Incretin-based Therapies: A Focus on Alpha Cells and Glucagon Secretion

Introduction

Type 2 diabetes mellitus (T2DM) is a clinical syndrome with varying phenotypic elements including beta-cell deficiency and insulin resistance. A gradual decline in glycemic control, despite medical therapy, is often present during the natural history of the disease. Insulin and glucagon are the primary hormones responsible for regulating blood glucose levels.1 Glucagon protects the brain against hypoglycemia and functions to ensure adequate blood glucose levels. Insulin reduces hyperglycemia through the stimulation of hepatic glycogen synthesis and glucose transport in adipose tissue and skeletal muscle.2, 3 After the ingestion of a meal, insulin secretion is increased, whereas glucagon secretion is decreased. Glucose and insulin regulate α-cell function under the following physiological conditions: low glucose and low insulin levels stimulate glucagon release, whereas both hyperglycemia and hyperinsulinemia suppress glucagon secretion. In T2DM, this equilibrium is impaired.4 In these patients, plasma glucagon levels are inappropriately high in both the basal and postprandial phase, despite the high circulating levels of glucose and insulin often observed in these subjects. This represents a key factor in determining the increased rate of hepatic glucose output in these patients.5–11 The mechanism of this functional defect is unknown. Several hypotheses can be formulated to explain why α-cells are less sensitive to the suppressive effects of glucose and insulin in patients with diabetes. Moreover, alterations in serum circulating levels of incretin or its biological action in target cells could add additional elements for investigating islet imbalance in these patients.

Abstract

Conventional therapies for type 2 diabetes mellitus effectively reduce hyperglycemia. However, they are often associated with hypoglycemia and other adverse side effects. In patients with diabetes, the secretion of glucagon is often not inhibited in the presence of elevated blood glucose, thus exacerbating hyperglycemia. Alpha-cell dysfunction is also a characteristic of type 2 diabetes. However, based solely on their mechanism of action, none of the conventional therapies represents a tool for modulating glucagon secretion. Incretin-based therapies lower glucose using novel mechanisms based on the action of the gut hormones GLP-1 and GIP. The physiological mechanism of incretin's action suggests different areas in which incretin therapies may be more advantageous compared to other medications. In particular, GLP-1 has been shown to inhibit glucagon release after meal ingestion with a decreased risk of hypoglycemic episodes compared to other therapies. Improvement in alpha-cell function via incretin-based therapies results in better postprandial and fasting glycemic profiles. Moreover, due to the wide distribution of GLP-1 receptors in human tissues, incretin-based therapies may have other beneficial effects on beta-cells, body weight, lipid profile, cardiovascular risk, and other extra-pancreatic properties.

Keywords

incretin therapies, pancreatic alpha-cell, glucagon, GLP-1, GIP