12882908

pubmed:Citation

8

In humans with obesity or type 2 diabetes, insulin target tissues are resistant to many actions of insulin. The atypical protein kinase C (PKC) isoforms lambda and zeta are downstream of phosphatidylinositol-3 kinase (PI3K) and are required for maximal insulin stimulation of glucose uptake. Phosphoinositide-dependent protein kinase-1 (PDK-1), also downstream of PI3K, mediates activation of atypical PKC isoforms and Akt. To determine whether impaired PKClambda/zeta or PDK-1 activation plays a role in the pathogenesis of insulin resistance, we measured the activities of PKClambda/zeta and PDK-1 in vastus lateralis muscle of lean, obese, and obese/type 2 diabetic humans. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic-euglycemic clamp. Obese subjects were also studied after weight loss on a very-low-calorie diet. Insulin-stimulated glucose disposal rate is reduced 26% in obese subjects and 62% in diabetic subjects (both comparisons P < 0.001). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and PI3K activity are impaired 40-50% in diabetic subjects compared with lean or obese subjects. Insulin stimulates PKClambda/zeta activity approximately 2.3-fold in lean subjects; the increment above basal is reduced 57% in obese and 65% in diabetic subjects. PKClambda/zeta protein amount is decreased 46% in diabetic subjects but is normal in obese nondiabetic subjects, indicating impaired insulin action on PKClambda/zeta. Importantly, weight loss in obese subjects normalizes PKClambda/zeta activation and increases IRS-1 phosphorylation and PI3K activity. Insulin also stimulates PDK-1 activity approximately twofold with no impairment in obese or diabetic subjects. In contrast to our previous data on Akt, reduced insulin-stimulated PKClambda/zeta activity could play a role in the pathogenesis of insulin resistance in muscle of obese and type 2 diabetic subjects.

eng

AIM

MEDLINE

0012-1797

Print

NLM

1935-42

pubmed-meshheading:12882908-Adult, pubmed-meshheading:12882908-Diabetes Mellitus, pubmed-meshheading:12882908-Diabetes Mellitus, Type 2, pubmed-meshheading:12882908-Diet, pubmed-meshheading:12882908-Energy Intake, pubmed-meshheading:12882908-Female, pubmed-meshheading:12882908-Humans, pubmed-meshheading:12882908-Insulin Receptor Substrate Proteins, pubmed-meshheading:12882908-Isoenzymes, pubmed-meshheading:12882908-Male, pubmed-meshheading:12882908-Middle Aged, pubmed-meshheading:12882908-Muscle, Skeletal, pubmed-meshheading:12882908-Obesity, pubmed-meshheading:12882908-Phosphatidylinositol 3-Kinases, pubmed-meshheading:12882908-Phosphoproteins, pubmed-meshheading:12882908-Phosphorylation, pubmed-meshheading:12882908-Protein Kinase C, pubmed-meshheading:12882908-Protein Kinase C-alpha, pubmed-meshheading:12882908-Protein Kinase C-epsilon, pubmed-meshheading:12882908-Protein-Serine-Threonine Kinases, pubmed-meshheading:12882908-Receptor, Insulin, pubmed-meshheading:12882908-Tyrosine, pubmed-meshheading:12882908-Weight Loss

Insulin-stimulated protein kinase C lambda/zeta activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes: reversal with weight reduction.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't