Intramyocellular Lipid and Insulin Resistance

Intramyocellular Lipid and Insulin Resistance A Longitudinal In Vivo 1 H-Spectroscopic Study in Zucker Diabetic Fatty Rats Johanna Kuhlmann , Claudia Neumann-Haefelin , Ulrich Belz , Jürgen Kalisch , Hans-Paul Juretschke , Marion Stein , Elke Kleinschmidt , Werner Kramer and Andreas W. Herling From Aventis Pharma Deutschland, Frankfurt am Main, Germany Abstract Insulin resistance plays an important role in the pathogenesis of human type 2 diabetes. In humans, a negative correlation between insulin sensitivity and intramyocellular lipid (IMCL) content has been shown; thus, IMCL becomes a marker for insulin resistance. Recently, magnetic resonance spectroscopy (MRS) has been established as a dependable method for selective detection and quantification of IMCL in humans. To validate the interrelation between insulin sensitivity and IMCL in an animal model of type 2 diabetes, we established volume selective 1 H-MRS at 7 Tesla to noninvasively assess IMCL in the rat. In male obese Zucker Diabetic Fatty rats and their lean littermates, IMCL levels were determined repeatedly over 4 months, and insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp method at 6–7 and at 22–24 weeks of age. A distinct relation between IMCL and insulin sensitivity was demonstrated as well as age dependence for both parameters. Rosiglitazone treatment caused a clear reduction of IMCL and hepatic fat despite increased body weight, and a marked improvement of insulin sensitivity. Thus, the insulin sensitizing properties of rosiglitazone were consistent with a redistribution of lipids from nonadipocytic (skeletal muscle, liver) back into fat tissue. Footnotes Address correspondence and reprint requests to Dr. Andreas W. Herling, Disease Group Metabolic Diseases, Pharmacology H 815/H 821, Aventis Pharma Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt/Main, Germany. E-mail: andreas.herling{at}aventis.com . Received for publication 25 March 2002 and accepted in revised form 23 September 2002. J.K. and C.N.-H. contributed equally to this study. All authors are employed by and hold stock in Aventis Pharma, which manufactures and markets pharmaceuticals related to the treatment of diabetes. EMCL, extramyocellular lipid; FFA, free fatty acid; GIR, glucose infusion rate; IMCL, intramyocellular lipid; IR, insulin resistance; IS, insulin sensitivity; MRS, magnetic resonance spectroscopy; PPAR-γ, peroxisome proliferator-activated receptor-γ; RGZ, rosiglitazone; tCR, tota