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

Metabolism. 1975 Nov;24(11):1287-97. doi: 10.1016/0026-0495(75)90067-0.


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 less than 0.01-0.05). When somatostatin was discontinued, glucagon rose and glucose increased 21% (p less than 0.05) in 30 min. Significant correlation between maximal changes in glucagon and glucose was observed (r = 0.81; p less than 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 less than 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 less than 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 less than 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / complications*
  • Diazoxide / pharmacology
  • Dogs
  • Glucagon / blood
  • Glucagon / physiology*
  • Hyperglycemia / etiology*
  • Pancreas / physiology
  • Pancreatectomy
  • Somatostatin / pharmacology


  • Blood Glucose
  • Somatostatin
  • Glucagon
  • Diazoxide