Contrasting insulin dose-dependent defects in activation of atypical protein kinase C and protein kinase B/Akt in muscles of obese diabetic humans

Abstract

Defective PKBbeta activation/phosphorylation, seen on submaximal insulin stimulation in diabetic muscle, may largely reflect impaired activation of insulin signalling factors present in concentrations greater than those needed for full PKB activation/phosphorylation. Defective aPKC activation, seen at all insulin levels, appears to reflect, at least partly, an impaired action of distal factors needed for aPKC activation, or poor aPKC responsiveness.

Effect of l-Arginine Infusion on Glucose Disposal during Exercise in Humans

“…3B, C) compared with the CON trial. To verify this potential additive signaling effect, we measured skeletal muscle AKT Thr^"** phosphorylation because it closely parallels increases in insulin-stimulated glucose uptake after exercise (II) and is an appropriate marker of skeletal muscle insulin signaling (6). We also found that exercise increased AKT Thr""* phosphorylation in human skeletal muscle (Fig.…”

Combined thiazolidinedione–metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle

“…We studied five type 2 diabetic patients (four men, one woman; results of aPKC and PKB activation in men and women are indistinguishable [2, 4, 10]), who were free of cardiovascular, renal, neuropathic and other medical problems. Procedures were approved by the Institutional Review Board of the University of South Florida College of Medicine and the Research and Development Committee of the James A. Haley Veterans Hospital, and were in accordance with the Declaration of Helsinki and Good Clinical Practice.…”

“…Euglycaemic–hyperinsulinaemic clamp/muscle biopsy studies were conducted after overnight fasting, as described [2, 4, 10]. After anaesthetising with 0.5% lidocaine, the skin was incised and a biopsy of the vastus lateralis muscle was performed with a 14-gauge needle.…”

“…In type 2 diabetic muscle, reductions in IRS-1-dependent PI3K (IRS-1/PI3K) [1] and aPKC activation [2–4] were seen in studies employing sub-maximal and/or maximal insulin stimulation. However, PKB activation was not reduced in some studies of maximal insulin stimulation [2, 5], but reduced PKB activation was evident with sub-maximal (more physiological) insulin stimulation [4, 6–8].…”

“…However, PKB activation was not reduced in some studies of maximal insulin stimulation [2, 5], but reduced PKB activation was evident with sub-maximal (more physiological) insulin stimulation [4, 6–8]. …”