Rosiglitazone, Insulin Treatment, and Fasting Correct Defective Activation of Protein Kinase C-ζ/λ by Insulin in Vastus Lateralis Muscles and Adipocytes of Diabetic Rats

• Published in: Endocrinology (Philadelphia) 2001-04, Vol.142 (4), p.1595-1605
• Main Authors: Kanoh, Yoshinori, Bandyopadhyay, Gautam, Sajan, Mini P., Standaert, Mary L., Farese, Robert V.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adipocytes; AKT protein; Defects; Diabetes; Diabetes mellitus; Fasting; Glucose; Glucose transport; Insulin; Insulin receptor substrate 1; Kinases; Muscles; Protein kinase C; Proteins; Rosiglitazone; Sensitizing; Skeletal muscle; Thiazolidinediones
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.142.4.8066

Abstract Atypical protein kinases C (PKCs), ζ and λ, and protein kinase B (PKB) are thought to function downstream of phosphatidylinositol 3-kinase (PI 3-kinase) and regulate glucose transport during insulin action in skeletal muscle and adipocytes. Insulin-stimulated glucose transport is defective in type II diabetes mellitus, and this defect is ameliorated by thiazolidinediones and lowering of blood glucose by chronic insulin therapy or short-term fasting. Presently, we evaluated the effects of these insulin-sensitizing modalities on the activation of insulin receptor substrate-1 (IRS-1)-dependent PI 3-kinase, PKC-ζ/λ, and PKB in vastus lateralis skeletal muscles and adipocytes of nondiabetic and Goto-Kakizaki (GK) diabetic rats. Insulin provoked rapid increases in the activity of PI 3-kinase, PKC-ζ/λ, and PKB in muscles and adipocytes of nondiabetic rats, but increases in IRS-1-dependent PI 3-kinase and PKC-ζ/λ, but not PKB, activity were substantially diminished in GK muscles and adipocytes. Rosiglitazone treatment for 10–14 days, 10-day insulin treatment, and 60-h fasting reversed defects in PKC-ζ/λ activation in GK muscles and adipocytes and increased glucose transport in GK adipocytes, without necessarily increasing IRS-1-dependent PI 3-kinase or PKB activation. Our findings suggest that insulin-sensitizing modalities, viz. thiazolidinediones, chronic insulin treatment, and short-term fasting, similarly improve defects in insulin-stimulated glucose transport at least partly by correcting defects in insulin-induced activation of PKC-ζ/λ.