Diabetes | 2019

1782-P: Mechanism of Lipid-Induced White Adipose Tissue Insulin Resistance



White adipose tissue (WAT), as an energy storage organ, plays a major role in regulating peripheral insulin resistance and hepatic gluconeogenesis, but the mechanism by which lipid induces insulin resistance in WAT is poorly understood. To examine the potential role of the diacylglycerol (DAG) - protein kinase Ce (PKCe) - insulin receptor (INSR) pathway in mediating lipid-induced WAT insulin resistance, we assessed insulin action in liver, muscle and WAT in 7-day high fat diet (HFD) and regular chow (RC) fed rats by hyperinsulinemic-euglycemic clamp (HEC) combined with [3- 3 H] glucose, [ 14 C] deoxyglucose and [ 2 H 5 ]glycerol infusions. Using this approach, we found that HFD induced WAT insulin resistance as reflected by impaired suppression (∼20%, P 1150 phosphorylation mediates lipid-induced WAT insulin resistance by inhibiting INSR kinase activity, we studied mice with a threonine-to-alanine knockin mutation at INSR Thr 1150 (Insr T1150A mice). Insr T1150A mice were protected from HFD-induced WAT insulin resistance as reflected by normalization of insulin’s ability to suppress WAT lipolysis and normalization of insulin’s ability to stimulate INSR and Akt2 phosphorylation in WAT, as well as a restoration of insulin’s ability to suppress phosphorylation of perilipin, HSL and ATGL (all P Conclusion: The DAG-PKCe-INSR Thr 1150 pathway plays a major role in mediating lipid-induced WAT insulin resistance and represents a potential therapeutic target to improve insulin sensitivity in WAT. Disclosure D. Zhang: None. K. Lyu: None. J.D. Song: None. X. Li: None. R.J. Perry: Research Support; Self; AstraZeneca. V. Samuel: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V. Funding National Institutes of Health (R01DK116774)

Volume 68
Pages None
DOI 10.2337/DB19-1782-P
Language English
Journal Diabetes

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