The role of glucagon in the pathogenesis of the endogenous hyperglycemia of diabetes mellitus

Hideo Sakurai, Richard E. Dobbs, Roger H Unger

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37 Scopus citations


The effect of glucagon suppression by somatostatin upon endogenous hyperglycemia was studied in three forms of experimental insulin deficiency in dogs: alloxan diabetes, total pancreatectomy, and diazoxide administration. In six insulin-requiring alloxan-diabetic dogs deprived of insulin for 24 hr, mean plasma glucose declined to 77% ± 6% of the baseline level of 350 ± 41 mg/dl during 3 hr of glucagon suppression, significantly below the unsuppressed saline controls (p < 0.01-0.05). When somatostatin was discontinued, glucagon rose and glucose increased 21% (p < 0.05) in 30 min. Significant correlation between maximal changes in glucagon and glucose was observed (r = 0.81; p < 0.001). Even during a 1-hr alanine infusion in such dogs, glucose declined an average of 36 ± 9 mg/dl, instead of rising 51 ± 7 mg/dl as in unsuppressed controls. Maximal changes in glucagon and glucose were correlated (r = 0.85; p < 0.01). In eight depancreatized dogs pretreated intravenously with continuous insulin and glucose infusions, withdrawal of insulin was followed by a rise in extrapancreatic glucagon; mean plasma glucose rose from 212 ± 43 to 415 ± 80 mg/dl 270 min after the end of the insulin infusion. However, when glucagon was suppressed after insulin withdrawal, glucose remained below 240 mg/dl, significantly less than the controls (p < 0.005); when somatostatin was stopped, glucagon rose and glucose increased 88 ± 19 mg/dl within an hour. The rises in glucagon and glucose were significantly correlated (r = 0.68; p < 0.05). Glucagon suppression by somatostatin during diazoxide-induced blockade of insulin secretion in four normal dogs reduced hyperglycemia significantly but did not prevent it. The results support the hypothesis that a relative or absolute excess of glucagon, as well as a relative or absolute deficiency of insulin, is etiologically important in the development of endogenous hyperglycemia in diabetes mellitus, the hyperglucagonemia probably mediating the glucose overproduction.

Original languageEnglish (US)
Pages (from-to)1287-1297
Number of pages11
Issue number11
StatePublished - Nov 1975

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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