Glucagonocentric Restructuring of Diabetes: A Pathophysiologic and Therapeutic Makeover

J Clin Invest. 2012 Jan;122(1):4-12. doi: 10.1172/JCI60016. Epub 2012 Jan 3.

Abstract

The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / physiopathology*
  • Glucagon / antagonists & inhibitors
  • Glucagon / physiology*
  • Glycogenolysis / physiology
  • Humans
  • Insulin / deficiency
  • Insulin / physiology
  • Insulin / therapeutic use
  • Liver / physiopathology
  • Mice
  • Pancreas / physiopathology

Substances

  • Insulin
  • Glucagon