Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes

To determine whether the serine/threonine kinase Akt (also known as protein kinase B) is activated in vivo by insulin administration in humans, and wh ether impaired activation of Akt could play a role in insulin resistance, w e measured the activity and phosphorylation of Akt isoforms in skeletal mus cle from 3 groups of subjects: lean, obese nondiabetic, and obese type 2 di abetic. Vastus lateralis biopsies were taken in the basal (overnight fast) and insulin-stimulated (euglycemic clamp) states. Insulin-stimulated glucos e disposal was reduced 31% in obese subjects and 63% in diabetic subjects, compared with lean subjects. Glycogen synthase (GS) activity in the basal s tate was reduced 28% in obese subjects and 49% in diabetic subjects, compar ed with lean subjects. Insulin-stimulated GS activity was reduced 30% in di abetic subjects. Insulin treatment activated the insulin receptor substrate -l-associated (IRS-l-associated) phosphoinositide 3-kinase (PI 3-kinase) 6. 1-fold in lean, 3.7-fold in obese, and 2.4-fold in diabetic subjects. Insul in also stimulated IRS-2-associated PI S-kinase activity 2.2-fold in lean s ubjects, but only IA-fold in diabetic subjects. Basal activity ofAkt1/Akt2 (Akt1/2) and Akt3 was similar in all groups. Insulin increased Akt1/2 activ ity 1.7- to 2.0-fold, and tended to activate Akt3, in all groups. Insulin-s timulated phosphorylation ofAkt1/2 was normal in obese and diabetic subject s. In lean subjects only, insulin-stimulated Akt1/2 activity correlated wit h glucose disposal rate. Thus, insulin activation of Akt isoforms is normal in muscle of obese nondiabetic and obese diabetic subjects, despite decrea ses of approximately 50% and 39% in IRS-1- and IRS-2-associated PI 3-kinase activity, respectively, in obese diabetic subjects. It is therefore unlike ly that Akt plays a major role in the resistance to insulin action on gluco se disposal or GS activation that is observed in muscle of obese type 2 dia betic subjects.