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Health Protocols

Diabetes and Glucose Control

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 85 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).