The operation of several "futile" cycles of the hepatic hexose phosphates is central to the maintenance of the proper balance of glycogen synthesis, glycolysis and gluconeogenesis. In this proposal, we hypothesize that, in patients with NIDDM, subtle abnormality may exist in these "futile" cycles which regulate hepatic glucose metabolism leading to excessive hepatic glucose production, glucose intolerance and fasting hyperglycemia. To test this hypothesis, we plan to determine the relative contribution of gluconeogenesis, glycogenolysis and glucose kinase to the intrahepatic hexose phosphate pool using tracer dilution technique with 2H-labeled glucose tracers (irreversible tracers) and [3- 13C]lactate (a 13C-labeled gluconeogenic substrate). The dilution of deuterium and 13C-label in the intrahepatic Hexose-P will be determined by sampling non-invasively in the urine the glucuronide of a xenobiotic (acetaminophen). Another key approach is the application of the new technique of mass isotopomer frequency distribution analysis (MIDA) which permits the determination of 13C enrichment of the triose phosphate pool, the precursor for gluconeogenesis. Specifically, we plan to compare the parameters of hepatic glucose metabolism in NIDDM with those of normal subjects by determining: 1) absolute gluconeogenesis using [3-13C]lactate and MIDA; 2) substrate cycling using [2-2H]glucose, [3-2H]glucose and [1- 2H]glucose; 3) the contribution to the hexose-phosphate flux from gluconeogenesis, glycogenolysis and glucose kinase; and 4) the parameters of the tricarboxylic acid (TCA) cycle. The molecular genetics of the enzymes of glucose production in NIDDM has been the subject of recent research focus. It is hoped that the data provided by this study will complement the understanding of the control of hexose phosphate flux by the changes in enzymes of the "futile" cycles in normal and abnormal glucose homeostasis.