Amylin analogs for the treatment of diabetes mellitus
- Kathleen Dungan, MD
Kathleen Dungan, MD
- Assistant Professor
- Ohio State University, Department of Endocrinology, Diabetes & Metabolism
Despite advances in options for the treatment of diabetes, optimal glycemic control is often not achieved . Hypoglycemia and weight gain associated with therapy may interfere with the implementation and long-term application of "intensive" therapies [2-4]. Treatment of type 1 diabetes is directed at physiologic insulin replacement. Many patients with type 2 diabetes also ultimately require insulin therapy as a result of progressive beta cell dysfunction . Starter insulin regimens (such as basal insulin monotherapy) for patients with type 2 diabetes commonly require repeated intensification over time to achieve even modest glycated hemoglobin (A1C) reductions . Therefore, other therapeutic approaches are needed.
Glucose homeostasis is dependent on a complex interplay of multiple hormones that may be targets for a multi-faceted treatment approach: insulin and amylin, produced by pancreatic beta cells; glucagon, produced by pancreatic alpha cells; and gastrointestinal peptides, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP; gastric inhibitory polypeptide) (figure 1) . Abnormal regulation of these substances may contribute to the clinical presentation of diabetes.
The mechanism of action and therapeutic utility of amylin analogs will be reviewed here. GLP-1-based therapies and overviews of pharmacologic therapy for type 1 and type 2 diabetes are presented separately. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus" and "Management of blood glucose in adults with type 1 diabetes mellitus" and "Initial management of blood glucose in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
Amylin is a 37-amino acid peptide that is stored in pancreatic beta cells and is co-secreted with insulin . Amylin and insulin levels rise and fall in a synchronous manner (figure 2) . Amylin and insulin have complementary actions in regulating nutrient levels in the circulation. Amylin is deficient in type 1 diabetes and relatively deficient in insulin-requiring type 2 diabetes (figure 2) .
Amylin affects glucose control through several mechanisms, including slowed gastric emptying, regulation of postprandial glucagon, and reduction of food intake (table 1). Glucagon-like peptide 1 (GLP-1) exhibits similar properties as amylin, with the exception of insulin secretory effects. Amylin, unlike GLP-1, does not have insulin secretory effects, but both regulate hyperglycemia in part through amelioration of inappropriate glucagon secretion and gastric emptying. GLP-1 and amylin appear to have differing magnitudes of physiologic effects and bind to different receptors in the area postrema, the part of the brain that may be key for their effects on satiety [9,10]. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus".)
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