Differential Effects of Rosiglitazone on Skeletal Muscle and Liver Insulin Resistance in A-ZIP/F-1 Fatless Mice

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 6; pp. 1311 - 1318
• Main Authors: Kim, Jason K, Fillmore, Jonathan J, Gavrilova, Oksana, Chao, Lily, Higashimori, Takamasa, Choi, Hyejeong, Kim, Hyo-Jeong, Yu, Chunli, Chen, Yan, Qu, Xianqin, Haluzik, Martin, Reitman, Marc L, Shulman, Gerald I
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2003
• Subjects: Adipocytes; Adipocytes - drug effects; Adipocytes - metabolism; Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Adipose Tissue - transplantation; Adipose tissues; Animals; Biological and medical sciences; Blood Glucose - drug effects; Body fat; Body Weight - drug effects; Chromatography; Diabetes; Dosage and administration; Drug therapy; Experiments; Female; Fundamental and applied biological sciences. Psychology; Glucose; Glucose Clamp Technique; Hypoglycemic agents; Hypoglycemic Agents - pharmacology; Hypotheses; Insulin - blood; Insulin resistance; Insulin Resistance - physiology; Liver; Liver - drug effects; Liver - metabolism; Male; Metabolism; Mice; Mice, Mutant Strains; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Physiological aspects; Plasma; Properties; Rosiglitazone; Rosiglitazone maleate; Skeletal muscle; Surgery; Thiazoles - pharmacology; Thiazolidinediones; United States
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.6.1311

Differential Effects of Rosiglitazone on Skeletal Muscle and Liver Insulin Resistance in A-ZIP/F-1 Fatless Mice Jason K. Kim 1 , Jonathan J. Fillmore 1 , Oksana Gavrilova 2 , Lily Chao 2 , Takamasa Higashimori 1 , Hyejeong Choi 1 , Hyo-Jeong Kim 1 , Chunli Yu 1 , Yan Chen 3 , Xianqin Qu 4 , Martin Haluzik 2 , Marc L. Reitman 2 and Gerald I. Shulman 1 3 5 1 Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 2 Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 3 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 4 Department of Health Sciences, University of Technology, Sydney, New South Wales, Australia 5 Department of Cellular and Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 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. Footnotes Address correspondence and reprint requests to Jason K. Kim, Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology, S269C CAB, P.O. Box 208020, New Haven, CT 06520-8020. E-mail: jason.k.kim{at}yale.edu . Received for publication 9 July 2002 and accepted in revised form 19 February 2003. M.L.R. is employed by Merck. G.I.S. has been on an advisory panel for and has received honoraria and consulting fees from GlaxoSmithKline. 2-DG-6-P, 2-[ 14 C]DG-6-phosphate; HGP, hepatic glucose production; IRS, insulin receptor substrate; LC/MS/MS, liquid chromatography tandem mass spectrometry; PI, phosphatidylinositol; PPAR-γ; peroxisome proliferator–activated receptor-γ; TNF-α, tumor necrosis factor-α; TZD, thiazolidinedione. DIABETES