Increased p85/55/50 Expression and Decreased Phosphotidylinositol 3-Kinase Activity in Insulin-Resistant Human Skeletal Muscle.

Bandyopadhyay, Gautam K.; Yu, Joseph G.; Ofrecio, Jachelle; Olefsky, Jerold M.

Insulin resistance is predominantly characterized by decreased insulin-stimulated glucose uptake into skeletal muscle. In the current study, we have assessed various aspects of the phosphatidylinositol (PI) 3-kinase pathway in skeletal muscle biopsies obtained from normal, obese nondiabetic, and type 2 diabetic subjects, before and after a 5-h insulin infusion. We found a highly significant inverse correlation between in vivo insulin sensitivity (as measured by the glucose infusion rate) and increased protein expression of p85/55/50, protein kinase C (PKC)-θ activity, levels of pSer[sup 307] insulin receptor substrate (IRS)-1 and p-Jun NH[sub 2]-terminal kinase (JNK)-1, and myosin heavy chain IIx fibers. Increased basal phosphorylation of Ser[sup 307] IRS-1 in the obese and type 2 diabetic subjects corresponds with decrease in insulin-stimulated IRS-1 tyrosine phosphorylation, PI 3-kinase activity, and insulin-induced activation of Akt and, more prominently, PKC-ζ/λ. In summary, increased expression of the PI 3-kinase adaptor subunits p85/55/50, as well as increased activity of the proinflammatory kinases JNK-1, PKC-θ, and, to a lesser extent, inhibitor of κB kinase-β, are associated with increased basal Ser[sup 307] IRS-1 phosphorylation and decreased PI 3-kinase activity and may follow a common pathway to attenuate in vivo insulin sensitivity in insulin-resistant subjects. These findings demonstrate interacting mechanisms that can lead to impaired insulin-stimulated PI 3-kinase activity in skeletal muscle from obese and type 2 diabetic subjects. Diabetes 54:2351-2359, 2005

INSULIN resistance; DIABETES complications; DRUG resistance; PHOSPHOINOSITIDES; INSULIN receptors

Diabetes, 2005, Vol 54, Issue 8, p2351

0012-1797

Academic Journal

10.2337/diabetes.54.8.2351