Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level.
Rad is a low molecular weight GTPase that is overexpressed in skeletal muscle of some patients with type 2 diabetes mellitus and/or obesity. Overexpression of Rad in adipocytes and muscle cells in culture results in diminished insulin-stimulated glucose uptake. To further elucidate the potential role of Rad in vivo, we have generated transgenic (tg) mice that overexpress Rad in muscle using the muscle creatine kinase (MCK) promoter-enhancer. Rad tg mice have a 6- to 12-fold increase in Rad expression in muscle as compared to wild-type littermates. Rad tg mice grow normally and have normal glucose tolerance and insulin sensitivity, but have reduced plasma triglyceride levels. On a high-fat diet, Rad tg mice develop more severe glucose intolerance than the wild-type mice; this is due to increased insulin resistance in muscle, as exemplified by a rightward shift in the dose-response curve for insulin stimulated 2-deoxyglucose uptake. There is also a unexpected further reduction of the plasma triglyceride levels that is associated with increased levels of lipoprotein lipase in the Rad tg mice. These results demonstrate a potential synergistic interaction between increased expression of Rad and high-fat diet in creation of insulin resistance and altered lipid metabolism present in type 2 diabetes.
Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
Jacob
J
Ilany
Philip J
PJ
Bilan
Sonia
S
Kapur
James S
JS
Caldwell
Mary-Elizabeth
ME
Patti
Andre
A
Marette
C Ronald
CR
Kahn
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D003402:Creatine Kinase / Q000235:genetics; D003847:Deoxyglucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D000596:Amino Acids; D004041:Dietary Fats; D007328:Insulin; C490030:Rrad protein, mouse; D014280:Triglycerides; D003847:Deoxyglucose; D003402:Creatine Kinase; D008071:Lipoprotein Lipase; D018631:ras Proteins; D005947:Glucose