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

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.