Differential effects of rosiglitazone on skeletal muscle and liver insulin resistance in A-ZIP/F-1 fatless mice. Journal   Diabetes. Citation   Diabetes. 52(6):1311-8 Publication date   2003 Jun Authors   Kim JK Fillmore JJ Gavrilova O Chao L Higashimori T Choi H Kim HJ Yu C Chen Y Qu X Haluzik M Reitman ML Shulman GI Investigators   Jason K. Kim Grant agencies   National Institute of Diabetes and Digestive and Kidney Diseases Grants   NIDDK P30 DK 45735 NIDDK R01 DK 40936 NIDDK U24 DK 59635 MeSH headings   Insulin Resistance Liver Muscle, Skeletal Thiazoles Thiazolidinediones MeSH qualifiers   physiology metabolism pharmacology Abstract   To determine the role of adipocytes and the tissue-specific nature in the insulin sensitizing action of rosiglitazone, we examined the effects of 3 weeks of rosiglitazone treatment on insulin signaling and action during hyperinsulinemic-euglycemic clamps in awake A-ZIP/F-1 (fatless), fat-transplanted fatless, and wild-type littermate mice. We found that 53 and 66% decreases in insulin-stimulated glucose uptake and insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle of fatless mice were normalized after rosiglitazone treatment. These effects of rosiglitazone treatment were associated with 50% decreases in triglyceride and fatty acyl-CoA contents in the skeletal muscle of rosiglitazone-treated fatless mice. In contrast, rosiglitazone treatment exacerbated hepatic insulin resistance in the fatless mice and did not affect already reduced IRS-2-associated PI 3-kinase activity in liver. The worsening of insulin action in liver was associated with 30% increases in triglyceride and fatty acyl-CoA contents in the liver of rosiglitazone-treated fatless mice. In conclusion, these data support the hypothesis that rosiglitazone treatment enhanced insulin action in skeletal muscle mostly by its ability to repartition fat away from skeletal muscle. Medline ID   22650724