Glucagonocentric restructuring of diabetes: A pathophysiologic and therapeutic makeover

Roger H Unger, Alan D. Cherrington

Research output: Contribution to journalReview article

379 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4-12
Number of pages9
JournalJournal of Clinical Investigation
Volume122
Issue number1
DOIs
StatePublished - Jan 3 2012

ASJC Scopus subject areas

  • Medicine(all)

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