Methods are to be developed and applied for quantitating pathways in physiological and pathological states with three specific aims. First, methods are to be developed for noninvasively sampling in humans intermediates of carbohydrate metabolism: a) The use of 13C rather than 14C to sample hepatic glucose-6-P with acetaminophen glucuronide will be examined and whether the glucuronide sample a single pool of hepatic glucose- 6-P and UDP-glucose will be further assessed by (1) administering various labeled substrates to normal subjects and comparing 14C distributions in glucuronide and blood glucose and (2) comparing distributions in glucuronide and glycogen from rats given 14C glucose and acetaminophen; b) Phenylacetate will be given to normals with 14C substrates to see if its urinary glutamine conjugate reflects hepatic alpha-ketoglutarate; c) Similary, it will be determine if the glycine conjugate of benzoic acid reflects hepatic 3-phosphoglyceric acid. Second, in part using these probes where applicable: a) The extent of futile cycling in normals, type II diabetics and thyrotoxics will be estimated correcting for (1) the extent of retention of 3H from (2- 3h)glucose-6-P, (2) the detritiation of (3-3H)glucose in the pentose cycle and (3) the retention of 3H of (6-3H)glucose in Cori cycling; b) The extent of isotopic equilibration of hepatic glucose-6-P with fructose-6-P and the pentose-5-P's will be estimated and the data applied to a model for quantitating pentose cycle activity in liver; c) The contribution of the indirect pathway in the fed state will be estimated from randomization of 14C from (6-14C)glucose, the site of the pathway assessed from comparisons of randomizations from 14C galactose, mannose, and the phenylacetate probe used to estimate 12C dilution of 14C in the Krebs cycle; d) If possible, the phenylacetate probe will also be to quantitate the pathways of acetaone metabolism. Third, by specifically labeling the acetyl CoA formed in the cellular evnironment of omega-oxidation and the peroxisomes and of NADPH formed in the endoplasmic reticulum in the rat, determine if there are specific pools of acetyl and NADPH used for cholesterol synthesis in liver.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Case Western Reserve University
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Bederman, Ilya R; Chandramouli, Visvanathan; Sandlers, Yana et al. (2013) Time course of hepatic gluconeogenesis during hindlimb suspension unloading. Exp Physiol 98:278-89
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