Alpha-cells and therapy of diabetes: inhibition, antagonism or death?

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Abstract

Absolute or relative hyperglucagonaemia is a characteristic of both Type 1 and Type 2 diabetes, resulting in fasting hyperglycaemia due in part to increased hepatic glucose production and lack of postprandial suppression of circulating glucagon concentrations. Consequently, therapeutics that target glucagon secretion or biological action may be effective antidiabetic agents. In this regard, specific glucagon receptor (GCGR) antagonists have been developed that exhibit impressive glucose-lowering actions, but unfortunately may cause off-target adverse effects in humans. Further to this, several currently approved antidiabetic agents, including GLP-1 mimetics, DPP-4 inhibitors, metformin, sulphonylureas and pramlintide likely exert part of their glucose homeostatic actions through direct or indirect inhibition of GCGR signalling. In addition to agents that inhibit the release of glucagon, compounds that enhance the transdifferentiation of glucagon secreting alpha-cells towards an insulin positive beta-cell phenotype could also help curb excess glucagon secretion in diabetes. Use of alpha-cell toxins represents another possible strategy to address hyperglucagonaemia in diabetes. In that respect, research from the 1920 s with diguanides such as synthalin A demonstrated effective glucose-lowering with alpha-cell ablation in both animal models and humans with diabetes. However, further clinical use of synthalin A was curtailed due its adverse effects and the increased availability of insulin. Overall, these observations with therapeutics that directly target alpha-cells, or GCGR signaling, highlight a largely untapped potential for diabetes therapy that merits further detailed consideration.

Original languageEnglish
Article number170877
Number of pages8
JournalPeptides
Volume157
Early online date12 Sept 2022
DOIs
Publication statusPublished (in print/issue) - 1 Nov 2022

Bibliographical note

Funding Information:
The authors work on glucagon and related peptides has been supported over many years by Diabetes UK, European Foundation for the Study of Diabetes ( EFSD ), Invest Northern Ireland, Irish Endocrine Society , SAAD Trading and Contracting Company , Department for the Economy ( DfE ) Northern Ireland, Diabetes Research & Wellness Foundation ( DRWF ) and University of Ulster strategic research funding .

Publisher Copyright:
© 2022 The Authors

Keywords

  • Alpha-cell
  • Glucagon
  • Glucagon receptor (GCGR)
  • Diabetes
  • Obesity
  • Synthalin A

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