Can Incretin Mimetics Improve Beta Cell Dysfunction

      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       This is a fascinating finding because salivary glands do not have known endocrine function in vertebrates and proteins generally have a decreased ability to cross cell membranes.10 Further studies are warranted to evaluate the mechanism by which exendin-4 is released into the bloodstream.

Pertinent Pearls On Using Byetta

      One would administer exenatide twice daily before meals as a subcutaneous injection, delivering doses of 5 mcg or 10 mcg.4,8,12 The use of the medication is contraindicated in patients with type 1 diabetes and for diabetic ketoacidosis treatment. The use of Byetta in patients with end-stage renal disease or severe renal insufficiency is not recommended due to a high reduction of clearance. However, a mild disease state does not limit use.8       The greatest adverse effect noted in all studies was gastrointestinal in nature, with nausea noted predominately. Although nausea was most commonly reported, researchers noted it was primarily limited to a few weeks after initiation of treatment.3,5,8,12 Due to the gastrointestinal nature of the side effects, the use of Byetta in patients with gastrointestinal disorders is also not recommended. In addition, Byetta may cause skeletal effects in fetuses and consequently should only be used in pregnancy if the benefit outweighs the risk.8       Hypoglycemia is of major concern with all anti-diabetic agents. While the combination of Byetta with metformin produced no increase in hypoglycemia, using Byetta with a sulfonylurea has shown an increased risk of hypoglycemia.3,5,6,8 This risk is highly dose-dependent. When using Byetta, one should lower the sulfonylurea to limit the incidence of hypoglycemia.

In Conclusion

      There is a great deal of ongoing research into new pharmacologic agents for diabetes. Ongoing research includes incretin enhancers as the next possible class of oral agents. Exenatide injection therapy has proven to be an effective adjunctive drug therapy for patients with uncontrolled diabetes. This therapy not only works to improve blood sugars but also helps improve beta cell function and beta cell mass. Indeed, this combination of benefits is unlike what one would obtain with most other blood glucose lowering agents. With the advent and use of Byetta, it seems that this drug can delay or even prevent the progression of the disease.       Dr. Nelson is a second-year podiatric resident at Washington Hospital Center in Washington, DC.       Dr. Steinberg (pictured) is an Associate Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C.       Editor’s note: For related articles, see “Is Inhaled Insulin A Viable Alternative For Patients With Diabetes?” in the October 2006 issue of Podiatry Today.       Also check out the archives at www.podiatrytoday.com.
 

References:

1. Kahn, C. Ronald, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ: “History of Diabetes.” Joslin’s Diabetes Mellitus, 14th Edition. 2005 ed.
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3. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG: Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Annals of Internal Medicine 2005; 143(8):559-569.
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8. Amylin Pharmaceuticals, Inc. https://www.BYETTA.com
9. Gila Monster Fact Sheet – National Zoo. https://nationalzoo.si.edu/animals/reptilesamphibians/facts/factsheets/gi...
10. Christel CM, DeNardo DF: Release of exendin-4 is controlled by mechanical action in Gila Monsters, Heloderma suspectum. Comparative Biochemistry and Physiology 2006; Part A 143:85-88.
11. Young A, Blasé E, Petrella E, Seward M: Exendin-4 is a circulating meal-related peptide in the Gila monster (Heloderma suspectum). Diabetes 1999a; 48:A425.
12. Diabetes Monitor. https://www.diabetesmonitor.com/byetta.htm.