A novel insulin sensitizer (S15511) enhances insulin-stimulated glucose uptake in rat skeletal muscles.
Type 2 diabetes is preceded by the presence of skeletal muscle insulin resistance, and drugs that increase insulin sensitivity in skeletal muscle prevent the disease. S15511 is an original compound with demonstrated effects on insulin sensitivity in animal models of insulin resistance. However, the mechanisms behind the insulin-sensitizing effect of S15511 are unknown. The aim of our study was to explore whether S15511 improves insulin sensitivity in skeletal muscles. Insulin sensitivity was assessed in skeletal muscles from S15511-treated rats by measuring intracellular insulin-signaling activity and insulin-stimulated glucose transport in isolated muscles. In addition, GLUT4 expression and glycogen levels were assessed after treatment. S15511 treatment was associated with an increase in insulin-stimulated glucose transport in type IIb fibers, while type I fibers were unaffected. The enhanced glucose transport was mirrored by a fiber type-specific increase in GLUT4 expression, while no improvement in insulin-signaling activity was observed. S15511 is a novel insulin sensitizer that is capable of improving glucose homeostasis in nondiabetic rats. The compound enhances skeletal muscle insulin sensitivity and specifically targets type IIb muscle fibers by increasing GLUT4 expression. Together these data show S15511 to be a potentially promising new drug in the treatment and prevention of type 2 diabetes.
Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus C, Denmark. Niels.Jessen@ki.au.dk
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Jessen
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Selmer Buhl
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Pold
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Schmitz
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Lund
D019325:3-O-Methylglucose / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005449:Fluorenes / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D005449:Fluorenes; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C518830:S 15511; D019325:3-O-Methylglucose; D006003:Glycogen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose