The focus of my research is to better understand the regulation of glucose metabolism. Hepatic glucose production is determined by gluconeogenesis and glycogenolysis, which are regulated, to a large extent, by insulin and glucagon. I have spent the last 19 years studying the physiologic role of this hormone in controlling these processes. It is clear that insulin exerts both direct and indirect effects on the liver. Following the binding of insulin to its hepatic receptor there is rapid suppression of hepatic glucose production due to the suppression of glycogenolysis. Although insulin also directly inhibits the release of gluconeogenically derived glucose into the blood stream, gluconeogenic flux (through phosphoenolpyruvate carboxykinase to glucose-6-phosphate) is not reduced at physiologic insulin concentrations; instead gluconeogenic carbon is diverted into glycogen stores. Insulin can reduce hepatic extraction and circulating availability of gluconeogenic precursors, but only at high concentrations of the hormone. Although the direct effects of insulin on the suppression of hepatic glucose production are dominant, insulin also has critical indirect effects; including inhibition of lipolysis, suppression of glucagon secretion, and potential effects on the central nervous system. Recently we sought to understand the relative importance of brain insulin action in regulating liver glucose metabolism. We found that while insulin in the brain has no apparent effect on the suppression of glucose production under physiologic insulin conditions (when insulin is elevated by the same fold at the liver and the brain), glycogen synthesis is augmented by the central effects of insulin. Additional research is necessary to determine the relevance of this effect under hyperglycemic conditions (at the time when insulin is typically elevated and when glycogen synthesis is most important). It is also critical to understand how these processes may be dysregulated in insulin resistance, allowing for improved treatment of individuals with diabetes.
