The long range objective of this proposal is to study the regulation of glucose production (glycogenolysis and gluconeogenesis) both in vivo, using the conscious and anesthetized dog, and in vitro using isolated dog hepatocytes and perfused rat liver. Gluconeogenesis will be studied by determining the hepatic and renal uptake of gluconeogenic precursors and by quantitating their conversion into glucose. Overall glucose production will be measured using A-V difference and tracer (3H-3-glucose) techniques. These measurements will be made possible by surgical implantation of catheters for blood sampling in the portal, hepatic and renal veins and femoral artery two weeks prior to study. Clear interpretation of data will be possible because both the pancreatic hormone levels and the plasma glucose concentrations will be controlled and in accordance with the need of an experiment. Regulation of insulin and glucagon secretion will be achieved surgically or pharmacologically by inhibiting the animal's pancreatic hormone secretion and quantitatively replacing both insulin and glucagon intraportally. The surgical approach involves a """"""""pancreatic autograft"""""""" technique and the pharmacological approach involves infusion of somatostatin (a potent inhibitor of insulin and glucagon secretion) coincident with pancreatic hormone replacement. Glucose will be regulated using a glucose-clamp technique. Studies will be carried out in vitro using isolated dog liver cells to study the mechanisms by which certain changes observed in vivo occur. Utilizing the above methods our main objectives will be to examine 1) the physiologic importance of the catecholamines in regulating glycogenolysis and gluconeogenesis in vivo; 2) the interaction between insulin and epinephrine in regulating these processes; 3) the interaction between cortisol and epinephrine in regulating these processes; 4) the role of glucagon in regulating glucose production in the fasting state; 5) the role of glucagon in regulating post-feeding lactate production and 6) the mechanism by which the effect of glucagon is turned off inside the liver cell.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018243-13
Application #
3225967
Study Section
Metabolism Study Section (MET)
Project Start
1978-06-01
Project End
1988-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
13
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
Moore, Mary Courtney; Smith, Marta S; Farmer, Ben et al. (2018) Morning Hyperinsulinemia Primes the Liver for Glucose Uptake and Glycogen Storage Later in the Day. Diabetes 67:1237-1245
Jenkins, Benjamin J; Seyssel, Kevin; Chiu, Sally et al. (2017) Odd Chain Fatty Acids; New Insights of the Relationship Between the Gut Microbiota, Dietary Intake, Biosynthesis and Glucose Intolerance. Sci Rep 7:44845
Gregory, Justin M; Rivera, Noelia; Kraft, Guillaume et al. (2017) Glucose autoregulation is the dominant component of the hormone-independent counterregulatory response to hypoglycemia in the conscious dog. Am J Physiol Endocrinol Metab 313:E273-E283
Edgerton, Dale S; Kraft, Guillaume; Smith, Marta et al. (2017) Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion. JCI Insight 2:e91863
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
Moore, Mary Courtney; Smith, Marta S; Farmer, Ben et al. (2017) Priming Effect of a Morning Meal on Hepatic Glucose Disposition Later in the Day. Diabetes 66:1136-1145
Yu, Erin Nz; Winnick, Jason J; Edgerton, Dale S et al. (2016) Hepatic and Whole-Body Insulin Metabolism during Proestrus and Estrus in Mongrel Dogs. Comp Med 66:235-40
Winnick, Jason J; Kraft, Guillaume; Gregory, Justin M et al. (2016) Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis. J Clin Invest 126:2236-48
Coate, Katie C; Kraft, Guillaume; Shiota, Masakazu et al. (2015) Chronic overeating impairs hepatic glucose uptake and disposition. Am J Physiol Endocrinol Metab 308:E860-7
Edgerton, Dale S; Cherrington, Alan D (2015) Is brain insulin action relevant to the control of plasma glucose in humans? Diabetes 64:696-9

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