Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and recent studies have established a strong relationship between intramyocellular triglyceride accumulation and insulin resistance in skeletal muscle. In this proposal the mechanism of fatty acid induced insulin resistance in skeletal muscle will be examined in awake rats and unique transgenic and knockout mouse models using state-of-the-art methodology including nuclear magnetic resonance spectroscopy (NMR), gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS) in combination with radioactive isotope techniques. Recent studies by our group have demonstrated that fatty acids induce insulin resistance in skeletal muscle by inhibiting insulin activation of IRS-1 associated phosphatidylinositol 3-kinase (PI 3-kinase) which we hypothesized was mediated by activation of a serine kinase cascade involving protein kinase C? (PKC?). This grant will further examine this hypothesis by examining the sequence of events leading to activation of PKC? in skeletal muscle. Specifically, increases in intramuscular content of fatty acyl CoA, ceramides, diacylglycerol, and triglyceride in relation to activation of PKC?, IRS-1 Ser307 phosphorylation and insulin simulated: 1) insulin receptor tyrosine phosphorylation, 2) IRS-1 tyrosine phosphorylation and 3) IRS-1 associated PI 3-kinase activity will be examined in awake rats during a lipid infusion designed to raise plasma fatty acid concentrations. In order to examine the putative roles of PKC? and Jun kinase 1 in mediating fatty acid induced insulin resistance, the effect of lipid infusion and high-fat feeding on insulin action and signaling in skeletal muscle will be examined in PKC? and Jun kinase 1 knockout mice. To test the hypothesis that accumulation of intramyocellular fatty acid metabolites are responsible for mediating insulin resistance in skeletal muscle, insulin signaling and action will be examined in UCP3 overexpressing mice (to promote increased muscle fatty acid oxidation) and fatty acid transport 1 (FATP1) gene knockout mice (to block fatty acid entry into skeletal muscle) following lipid infusion and high-fat feeding. Finally, in order to test the hypothesis that n-3 fatty acids protect against fat induced insulin resistance by serving as natural ligands for PPAR? resulting in peroxisome proliferation and increased hepatic fatty acid oxidation, the effect of feeding a diet enriched with n-3 fatty acids versus isocaloric control and safflower (% fat matched) diets on insulin signaling and action in PPAR? knockout and wild type littermates will be examined. The results from these studies should yield important new insights into the mechanism of fatty acid induced insulin resistance in skeletal muscle leading to the identification of potential novel targets for treatment of type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK040936-15
Application #
6579763
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
1988-12-01
Project End
2006-11-30
Budget Start
2003-01-01
Budget End
2003-11-30
Support Year
15
Fiscal Year
2003
Total Cost
$323,730
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Corbit, Kevin C; Camporez, João Paulo G; Edmunds, Lia R et al. (2018) Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling. Diabetes 67:208-221
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Samuel, Varman T; Shulman, Gerald I (2018) Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metab 27:22-41
Price, Nathan L; Singh, Abhishek K; Rotllan, Noemi et al. (2018) Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance. Cell Rep 22:2133-2145
Perry, Rachel J; Wang, Yongliang; Cline, Gary W et al. (2018) Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation. Cell 172:234-248.e17
Vatner, Daniel F; Goedeke, Leigh; Camporez, Joao-Paulo G et al. (2018) Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents. Diabetologia 61:1435-1446
Wang, Yongliang; Nasiri, Ali R; Damsky, William E et al. (2018) Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer. Cell Rep 24:47-55
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315
Qiu, Yang; Perry, Rachel J; Camporez, João-Paulo G et al. (2018) In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia. Biochem J 475:1063-1074

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