Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise

Diabetes. 2003 Aug;52(8):1926-34. doi: 10.2337/diabetes.52.8.1926.

Abstract

Insulin resistance in type 2 diabetes is partly due to impaired glucose transport in skeletal muscle. Atypical protein kinase C (aPKC) and protein kinase B (PKB), operating downstream of phosphatidylinositol (PI) 3-kinase and its lipid product, PI-3,4,5-(PO(4))(3) (PIP(3)), apparently mediate insulin effects on glucose transport. We examined these signaling factors during hyperinsulinemic-euglycemic clamp studies in nondiabetic subjects, subjects with impaired glucose tolerance (IGT), and type 2 diabetic subjects. In nondiabetic control subjects, insulin provoked twofold increases in muscle aPKC activity. In both IGT and diabetes, aPKC activation was markedly (70-80%) diminished, most likely reflecting impaired activation of insulin receptor substrate (IRS)-1-dependent PI 3-kinase and decreased ability of PIP(3) to directly activate aPKCs; additionally, muscle PKC-zeta levels were diminished by 40%. PKB activation was diminished in patients with IGT but not significantly in diabetic patients. The insulin sensitizer rosiglitazone improved insulin-stimulated IRS-1-dependent PI 3-kinase and aPKC activation, as well as glucose disposal rates. Bicycle exercise, which activates aPKCs and stimulates glucose transport independently of PI 3-kinase, activated aPKCs comparably to insulin in nondiabetic subjects and better than insulin in diabetic patients. Defective aPKC activation contributes to skeletal muscle insulin resistance in IGT and type 2 diabetes, rosiglitazone improves insulin-stimulated aPKC activation, and exercise directly activates aPKCs in diabetic muscle.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Exercise / physiology
  • Fatty Acids, Nonesterified / blood
  • Female
  • Glucose Intolerance / drug therapy
  • Glucose Intolerance / metabolism
  • Glucose Transporter Type 4
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology
  • Isoenzymes / metabolism
  • Male
  • Middle Aged
  • Monosaccharide Transport Proteins / metabolism
  • Muscle Proteins*
  • Muscle, Skeletal / enzymology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase C / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Rosiglitazone
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Thiazoles / administration & dosage*
  • Thiazolidinediones*

Substances

  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Glucose Transporter Type 4
  • Hypoglycemic Agents
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Isoenzymes
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Phosphatidylinositol Phosphates
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • SLC2A4 protein, human
  • Thiazoles
  • Thiazolidinediones
  • phosphatidylinositol 3,4,5-triphosphate
  • Rosiglitazone
  • protein kinase C gamma
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • protein kinase C zeta
  • Protein Kinase C
  • protein kinase C lambda