Our earlier work defined and characterized the ability of glucagon, epinephrine, norepinephrine and cortisol to independently stimulate glucose production (glycogenolysis and gluconeogenesis) and ketogenesis in vivo.
The aim of the work proposed in this application is to study the interaction of these hormones in the regulation of glucose production and ketogenesis in vivo and, specifically, to delineate their roles in two physiologic circumstances: hypoglycemia and exercise. Experiments will be carried out in overnight-fasted, conscious dogs in which hormone levels and neural outflow are controlled using surgical and pharmacologic methods. To control epinephrine and cortisol levels, adrenalectomy and hormone replacement will be used; to control glucagon and growth hormone concentrations, somatostatin and hormone replacement will be used; and to control neural outflow, the hepatic nerves will be cut and/or the head glucose level will be clamped (glucose infusion into the carotid and vertebral arteries). Glucose production (gluconeogenesis, glycogenolysis) will be measured using tracer and A-V difference techniques, and ketogenesis will be measured using the A-V difference technique. In the first group of studies the role of each counterregulatory hormone in the metabolic response to the hypoglycemia resulting from constant intravenous insulin infusion will be determined. The second set of experiments will define the role neural outflow and local hypoglycemia autoregulation) play in that response. In the third set of studies the ability of hypoglycemia to modify the sensitivity of the liver to the counterregulatory hormones will be assessed. The fourth and fifth sets of studies will determine the role of each counterregulatory hormone in the metabolic response to exercise and the effect of a mild accompanying hypoglycemia on their actions. In the sixth set of studies the by which cortisol modifies the metabolic effects of epinephrine and glucagon will be determined. Finally, the metabolic effects of synchronous and prolonged elevations in the counterregulatory hormones will be determined, and the role of each individual hormone in the overall response will be defined. These studies should further our understanding of the metabolic roles of glucagon, epinephrine, norepinephrine and cortisol in various physiologic circumstances; they should identify the processes activated (glycogenolysis, gluconeogenesis, ketogenesis) and the site (adipose tissue, muscle, liver) at which the stimulation occurs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018243-15
Application #
3225968
Study Section
Endocrinology Study Section (END)
Project Start
1978-06-01
Project End
1993-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
15
Fiscal Year
1989
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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