Carbohydrate, protein and lipid abnormalities characterize diabetes mellitus. Long-term objectives are to develop and apply novel methods significantly advancing understanding of those metabolic processes and their regulation in physiological and pathological states in human, and particularly in diabetes. Advantage is taken of 2H2O use to quantitate the pathways followed. Methods have been introduced for carbohydrate and lipid. The major new goal is to develop and apply a method for quantitating protein metabolism. The method for quantitating carbohydrate metabolism will also be further extended. Focus then is on 1) the quantitation of protein synthesis and proteolysis; 2) the contribution to glucose production of gluconeogenesis whose increase in diabetes has been related to the degree of hyperglycemia and 3) the extent of simultaneous hepatic glycogen synthesis and breakdown, called glycogen cycling, which could help explain decreased liver glycogen content found in type 2 diabetes and exacerbate hyperglycemia on glucose ingestion. There are 4 specific aims: 1) To develop and apply a method for quantitating the extent transaldolase reactions contribute to estimates of gluconeogenesis; 2) To evaluate the validity of a method using glucose isotopomers, introduced as a simple method to measure the contribution of gluconeogenesis, in comparison with 2H2O use; 3) To develop a method for quantitating glycogen cycling in the fed state by measuring, along with the rate of hepatic glycogen deposition on glucose intake, how much of the glycogen is formed directly from the glucose, how much from three carbon compounds, and how much from glycogen that is reconverted to glycogen, i.e. glycogen cycling; 4) To develop a method to estimate protein synthesis from labeling of protein by 2H2O, and proteolysis from loss of that label. Initial application of this method will be to renal failure patients undergoing hemodialysis, in whom ingested 2H2O can be removed by dialysis to readily follow loss of incorporated label without continued synthesis of labeled protein. Application first to the renal failure state is done with recognition that nephropathy is a major complication in the diabetic and the potential benefit of a simple method for evaluating the effects of the therapeutic approaches on protein dynamics in that condition.
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