The role of glucagon in the regulation of plasma lipids.

The role of glucagon in regulating plasma lipid concentrations (nonesterified fatty acids, ketone bodies, and triglycerides) is reviewed. The effects of glucagon-induced insulin secretion upon this lipid regulation are discussed that may resolve conflicting reports in the literature are resolved. In addition, the unresolved problem concerning the pharmacologic versus physiologic effects of glucagon is stressed. Glucagon's role in stimulating lipolysis at the adipocyte serves two important functions. First, it provides plasma nonesterified fatty acids for energy metabolism and secondly, it ensures substrate for hepatic ketogenesis. In vitro, glucagon's lipolytic activity has been consistently observed, but in vivo, this activity has sometimes been obscured by the effects of glucagon-induced insulin secretion. Frequently, a biphasic response has been reported in which a direct lipolytic response is followed by a glucagon-induced insulin suppression of plasma nonesterified fatty acid concentration. When the glucagon-induced insulin secretion has been controlled by various in vivo techniques, glucagon's lipolytic activity in vivo has frequently been demonstrable. In the 1960s, in vitro liver perfusion experiments demonstrated that glucagon enhanced hepatic ketogenesis independent of glucagon's lipolytic activity. However, this direct effect of glucagon on the hepatocyte was not universally accepted because of conflicting reports in the literature. Failure to observe an in vitro ketogenic effect of the hormone in some studies may have been due to suboptimal experimental conditions. Certain factors are now known to influence the ketogenic response, such as the concentration of fatty acids in the media and the nutritional status of the animal. Under optimal in vitro conditions with liver preparations from fed animals, the ketogenic response to physiologic concentrations of glucagon has been demonstrated. However, further study is necessary to define the quantitative ketogenic role of the hormone. In spite of this early in vitro work, glucagon was not definitely shown to be ketogenic in vivo (independent of fatty acid availability) both in the rat and in diabetic man until 1975. Since these observations, several reports have confirmed the ketogenic action of glucagon in vivo by direct hepatic catheterization experiments. Glucagon's role in decreasing hepatic triglyceride synthesis and secretion in vitro has been repeatedly shown but the mechanism is unresolved. This lipid regulatory action of glucagon has been more difficult to demonstrate in vivo because of the many variables that affect triglyceride synthesis. Under specific experimental conditions, however, glucagon has been shown to decrease plasma triglyceride concentration in man at both physiologic and pharmacologic concentrations. Hepatic catheterization experiments have also confirmed this effect in man. The regulation of lipids by glucagon fits well into its role as a stress hormone...