Excessive postprandial hyperglycemia and a defect in hepatic glucose uptake are common features of obesity and type 2 diabetes. Glucokinase is critical to the entry of glucose into the liver. We hypothesize that the defect in hepatic glucose uptake seen in obesity related type 2 diabetes results from impaired regulation of glucokinase activity. This proposal contains experiments designed to further our understanding of the relationship between impaired hepatic glucose uptake and the regulation of glucokinase in obese-type 2 diabetes mellitus. To quantify the altered distribution of glucokinase and its regulatory protein in the cell and to evaluate the impairment of hepatic glucose metabolism and the disturbance of glucose homeostasis in type 2 diabetes, we will use isotopic and chronic catheterization techniques, as well as glucose and pancreatic damp techniques in conscious pre-diabetic (10 weeks old) and diabetic (13 weeks old) ZDF rats. In some experiments, we will use adenoviral gene transfection technique is maniplate glucokinase levels with the liver in vivo. We will estimate the whole body glucose turnover rate, hepatic glucose phosphorylation and glycogen synthesis using [3H]glucose. The intracellular distribution of glucokinase and its regulatory protein will be estimated immunohistochemically. The proposal has four aims. First, we propose experiments to clarify the effect of insulin, glucose, and/or the portal signal on glucokinase translocation and glucose metabolism in the liver on lean and pre-diabetic ZDF rats. Second, we will examine the role of lipid levels and TNF- alpha on glucokinase translocation, glucose phosphorylation, and hepatic glucose disposition in pre-diabetic ZDF rats. Thirdly, we will clarify the influence of glycogenolytic and gluconeogenic flux on glucokinase translocation and glucose metabolism in the liver. Fourthly, we will examine the effects of increasing free (unbound) glucokinase in the cytoplasm of the liver on hepatic glucose metabolism. Tosee experiments should shed light on the pathogenic role that impaired glucokinase regulation plays in the defective liver response to glucose in obesity related type 2 diabetes mellitus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060667-05
Application #
7008611
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
2002-02-20
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2008-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$237,306
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Syring, Kristen E; Bosma, Karin J; Oeser, James K et al. (2018) The Diabetes Susceptibility Gene SLC30A8 that Encodes the Zinc Transporter ZnT8 is a Pseudogene in Guinea Pigs Potentially Contributing to Low Guinea Pig Islet Zinc Content. J Mol Evol 86:613-617
O'Brien, Tracy P; Jenkins, Erin C; Estes, Shanea K et al. (2017) Correcting Postprandial Hyperglycemia in Zucker Diabetic Fatty Rats With an SGLT2 Inhibitor Restores Glucose Effectiveness in the Liver and Reduces Insulin Resistance in Skeletal Muscle. Diabetes 66:1172-1184
Leamy, Alexandra K; Hasenour, Clinton M; Egnatchik, Robert A et al. (2016) Knockdown of triglyceride synthesis does not enhance palmitate lipotoxicity or prevent oleate-mediated rescue in rat hepatocytes. Biochim Biophys Acta 1861:1005-1014
Farmer, Tiffany D; Jenkins, Erin C; O'Brien, Tracy P et al. (2015) Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp. Am J Physiol Endocrinol Metab 308:E206-22
Leamy, Alexandra K; Egnatchik, Robert A; Shiota, Masakazu et al. (2014) Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells. J Lipid Res 55:1478-88
Ueta, Kiichiro; O'Brien, Tracy P; McCoy, Gregory A et al. (2014) Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity. Am J Physiol Endocrinol Metab 306:E1225-38
Pound, Lynley D; Oeser, James K; O'Brien, Tracy P et al. (2013) G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Diabetes 62:1547-56
Torres, Tracy P; Fujimoto, Yuka; Donahue, E P et al. (2011) Defective glycogenesis contributes toward the inability to suppress hepatic glucose production in response to hyperglycemia and hyperinsulinemia in zucker diabetic fatty rats. Diabetes 60:2225-33
Torres, Tracy P; Catlin, Reetta L; Chan, Robert et al. (2009) Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats. Diabetes 58:78-86
Fujimoto, Yuka; Torres, Tracy P; Donahue, E Patrick et al. (2006) Glucose toxicity is responsible for the development of impaired regulation of endogenous glucose production and hepatic glucokinase in Zucker diabetic fatty rats. Diabetes 55:2479-90

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