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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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Science in Medicine

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

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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 1

Relationship between hepatic sinusoidal glucagon and glucose production in vivo.

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Relationship between hepatic sinusoidal glucagon and glucose production ...
A pancreatic clamp was used to keep plasma insulin basal and constant. The glucose production rate reflects the maximal effect of glucagon and was observed approximately 15 minutes after the change in the hormone level. In this way, the accompanying hyperglycemia was limited such that its inhibitory effect on glucose production was minimal. When glucagon was made deficient (i.e., 0 pg/ml), euglycemia was maintained by glucose infusion. The region shaded blue denotes the physiologic range of plasma glucagon. Figure adapted with permission from Handbook of Physiology (96).

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