Inhibition of Glucagon Secretion by GLP-1 Agonists and DPP4 Inhibitors

Introduction

It has been acknowledged for decades that the pathophysiology of type 2 diabetes mellitus (T2DM), in addition to insulin deficiency and insulin resistance, involves hyperglucagonemia. Also, hyperglucagonemia has been shown to contribute to the glucose intolerance of these patients. Nevertheless, agents for treatment of T2DM have previously been selected on the basis of their ability to increase insulin secretion (sulphonylureas) or to enhance insulin sensitivity (metformin and glitazones); alternatively, insulin has simply been provided. New drugs based on the antidiabetic effects of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1), have been available for clinical use for some years now. Two types of incretin-based treatment exist: GLP-1 receptor agonists and inhibitors of the enzyme dipeptidyl peptidase 4 (DPP4), which otherwise rapidly inactivates endogenously secreted GLP-1. The GLP-1 has been shown to counteract several pathophysiological traits of T2DM, and the two existing incretin-based treatment modalities both seem to potentiate or even normalize glucose induced beta cell secretion and suppress glucagon secretion from the alpha cell. In the present article the physiology of the incretin hormone GLP-1 in healthy humans and in the setting of T2DM is outlined, and published data about the glucagonostatic effect of incretin-based treatment in T2DM is reviewed.

Abstract

Incretin-based treatments have emerged as new modalities for the treatment of type 2 diabetes mellitus (T2DM). In contrast to current antidiabetic treatments, these agents target both insulin insufficiency and inappropriate hyperglucagonemia—two major components of type 2 diabetic pathophysiology—both known to contribute significantly to the hyperglycemic state of patients with T2DM. This article outlines the role of hyperglucagonemia in type 2 diabetic pathophysiology, summarizes the physiologic effects of glucagon-like peptide-1 (GLP-1), and gives an introduction to incretin-based treatments with emphasis on their glucagon-lowering effects. Finally, we review available glucagon data from current clinical studies on incretin-based treatment modalities (dipeptidyl peptidase 4 [DPP4] inhibitors and GLP-1 receptor agonists). Most of these studies suggest that both DPP4 inhibitors and GLP-1 receptor agonists lower fasting and postprandial plasma glucagon, and recent data suggest that these effects contribute importantly to the glucose-lowering effect of these treatments.

Keywords

dipeptidyl peptidase 4 (DPP4), DPP4 inhibitors, glucagon, glucagon-like peptide-1 (GLP-1), GLP-1 receptor agonists, hyperglucagonemia, type 2 diabetes mellitus