Diabetes and Glucose Control
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 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.
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).
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).