three doses of tirzepatide resulted in greater reductions in weight and HbA1C compared to insulin treatment. The percentage of participants who achieved target HbA1C levels below 5.7% and 7% at 52 weeks was greater with all doses of tirzepatide than with insulin glargine. Additionally, the percentage of participants who developed hypoglycemia was markedly lower in those receiving tirzepatide, although side effects of nausea, diarrhea, loss of appetite, and vomiting were considerably more common.

The SURPASS-5 trial examined tirzepatide (5, 10, and 15 mg) in 475 subjects taking insulin glargine for type 2 diabetes, with or without metformin, over 40 weeks (Dahl 2021). Tirzepatide at all three dosages resulted in clinically significant reductions in weight and HbA1C levels compared with placebo. Those on tirzepatide were nearly three times more likely to achieve a target HbA1C of < 7.0% than those who received placebo. More aggressive HbA1C targets of ≤ 6.5% and < 5.7% were also reached by large percentages of tirzepatide recipients, but relatively infrequently in those who received placebo. There was no significant difference in incidence of events of moderate hypoglycemia with tirzepatide versus placebo, though there were some occurrences of severe hypoglycemia. The most frequent adverse events, which occurred more frequently in the tirzepatide group, were nausea, diarrhea, constipation, and vomiting (Lilly 2021).

Incretin-Based Drugs and Pancreatic Disease

Incretin-based drugs, which include dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) and GLP-1 receptor agonists, are among the newest blood glucose-lowering medications for treating type 2 diabetes. Despite the growing body of evidence for their favorable effects on HbA1C, body weight, and possibly cardiovascular risk, as well as their low risk of hypoglycemia as a side effect, questions remain about their possible connections with acute pancreatitis and pancreatic cancer (Azoulay 2015; Suarez 2014). Findings from animal research suggest a high-fat diet may increase risk of pancreatic harm from these medications (Williams 2016).

Pancreatic cancer. Observational studies examining the relationship between incretin-based medications and pancreatic cancer have had mixed findings; furthermore, they have been hampered by challenges such as confounding risk factors, a long latency between treatment initiation and cancer diagnosis, and low frequency of occurrence of pancreatic cancer (de Heer 2014; Azoulay 2015). Some of the most recent studies are detailed below:

  • One new study used data collected by the FDA Adverse Event Reporting System (FAERS) database from 1968–2013. Based on the FAERS standard for identifying potential relationships, an association between the use of DPP-4 inhibitors and pancreatic cancer was identified (Nagel 2016).
  • A recent study analyzed data from 182 428 individuals and compared those using incretin-based drugs to individuals using other non-insulin anti-diabetes drugs and people not being treated for diabetes. The participants were followed for an average of 4.1 years. When diabetes severity was taken into account, there was no difference in pancreatic cancer risk between incretin-based drug users, other anti-diabetes drug users, and untreated subjects with diabetes; however, an unexplained two-fold increase in risk was seen in new users of incretin-based drugs, though this effect leveled out with longer use (Knapen 2016).
  • The largest study to date included data collected at six sites in three countries and represented medical information from 972,384 patients initiating medical treatment for diabetes and followed for an average of 1.3–2.8 years. Using patients taking sulfonylureas as the control group, the analysis found no increase in pancreatic cancer rates among those taking incretin-based drugs (Azoulay 2016).
  • A 2018 retrospective cohort study obtained information from 525,733 patients treated with non-insulin antidiabetic drugs and 33,292 with incretin drugs and found that those who were prescribed incretin drugs displayed a 114% increased risk of pancreatic cancer (Boniol 2018).
  • A 2019 retrospective study analyzed 33,208 individuals newly diagnosed with type 2 diabetes, of which 10,218 were new users of DPP-4 inhibitors and 22,990 were new users of other diabetes drugs. Those taking DPP-4 inhibitors had a 24% increased risk of pancreatitis and 81% increased risk of pancreatic cancer. These risks were consistent in the first year after initial prescription without showing an increasing trend according to exposure duration, but long-term pancreatic safety must be further investigated (Lee 2019).
  • Some studies do not suggest an increased risk of pancreatic cancer in users of DPP-4 inhibitors. A 2018 meta-analysis analyzed 38 studies including 59,404 individuals with type 2 diabetes on DPP-4 inhibitors for at least 24 weeks and found no association between the DPP-4 inhibitor use and pancreatic cancer (Pinto 2018). Further, two separate meta-analyses conducted in 2020 examining cardiovascular outcome trials in individuals with type 2 diabetes found no association between DPP-4 inhibitor use and pancreatic cancer (Abd 2020; Dicembrini 2020).

Acute pancreatitis. Evidence linking incretin-based drugs and acute pancreatitis is also conflicting, and determining the nature of the relationship appears to be confounded by the impact of diabetes severity on pancreatitis risk (Chou 2014). Findings from one study suggest the risk of DPP-4 inhibitor-induced pancreatitis may be higher in females and in the elderly (Lai 2015).

A recent analysis of available research found the overall occurrence of pancreatitis in diabetics using incretin-based drugs is low, and deemed the evidence too weak to support the notion of a cause and effect relationship (Li, Shen 2014); another study analyzed results from three recent large trials and concluded that incretin-based drugs were associated with an 82% increased risk of acute pancreatitis compared with other anti-diabetes drugs (Roshanov 2015). Based on current information, the FDA and the European Medicines Agency (EMA) continue to advise caution until definitive evidence emerges (Egan 2014); therefore, it is recommended that incretin-based drugs should be discontinued in patients with suspected acute pancreatitis and should not be initiated in diabetics with a history of acute pancreatitis (de Heer 2014). Despite conflicting findings on the association between DPP-4 inhibitor use and pancreatic cancer, clinical studies and meta-analyses support the association between DPP-4 inhibitor use and acute pancreatitis (Lee 2019; Pinto 2018; Abd 2020).

Pramlintide. Pramlintide (Symlin) is an injectable drug used along with insulin when after-meal hyperglycemia cannot be controlled with insulin alone (Cohen 2013). Pramlintide is a synthetic version of the hormone amylin, which is normally secreted along with insulin by pancreatic beta cells after a meal. Amylin slows gastric emptying and helps control postprandial glucose spikes (Schmitz 2004; Boyle 2018). Pramlintide is associated with severe hypoglycemia and weight loss. Also, due to the fact that it delays emptying of the stomach, it can delay absorption of drugs taken at the same time (Cohen 2013).

Insulin

Treatment with insulin may be necessary for type 2 diabetics who are already managed on multiple oral medications and are unable to achieve HbA1C goals. Because insulin can more rapidly lower glucose than oral medications, it also may be initiated at the time of diagnosis in individuals with severe hyperglycemia (HbA1C >9.0%). However, along with its potent anti-hyperglycemia effects, insulin also carries a high risk of hypoglycemia, often leads to weight gain, and some types of insulin have been linked to increased rates of several cancers (Karlstad 2013; Hodish 2018). Insulin treatment must be closely monitored with regular glucose measurements (fasting and post-prandial measurements, or via the use of continuous glucose monitoring if available) and adjusted as therapeutic goals are achieved (Garber 2020).

Because of its higher level of safety and ease of use, long-acting basal insulin (a once daily injection), which has the ability to sustain insulin levels up to 24 hours, rather than a short-acting mealtime insulin injection, is preferred for patients who are insulin naïve or at greater risk for hypoglycemia (Garber 2020). Prandial (mealtime) insulin is a short-acting insulin that may be added if post-prandial glucose goals are not being achieved; however, this approach carries a greater risk of hypoglycemia. Thus, treatment should be closely monitored and prandial insulin is not recommended as an initial therapy. Prandial insulin may be considered in patients resistant to other treatments, and if so, will often only be used with the largest meal initially.

Because GLP-1 receptor agonists (typically employed as injectables) increase mealtime insulin secretion and reduce postprandial serum glucose, they may work complementarily with basal insulin treatment to achieve blood sugar goals, especially if basal insulin has not been effective in improving after-meal sugar spikes. While insulin treatment is associated with weight gain, GLP-1 agonists promote weight loss, and may help patients achieve this goal even in combination with insulin (Maiorino 2018). Fixed-ratio combinations of basal insulin along with GLP-1 receptor agonists (as injectables) are available (Garber 2020).

Insulin cannot be taken orally because it would be degraded by stomach acid. Insulin is almost always injected subcutaneously (into the fat under the skin). Specific types of short- and long-acting insulin include (ADA 2015c; Vimalananda 2014):

  1. long-acting insulin (detemir, glargine) or intermediate-acting insulin (neutral protamine hagedorn [NPH]) to provide a steady basal effect of up to 12‒24 hours;
  2. rapid-acting insulin (lispro, aspart, insulin glulisine) to be used at mealtime to cover after-meal spikes in blood glucose.

Potential Concerns with Inhaled Insulin

In 2014, the FDA approved a new, rapid-acting inhaled insulin (Afrezza) for adults with diabetes as an alternative to injectable insulin for mealtime use. However, the long-term risks of this route of administration have not been conclusively determined (FDA 2014; Fleming 2015; Al-Tabakha 2015).

Insulin is a mild growth factor itself, but high concentrations of insulin in tissues can lead to overstimulation of other, more potent growth factors such as insulin-like growth factor-1 (IGF-1), which in turn can promote the growth and spread of cancer (Draznin 2011; Stattin 2007; NPG 2012; Humpert 2008; Kaaks 2004; Hiraga 2012; Bahr 2005). Compared with normal cells, cancer cells have more receptors for insulin and IGF-1, making them much more responsive to hormone stimulation (Ouban 2003; Belfiore 2011; Godsland 2009; Aleem 2011).

Powdered inhaled insulin comes in contact with tissues of the upper respiratory tract on its way to the lungs (von Kriegstein 2007; Graff 2005), which may increase risk of tumors in the respiratory tract. Since only 25% of insulin reaching the lungs is absorbed, most of the insulin builds up in the lungs. In fact, prior to Afrezza’s approval, Exubera—the first inhaled insulin drug developed—was linked to lung cancer and withdrawn from the market (Al-Tabakha 2015; Neumiller 2010; FDA 2009; von Kriegstein 2007; Heinemann 2008). Despite these findings, Afrezza offers a relatively safe form of inhaled insulin. A study analyzing pooled data from 13 phase 2 and 3 clinical studies enrolling 5,505 patients with type 1 or type 2 diabetes receiving inhaled insulin or placebo found that adverse events were comparable across treatments, with the exception of a higher incidence of mild cough in the insulin group (McGill 2020). Inhaled insulin poses a promising alternative for individuals at risk of nonadherence due to aversion to frequent injections, but Afrezza is not suitable as a long-acting insulin and is not recommended as treatment for diabetic ketoacidosis or in patients who smoke (Mohanty 2017; Chan 2017).

Apart from cancer, other health risks of insulin inhalation therapy include respiratory tract irritation, exacerbation of asthma symptoms, and adverse effects in people with pre-existing respiratory diseases such as COPD, for whom it is contraindicated (Fleming 2015; Selam 2008; Schaafsma 2007; Henry 2003; Siekmeier 2008; Mudaliar 2007).

12 Metabolic Surgery for Longstanding Type 2 Diabetes

For people with longstanding diabetes that cannot be adequately controlled with diet and lifestyle changes in conjunction with optimal drug therapy, metabolic surgery (bariatric surgery) may be indicated.

Researchers and physicians have known for many years that weight loss (bariatric) surgery can cause rapid and profound improvement in glucose metabolism among people with diabetes (Ilyas 2020). In addition, bariatric surgery has been associated with long-term improvements in metabolic health leading to reductions in cardiovascular risk factors, cardiovascular events, microvascular complications of diabetes, cancer, and mortality (Cummings 2018). Given that benefits of bariatric surgery can extend well beyond weight loss, it is now frequently referred to as “metabolic surgery” (Cummings 2018; Chen 2019; La Sala 2020).

The benefits of metabolic surgery appear to be sustained for many years. A study that followed 1,156 patients with severe obesity for 12 years found those who underwent gastric bypass surgery at the beginning of the study maintained an average weight loss of 35 kg while those who did not have surgery maintained an average weight loss of 0–2.9 kg. In addition, among participants with diabetes at the beginning of the study, metabolic surgery was associated with a 51% remission rate at the 12-year follow-up (Adams 2017).

Several randomized controlled trials have found metabolic surgery in addition to lifestyle and medical interventions is more effective than intensive medical and lifestyle interventions alone for inducing weight loss, improving metabolic health, and resulting in diabetes remission (Courcoulas 2015; Ikramuddin 2018; Schauer 2017). In one randomized controlled trial that included 60 participants with a BMI of 35 or higher and type 2 diabetes for ≥ 5 years, 75% of those who underwent gastric bypass surgery and 95% of those who underwent a type of metabolic surgery known as biliopancreatic diversion were diabetes-free two years later, but no one treated with non-surgical interventions alone experienced diabetes remission (Mingrone 2012). Ten years later, 25% of those treated with gastric bypass, 50% of those treated with biliopancreatic diversion, and 5.5% of those treated with conventional medical therapy were diabetes-free. Notably, surgically treated patients whose diabetes recurred maintained adequate blood glucose control and had fewer diabetes-related complications at 10 years than medically-treated patients (Mingrone 2021).

In early 2016, 45 worldwide medical and scientific societies endorsed new guidelines that recommend metabolic surgery in type 2 diabetics with a BMI ≥ 40 and in type 2 diabetics with a BMI of 35–39.9 whose hyperglycemia is not adequately controlled by lifestyle and medical therapy. These guidelines, put forth at the 2nd Diabetes Surgery Summit (DSS-II), also suggest metabolic surgery be considered in type 2 diabetic patients with a BMI of 30–34.9 and inadequately controlled hyperglycemia (Rubino 2017). Evidence supporting these guidelines continues to grow, and the safety of metabolic surgery has increased over the past two decades (Arterburn 2020). The 2022 ADA Standards of Medical Care in Diabetes guidelines propose metabolic surgery as an effective way to strongly improve glycemic control which often leads to remission of diabetes, improved quality of life, improved cardiovascular outcomes, and reduced mortality (ADA 2022).

The mechanisms behind the benefits of metabolic surgery are still being investigated. Changes in glucose, lipid, and bile acid metabolism as a result of metabolic surgery are believed to act in concert to improve energy metabolism and glucose tolerance (Xu 2021). Metabolic surgery has also been found to alter production of gut hormones and may cause changes in the gut microbiome, thereby affecting signaling pathways related to appetite, glycemic control, and inflammation (Xu 2021; Valenzano 2020). Type 2 diabetic patients have even been noted to have improved β-cell function after metabolic surgery (Chen 2019; Malin 2016). Another way metabolic surgery may improve health is by modifying adipose tissue-derived microRNA levels. MicroRNAs are small molecules of non-coding RNA, meaning unlike other types of RNA, they are not used for protein assembly. Instead, microRNAs regulate gene expression by preventing translation of targeted protein-coding RNA, in effect, silencing specific parts of the genetic code. Metabolic surgery appears to lead to changes in levels of adipose tissue-derived microRNAs involved in obesity, insulin resistance, systemic inflammation, and the progression from pre-diabetes to type 2 diabetes, and these changes are correlated with clinical benefits (La Sala 2020; Xu 2021). A small clinical trial of 20 patients randomized to metabolic surgery or standard medical therapy found that metabolic surgery can positively affect the gut microbiota. Patients who underwent metabolic surgery showed significantly increased genus richness (ie, diversity) in the gut microbiota compared with those on standard medical therapy, which was correlated with an improvement in metabolic and inflammatory biomarkers (Lau 2021).

Although metabolic surgeries have a good safety profile, problems can occur. The possible adverse outcomes vary somewhat depending on the type of surgery performed; in general, post-surgical problems include short-term complications, such as blood clots, bleeding, leakage, and infection, and long-term complications, such as strictures and obstruction, gallstones, gastroesophageal reflux, and nutritional and vitamin deficiencies. These possible adverse outcomes should be considered alongside the potential metabolic health benefits during the decision-making process for each individual considering metabolic surgery (Arterburn 2020).

13 Novel And Emerging Strategies

As the epidemic of diabetes continues to grow, new therapies are being developed that allow treatment customization, with a focus on weight management and preventing diabetes complications (Mazzola 2012; DeFronzo 2014).

Stem Cell Therapy

Stem cell therapy is aimed at replacing damaged or destroyed insulin-secreting pancreatic beta cells in diabetics with new beta cells developed from human stem cells (Bruin 2015).

Recently, scientists have developed a protocol that can generate pancreatic beta cells. These stem cell-derived beta cells normalized hyperglycemia when transplanted in diabetic mice (Pagliuca 2014). In a separate study, a combination of human stem cell transplantation and antidiabetic drugs was highly effective in improving body weight and glucose metabolism in a mouse model of type 2 diabetes (Bruin 2015).

Glucokinase Activators

Glucokinase is an enzyme that acts as a “glucose sensor,” primarily in the pancreas and liver. It regulates the amount of insulin released in response to glucose in the blood. Small molecules known as glucokinase activators (GKAs) have been developed that enhance the enzymatic activity of glucokinase. Glucokinase activators have been shown to lower glucose levels and stimulate proliferation of pancreatic beta cells in animal models of type 2 diabetes. However, results of recent early-stage clinical trials indicate GKAs lose their efficacy after several months of use. Also, an increased incidence of hypoglycemia and elevated blood fats was observed. Further drug development is needed to address these issues (Nakamura 2015; Rochester 2014).

Smad7 Antisense Oligonucleotides

Emerging technologies are allowing researchers to manipulate specific biochemical pathways more precisely than ever before. One technique that allows selective downregulation of a specific pathway involves antisense oligonucleotides. These small molecules bind to mRNA and prevent it from being translated into a protein in the cell ribosome, thus abrogating the downstream effects of that protein’s signaling (Chan 2006; Visser 2012).

One pathway scientists are interested in targeting in type 1 diabetes is that which results from Smad7 signaling. Smad7 is a protein that interferes with TGF-β signaling inside cells. TGF-β signaling is involved in a broad range of cellular functions and disease processes, including normal pancreatic beta-cell function (Yan 2016; Smart 2006). The interaction of Smad7 and TGF-β signaling is emerging as an important factor in pancreatic beta-cell homeostasis and formation (El-Gohary 2013).

Ongoing research is exploring the potential of antisense oligonucleotides against Smad7 to increase TGF-β signaling and subsequently improve beta-cell function (Monteleone 2013). Interestingly, one Smad7 antisense oligonucleotide, mongersen, was recently shown in a double-blind controlled trial to enhance the 15-day remission rate versus placebo in patients with Crohn’s disease (Monteleone 2015). More research is needed before the role of Smad7 antisense oligonucleotides in the treatment of diabetes is fully understood.

Anti-inflammatory Agents

Chronic, insidious inflammation is a central feature of type 2 diabetes and obesity, and contributes to cardiovascular disease associated with diabetes. Accordingly, anti-inflammatory pharmaceuticals may be therapeutic in these conditions (Esser 2015).

Salsalate has been used for many years to treat pain and inflammation in arthritis, and was recently shown to lower hemoglobin A1C (HbA1C) and markers of inflammation in patients with inadequately controlled type 2 diabetes. Salicylate, the major breakdown product of salsalate, has been shown to activate the metabolic regulator AMPK (adenosine monophosphate-activated protein kinase) in cultured human cells (McPherson 1984; Fleischman 2008; Hardie 2013; Goldfine 2010).

Another anti-inflammatory medication, anakinra (Kineret), blocks the inflammatory cytokine interleukin-1 (IL-1). Anakinra is undergoing clinical trials for safety and effectiveness in diabetes treatment. Neither salsalate nor anakinra are yet FDA approved for diabetes (van Poppel 2014; Esser 2015).

Anti-obesity Medications

Obesity, particularly excess visceral fat, greatly increases risk of developing type 2 diabetes. Two anti-obesity agents have been shown to improve glycemic control in obese individuals with type 2 diabetes (DeFronzo 2014; O’Neil 2012; Garvey 2013; Fonseca 2013).

Lorcaserin (Belviq) is FDA approved for weight loss in obese individuals. It increases satiety and decreases hunger, and is believed to work by influencing serotonin signaling (Gold Standard 2015b). A clinical trial in over 600 patients with type 2 diabetes assessed the effect of lorcaserin on weight loss and metabolic parameters. The study subjects were all undergoing standard treatment with metformin, sulfonylureas, or both; ranged from overweight to morbidly obese; and all received dietary and exercise counseling. Compared with the placebo group, subjects who received lorcaserin were more than twice as likely to lose 5% or more of their body weight, and more than three times as likely to lose 10% or more of their body weight. Fasting glucose and HbA1C both decreased more than twice as much in those receiving lorcaserin than placebo (O’Neil 2012).

Another FDA-approved weight loss medication, a combination of phentermine and topiramate, used in conjunction with lifestyle modification in a late-stage trial, produced significant two-year sustained weight loss in overweight and obese volunteers. Importantly, progression to type 2 diabetes was reduced by up to 76% in nondiabetic subjects treated with phentermine and topiramate (Garvey 2013; Garvey 2012). The combination of phentermine, a psychostimulant, and topiramate, a carbonic anhydrase inhibitor, has been associated with increased heart rate (Alfaris 2015). However, the combination may be safe in people with low-to-moderate cardiovascular risk (Jordan 2014). Phentermine-topiramate should be used cautiously in women of childbearing age because this drug combination may increase risk of oral cleft in children (Alfaris 2015). Other serious side effects of phentermine-topiramate include suicidal behavior and ideation and serious eye problems possibly leading to permanent vision loss (Vivus 2014).

Closed-Loop Artificial Pancreas Systems

A major challenge in the management of type 1 diabetes and late-stage type 2 diabetes is 24-hour glucose and insulin control. Because traditional management strategies necessitate that the patient must be self-reliant for glucose monitoring and insulin delivery, periods when he or she cannot be as vigilant, such as while sleeping, can present problems. Overcoming these barriers and improving the patient experience is the focus of much ongoing research. One solution that appears especially promising is an artificial pancreas and complete closed-loop glucose monitoring and insulin delivery system (Karoff 2016; Heinemann 2016; Russell 2015; Peyser 2014).

With these systems, a glucose monitor and insulin pump are placed under the patient’s skin, and software algorithms closely monitor glucose levels and deliver insulin as necessary to maintain blood sugar near a specified range (Karoff 2016; Peyser 2014; Heinemann 2016; Russell 2015). Some artificial pancreas models also deliver glucagon as needed to help avoid hypoglycemia (Peyser 2014).

Early clinical trials indicate artificial pancreas systems are superior to conventional insulin pump strategies, which require input from the user and therefore are prone to human error (Heinemann 2015; Capel 2014; Haidar 2015; Kovatchev 2014; Oron 2014). Although the FDA has yet to approve a closed-loop artificial pancreas system, research is ongoing and these devices will likely become increasingly available in the coming years as technology improves (FDA 2016).

14 Nutrients

NOTE: Under no circumstances should people suddenly stop taking antidiabetic drugs, especially insulin. Individuals with diabetes should work closely with their healthcare provider before initiating a supplement regimen due to the potential risk of hypoglycemia.

Antiglycation Agents

Advanced glycation end products (AGEs) form when sugars bond with proteins, lipids, and nucleic acids. This process contributes to the toxic effects of high blood sugar (Uribarri 2010; Ceriello 2012). Fortunately, several nutrients can counter these processes.

Benfotiamine. Diabetes and obesity often induce a relative thiamine (vitamin B1) deficiency, which contributes to some of the damaging consequences of hyperglycemia (Beltramo 2008; Page 2011; Via 2012). Benfotiamine is a fat-soluble derivative of thiamine that has much greater bioavailability than other forms of thiamine, and is capable of reaching concentrations in the bloodstream several times that of orally administered thiamine (Greb 1998; Xie 2014). This unique form of vitamin B1 inhibits AGE formation, inflammation, and oxidative stress (Hammes 2003; Du 2008; Balakumar 2010; Shoeb 2012).

A clinical trial in 165 patients with diabetic neuropathy found benfotiamine supplementation for six weeks reduced diabetic neuropathy pain. The benefits were clearer in subjects who consumed 600 mg of benfotiamine daily compared with those who took 300 mg, and in those who took benfotiamine for a longer period of time (Stracke 2008).

In a clinical trial in 13 subjects with type 2 diabetes, participants consumed a high-AGE meal before and after a 3-day course of benfotiamine, 1050 mg per day. The subjects’ vascular and endothelial function were assessed after both high-AGE meals. Signs of vascular dysfunction were completely prevented by benfotiamine administration, and biomarkers of endothelial dysfunction and oxidative stress were significantly reduced (Stirban 2006).

Clinical and animal studies have demonstrated the efficacy of benfotiamine in the treatment of diabetes-related neuropathy, kidney disease, peripheral vascular disease, and retinopathy (Stirban 2006; Chakrabarti 2011; Stracke 1996; Simeonov 1997; Winkler 1999; Haupt 2005; Nikolic 2009).

Carnosine. The peptide carnosine is capable of inhibiting formation of AGEs and even reversing protein glycation (Boldyrev 2013; Seidler 2004). In a study on diabetic mice, carnosine supplementation increased plasma levels of carnosine 20-fold, reduced triglyceride levels by 23%, and increased stability of atherosclerotic lesions (Brown 2014). Carnosine has also been shown to improve the ability of cells to survive in the presence of high glucose concentrations, and improve wound healing in diabetic animals (Ansurudeen 2012). An animal model of diabetes showed carnosine supplementation improved the ability of red blood cells to change their shape as necessitated by mechanical forces encountered during blood flow; this process is impaired in diabetes, contributing to diabetic complications (Yapislar 2012).

Vitamin B6. Vitamin B6—and in particular its active form, pyridoxal 5’-phosphate (PLP)—is involved in several aspects of glucose metabolism and is an effective anti-glycation agent (Mascolo 2020). In addition to preventing protein glycation, PLP is an effective inhibitor of lipid (fat) glycation (Higuchi 2006). Lipid AGEs are elevated in diabetic patients compared with healthy controls, and accumulation of lipid AGEs appears to contribute to vascular diseases related to diabetes (Fishman 2018). High dietary intake of AGEs also contribute to increased cardiovascular disease risk in diabetic patients (Di Pino 2017).

Lower serum levels of PLP have been linked to diabetes incidence and progression, and vitamin B6’s anti-glycation properties may help prevent complications of diabetes (Mascolo 2020). Indeed, higher intake of vitamin B6 has been associated with a lower incidence of diabetic retinopathy among Japanese people with type 2 diabetes (Horikawa 2020).

Interventional studies in humans and animals have been promising as well. For instance, treating 20 type 2 diabetics with 35 mg PLP along with 3 mg activated folate and 2 mg vitamin B12 improved skin sensation in diabetic peripheral neuropathy (Walker 2010). In a randomized controlled trial, 44 obese or overweight women treated with 80 mg of pyridoxine hydrochloride (a form of vitamin B6) for eight weeks experienced improved insulin sensitivity and decreased fat mass compared with placebo (Haidari 2021). Supplementation with PLP significantly decreased high concentrations of glycation-induced toxic compounds in diabetic rats and prevented the progression of diabetic nephropathy (Higuchi 2006; Nakamura 2007). A recent study further identified that diabetic rats treated with PLP experienced a reduction in problems associated with diabetes, including a decline in oxidative stress parameters, reductions in blood glucose levels, and damage recovery in the liver and kidneys (Abdullah 2019). Furthermore, pyridoxamine (another form of vitamin B6) improved insulin sensitivity in obese type 2 diabetic mice (Mastrocola 2021).

Phytochemical AMPK Activators

AMPK (adenosine monophosphate-activated protein kinase) is a critical energy sensor in the body. Activation of AMPK helps regulate energy metabolism, increasing fat burning and glucose utilization while blocking fat and cholesterol synthesis (Coughlan 2014; Park, Huh 2014). AMPK activation is a mechanism by which the preeminent antidiabetic drug metformin exerts some of its well-known metabolic benefits (Choi 2013; Yue 2014).

Gynostemma pentaphyllum. Gynostemma pentaphyllum (G. pentaphyllum) is a climbing vine of the family Cucurbitaceae (cucumber or gourd family) that is native to Asian countries including Korea, China, and Japan, where it is used as tea and in traditional medicine. Like metformin, gynostemma extract activates AMPK (Park, Huh 2014).

In animal and human cell cultures, extracts from G. pentaphyllum have been shown to improve insulin sensitivity, reduce levels of glucose and cholesterol, enhance immune function, and inhibit cancer growth (Lu 2008; Yeo 2008; Megalli 2006; Liu, Zhang, 2014). In a randomized controlled trial, an extract from gynostemma modestly reduced body weight and fat mass in obese subjects (Park, Huh 2014). Results from another trial found gynostemma tea improved insulin sensitivity, and lowered fasting glucose nearly ten times more than placebo (Huyen 2013).

In a clinical trial involving 25 diabetics, a gynostemma extract was tested as add-on therapy to the sulfonylurea drug gliclazide. Reductions in plasma glucose and HbA1C were nearly three times greater in the gynostemma extract group compared with placebo. Gynostemma acted by increasing insulin sensitivity rather than stimulating insulin release. It also prevented weight gain and hypoglycemia, which are often associated with sulfonylurea drugs (Huyen 2012).

In a trial in participants with non-alcoholic fatty liver disease, a condition strongly linked to insulin resistance, treatment with gynostemma extract, as an adjunct to diet, resulted in a significant reduction in liver enzymes and insulin levels, a decrease in body mass index, and increased insulin sensitivity (Chou 2006; Utzschneider 2006).

Hesperidin. Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels (Umeno 2016; Devi 2015). Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity (Li 2017; Roohbakhsh 2014). Findings from animal and in vitro research suggest hesperidin’s positive effects on blood glucose and lipid levels may be related in part to activation of the AMP-activated protein kinase (AMPK) pathway (Jia 2015; Rizza 2011; Zhang 2012). Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging (Li 2017).

Hesperidin may protect against diabetes and its complications, partly through activation of the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury (Homayouni 2017). Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level (Sun 2015).

In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin and placebo assignments reversed. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker high-sensitivity C-reactive protein (hs-CRP), as well as significant decreases in levels of total cholesterol, apolipoprotein B (apoB), and markers of vascular inflammation, relative to placebo (Rizza 2011). In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and a decrease in markers of vascular inflammation (Salden 2016). Another controlled clinical trial included 75 heart attack patients who were randomly assigned to receive 600 mg hesperidin per day or placebo for four weeks. Those taking hesperidin had significant improvements in levels of high-density lipoprotein (HDL) cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism (Haidari 2015).

Green tea extract. Green tea extract, a major constituent of which is epigallocatechin-3-gallate (EGCG), has been shown to reduce glucose and insulin levels and improve insulin sensitivity. In a rodent model of accelerated aging, EGCG supplementation lowered glucose and insulin levels. EGCG also increased insulin sensitivity, decreased liver fat accumulation, and improved markers of mitochondrial function (Liu, Chan 2015). In animal models of diabetes, green tea has been shown to protect against diabetic retinopathy (Silva 2013; Kumar 2012).

In a 16-week randomized controlled trial in 92 subjects with type 2 diabetes and blood lipid abnormalities, participants took 500 mg green tea extract three times daily. The green tea group showed significant increases in insulin sensitivity and HDL cholesterol levels, as well as a significant decrease in serum triglycerides (Liu, Huang, 2014). A two-month trial in 103 healthy postmenopausal women found a significant difference in glucose and insulin levels between a group that took up to 800 mg EGCG per day and a placebo group. Glucose and insulin levels fell in the EGCG group, but rose in the placebo group (Wu 2012). At the end of a four-week trial of catechin-rich green tea in 22 postmenopausal women, those in the green tea group had significantly lower postprandial glucose and significantly better after-meal oxidative stress parameters (Takahashi 2014).

Elevated blood pressure is one of the characteristic cardiovascular risk factors often found in diabetics and prediabetics. A randomized controlled trial administered daily a green tea extract powder containing a total of 544 mg polyphenols to 60 prediabetic subjects. This led to significantly reduced HbA1C and diastolic blood pressure (Fukino 2008). Similarly, a trial in overweight or obese middle-aged men found 800 mg EGCG daily significantly reduced diastolic blood pressure (Brown 2009).

Among additional possible mechanisms underlying green tea’s benefits are suppression of inflammatory genes and mitigation of oxidative damage (Uchiyama 2013; Jang 2013; Yang 2013). Also, green tea, black tea (a rich source of theaflavin polyphenols), and oolong tea have been reported to inhibit the alpha-glucosidase enzyme, causing less carbohydrate to be digested and absorbed (Satoh 2015; Yang 2015; Oh 2015). Other evidence suggests green tea constituents may activate AMPK (Liu, Chan 2015).

Bilberry extract. Closely related to blueberry, bilberry is rich in polyphenols and anthocyanins. In a study in diabetic mice, a bilberry extract reduced blood glucose and enhanced insulin sensitivity by activating AMPK (Ogawa 2014; Takikawa 2010). Bilberry polyphenols also have potent anti-inflammatory and free radical-scavenging actions (Subash 2014; Kolehmainen 2012). Bilberry has also been shown in animal studies to combat diabetic retinopathy (Kim, Kim 2015); and a clinical study in 180 type 2 diabetics showed that bilberry, in combination with several other micronutrients, improved measures of ocular health and visual acuity in subjects with preclinical or early diabetic retinopathy (Moshetova 2015).

In a preliminary controlled trial in eight type 2 diabetic males, a concentrated bilberry extract significantly lowered after-meal glucose and insulin levels compared with placebo. Reduced rates of carbohydrate digestion and absorption likely accounted for these effects. Specifically, bilberry polyphenols may have inhibited the action of alpha-glucosidase, preventing the breakdown of carbohydrates into glucose (Hoggard 2013).

Prevention of Exaggerated Post-Meal Blood Glucose Elevations

Several natural compounds can help prevent post-meal surges in blood glucose. These postprandial glucose spikes increase the risk of cardiometabolic diseases not only for diabetics and prediabetics, but also for people whose fasting glucose level is in the conventional “normal” range. Among the mechanisms that natural substances target to allow tighter control of post-meal glucose levels are alpha-glucosidase inhibition, alpha-amylase inhibition, SGLT1 inhibition, and sucrase inhibition (Van de Laar 2005; Matsuo 1992; Melzig 2007; Kinne 2011; Lee 1982).

Alpha-glucosidase inhibition. The alpha-glucosidase enzymes in the intestine break down carbohydrates into simple sugars so they can be absorbed. Inhibiting alpha-glucosidase reduces the amount of simple sugars available for absorption, mitigating postprandial glucose surges (Tundis 2010).

  • White mulberry leaf extract. White mulberry leaf has a long history of use in traditional Chinese medicine for preventing and treating diabetes (Mudra 2007). A component of white mulberry, called 1-deoxynojirimycin, impedes the action of alpha-glucosidase, slowing carbohydrate absorption and preventing post-meal blood sugar spikes (Banu 2015; Naowaboot 2012; Nakanishi 2011). This effect of the white mulberry leaf extract has been demonstrated in healthy subjects, type 2 diabetics, and those with impaired glucose tolerance (Asai 2011; Banu 2015; Mudra 2007).
  • A 4-week randomized controlled trial in 36 subjects with impaired fasting glucose found white mulberry leaf extract significantly reduced post-meal glucose and insulin levels (Kim, Ok 2015). A trial in 24 subjects with type 2 diabetes compared a white mulberry leaf product to the sulfonylurea drug glyburide. White mulberry decreased total cholesterol by 12%, LDL cholesterol by 23%, and triglycerides by 16%; raised HDL cholesterol by 18%; and reduced fasting blood glucose and oxidative stress markers. Glyburide only slightly improved glycemic control and triglycerides (Andallu 2001). A clinical study in healthy volunteers found that 1-deoxynojirimycin-enriched white mulberry powder suppressed post-prandial blood glucose surge and lowered insulin levels (Kimura 2007).

  • Specially roasted coffee and green coffee bean extract. Epidemiologic studies have linked coffee consumption with reduced risk of type 2 diabetes, Alzheimer disease, Parkinson disease, and certain cancers. This association may be explained by the chlorogenic acid content of coffee (Song 2014; Ong 2012; Meng, Cao 2013). Chlorogenic acid, a polyphenol, has demonstrated multiple mechanisms through which it exerts antidiabetic activity, including inhibition of alpha-glucosidase and the glucose-elevating liver enzyme glucose-6-phosphatase, oxidative stress modulation, insulin sensitization, and AMPK activation (Bassoli 2008; Ishikawa 2007; Rodriguez de Sotillo 2006; Simsek 2015; Henry-Vitrac 2010; Andrade-Cetto 2010). Chlorogenic acid also lowers levels of blood lipids (Meng, Cao 2013). Chlorogenic acid’s inhibition of alpha-glucosidase allows it to delay glucose absorption, which can result in a more gradual rise in postprandial glucose levels (Johnston 2003).
  • In a clinical trial in 42 individuals with type 2 diabetes, 300 mg of a chlorogenic acid-containing plant extract daily for four weeks significantly reduced fasting plasma glucose, C-reactive protein (CRP), and liver enzymes compared with placebo (Abidov 2006). In another trial, a single dose of coffee polyphenols during a glucose-loading test in healthy individuals significantly protected endothelial function (Ochiai 2014). In a mouse study, green coffee bean extract, a rich source of chlorogenic acid, significantly reduced visceral fat accumulation and improved insulin sensitivity, effects that may have been due to suppression of genes associated with fat deposition and inflammation (Song 2014).

    Raw green coffee beans are rich in chlorogenic acid (Farah 2008). However, the conventional coffee roasting process appears to significantly reduce the chlorogenic acid content of brewed coffee (Moon 2009; Zapp 2013). Although several studies have shown conventional coffee has meaningful health benefits, consuming a coffee high in chlorogenic acid may extend these benefits further (Johnston 2003; Hemmerle 1997). Fortunately, scientists have developed a method for roasting coffee that yields brewed coffee with higher-than-typical chlorogenic acid content (Zapp 2013). Individuals who wish to attain the most benefit from coffee polyphenols should consume coffee specially prepared to ensure that chlorogenic acid is retained during the roasting process.

  • Brown seaweed extract. Metabolic syndrome prevalence is lower in some Asian countries than in other parts of the world, and some researchers suspect dietary brown seaweed may be protecting these populations (Teas 2009). In laboratory experiments, brown seaweed extracts from Ascophyllum nodosum and Fucus vesiculosus inhibited alpha-glucosidase and alpha amylase enzymes (Roy 2011).
  • In a randomized controlled trial in 23 healthy subjects, a single 500-mg dose of brown seaweed extract caused a 48.3% decrease in post-meal blood sugar spikes. Significant reductions in post-meal insulin concentrations and improved insulin sensitivity were also observed (Paradis 2011).

    In a study in diabetic mice, polyphenolic fractions prepared from brown seaweed extract were shown to improve fasting serum glucose levels and blunt the rise in blood glucose following an oral sugar challenge. Compared with untreated mice, the mice given the polyphenol extract exhibited decreased total blood cholesterol. The seaweed-derived polyphenols also restored liver glycogen (stored carbohydrate) content (Zhang 2007).

Alpha-amylase inhibition. Like alpha-glucosidase, alpha-amylase is an enzyme that breaks down larger sugars and starches into smaller molecules that can be rapidly absorbed. Inhibition of alpha-amylase is another way to reduce the rate of sugar absorption (Tundis 2010).

  • Sorghum extract. Grain sorghum (Sorghum bicolor) is cultivated for animal and human consumption in several parts of the world, especially Africa, Asia, and Latin America. The grain’s unique protein and starch composition reduce its digestibility and cause it to slow glucose absorption (Poquette 2014). Also, in animal models of diabetes, sorghum inhibited glucose production in the liver (gluconeogenesis) and improved insulin sensitivity. In a laboratory experiment, a flavonoid- and proanthocyanidin-rich sorghum extract inhibited the alpha-amylase enzymes that convert starch into sugars. In a randomized trial in 10 healthy men, muffins made with sorghum were shown to reduce average after-meal glucose and insulin responses (Hargrove 2011; Poquette 2014; Kim 2012; Park 2012).

Additional mechanisms. Some natural products suppress postprandial hyperglycemia via other mechanisms, including inhibition of glucose transporters or sucrase, an enzyme that facilitates digestion and absorption of sucrose (table sugar).

  • Phloridzin. Phloridzin is a unique polyphenol found in high concentrations in apples and apple trees. This compound appears to suppress glucose absorption in the intestine by inhibiting sugar transporter systems in the intestine (SGLT1) and kidney (SGLT2). As a result, glucose reabsorption in the kidney is reduced and glucose excretion into the urine is promoted. The oral diabetes medication canagliflozin (Invokana) is also based on this mechanism (Sarnoski-Brocavich 2013; Najafian 2012; Masumoto 2009).
  • L-arabinose. L-arabinose is a poorly-absorbed five-carbon sugar found in the cell walls of many plants. L-arabinose inhibits the activity of sucrase, which is an intestinal enzyme that breaks down sucrose (table sugar) into the absorbable sugars glucose and fructose. When l-arabinose is consumed in combination with sucrose, the breakdown of sucrose is delayed, so that glucose is absorbed more slowly, which results in less exaggerated blood glucose and insulin responses. L-arabinose in combination with chromium, a natural insulin sensitizer, significantly lowered circulating glucose and insulin levels in nondiabetic subjects who underwent an oral sucrose challenge (Karley 2005; Kaats 2011; Krog-Mikkelsen 2011).
  • Maqui berry extract. Maqui berries (Aristotelia chilensis) are a purple-black fruit native to Chile that have garnered attention for their strong capacity to quench free radicals. They are also the richest known source of highly active polyphenolic compounds called delphinidins. When compared with other berries such as cranberries, blueberries, raspberries, and blackberries, maqui berries were found to be at least three times higher in total polyphenols and to have approximately three times greater free radical-quenching capacity (Watson 2015).
  • In a 2014 study to investigate its effects on blood glucose control, a single 200 mg dose of a standardized maqui berry extract 30 minutes prior to ingesting a serving of white rice was found to delay and decrease the rising levels of blood glucose and insulin better than placebo in 10 volunteers with moderate glucose intolerance (Hidalgo 2014). Similarly, single doses of 60 mg, 120 mg, and 180 mg taken one hour before oral glucose tolerance testing effectively improved fasting blood glucose levels as well as glucose and insulin responses in pre-diabetic individuals, with 180 mg having the greatest impact on blood glucose levels (Alvarado, Leschot 2016). To assess its long-term effects, a group of 31 moderately glucose-intolerant subjects were treated with 180 mg standardized maqui berry extract daily for three months. Results showed progressive decreases in HbA1c values at 30, 60, and 90 days. In addition, LDL-cholesterol levels were lower and HDL-cholesterol levels were higher at the end of the trial, indicating improved lipid metabolism (Alvarado, Schoenlau 2016).

    Several mechanisms may contribute to the positive effects of maqui berries on glucose regulation. Findings from preclinical research suggest maqui berry extract may decrease glucose production in the liver and increase insulin sensitivity (Rojo 2012). In an animal model of diabetes, maqui berry extract reduced intestinal absorption of glucose (Hidalgo 2014). Other research has indicated that maqui berry extract inhibits the inflammatory signaling between fat cells and immune cells that is associated with the development of insulin resistance (Reyes-Farias 2015).

  • Clove bud extract. Clove (Syzygium aromaticum), a well-known spice, has shown potential to improve glucose levels and aid in overall metabolism (Tu 2014; Kuroda 2012). An ethanol extract of clove flower buds was found to decrease blood glucose levels in diabetic mice (Kuroda 2012); in diabetic and lipid-disordered mice, supplementation with an alcohol clove extract resulted in lower glucose, triglyceride, free fatty acid, HbA1C levels (Sanae 2014). Its positive effects on metabolism were further demonstrated in an animal model of obesity, in which treatment with an alcohol extract of clove reduced the negative impact of a high-fat diet on body weight as well as lipid, glucose, and insulin levels (Jung 2012).
  • Findings from a clinical study on human subjects, which are not yet published, add more support for the potential anti-diabetic effects of clove. After 30 days of supplementation with 250 mg per day of a water extract of clove, participants had lower after-meal blood glucose levels. Furthermore, participants with higher blood glucose levels before the trial experienced greater reductions in after-meal glucose levels (AKAY 2017).

    In vitro research has shown that a clove extract has insulin-like effects on liver cells, inhibiting the breakdown of stored carbohydrates into glucose and preventing a subsequent rise in levels of circulating glucose (Prasad 2005; Sanae 2014). In muscle cells, clove extract stimulated the conversion of glucose into energy and enhanced mitochondrial function (Tu 2014). Some individual compounds from an ethanol extract of clove have been found to activate cellular pathways that increase glucose and lipid uptake (Kuroda 2012).

Insulin Sensitizers

Chromium. Chromium, a trace mineral, is essential for carbohydrate and fat metabolism, and is believed to act as an insulin-sensitizing agent. Chromium deficiency has been associated with insulin resistance and diabetes (Suksomboon 2014; Anderson 1997). A 2014 study found chromium deficiency was common in people with prediabetes. The authors recommended screening for chromium deficiency in both prediabetics and diabetics, and supplementing if a deficiency was identified (Rafiei 2014).

Evidence suggests chromium supplementation may improve control of blood glucose, raise HDL cholesterol, and lower triglycerides in type 2 diabetes. Chromium has also been shown to significantly lower HbA1C in type 2 diabetics (Suksomboon 2014; Rabinovitz 2004).

Cinnamon. The culinary spice cinnamon has been shown to promote healthy glucose metabolism and improve insulin sensitivity (Anderson 2013; Couturier 2010; Sartorius 2014; Ranasinghe 2012). Studies that supplemented type 2 diabetics and healthy individuals with 1‒6 g of cinnamon reported lower levels of fasting glucose, HbA1C and after-meal glucose and insulin concentrations, as well as improvements in insulin sensitivity. These effects have been demonstrated even in those already taking glucose-lowering medication (Lu 2012; Davis 2011; Magistrelli 2012; Hoehn 2012).

In a study in type 2 diabetics, a water-soluble cinnamon extract given at a dosage of 360 mg daily lowered HbA1C from 8.9% to 8.0%. The antidiabetic effects of cinnamon extracts have been attributed in part to activation of peroxisome proliferator-activated receptors, key regulators of glucose and fat metabolism (Sheng 2008; Lu 2012; Ferre’ 2004).

Several polyphenol compounds in cinnamon have free-radical-scavenging properties. In a rodent study, a specific cinnamon polyphenol, procyanidin B2, was shown to delay the formation of advanced glycation end products (AGEs) and diabetic cataracts (Muthenna 2013; Jayaprakasha 2006).

Omega-3 fatty acids. Omega-3 fats are healthy fats found in fish and some nuts, seeds, vegetables, and algae (Higdon 2014). Diets rich in omega-3 fatty acids have been shown to promote weight loss, enhance insulin sensitivity, and reduce death from cardiovascular disease by reducing inflammation, improving lipid profiles, and reducing blood clotting. When omega-3 fats are incorporated into cell membranes, they make the cell surface more fluid and pliable and appear to enhance cells’ ability to remove glucose from the bloodstream (McEwen 2010; Udupa 2013; Albert 2014; Franekova 2015). A large study in older adults demonstrated individuals with the highest blood concentrations of omega-3 fats, compared with the lowest, had up to 43% lower risk of diabetes (Djousse 2011).

In a randomized controlled trial in overweight type 2 diabetic patients, supplementation with the omega-3 fatty acid eicosapentaenoic acid (EPA) significantly decreased serum insulin, fasting glucose, HbA1C, and insulin resistance (Sarbolouki 2013). Another trial of supplementation with 2.3 g of the omega-3 fats EPA and docosahexaenoic acid (DHA) in 84 subjects with type 2 diabetes found a significant reduction in serum inflammatory biomarkers (Malekshahi Moghadam 2012). An eight-week trial in individuals with metabolic syndrome or early type 2 diabetes found fish oil lowered triglycerides and HbA1C and raised HDL cholesterol (Lee, Ivester 2014). Another trial in 44 type 2 diabetics found omega-3 supplementation for 10 weeks improved insulin sensitivity (Farsi 2014).

A randomized placebo-controlled trial tested a combination of EPA, DHA, and the plant-sourced omega-3 fatty acid alpha-linolenic acid in over 1000 diabetics with a history of heart attack. Subjects receiving the omega-3 preparation had 84% lower risk of a ventricular arrhythmic event, and 72% lower risk of a combined outcome of fatal heart attacks and ventricular arrhythmic events (Kromhout 2011).

Omega-3 fatty acids from fish oil, DHA and EPA, appear to protect against some of the changes in blood vessel function associated with post-meal blood sugar surges. A six-week trial in 34 subjects with type 2 diabetes found omega-3 fatty acid supplementation significantly protected against post-meal dysfunction in small and large blood vessels (Stirban 2010).

A review found greater consumption of omega-3 fats from fish was associated with a 15‒19% lower rate of death from cardiovascular disease, as well as lower triglycerides, decreased inflammation, lower blood pressure, and diminished platelet activation and aggregation (McEwen 2010).

Magnesium. Magnesium is involved in more than 300 metabolic reactions and plays a key role in carbohydrate metabolism. Magnesium participates in insulin secretion and function, and low magnesium levels are correlated with insulin resistance (Gums 2004; Bertinato 2015; Paolisso 1990). Low magnesium levels are significantly more common in people with diabetes and impaired glucose tolerance compared with the general population, and higher magnesium levels correlate with lower HbA1C (Hata 2013; Hruby 2014; Hyassat 2014; Galli-Tsinopoulou 2014; Azad 2014). Higher magnesium intake is associated with decreased risk of developing type 2 diabetes (Guerrero-Romero 2014).

Magnesium supplementation has been shown to lower blood levels of glucose and lipids, as well as blood pressure, in type 2 diabetics. Magnesium supplements were also found to lower highly-sensitive C-reactive protein (hs-CRP), a marker of inflammation, in prediabetics with low serum magnesium (Solati 2014; Simental-Mendia 2014).

Magnesium plays a critical role in cardiovascular health. A study in over 13 000 US adults found women with the highest serum magnesium levels had a 56% lower risk of coronary artery disease compared with those with the lowest levels; in men, those with the highest serum magnesium had a 27% less risk compared with those whose levels were lowest. Similarly, women with the lowest dietary magnesium intake had a more than 1.3-fold greater risk of cardiovascular disease (Kolte 2014). One study found that, in diabetic patients with coronary artery or peripheral vascular disease, there was a significant correlation between low magnesium and high fasting plasma glucose and HbA1C (Agrawal 2011).

Dehydroepiandrosterone (DHEA). DHEA is the most abundant adrenal steroid hormone in healthy adults, and a precursor to the sex hormones (androgens and estrogens) (Mayo Clinic 2017; Brahimaj 2017). DHEA levels decline with age. However, youthful DHEA levels, as well as DHEA replacement therapy, have been associated with benefits for cardiovascular health, bone strength, mood, and cognitive function (Samaras 2013; Weiss 2012; Kawano 2003; Jankowski 2006; Weiss 2009; Alhaj 2006).

DHEA has also received attention for its potential to modulate insulin sensitivity. A two-year randomized controlled trial administered 50 mg of DHEA, or placebo, to 125 men and women aged 65 to 75. In those on DHEA, insulin resistance decreased significantly, by 22%, compared with placebo. This effect was accounted for largely by the response of those with abnormal glucose tolerance (Weiss 2011). In another randomized controlled trial of 56 men and women aged 65 to 78 with age-related decreases in DHEA levels, 50 mg DHEA daily for six months resulted in improved insulin sensitivity and decreased body fat (Villareal 2004).

An observational study in which serum DHEA and DHEA-sulfate (DHEA-s) levels were assessed followed over 5,000 Northern European men and women for close to 11 years. Both DHEA and DHEA-s levels were significantly correlated with lower risk of type II diabetes (Brahimaj 2017). Mechanistic studies have found that DHEA modulates insulin signaling pathways, increasing the insulin sensitivity of liver, muscle, and fat cells, which may explain its beneficial metabolic effects (Aoki 2018; Karbowska 2013).

For additional information, please review our DHEA Restoration Therapy protocol.

Oxidative Stress Inhibitors and Anti-Inflammatory Agents

Coenzyme Q10. Coenzyme Q10 (CoQ10) is essential to mitochondrial energy metabolism, and a powerful inhibitor of oxidative stress (Littarru 2007). CoQ10 deficiency has been associated with diabetes (Amin 2014; Kolahdouz 2013; Eriksson 1999). In a randomized controlled trial in 64 type 2 diabetic patients, supplementation with 200 mg CoQ10 per day for 12 weeks decreased serum HbA1C concentration and lowered levels of total and LDL cholesterol (Kolahdouz 2013). A clinical trial in 74 type 2 diabetic subjects found 100 mg CoQ10 twice daily resulted in significantly decreased HbA1C and blood pressure (Hodgson 2002). In a placebo-controlled trial in 23 statin-treated type 2 diabetics, 200 mg CoQ10 per day significantly improved a marker of vascular endothelial dysfunction (Hamilton 2009; Watts 2002).

In an animal model of diabetes, CoQ10 treatment significantly improved insulin resistance, reduced serum levels of insulin and glucose, and increased levels of the energy-regulating hormone adiponectin six-fold (Amin 2014). High levels of adiponectin have been linked to decreased risk of diabetes and cardiovascular complications (Lindberg 2015; Zoico 2004; Yamamoto 2014).

Long-term use of CoQ10 was demonstrated in two animal studies to be protective against progressive diabetic neuropathy. The beneficial effects of CoQ10 may have been attributable to reduction of oxidative damage and inflammation, both key factors implicated in diabetic neuropathy (Zhang, Eber 2013; Shi 2013).

The reduced form of CoQ10—ubiquinol— is absorbed more efficiently than the ubiquinone form (Langsjoen 2008; Hosoe 2007).

Curcumin. Curcumin is a major active component of turmeric, the spice derived from the plant Curcuma longa. Turmeric has been used as a treatment for diabetes in Ayurvedic and traditional Chinese medicine for centuries. Curcumin’s primary mechanisms of action are its ability to neutralize reactive free radicals and reduce inflammation (Nabavi 2015; Zhang, Fu 2013; Meng, Li 2013).

A randomized controlled trial in 240 prediabetic subjects showed curcumin supplementation significantly lowered risk of progressing from prediabetes to type 2 diabetes. During the nine-month trial, none of the prediabetic subjects treated with curcumin progressed to diabetes, whereas over 16% of subjects in the control group were diagnosed with type 2 diabetes. By the end of the study, subjects in the curcumin group had significantly greater insulin sensitivity and beta-cell function, as well as higher adiponectin levels than the placebo group (Chuengsamarn 2012).

Additional experimental studies and human trials indicate curcumin is a promising natural agent for the prevention and treatment of diabetes and its complications. Curcumin appears to increase insulin sensitivity and reduce blood levels of glucose and lipids. It also may protect insulin-producing beta cells in the pancreas (Nabavi 2015; Zhang, Fu 2013).

Resveratrol. Resveratrol, a polyphenol that has received widespread attention for its anti-aging effects, holds promise in type 2 diabetes (Hausenblas 2015; Bruckbauer 2013; Fiori 2013; Tome’-Carneiro 2013; Mozafari 2015). A rigorous review of randomized controlled trials found resveratrol improved systolic blood pressure, HbA1C, and creatinine when used as an adjunct to drug treatment in type 2 diabetes (Hausenblas 2015). In one of these studies, supplementation with resveratrol at 1 g per day for 45 days resulted in a significant decrease in fasting glucose, insulin, and HbA1C and an increase in insulin sensitivity and HDL cholesterol levels. Notably, the improvements in HbA1C and HDL cholesterol were comparable to those achieved by leading antidiabetic drugs (Movahed 2013).

Lipoic acid. Lipoic acid is a free radical scavenger made by the body in small quantities, though levels decline significantly with age (Park, Karuna 2014; Higdon 2012). Lipoic acid may support healthy blood glucose control by activating AMPK, protecting pancreatic beta cells, and augmenting glucose removal from the bloodstream. Lipoic acid has been used for the prevention and treatment of diabetic neuropathy in Germany for several decades (Ziegler 1999; Gomes 2014; Golbidi 2011; Ibrahimpasic 2013).

In a study in subjects with impaired glucose tolerance, arterial flow (a measure of endothelial function) was markedly decreased during fasting and after a glucose challenge. Intravenous administration of 300 mg lipoic acid before the glucose challenge prevented the endothelial dysfunction induced by high blood glucose. Lipoic acid decreases oxygen free radicals, which in excess promote endothelial dysfunction and contribute to diabetes, high blood pressure, and cardiovascular disease (Xiang 2008; Park, Karuna 2014; Gomes 2014).

Lipoic acid comes in two “mirror image” forms labeled “R” and “S.” The R form is the active form produced and used in living systems (Gomes 2014). Inexpensive chemical manufacturing produces equal quantities of R and S lipoic acid, often labeled “R/S lipoic acid” or simply “alpha-lipoic acid” (Flora 2009). Newer precision techniques allow production of a pure, more stable R-lipoic acid supplement, delivering the most bioavailable form. This form is known as sodium R-lipoate, or Na-RALA.

A dose of pure R-lipoic acid provides twice the active ingredient compared with typical alpha-lipoic acid supplements, simply because the whole dose consists of the active “R” molecule. Look for the “R” label to ensure you are getting the most potent form of lipoic acid (Smith 2005; Streeper 1997).

Blueberry extract. Blueberries are a concentrated source of polyphenols and anthocyanins that have multiple antidiabetic effects, including protection of pancreatic beta cells, anti-inflammatory properties, and free-radical-scavenging abilities (Liu, Gao 2015; Martineau 2006; Abidov 2006).

A four-week randomized controlled trial of blueberry supplementation was conducted in 32 obese, insulin-resistant adults without diabetes. Subjects were given 45 g of freeze-dried blueberry powder—the equivalent of two cups of whole blueberries—daily for six weeks. Compared with placebo, blueberry treatment significantly improved insulin sensitivity (Stull 2010).

In a study in rodents fed a high-fructose diet, fasting insulin was elevated, and insulin sensitivity and pancreatic beta-cell function declined. However, when the diet was supplemented with blueberries, these changes were minimized; and when a larger percentage of the diet was derived from blueberries, the effect was greater. Cholesterol and abdominal fat also decreased in the blueberry-fed animals (Khanal 2012).

In a rodent model of diet-induced inflammation similar to that observed in diabetes, the addition of blueberry powder to the animals’ diet prevented inflammatory changes, and protected the mice from developing insulin resistance and high blood sugar (DeFuria 2009). Soybean flour enriched with a concentrate of blueberry polyphenols was shown to reduce hyperglycemia, weight gain, and serum cholesterol in mice. The blueberry-fortified flour also reduced glucose production in the liver by 24‒74% (Roopchand 2013).

In cell culture studies, an anthocyanin-rich blueberry extract exhibited insulin-sensitizing properties, conferred protection against glucose and fatty acid toxicity, and enhanced proliferation of insulin-producing pancreatic beta cells (Martineau 2006; Liu, Gao 2015).

Grape polyphenols. Grapes are a source of polyphenols, proanthocyanidins, and resveratrol, all of which modulate oxidative stress and have been studied in a wide range of health conditions, including high blood pressure, cancer, and Alzheimer disease (Pasinetti 2014; Kaur 2009; Feringa 2011). Grape polyphenols appear to have important antidiabetic effects and protect tissues from the damaging effects of blood sugar elevations.

In a four-week, randomized, placebo-controlled trial in 32 type 2 diabetics, consumption of 600 mg per day of grape seed extract significantly lowered fructosamine compared with placebo. Fructosamine is a test similar to HbA1C that measures blood sugar level over several weeks. Grape seed extract also lowered total cholesterol and hs-CRP, and significantly elevated blood glutathione, one of the body’s primary internal antioxidants (Kar 2009). Another trial found the non-alcoholic portion of red wine, which is rich in grape polyphenols, increased insulin sensitivity and reduced cardiovascular risk (Chiva-Blanch 2013).

A randomized controlled trial administered 2 g of grape polyphenols per day to healthy but overweight first-degree relatives of type 2 diabetics for eight weeks. Subjects were then challenged with substantial doses of fructose, the sugar present in fruit juices and many sweetened beverages. In the placebo group, the fructose challenge resulted in increased oxidative stress and decreased insulin sensitivity and mitochondrial activity. All of these negative effects were prevented in the polyphenol group (Hokayem 2013).

Gamma tocopherol. After-meal blood sugar surges can injure the lining of blood vessels, causing endothelial dysfunction and vascular disease. Gamma tocopherol is a form of vitamin E with both anti-inflammatory and free-radical-scavenging activity. Two trials in healthy men found gamma tocopherol supplementation protected against changes associated with endothelial dysfunction induced by after-meal glucose spikes (Mah, Noh 2013; Masterjohn 2012; Mah, Pei 2013).

Ginkgo biloba. A randomized controlled trial tested the effects of adding Ginkgo biloba to metformin therapy in patients with metabolic syndrome. Forty participants received—in addition to their ongoing metformin treatment—either a Ginkgo biloba extract, administered in a single daily dose as a 120 mg capsule, or a placebo, for 90 days. At completion, participants who received the extract had significant decreases in HbA1c (8%), fasting serum glucose (12%), insulin levels (44%), insulin resistance (19%), body mass index (7%), abdominal body fat (23%), and serum leptin (43%) compared with their levels at the beginning of the study. Several inflammatory markers also showed decreases, including high-sensitivity C-reactive protein (20%), TNF-alpha (48%), and IL-6 (37%). These benefits were not seen in the placebo group. The combination of metformin and Ginkgo biloba extract did not lead to any observable adverse effects during the course of study (Aziz, Hussain, Mahwi, Ahmed 2018).

Another randomized controlled trial showed similar benefits. In the trial, patients with type 2 diabetes, which was poorly controlled with metformin, received Ginkgo biloba extract supplementation. After 90 days, participants who received the extract had decreased blood levels of HbA1c (10.5%), fasting serum glucose (20%), and insulin (28%); and reduced BMI (7%), waist circumference (3%), and abdominal fat (17%) (Aziz, Hussain, Mahwi, Ahmed, Rahman 2018). Previously, a double-blind clinical trial reported that the co-ingestion of 120 mg of a Ginkgo biloba extract together with 500 mg metformin did not significantly change the metabolism of metformin in healthy individuals or in individuals with type 2 diabetes mellitus (Kudolo 2006).

Additional Support

Vitamin D. Vitamin D deficiency has been associated with both diabetes and obesity, and evidence suggests vitamin D status is closely related to glucose metabolism. People with low vitamin D were more likely to have diabetes, independent of their body weight (Clemente-Postigo 2015).

Several mechanisms have been suggested to account for the association between vitamin D levels and poor blood glucose control. Through its role in calcium regulation, vitamin D may improve insulin sensitivity and regulate pancreatic beta cell function. Vitamin D may also modulate systemic inflammation, which is associated with insulin resistance and type 2 diabetes. Finally, vitamin D may directly stimulate production of insulin receptors in target tissues and thus enhance glucose clearance from the blood (Clemente-Postigo 2015; Pittas 2007). An optimal target range for vitamin D blood levels is between 50 and 80 ng/mL.

Folate. In type 2 diabetes, elevated plasma homocysteine is strongly linked to increased risk of cardiovascular disease and death. Homocysteine promotes endothelial dysfunction through a number of different mechanisms. The B vitamin folate, in concert with vitamin B12, lowers homocysteine by converting it back to the amino acid methionine. Both low folate intake and low blood folate levels are strongly associated with high plasma homocysteine (Selhub 2000; Moat 2004; Sudchada 2012; Van Guelpen 2009; Miller 2003; de Bree 2001; Koehler 2001).

A thorough review and analysis of randomized controlled trials assessed the effect of folic acid supplementation on homocysteine levels in type 2 diabetics. In this population, 5 mg per day of folic acid significantly decreased homocysteine levels, to a degree believed to lower the risk of cardiovascular disease, and improved glycemic control (Sudchada 2012).

Genetic predisposition to inefficient conversion of folic acid into the metabolically active 5-methyltetrahydrofolate (5-MTHF) is common (Huo 2015). Supplementation with L-methylfolate (instead of folic acid) avoids this potential problem and is preferable to folic acid.

Irvingia gabonensis. Also known as African mango, Irvingia gabonensis is an African tree that bears mango-like fruit (MMSCC 2015). An extract of irvingia seed has been shown to lower blood glucose and lipid levels, and reduce excess body weight (Ross 2011; Ngondi 2009; Ngondi 2005). In a randomized controlled trial, 150 mg of a proprietary extract from Irvingia gabonensis, taken twice daily for 10 weeks, significantly decreased body weight, body fat, and waist circumference in overweight subjects. There were also improvements in several metabolic parameters related to insulin resistance, including increased adiponectin and decreased leptin and CRP (Ngondi 2009).

In another trial, a combination of extracts from irvingia and Cissus quadrangularis, a West African vine, produced significantly larger reductions in body weight and fat, total cholesterol, LDL cholesterol, and fasting blood glucose compared with the Cissus extract alone (Oben, Ngondi, Momo 2008).

Nicotinamide riboside. Nicotinamide adenine dinucleotide (NAD+) is a critical regulator of cellular energy (Kim, Oh 2015). It is also a cofactor for sirtuin proteins, which are involved in many metabolic activities and associated with longevity. Aging is associated with declining activity of SIRT1, the gene that encodes the sirtuin 1 protein, and preclinical studies have shown increasing SIRT1 expression prolongs lifespan (Poulose 2015). Age-related decline of NAD+ levels has been associated with a reduction in SIRT1 activity (Braidy 2011; Gomes 2013). NAD+ metabolism is also implicated in the causation and complications of diabetes (Yoshino 2011; Canto 2015; Imai 2009).

Supplementation with nicotinamide riboside, an NAD+ precursor, boosts cellular NAD+ levels (Bogan 2008; Khan 2014). Animal research has shown nicotinamide riboside can improve insulin sensitivity, augment the benefits of exercise, combat neurodegeneration, and mitigate the negative effects of a high-fat diet (Chi 2013; Canto 2012). In an animal model of type 2 diabetes, nicotinamide riboside supplementation reduced liver inflammation and improved glucose control (Lee, Hong 2015).

2022

  • May: Updated section on injectable (non-insulin) type 2 diabetes drugs in Overview of Type 2 Diabetes Drugs
  • May: Updated section on tirzepatide in Type 2 Diabetes Drugs – Additional Details
  • Feb: Updated section on Metabolic Surgery for Longstanding Type 2 Diabetes
  • Feb: Added section on Type 2 Diabetes Drugs – Additional Details
  • Feb: Added section on Overview of Type 2 Diabetes Drugs
  • Feb: Added section on Starting Drug Therapy for Type 2 Diabetes: What to Expect
  • Feb: Updated section on Dietary & Lifestyle Changes for Type 2 Diabetes
  • Feb: Updated section on Type 2 Diabetes Treatment: Overview & Goals
  • Feb: Added section on tirazepatide to Novel and Emerging Strategies

2021

  • Nov: Added section on SGLT2 inhibitors to Treatment of Type 2 Diabetes
  • Sept: Updated section on vitamin B6 in Nutrients
  • Mar: Added section on Metabolic Surgery for Longstanding Type 2 Diabetes

2016

  • Aug: Comprehensive update & review

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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ADA. American Diabetes Association. Glycemic Index and Diabetes. http://www.diabetes.org/food-and-fitness/food/what-can-i-eat/understanding-carbohydrates/glycemic-index-and-diabetes.html?referrer=https://www.google.com/. Last updated 5/14/2014b. Accessed 8/24/2015.

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