NMR STUDIES:HEPATIC GLUCOSE METABOL IN HUMANS EXERCISING

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DESCRIPTION (adapted from the application) During exercise plasma glucose concentrations remain relatively constant despite increased muscle glucose uptake. This occurs because endogenous glucose production (EGP) increases to match the increased requirements. Despite many studies that have examined the hormonal/neuronal regulation of hepatic glucose production, little is known about the mechanism by which this occurs (i.e., whether glycogenolysis and/or gluconeogenesis increases). Furthermore, very little is known about the regulation of hepatic glycogen metabolism at rest or during exercise in patients with type 1 diabetes. Recent studies have demonstrated that poorly controlled type 1 diabetic subjects have hepatic glycogen stores that are approximately one-third of healthy control subjects. Given the importance of hepatic glycogenolysis in maintaining EGP in the fasting state and during exercise, it might be anticipated that this process would be deficient in both of these states. The overall goal of this application is to address these questions using 13C nuclear magnetic resonance (NMR) spectroscopy techniques in conjunction with Gas Chromatography Mass Spectroscopy (GC-MS) and magnetic resonance imaging (MRI) to non invasively examine the contributions of net hepatic glycogenolysis and gluconeogenesis to EGP during rest and exercise in healthy and type 1 diabetic (well controlled and poorly controlled) subjects. The specific aims of these studies are: 1) To examine the regulation of hepatic glycogenolysis and gluconeogenesis at rest and during exercise in healthy subjects and in patients with type 1 diabetes and 2) To determine the roles of epinephrine and glucagon on the relative contributions of hepatic glycogenolysis and gluconeogenesis in healthy and type 1 diabetic subjects. The hypotheses that will be tested are i) That in healthy subjects the relative contribution of net hepatic glycogenolysis to EGP will increase in proportion to the intensity of exercise. ii) In contrast, subjects with poorly controlled type 1 diabetes will have low hepatic glycogen stores and gluconeogenesis will be the main factor responsible for sustaining EGP at rest and during exercise, (iii) Epinephrine and glucagon will stimulate EGP in healthy subjects primarily by increasing net hepatic glycogenolysis, whereas in the patients with poorly controlled diabetes these hormones will stimulate EGP mostly by increasing gluconeogenesis. The results of these studies should provide important new insight into the regulation of hepatic glucose metabolism in healthy and type 1 diabetic subjects.