Defective activation of atypical protein kinase C zeta and lambda by insulin and phosphatidylinositol-3,4,5-(PO4)(3) in skeletal muscle of rats following high-fat feeding and streptozotocin-induced diabetes

Endocrinology. 2003 Mar;144(3):947-54. doi: 10.1210/en.2002-221017.

Abstract

Insulin-stimulated glucose transport in skeletal muscle is thought to be effected at least partly through atypical protein kinase C isoforms (aPKCs) operating downstream of phosphatidylinositol (PI) 3-kinase and 3-phosphoinositide-dependent protein kinase-1 (PDK-1). However, relatively little is known about the activation of aPKCs in physiological conditions or insulin-resistant states. Presently, we studied aPKC activation in vastus lateralis muscles of normal chow-fed and high-fat-fed rats and after streptozotocin (STZ)-induced diabetes. In normal chow-fed rats, dose-dependent increases in aPKC activity approached maximal levels after 15-30 min of stimulation by relatively high and lower, presumably more physiological, insulin concentrations, achieved by im insulin or ip glucose administration. Insulin-induced activation of aPKCs was impaired in both high-fat-fed and STZ-diabetic rats, but, surprisingly, IRS-1-dependent and IRS-2-dependent PI 3-kinase activation was not appreciably compromised. Most interestingly, direct in vitro activation of aPKCs by PI-3,4,5-(PO(4))(3), the lipid product of PI 3-kinase, was impaired in both high-fat-fed and STZ-diabetic rats. Defects in activation of aPKCs by insulin and PI-3,4,5-(PO(4))(3) could not be explained by diminished PDK-1-dependent phosphorylation of threonine-410 in the PKC-zeta activation loop, as this phosphorylation was increased even in the absence of insulin treatment in high-fat-fed rats.

Conclusions: 1) muscle aPKCs are activated at relatively low, presumably physiological, as well as higher supraphysiological, insulin concentrations; 2) aPKC activation is defective in muscles of high-fat-fed and STZ-diabetic rats; and 3) defective aPKC activation in these states is at least partly due to impaired responsiveness to PI-3,4,5-(PO(4))(3), apparently at activation steps distal to PDK-1-dependent loop phosphorylation.

Publication types

  • 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

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Diabetes Mellitus, Experimental / enzymology*
  • Dietary Fats / administration & dosage
  • Enzyme Activation / drug effects
  • Glucose / administration & dosage
  • Insulin / pharmacology*
  • Isoenzymes
  • Muscle, Skeletal / enzymology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol Phosphates / pharmacology*
  • Phosphorylation
  • Protein Kinase C / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Dietary Fats
  • Insulin
  • Isoenzymes
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4,5-triphosphate
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • protein kinase C zeta
  • Protein Kinase C
  • protein kinase C lambda
  • Glucose