The objective of this proposal is to better understand the role of liver afferent and efferent nerves as they relate to insulin action in the liver, hypoglycemic counterregulation and the deleterious effect of a diet high in fat and fructose on hepatic metabolism.
The specific aims are 1) To further our understanding of the interaction between the direct effects of insulin on the liver and its indirect effects mediated by insulin acton in the brain, 2) to determine the mechanism by which liver glycogen loading enhances the hormonal response to insulin induced hypoglycemia, and 3) to determine the physiologic basis for the rapid deleterious effect of a high fat/high fructose diet on hepatic glucose uptake. Studie will be carried out in normal and diet induced insulin resistant conscious dogs. Three weeks before study catheters will be inserted under general anesthesia into the femoral artery, the hepatic portal vein and the hepatic vein, as well as in other vessels and sites as needed (splenic and jejunal veins, carotid and vertebral arteries, the 3rd ventricle etc.). The canine model is unique in that it allows hepatic portal vein infusion, while at the same time permitting the direct measurement of hepatic glucose output and uptake in vivo. Somatostatin will be used when required to disable the endocrine pancreas, along with intraportal infusion of insulin and glucagon at the rates required by the experimental design. Liver glucose metabolism will be assessed using a variety of tracer and A-V difference techniques. Metabolic clamps (glucose, NEFA, amino acids) will be used as needed to fix substrate levels. Surgical (hepatic denervation etc) and pharmacologic (i.e. hepatic portal vein infusion of drugs) tools will be used to bring about the desired experimental conditions. Tissues will be taken at the end of experiments so that the physiologic response can be correlated to the associated molecular alterations. The proposed studies will clarify the role of brain insulin action in the disposition of glucose absorbd from the gut. They will also lead to a better understanding of the way in which nerves originating in the liver can impact hypoglycemic counterregulation. Finally, they will increase our understanding of how a diet high in fat and fructose can quickly impair the ability of the liver to take up and storage glucose. The knowledge gained from the proposed experiments will help lead to the development of new therapeutic approaches to the treatment of glucose intolerance and diabetes.

Public Health Relevance

The role of efferent and afferent nerves connecting the brain and liver in the control of hepatic glucose metabolism is unclear, in part because of the difficult in examining their function in a conscious animal. We propose to use normal and insulin resistant dogs to address this topic since the dog lends itself to surgical and pharmacologic approaches not possible in the human or rodent. The experiments proposed will generate a unique data set that will increase our understanding of 1) the importance of brain insulin action to insulin's overall effect on the liver, 2) hypoglycemic counterregulation and 3) diet induced hepatic glucose intolerance.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Schools of Medicine
United States
Zip Code
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
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
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
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
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
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
Coate, Katie C; Kraft, Guillaume; Moore, Mary Courtney et al. (2014) Hepatic glucose uptake and disposition during short-term high-fat vs. high-fructose feeding. Am J Physiol Endocrinol Metab 307:E151-60

Showing the most recent 10 out of 72 publications