The long term objective is to develop and apply methods for quantitating pathways of carbohydrate and lipid metabolism.
The specific aim i s to develop a method for estimating rates of gluconeogenesis which is safe, reliable, definitive, easily performed, and broadly applicable, an apply it to the testing of hypotheses with regard to carbohydrate metabolism in physiological and pathological conditions with emphasis on the diabetic state. D2O is administered at a safe, well tolerated dose. In the fasted state hexamethylenetetramine, formed from 6 equivalents of formaldehyde, is used to measure the enrichment of the deuteriums bound to carbons 2,5 and 6 of glucose. Formaldehyde containing the deuterium bound to carbon 6 is formed on periodic acid oxidation of blood glucose. Formaldehyde containing deuterium bound to carbon 5 is formed on oxidation of xylose formed from the glucose. Formaldehyde containing deuterium at carbon 2 is formed by oxidation of ribitol-5-P formed from the glucose. In the fed state, the D2O is given with acetaminophen. Deuterium bound to carbon 2 and 5 of glucose formed from the glucuronic acid moiety of the excreted glucuronide is determined. The fraction of glucose output formed by gluconeogenesis in the fasted state and the fraction of glycogen formation by gluconeogenesis in the fed state, also to the ratio of the enrichment at carbon 5 to that in body water. The carbon 5 to carbon 6 ratio is a measure of the contribution of glycerol to gluconeogenesis and the extend of equilibration of the hydrogens of pyruvate with those in water. Absolute rates of gluconeogenesis in the fasted state are estimated by multiplying the fraction via gluconeogenesis by glucose output measured using tritiated glucose or (6,6-D2) glucose. In the fed state the quantity of glycogen formed is measured using MRI to estimate liver volume and 13CNMR glycogen concentration. In the fasted state MRI and NMR are used to relate estimates of rates of gluconeogenesis to rates of glycogenolysis. Measurements will be made in normal subjects, in subjects who are obese and in NIDDM and MODY subjects. The findings should bear on the role of the liver in producing hyperglycemia in the diabetic. This in turn bears on the design of therapeutic agents and the adequacy of insulin given systemically in returning metabolism, not just blood glucose concentration, to normal. The approach for the first time allows the giving of D2O in safe and convenient doses to obtain adequate labeling in glucose for measurements of the pathways of its formation and conversion to glycogen. Because of the small dose of deuterated water that has to be given and the small amount of glucose that is required for analysis, the approach should be useful in pediatric as well s adult clinical studies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Metabolism Study Section (MET)
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Laughlin, Maren R
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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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