TY - JOUR
T1 - A central role of RLIP76 in regulation of glycemic control
AU - Awasthi, Sanjay
AU - Singhal, Sharad S.
AU - Yadav, Sushma
AU - Singhal, Jyotsana
AU - Vatsyayan, Rit
AU - Zajac, Ewa
AU - Luchowski, Rafal
AU - Borvak, Jozef
AU - Gryczynski, Karol
AU - Awasthi, Yogesh C.
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77950354986&partnerID=8YFLogxK
U2 - 10.2337/db09-0911
DO - 10.2337/db09-0911
M3 - Article
C2 - 20007934
AN - SCOPUS:77950354986
SN - 0012-1797
VL - 59
SP - 714
EP - 725
JO - Diabetes
JF - Diabetes
IS - 3
ER -