Glucose control of glucagon secretion—‘There’s a brand-new gimmick every year’

Abstract

Glucagon from the pancreatic α-cells is a major blood glucose-regulating hormone whose most important role is to prevent hypoglycaemia that can be life-threatening due to the brain’s strong dependence on glucose as energy source. Lack of blood glucose-lowering insulin after malfunction or autoimmune destruction of the pancreatic β-cells is the recognized cause of diabetes, but recent evidence indicates that diabetic hyperglycaemia would not develop unless lack of insulin was accompanied by hypersecretion of glucagon. Glucagon release has therefore become an increasingly important target in diabetes management. Despite decades of research, an understanding of how glucagon secretion is regulated remains elusive, and fundamentally different mechanisms continue to be proposed. The autonomous nervous system is an important determinant of glucagon release, but it is clear that secretion is also directly regulated within the pancreatic islets. The present review focuses on pancreatic islet mechanisms involved in glucose regulation of glucagon release. It will be argued that α-cell-intrinsic processes are most important for regulation of glucagon release during recovery from hypoglycaemia and that paracrine inhibition by somatostatin from the δ-cells shapes pulsatile glucagon release in hyperglycaemia. The electrically coupled β-cells ultimately determine islet hormone pulsatility by releasing synchronizing factors that affect the α- and δ-cells.

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

“…We show that in the absence of paracrine influence, isolated α-cells respond appropriately to hypoglycemia with an increase in glucagon granule exocytosis. This is consistent with the glucose dependence of glucagon secretion from intact islets (but not FACS sorted rat α-cells) 52,53 , and indicates that glucagon secretion is mostly under intrinsic control in the lower glucose-concentration range. With only 2-fold difference in the exocytosis rate between minimal secretion at 7 mM and maximal secretion at 1 mM glucose, the dynamic range is small compared with β-cells.…”

“…Glucose controls glucagon secretion by intrinsic and paracrine mechanisms, but their relative significance is still debated 52 and secretory defects in type-2 diabetes are not well understood. The current work is first in using high resolution microscopy to study glucagon secretion in single, undisturbed α-cells of healthy and type-2 diabetic donors, thus isolating intrinsic from paracrine mechanisms while having full control over paracrine signaling.…”

Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx

“…We showed that Na + channel inactivation, a classical electrophysiological marker for distinguishing mouse α-cells versus β-cells, shifts from an α-cell phenotype to a β-cell phenotype in converted α-cells. Moreover, we showed that converted α-cells, like normal β-cells, secrete insulin and show a clear switch to high glucose-amplification of exocytosis, in contrast to unconverted α-cells which secrete glucagon and have exocytotic responses blunted by high glucose (Gylfe et al, 2016). We postulate that loss of Arx and Dnmt1 in α-cells triggers the upregulation of gene regulatory networks controlling metabolic sensing pathways that are intrinsic to β-cells.…”

Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

“…insulin, Zn 2+ , GABA and its metabolite gamma-hydroxybutyrate (GHB), ATP, glutamate, somatostatin; reviewed in (Briant et al, 2016; Gromada et al, 2007; Gylfe, 2016)]. The multitude of signals that mediate paracrine inhibition of alpha cells during hyperglycemia suggest that this is an important physiological mechanism that requires redundant signaling pathways.…”