Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3' kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance.
Impaired glucose tolerance (IGT) is characterized by insulin resistance. Recently, defects in the insulin-signaling cascade have been implicated in the pathogenesis of insulin resistance. To study insulin signaling in IGT, we used human skeletal muscle cells in primary culture from patients with IGT and control subjects. In these cultured myotubes, we assessed insulin-induced 2-deoxyglucose uptake and early steps of the metabolic insulin-signaling cascade. Myotubes in culture from patients with IGT had insulin-induced glucose uptake that was roughly 30-50% less than that from control subjects. This insulin resistance was associated with impaired insulin receptor substrate (IRS)-2-associated phosphatidylinositol 3' (PI3) kinase activation and IRS-2 tyrosine phosphorylation as well as significantly decreased protein kinase C (PKC)-zeta/lambda activation in response to insulin. IRS-1- associated PI3 kinase activation and insulin receptor autophosphorylation were comparable in the two groups. Protein expression levels for the insulin receptor, IRS-1, IRS-2, the p85 regulatory subunit of PI3 kinase, Akt, PKC-zeta/lambda, GLUT1, and GLUT4 were also similar in the two groups. In conclusion, myotubes from patients with IGT have impaired insulin-induced glucose uptake. This is associated with impaired IRS-2-associated PI3 kinase activation and PKC-zeta/lambda activation. Our results suggest that these defects may contribute to insulin resistance in IGT patients.
Vollenweider
Peter
P
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. peter.vollenweider@ibcm.unil.ch
Ménard
Barbara
B
Nicod
Pascal
P
D000273:Adipose Tissue / Q000033:anatomy & histology; D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose; D001794:Blood Pressure; D015992:Body Mass Index; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004789:Enzyme Activation; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D012016:Reference Values
D001786:Blood Glucose; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D019000:Phosphotyrosine; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D011493:Protein Kinase C