Can Incretin Mimetics Improve Beta Cell Dysfunction

By Mackenzi Nelson, DPM, and John S. Steinberg, DPM

      Since the discovery of diabetes, researchers have worked diligently to extend the life expectancy of those affected by diabetes. From the advent of insulin in 1921 until the present day, advances in medical management have had a very significant impact on life expectancy and glycemic control in this population.1 Helpful treatments ranging from diet and exercise to oral drug therapy and exogenous insulin have steady advances in the treatment of this patient population.

      Medications that are currently available for the management of blood glucose levels include sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, D-phenylalanine derivatives, amylin synthetic derivatives and insulin. Each category of drug therapy works differently but the therapies primarily function to improve blood sugar control without directly improving beta cell function in the pancreas.2 Now a new class of pharmaceuticals has emerged which may be able to do both.

How Do Incretin Mimetics Work?

      Incretin mimetics are a new class of anti-diabetic agents that “mimic” the actions of naturally occurring hormones and can help restore insulin secretion. Glucagon-like peptide-1 (GLP-1) is the incretin hormone that these agents mimic. This hormone has glucoregulatory properties that enhance the secretion of insulin, decrease glucagon release and prolong the rate of gastric emptying. These properties result in improved glycemic control, weight loss and increased insulin sensitivity.3-6 Studies have shown that GLP-1 increases beta cell mass and decreases cell death.5 The incretin mimetics allow for a longer duration of action and are of great use due to their resistance to breakdown.3

      Exenatide injection (Byetta, Amylin Pharmaceuticals/Eli Lilly) is the first drug therapy in the incretin mimetics class to be marketed in the United States. Byetta has been approved as an adjunctive therapy for use in patients with type 2 diabetes who take metformin, a sulfonylurea or a combination of the two. Byetta has an amino acid peptide called exendin-4, which functions in the same capacity of GLP-1.

      Exendin-4 shows 53 percent amino acid homology to GLP-1.7 It has positive effects on the response of beta cells to glucose and regulates glucagon secretion, which ultimately decreases the demand of insulin. In addition, there is a slowing of gastric emptying and a reduction of food intake that allows for weight loss.6,8 Studies have also shown significant decreases in hemoglobin A1C, body weight, nocturnal hypoglycemia and improved postprandial glucose control.3,4,6

      Interestingly, exendin-4 is derived from the salivary glands of the Gila monster, Heloderma suspectum.9-11 The Gila monster is one of the two most venomous lizards in the world. The venom is excreted via mastication.10 These lizards are also unique in that they house fat in their tails and bodies, are capable of digesting very large meals and have low resting metabolic rates. With their eating habits and ability to store energy, the Gila monsters can limit their dietary intake to three to four meals per year, which requires great ability to regulate digestive processes.9,10

      Exendin-4, an amino-acid peptide, was initially thought to be a toxic part of the lizard’s venom. However, studies have shown this peptide has limited defense value.10-11 The actions of exendin-4, demonstrated by Young, et. al., suggest that it has a feed-forward metabolic mechanism. Researchers showed that exendin-4 is released into the blood after the ingestion of large meals, which may inhibit further intake.10-11

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