Our long-term objective is to develop and apply novel methods that will significantly advance our understanding of carbohydrate and lipid metabolism in physiological and pathological states, in particular diabetes. These methods have in common the safe 2H- enrichment of body water with 2H20. We plan to achieve the following seven interrelated specific aims. 1. To quantitate glycogen hydrolysis, cycling, and turnover as a function of liver glycogen content. 2. To measure the rate of de novo glycerol formation via labeling from 2H20, and to define: (i)the role of liver and kidney in glycerol production, fatty acid reesterification, and lipolysis quantitation., and (ii) the source of carbon of glycerol-3-P used by adipose tissue to reesterify fatty acids. 3. To determine the pathway(s) by which 2H20 labels H on C1 of glucose, and to define how this labeling affects calculations of gluconeogenesis and glycogenolysis. 4. To develop a method for quantitating glyconeogenesis, based on 2H-enrichment of body water. 5. To evaluate to what extent the transaldolase reactions affect quantitations of gluconeogenesis and glycogenolysis 6. To apply these techniques to measurements of gluconeogenesis (i) in subjects who are at high risk for NIDDM. (ii) in NIDDM patients, and (iii) in the NIDDM patients then treated with metformin. 7. To apply these techniques to measurements of gluconeogenesis in obese patients. The subjects will ingest 2H2O (to measure the contribution of gluconeogenesis to glucose production from the C5/C2 2H-labeling ratio in glucose), and will be infused with (6,6-2H2) glucose (to measure glucose turnover). The 2H-enrichment at the glucose carbons will be amplified six-fold by incorporating them into hexamethylenetetramine for assay. The contribution of gluconeogenesis will be related to hepatic glycogen content measured by 13C-NMR spectroscopy. Our studies will define the role of gluconeogenesis (i) in diabetic hyperglycemia, (ii) as a possible etiologic factor in the onset of NIDDM, and (iii) in the mechanism of metformin's action. They will help establish whether the propensity of upper body obese subjects to insulin resistance, NlDDM, and cardiovascular disease is related to increased gluconeogenesis. Also, the direct conversion of glycogen to glucose may prove to be an important regulator of glycogen content. Our studies will shed new light on how glucose and lipid metabolism in adipose tissue adapts to fasting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK014507-31
Application #
6380365
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
1978-05-01
Project End
2002-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
31
Fiscal Year
2001
Total Cost
$421,633
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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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