The Role of Glucagon in the Pathophysiology and Treatment of Type 2 Diabetes

Abstract

Type 2 diabetes is a disease involving both inadequate insulin levels and increased glucagon levels. While glucagon and insulin work together to achieve optimal plasma glucose concentrations in healthy individuals, the usual regulatory balance between these 2 critical pancreatic hormones is awry in patients with diabetes. Although clinical discussion often focuses on the role of insulin, glucagon is equally important in understanding type 2 diabetes. Furthermore, an awareness of the role of glucagon is essential to appreciate differences in the mechanisms of action of various classes of glucose-lowering therapies. Newer drug classes such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists improve glycemic control, in part, by affecting glucagon levels. This review provides an overview of the effect of glucose-lowering therapies on glucagon on the basis of an extensive PubMed literature search to identify clinical studies of glucose-lowering therapies in type 2 diabetes that included assessment of glucagon. Clinical practice currently benefits from available therapies that impact the glucagon regulatory pathway. As clinicians look to the future, improved treatment strategies are likely to emerge that will either use currently available therapies whose mechanisms of action complement each other or take advantage of new therapies based on an improved understanding of glucagon pathophysiology.

Mechanisms of action of metformin with special reference to cardiovascular protection

“…Most people with type 2 diabetes display a paradoxical increase in glucagon levels during the postprandial state, rather than the decrease seen in normoglycaemic individuals . Another cellular action described for metformin is an inhibition of cAMP accumulation, which leads to reduced activity of adenylate cyclase and a functional inhibition of the stimulatory effect of glucagon on hepatic glucose production .…”

“…Another cellular action described for metformin is an inhibition of cAMP accumulation, which leads to reduced activity of adenylate cyclase and a functional inhibition of the stimulatory effect of glucagon on hepatic glucose production . Incretin‐based therapies and glucagon antagonists (currently in clinical development for the treatment of type 2 diabetes) improve glucose homoeostasis at least in part by suppression of glucagon signalling pathways: this action of metformin may therefore have important functional significance …”

“…15 Incretin-based therapies and glucagon antagonists (currently in clinical development for the treatment of type 2 diabetes) improve glucose homoeostasis at least in part by suppression of glucagon signalling pathways: this action of metformin may therefore have important functional significance. 14…”

GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1α Mutation Carriers

“…The nature of postprandial hyperglucagonemia could theoretically be due to insufficient glucose sensing in the glucagon-producing α-cells (like that observed in β-cells); however, the normal suppression of glucagon during intravenous glucose infusion in our and other studies contradicts this ( 14 , 22 ). Insulin is also known as an inhibitor of glucagon secretion ( 27 ), which is why hypoinsulinemia could disrupt the normal paracrine signaling between β- and α-cells, resulting in increased glucagon concentrations. Finally, an explanation could be that the total α-cell mass or α- to β-cell ratio could be increased.…”

Carotid Body and Metabolic Syndrome: Mechanisms and Potential Therapeutic Targets

“…; if so, (4) can CB malfunctions induce insulin resistance? These inquiries are particularly important in the context of the pathophysiology of type 2 diabetes, in which hyperinsulinemia, an imbalance in insulin/glucagon levels, and insulin resistance are associated with the development and progression of the disease [ 124 , 125 , 126 ].…”