Pancreatic α-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block

Abstract

Type 2 diabetes (T2D) has been known as 'bi-hormonal disorder' since decades ago, the role of glucagon from α-cell has languished whereas β-cell taking center stage. Recently, numerous findings indicate that the defects of glucagon secretion get involve with development and exacerbation of hyperglycemia in T2D. Aberrant α-cell responses exhibit both fasting and postprandial states: hyperglucagonemia contributes to fasting hyperglycemia caused by inappropriate hepatic glucose production, and to postprandial hyperglycemia owing to blunted α-cell suppression. During hypoglycemia, insufficient counter-regulation response is also observed in advanced T2D. Though many debates still remained for exact mechanisms behind the dysregulation of α-cell in T2D, it is clear that the blockade of glucagon receptor or suppression of glucagon secretion from α-cell would be novel therapeutic targets for control of hyperglycemia. Whereas there have not been remarkable advances in developing new class of drugs, currently available glucagon-like peptide-1 and dipeptidyl peptidase-IV inhibitors could be options for treatment of hyperglucagonemia. In this review, we focus on α-cell dysfunction and therapeutic potentials of targeting α-cell in T2D.

Keywords: Diabetes mellitus, type 2; Glucagon; Glucagon-secreting cells; Insulin; Insulin-secreting cells.

Fig. 1. Intra-islet insulin & glucagon secretion. Normal (in nondiabetes) and advanced type 2 diabetes (T2D) of the relationship between the inhibitory effects of pancreatic β-cell insulin secretion on pancreatic α-cell glucagon secretion. Normally, an increase in plasma glucose level causes an increase in β-cell insulin secretion that prevents an increase in α-cell glucagon secretion in response to meal. In advanced T2D, however, β-cell failure which is lack of intra-islet signaling result in not only fail to suppress but also an increase in pancreatic α-cell glucagon secretion (A). A decrease in plasma glucose level causes a decrease in β-cell insulin secretion that signals an increase in α-cell glucagon secretion during hypoglycemia. On the other hand, in the advanced T2D, a decrease in plasma glucose cannot cause a decrease in β-cell insulin secretion, and the absence of that signal results in no increase in pancreatic α-cell glucagon secretion during hypoglycemia (B).