New and improved methods are to be developed and applied for quantitating abnormalities in pathways of carbohydrate metabolism important to understanding the pathophysiology of diabetes and its treatment. There are 5 specific aims. 1) To quantitate transaldolase reaction rates in type 2 diabetes. To their extent gluconeogenesis (GNG) is overestimated by tracer methods. Increased GNG is believed a major contributor to diabetic hyperglycemia. Quantitation is done by tracing the fate of the hydrogens of galactose on their conversion to glucose. 2) To determine the ability of the type 2 diabetic liver to regulate glucose output by changing GNG rates in response to changing glycogenolytic rates. Success reducing output in diabetics by inhibiting GNG and glycogenolysis depends on hepatic regulatory responses. Output is measured using [6,6- 2H2]glucose, GNG using D2O, and increased glycogenolysis simulated by galactose infusion. 3) To quantitate simultaneous hepatic glycogen synthesis and breakdown, i.e. cycling in type 2 diabetes. Cycling can explain in the diabetic decreased hepatic glycogen content and hyperglycemia due to decreased storage of glucose in glycogen. Cycling is equated to the extent glycogen is not formed by the direct and indirect pathways of glycogen formation. 4) To test whether thiamine's prevention of experimental diabetic complications is by shunting glycolytic intermediates from pathways of hyperglycemic damage to the pentose phosphate pathway or generating intermediate(s) of that pathway stimulating utilization of glycolytic intermediates. Therapeutic approaches developed in response to thiamine's actions depend on understanding the mechanism of those actions. Tested by quantitating the pathways in vitro and in vivo in normal and diabetic animals with imidazole acetic acid used to non-invasively sample hepatic ribose formation. 5) To assess possible use of 6-fluoro-6-deoxyglucose (6FDG) as a tracer of glucose transport. Tracers presently used to characterize rates of glucose transport in the diabetic are not specific or difficult to use. Uptake in diabetic animals will be imaged by PET using 6-18FDG and 6FDG's metabolic fate determined using 19F-NMR.
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