Hepatic Glucagon Clearance During Insulin Induced Hypoglycemia

Abstract

Studies concerning the importance of glucagon secretion in hypoglycemic counterregulation have assumed that peripheral levels of glucagon are representative of rates of pancreatic glucagon secretion. The measurement of peripheral levels of this hormone, however, may be a poor reflection of secretion rates because of glucagon's metabolism by the liver. Therefore, in order to understand the relationship between pancreatic glucagon secretion and levels of glucagon in the peripheral blood during hypoglycemia, we evaluated hepatic glucagon metabolism during insulin induced hypoglycemia. Four dogs received an insulin infusion to produce glucose levels less than 50 mg/dl for 45 minutes. In response to this, the delivery of glucagon to the liver increased from 36.7 +/- 5.9 ng/min in the baseline to 322.6 +/- 6.3 ng/min during hypoglycemia. Hepatic glucagon uptake increased proportionally from 13.6 +/- 7.2 ng/min to 103.1 +/- 28.3 ng/min and the percentage of delivered hormone that was extracted did not change (30.8 +/- 13.8% vs 32.9 +/- 11.6%). The absolute amount of glucagon metabolized by the liver was dependent on the rate of delivery and was not directly affected by plasma glucose level per se. To directly study the effect of hypoglycemia on hepatic glucagon metabolism, five dogs were given an exogenous infusion of somatostatin followed by an infusion of glucagon and then administered insulin to produce hypoglycemia. The percent of glucagon extracted by the liver (19.5 +/- 4.9% and 21.3 +/- 6.4%) was not affected by a fall in the plasma glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)

A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism

“…(C) Glucagon concentration in the central vein in dependence of portal glucagon concentration. Experimental data from [ 43 ].…”

Ratiometric Measurements of Adiponectin by Mass Spectrometry in Bottlenose Dolphins (Tursiops truncatus) with Iron Overload Reveal an Association with Insulin Resistance and Glucagon

“…It is possible that in healthy mammals, serum glucagon and adiponectin multimer concentrations are tightly controlled through mechanisms of clearance and that the correlation is lost in dolphins with hepatic dysfunction where glucagon is unable to be efficiently cleared and/or only higher molecular weight adiponectin is selectively cleared. In pigs, the clearance of glucagon largely occurs through elimination via the kidney and in dogs the fraction of glucagon extracted by the liver is only approximately 20% (58) suggesting that renal clearance, not hepatic clearance is the main sink. In this study there was no difference in eGFR between dolphin groups indicating that impaired renal clearance is an unlikely reason for preferential clearance of adiponectin forms.…”

The Physiology of Glucagon

“…First, the liver is exposed to glucagon concentrations that are two to three times higher than the levels to which other organs are exposed. Glucagon is secreted into the portal vein and partially extracted by the liver 22 before it is diluted by the glucagon-poor blood of the systemic circulation. Second, the systemic levels of endogenous glucagon are usually below those needed to affect the glucagon receptors on adipose tissue to cause lipolysis.…”