A central role of RLIP76 in regulation of glycemic control

Sanjay Awasthi, Sharad S. Singhal, Sushma Yadav, Jyotsana Singhal, Rit Vatsyayan, Ewa Zajac, Rafal Luchowski, Jozef Borvak, Karol Gryczynski, Yogesh C. Awasthi

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Abstract

OBJECTIVE - Pathology associated with oxidative stress frequently results in insulin resistance. Glutathione (GSH) and GSH-linked metabolism is a primary defense against oxidative stress. Electrophilic lipid alkenals, such as 4-hydroxy-t-2-nonenal (4HNE), generated during oxidative stress are metabolized primarily to glutathione electrophile (GS-E) conjugates. Recent studies show that RLIP76 is the primary GS-E conjugate transporter in cells, and a regulator of oxidative-stress response. Because RLIP76-/- mice are hypoglycemic, we studied the role of RLIP76 in insulin resistance. RESEARCH DESIGN AND METHODS - Blood glucose, insulin, lipid measurements, and hyperinsulinemic-euglycemic and hyperglycemic clamp experiments were performed in RLIP76+/+ and RLIP76+/+ C57B mice, using Institutional Animal Care and Use Committee-approved protocols. Time-resolved three-dimensional confocal fluorescence microscopy was used to study insulin endocytosis. RESULTS - The plasma insulin/glucose ratio was ordered RLIP76 -/- < RLIP76-/+ < RLIP76+/+; administration of purified RLIP76 in proteoliposomes to RLIP76+/+ animals further increased this ratio. RLIP76 was induced by oxidative or hyperglycemic stress; the concomitant increase in insulin endocytosis was completely abrogated by inhibiting the transport activity of RLIP76. Hydrocortisone could transiently correct hypoglycemia in RLIP76+/+ animals, despite inhibited activity of key glucocorticoid-regulated hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose 1,6-bisphosphatase, in RLIP76-/-. CONCLUSIONS - The GS-E conjugate transport activity of RLIP76 mediates insulin resistance by enhancing the rate of clathrin-dependent endocytosis of insulin. Because RLIP76 is induced by oxidative stress, it could play a role in insulin resistance seen in pathological conditions characterized by increased oxidative stress.

Original languageEnglish
Pages (from-to)714-725
Number of pages12
JournalDiabetes
Volume59
Issue number3
DOIs
StatePublished - 1 Mar 2010

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Awasthi, S., Singhal, S. S., Yadav, S., Singhal, J., Vatsyayan, R., Zajac, E., Luchowski, R., Borvak, J., Gryczynski, K., & Awasthi, Y. C. (2010). A central role of RLIP76 in regulation of glycemic control. Diabetes, 59(3), 714-725. https://doi.org/10.2337/db09-0911