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      Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover.

      The Journal of clinical investigation

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

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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.

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          Author and article information

          Journal
          22214853
          3248306
          10.1172/JCI60016

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