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Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus

Authors
Kathleen Dungan, MD
Anthony DeSantis, MD
Section Editor
David M Nathan, MD
Deputy Editor
Jean E Mulder, MD

INTRODUCTION

Despite advances in options for the treatment of diabetes, optimal glycemic control is often not achieved. Hypoglycemia and weight gain associated with many antidiabetic medications may interfere with the implementation and long-term application of “intensive” therapies [1]. Current treatments have centered on increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and absorption of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion.

Glucagon-like peptide-1 (GLP-1)-based therapies (eg, GLP-1 receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors) affect glucose control through several mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon and of food intake (table 1). These agents do not usually cause hypoglycemia in the absence of therapies that otherwise cause hypoglycemia.

This topic will review the mechanism of action and therapeutic utility of GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus. DPP-4 inhibitors are discussed separately. A general discussion of the initial management of blood glucose and the management of persistent hyperglycemia in adults with type 2 diabetes is also presented separately. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 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".)

GLUCAGON-LIKE PEPTIDE-1

Glucose homeostasis is dependent upon a complex interplay of multiple hormones: 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 role of GLP-1 in glucose homeostasis is illustrative of the incretin effect, in which oral glucose has a greater stimulatory effect on insulin secretion than intravenous glucose [2]. This effect is mediated by several gastrointestinal peptides, particularly GLP-1, that are released in the setting of a meal and stimulate insulin synthesis and insulin secretion, which does not occur when carbohydrate is administered intravenously.

GLP-1 is produced from the proglucagon gene in L-cells of the small intestine and is secreted in response to nutrients (figure 1) [3]. GLP-1 binds to a specific GLP-1 receptor, which is expressed in various tissues including pancreatic beta cells, pancreatic ducts, gastric mucosa, kidney, lung, heart, skin, immune cells, and the hypothalamus [2,4]. GLP-1 exerts its main effect by stimulating glucose-dependent insulin release from the pancreatic islets [2]. It has also been shown to slow gastric emptying [5], inhibit inappropriate post-meal glucagon release [3,6], and reduce food intake (table 1) [3]. Owing in part to the effects of GLP-1 on slowed gastric emptying and appetite centers in the brain, therapy with GLP-1 and its receptor agonists is associated with weight loss, even among patients without significant nausea and vomiting. (See 'Weight loss' below.)

                                        

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Literature review current through: Nov 2016. | This topic last updated: Thu Aug 25 00:00:00 GMT+00:00 2016.
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