Glucagon secretion and action in humans

The overall aim of this application is to better understand the heterogeneity in glucagon secretion and action that we have observed in nondiabetic subjects. Abnormal glucagon secretion in the post-prandial period is recognized to play a key role in the pathogenesis of type 2 diabetes. While glucagon’s actions on glucose metabolism are reasonably well characterized, there is little understanding as to why individuals differ in their hepatic responses to this hormone. More importantly, it appears that the actions of glucagon to enhance hepatic clearance of amino acids is impaired in people with hepatic steatosis. Although there is some evidence that glucagon stimulates lipolysis and fatty acid oxidation, a review of the literature suggests that these aspects of glucagon’s actions have been ignored. In addition, there is no understanding as to whether the ability to stimulate endogenous glucose production and gluconeogenesis is independent of actions on amino acid and lipid metabolism. In rodents, α-cells mass is, in part, regulated by circulating amino acid concentrations which, in turn stimulate glucagon secretion (increasing hepatic clearance of amino acids). Whether this liver-α-cell axis is extant in humans is uncertain. However, our preliminary data shows that with caloric restriction fasting glucagon decreases in concert with fasting concentrations of several amino acids. Since caloric restriction is known to ameliorate hepatic steatosis and improve insulin action, this provides an opportunity to assess how changes in hepatic fat content alter the response to glucagon – specifically as it applies to carbohydrate, protein, and fat metabolism. As part of our prior work we have developed new methods to quantify glucagon secretion in vivo so that our proposed experiments will also examine how acute changes in circulating amino acid concentrations alter α-cell function. The experiments we propose will provide novel new information about glucagon secretion and action in humans.