Glucose uptake by the liver is now recognized as being an important component of glucose homeostasis and to be defective in the diabetic state thereby contributing to post-prandial hyperglycemia, elevated HBA1c, and cardiovascular disease. It is difficult to measure hepatic glucose uptake in man and as a result its regulation is not well understood. Net hepatic glucose balance (NHGU) can be measured in the conscious dog and metabolic control in the dog is known to resemble that in the human. Our goal therefore is to explore the regulation of NHGU and muscle glucose uptake in the conscious dog. We will break metabolic feedback loops using pharmacologic and surgical approaches and we will assess hepatic and limb glucose metabolism in vivo using arteriovenous difference and tracer techniques. We will assess the physiological response to the designated perturbation and we will concurrently measure the biochemical changes which accompany it by taking hepatic biopsies.
The aims of the proposed studies are to assess 1) the role of brain insulin and glucose levels in regulating hepatic uptake and disposition of glucose; 2) the role of signaling molecules (NO, GLP-1) in regulating hepatic uptake & disposition of glucose; 3) the role of the sympathetic, parasympathetic and serotonergic nervous systems in regulating the hepatic uptake and disposition of glucose; 4) the effect of the hepatic glycogen level on the uptake and disposition of glucose by the liver and 5) the biochemical changes associated with the actions of glucose, the portal glucose signal and fructose on glucose uptake by the liver. Data from the proposed experiments will further our understanding of the control of NHGU in vivo and should be of value in the development of new therapeutic approaches to control of the glucose level in the individual with diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Laughlin, Maren R
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Vanderbilt University Medical Center
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United States
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Kraft, Guillaume; Coate, Katie C; Winnick, Jason J et al. (2017) Glucagon's effect on liver protein metabolism in vivo. Am J Physiol Endocrinol Metab 313:E263-E272
Winnick, Jason J; An, Zhibo; Kraft, Guillaume et al. (2013) Liver glycogen loading dampens glycogen synthesis seen in response to either hyperinsulinemia or intraportal glucose infusion. Diabetes 62:96-101
Moore, Mary Courtney; Coate, Katie C; Winnick, Jason J et al. (2012) Regulation of hepatic glucose uptake and storage in vivo. Adv Nutr 3:286-94
Kraft, Guillaume; Coate, Katie C; Dardevet, Dominique et al. (2012) Portal glucose delivery stimulates muscle but not liver protein metabolism. Am J Physiol Endocrinol Metab 303:E1202-11
An, Zhibo; Winnick, Jason J; Moore, Mary C et al. (2012) A cyclic guanosine monophosphate-dependent pathway can regulate net hepatic glucose uptake in vivo. Diabetes 61:2433-41
Johnson, Kathryn M S; Farmer, Tiffany; Schurr, Kathleen et al. (2011) Endogenously released GLP-1 is not sufficient to alter postprandial glucose regulation in the dog. Endocrine 39:229-34
Winnick, Jason J; An, Zhibo; Ramnanan, Christopher J et al. (2011) Hepatic glycogen supercompensation activates AMP-activated protein kinase, impairs insulin signaling, and reduces glycogen deposition in the liver. Diabetes 60:398-407
An, Zhibo; Winnick, Jason J; Farmer, Ben et al. (2010) A soluble guanylate cyclase-dependent mechanism is involved in the regulation of net hepatic glucose uptake by nitric oxide in vivo. Diabetes 59:2999-3007
An, Zhibo; Moore, Mary C; Winnick, Jason J et al. (2009) Portal infusion of escitalopram enhances hepatic glucose disposal in conscious dogs. Eur J Pharmacol 607:251-7
Winnick, Jason J; An, Zhibo; Moore, Mary Courtney et al. (2009) A physiological increase in the hepatic glycogen level does not affect the response of net hepatic glucose uptake to insulin. Am J Physiol Endocrinol Metab 297:E358-66

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