The Regulation and Secretion of Glucagon in Response to Nutrient Composition: Unraveling Their Intricate Mechanisms

Abstract

Glucagon was initially regarded as a hyperglycemic substance; however, recent research has revealed its broader role in metabolism, encompassing effects on glucose, amino acids (AAs), and lipid metabolism. Notably, the interplay of glucagon with nutrient intake, particularly of AAs, and non-nutrient components is central to its secretion. Fasting and postprandial hyperglucagonemia have long been linked to the development and progression of type 2 diabetes (T2DM). However, recent studies have brought to light the positive impact of glucagon agonists on lipid metabolism and energy homeostasis. This review explores the multifaceted actions of glucagon, focusing on its regulation, signaling pathways, and effects on glucose, AAs, and lipid metabolism. The interplay between glucagon and other hormones, including insulin and incretins, is examined to provide a mechanistic understanding of its functions. Notably, the liver–α-cell axis, which involves glucagon and amino acids, emerges as a critical aspect of metabolic regulation. The dysregulation of glucagon secretion and its impact on conditions such as T2DM are discussed. The review highlights the potential therapeutic applications of targeting the glucagon pathway in the treatment of metabolic disorders.

The role of mu-opioid receptors in pancreatic islet alpha cells

“…Though not explored in this study, it would be interesting to examine how the long-term upregulation of glucagon secretion from MOPR cKO mice impacts liver function gluconeogenesis or lipid metabolism. Indeed, some evidence points to changes in hepatic responses to glucagon as a major driver of hyperglucagonemia [38,39]. In either individuals with T2D, or in mice with chronically enhanced glucagon secretion, long-term overstimulation of the liver could result in impaired metabolic phenotypes.…”