Transient Stimulatory Effect of Sustained Hyperglucagonemia on Splanchnic Glucose Production in Normal and Diabetic Man

Abstract

Insulin can modulate glucagon-stimulated hepatic glucose production and is considered to be the major factor acting in vivo to exert a couterregulatory action to glucagon. The insulin-dependent diabetic, therefore, might be especially vulnerable to enhanced hepatic glucose production promoted by glucagon. To investigate this hypothesis, low-dose glucagon infusions were administered to normal and diabetic men to compare the effects of glucagon on net splanchnic glucose production (NSGP). Four normal and three insulin-dependent, ketosis-prone, hyperglycemic diabetic men (insulin withheld for 24 hours) underwent brachial-artery-hepatic-vein catheterization. Each received a 90-minute glucagon infusion at 5 ng/kg./min. Glucagon levels rose four-to-fivefold in both groups, plateauing at 300-600 pg./ml. In the normals, NSGP rose from 92+/-12 to 211+/-31 mg./min. at 15 minutes and returned to basal levels by 45 minutes. Insulin measured in the hepatic vein rose from 19+/-6 to 33+/-11 muU/.ml., while plasma glucose rose 17 mg./dl. In the insulin-dependent diabetics, NSGP rose from 78+/-24 to a peak of 221+/-33 mg./min. at 30 minutes and then fell sharply to 113+/-15 mg./min. at 60 minutes despite continuing hyperglucagonemia. Plasma glucose in the diabetics rose 21 mg./dl. These data suggest a mechanism that acts to rapidly diminish glucagon-induced hepatic glucose production in diabetic man but does not appear to be mediated by increased insulin secretion.

Evaluation of the specific effects of intranasal glucagon on glucose production and lipid concentration in healthy men during a pancreatic clamp

“…We and others have previously shown that intranasally administered peptides can have metabolic effects independent of systemic absorption and plasma concentration of the hormones . Intriguingly, when administered exogenously, glucagon increases EGP transiently followed by a decline below baseline over a few hours . We therefore sought to assess the effect of 1 mg ING on plasma glucose and lipids, independent of peripheral spillover, over 6 hours.…”

“…Although glucagon rapidly increases hepatic glucose output and plasma glucose concentration within 1 hour of administration, subsequently plasma glucose concentration declines to below baseline concentration, even with continuous intravenous (i.v.) glucagon infusion . A potential cause of this may be glucagon‐mediated insulin secretion .…”

Protein and diabetes: Much advice, little research

“…The net effect on glucose output by the liver depends on the ratio of insulin concentration to glucagon concentration. However, the effects of glucagon appear to be short-lived and transient [23,24].…”

The Metabolic Effects of Chronic Hyperglucagonaemia

“…There was no plasma cyclic AMP response to a glucagon infusion, suggesting down-regulation of the glucagon receptor by the chronic hyperglucagonaemia. Post-operatively the hepatic glucose production and clearance rate of glucose fell, whereas the plasma cyclic AMP responses to the glucagon infusion reverted to a normal pattern.It is concluded that chronic hyperglucagonaemia is not a major factor in the development of the glucose intolerance, but it may lead to down-regulation of the biological action of glucagon.From studies employing the acute administration of somatostatin in man and experimental animals, it has been concluded that glucagon plays a major role in maintaining basal hepatic glucose production (HGP) (Alford et al, 1974; Cherrington et al, 1976;Liljenquist et al, 1977). Furthermore, it has been shown that glucagon excess can lead to…”

“…From studies employing the acute administration of somatostatin in man and experimental animals, it has been concluded that glucagon plays a major role in maintaining basal hepatic glucose production (HGP) (Alford et al, 1974; Cherrington et al, 1976;Liljenquist et al, 1977). Furthermore, it has been shown that glucagon excess can lead to…”