Lipid abnormalities, such as obesity, hyperlipidemia, and elevated intramyocellular lipid levels have been correlated with the development of insulin resistance, a subnormal metabolic response to insulin. Previous research by our laboratory indicates that ceramide is necessary and sufficient for saturated-fatty-acid-induced insulin resistance in cultured muscle cells. Elevations of ceramide concentration, similar to those seen in cell culture, have been observed in insulin resistant animals and humans. We hypothesize that ceramide is an obligate intermediate in the induction of insulin resistance by saturated fatty acids in vivo. In the project described herein, we will quantitatively determine the role of ceramide in fatty-acid-induced insulin resistance in vivo. Intravenous infusion of saturated and unsaturated lipid emulsions and administration of high fat diets will be used to promote elevations in serum free fatty acids. We will correlate concentrations of total ceramide and individual ceramide species with insulin sensitivity in muscle and liver. Additionally, we will determine whether pharmacological inhibition of ceramide synthesis will prevent the induction of insulin resistance by free fatty acids.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK070565-03
Application #
7038263
Study Section
Special Emphasis Panel (ZRG1-IDM-L (29))
Program Officer
Agodoa, Lawrence Y
Project Start
2005-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2006
Total Cost
$33,944
Indirect Cost
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Holland, William L; Summers, Scott A (2008) Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 29:381-402
Holland, William L; Knotts, Trina A; Chavez, Jose A et al. (2007) Lipid mediators of insulin resistance. Nutr Rev 65:S39-46
Holland, William L; Brozinick, Joseph T; Wang, Li-Ping et al. (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5:167-79