Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover.
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.
Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854, USA. roger.unger@utsouthwestern.edu
Roger H
RH
Unger
Alan D
AD
Cherrington
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000503:physiopathology*; D005934:Glucagon / Q000037:antagonists & inhibitors / Q000502:physiology*; D050261:Glycogenolysis / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000172:deficiency / Q000502:physiology / Q000627:therapeutic use; D008099:Liver / Q000503:physiopathology; D051379:Mice; D010179:Pancreas / Q000503:physiopathology
D007328:Insulin; D005934:Glucagon