Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK014507-21
Application #
3483065
Study Section
Metabolism Study Section (MET)
Project Start
1978-05-01
Project End
1993-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
21
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

Bederman, Ilya R; Chandramouli, Visvanathan; Sandlers, Yana et al. (2013) Time course of hepatic gluconeogenesis during hindlimb suspension unloading. Exp Physiol 98:278-89
Basu, Rita; Chandramouli, Visvanthan; Schumann, William et al. (2009) Additional evidence that transaldolase exchange, isotope discrimination during the triose-isomerase reaction, or both occur in humans: effects of type 2 diabetes. Diabetes 58:1539-43
Spring-Robinson, Chandra; Chandramouli, Visvanathan; Schumann, William C et al. (2009) Uptake of 18F-labeled 6-fluoro-6-deoxy-D-glucose by skeletal muscle is responsive to insulin stimulation. J Nucl Med 50:912-9
Basu, R; Basu, A; Chandramouli, V et al. (2008) Effects of pioglitazone and metformin on NEFA-induced insulin resistance in type 2 diabetes. Diabetologia 51:2031-40
Basu, Rita; Chandramouli, Visvanathan; Dicke, Betty et al. (2008) Plasma C5 glucose-to-2H2O ratio does not provide an accurate assessment of gluconeogenesis during hyperinsulinemic-euglycemic clamps in either nondiabetic or diabetic humans. Diabetes 57:1800-4
Burgess, Shawn C; Chandramouli, Visvanathan; Browning, Jeffrey D et al. (2008) Complicating factors in the application of the ""average method"" for determining the contribution of gluconeogenesis. J Appl Physiol 104:1852-3;author reply 1854-5
Bock, Gerlies; Schumann, William C; Basu, Rita et al. (2008) Evidence that processes other than gluconeogenesis may influence the ratio of deuterium on the fifth and third carbons of glucose: implications for the use of 2H2O to measure gluconeogenesis in humans. Diabetes 57:50-5
Basu, Rita; Shah, Pankaj; Basu, Ananda et al. (2008) Comparison of the effects of pioglitazone and metformin on hepatic and extra-hepatic insulin action in people with type 2 diabetes. Diabetes 57:24-31
Weickert, Martin O; Loeffelholz, Christian V; Roden, Michael et al. (2007) A Thr94Ala mutation in human liver fatty acid-binding protein contributes to reduced hepatic glycogenolysis and blunted elevation of plasma glucose levels in lipid-exposed subjects. Am J Physiol Endocrinol Metab 293:E1078-84
Bock, Gerlies; Chittilapilly, Elizabeth; Basu, Rita et al. (2007) Contribution of hepatic and extrahepatic insulin resistance to the pathogenesis of impaired fasting glucose: role of increased rates of gluconeogenesis. Diabetes 56:1703-11

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