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.

Comparison of the effects of gemigliptin and dapagliflozin on glycaemic variability in type 2 diabetes: A randomized, open‐label, active‐controlled, 12‐week study (STABLE II study)

“…One of the key pathophysiologies of type 2 diabetes is α-cell dysfunction and hyperglucagonaemia, which results in both fasting and postprandial hyperglycaemia. 28 It has been reported that, compared to SGLT2 inhibition by dapagliflozin, DPP-4 inhibition by vildagliptin results in a 5% lower fasting and postprandial glucagon level after 2 weeks of treatment in type 2 diabetes patients. 29 In addition, compared to SGLT2 inhibition, DPP-4 inhibition resulted in more rapid insulin secretion, with higher C-peptide, intact GLP-1 and glucose-dependent insulinotropic polypeptide levels.…”

“…It could be speculated that the glucagon level might explain the difference in glycaemic variability between the two groups, at least in part. One of the key pathophysiologies of type 2 diabetes is α‐cell dysfunction and hyperglucagonaemia, which results in both fasting and postprandial hyperglycaemia . It has been reported that, compared to SGLT2 inhibition by dapagliflozin, DPP‐4 inhibition by vildagliptin results in a 5% lower fasting and postprandial glucagon level after 2 weeks of treatment in type 2 diabetes patients .…”

Blood Glucagon Levels Predict the Hemoglobin A1c Response to Saxagliptin in Patients with Type 2 Diabetes Inadequately Controlled with Metformin

“…Gromada et al found that GLP-1 has minimal activity with glucagon receptor [27]. However, most studies have not localized the GLP-1 receptor to α-cells [28]. Blood glucagon level may correlate with the capacity of GLP-1 production in vivo, because GLP-1 is a product of proglucagon that has nearly 50% homology to glucagon [29].…”

Prediabetes linked to excess glucagon in transgenic mice with pancreatic active AKT1

“…Glucagon, which is secreted by pancreatic α–cells when blood glucose levels are low, is known as the antagonist to insulin. When glucagon binds to its receptor it activates cellular adenosine-3′-5′-cyclic monophosphate (cAMP) and protein kinase A (PKA) signaling to induce hepatic gluconeogenesis and glycogenolysis restoring glucose homeostasis during fasting (Moon & Won 2015). Increased PKA activity impairs glucose stimulated insulin secretion (GSIS), which is needed to prevent the immediate secretion and glucose disposing action of insulin (Song et al 2014).…”