Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover
Roger H. Unger, Alan D. Cherrington
Roger H. Unger, Alan D. Cherrington
Published January 3, 2012
Citation Information: J Clin Invest. 2012;122(1):4-12. https://doi.org/10.1172/JCI60016.
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Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

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.

Authors

Roger H. Unger, Alan D. Cherrington

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Figure 4

Glucagon is the sine qua non of diabetes in mice.

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Glucagon is the sine qua non of diabetes in mice. (A) Glucose levels in ...
(A) Glucose levels in normal wild-type mice and in Gcgr–/– mice after destruction of β cells by double-dose streptozotocin treatment. Gcgr–/– mice remain normoglycemic and exhibit no detectable metabolic consequence of total insulin deficiency. (B) Insulin response to oral glucose in Gcgr–/– mice before and after β cell destruction. (C) Oral glucose tolerance curve of Gcgr–/– mice before and after β cell destruction. Remarkably, although streptozotocin-treated Gcgr–/– mice were incapable of secreting insulin in response to an oral glucose tolerance test, their glucose tolerance curves did not differ significantly from Gcgr–/– mice with intact β cells and a robust insulin response. In other words, in this model of congenital absence of glucagon activity, insulin has become irrelevant. (A–C) Figure adapted with permission from Diabetes (71).