Activation of Protein Kinase C-ζ by Insulin and Phosphatidylinositol-3,4,5-(PO4)3 Is Defective in Muscle in Type 2 Diabetes and Impaired Glucose Tolerance

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-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.

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

“…This probably explains the moderate degree of insulin resistance. Thus, blunted activation of PI3K has been observed in several insulin-resistant states [14][15][16]27]. Reduced Thr308 phosphorylation of Akt has been reported in obese non-diabetic subjects [28] and in nonobese patients with type 2 diabetes [29], but contrasts with findings in skeletal muscle of obese patients with type 2 diabetes and cultured muscle cells established from such patients [10,15,17].…”

“…In patients with type 2 diabetes, failure of insulin to activate glycogen synthase is a hallmark feature of skeletal muscle insulin resistance [10][11][12][13][14][15]. However, despite reports of impaired activation of PI3K by insulin [14][15][16], most studies have failed to demonstrate impaired insulin signalling downstream of PI3K, including activation of Akt, inhibition of GSK-3 and dephosphorylation of glycogen synthase at sites 3a+3b in muscle from subjects with type 2 diabetes both in vivo and in vitro [10,15,17,18]. Recently, impaired activation of glycogen synthase in type 2 diabetes was linked to increased phosphorylation at NH 2 -terminal residues Ser7 (site 2) and Ser10 (site 2a), suggesting that other pathways downstream of the insulin receptor could be involved [10].…”

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

“…Reduced insulin-stimulated PI3K was observed in muscle biopsies [16][17][18][19] and in primary culture of human skeletal muscle established from type 2 diabetic patients [20,21]. However, deregulation of Akt is more controversial, with studies reporting significant reductions of insulin-stimulated Ser 473 or Thr 308 phosphorylations [22,23], and others showing no difference in phosphorylation or enzymatic activity of Akt between control participants and type 2 diabetic patients [18,24].…”

Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

“…In this regard, it should be noted that: (1) aPKC activation is defective in muscles of type 2 diabetic [16,17], obese glucoseintolerant [16,18] and obese glucose-tolerant [17,19] humans; and (2) the activities of IRS-1-dependent PI 3-kinase and PKB/Akt are unchanged in muscles of diabetic subjects following metformin treatment [20]. On the other hand, it is not known if basal or insulin-stimulated aPKC activity in muscle is altered by metformin treatment.…”