title: 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.
abstract: 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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Ko
authors.initials: K
authors.lastname: Kotani
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Ciaraldi
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000328:Adult; D003920:Diabetes Mellitus / Q000178:diet therapy / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000378:metabolism*; D004032:Diet; D002149:Energy Intake; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology*; D009765:Obesity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015431:Weight Loss / Q000502:physiology; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases; D011972:Receptor, Insulin; D014443:Tyrosine; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C526292:IRS1 protein, human; C087857:protein kinase C gamma; C496628:PRKCA protein, human; C497255:PRKCE protein, human; C076233:PRKCQ protein, human