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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK018243-39
Application #
8577585
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
1978-06-01
Project End
2017-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
39
Fiscal Year
2013
Total Cost
$706,462
Indirect Cost
$256,486
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Gifford, Aliya; Kullberg, Joel; Berglund, Johan et al. (2014) Canine body composition quantification using 3 tesla fat-water MRI. J Magn Reson Imaging 39:485-91
Coate, Katie C; Kraft, Guillaume; Irimia, Jose M et al. (2013) Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs. Diabetes 62:392-400
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Coate, Katie Colbert; Kraft, Guillaume; Lautz, Margaret et al. (2011) A high-fat, high-fructose diet accelerates nutrient absorption and impairs net hepatic glucose uptake in response to a mixed meal in partially pancreatectomized dogs. J Nutr 141:1643-51
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Coate, Katie Colbert; Scott, Melanie; Farmer, Ben et al. (2010) Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake. Am J Physiol Endocrinol Metab 299:E887-98
Nelson, Robert H; Edgerton, Dale S; Basu, Rita et al. (2007) Triglyceride uptake and lipoprotein lipase-generated fatty acid spillover in the splanchnic bed of dogs. Diabetes 56:1850-5

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