Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo

Wortmannin, an inhibitor of phosphatidylinositol 3- kinase, was systemically infused during a hyperinsulinemic euglycemic clamp to investigate its effects in vivo. Rats were infused under anesthesia with saline, 10 or 20 mU . min(-1) . kg(-1) insulin, wortmannin ( 1 mu g . min(-1) . kg(-1)) + saline, or wortmannin + insulin ( 10 mU . min(-1) . kg(-1)); wortmannin was present for 1 h before and throughout the 2- h clamp. Femoral blood flow ( FBF), glucose infusion rate to maintain euglycemia ( GIR), glucose appearance ( R-a), glucose disappearance ( R-d), capillary recruitment by 1- methylxanthine metabolism ( MXD), hindleg glucose uptake ( HLGU), liver, muscle, and aorta Akt phosphorylation ( P- Akt/ Akt), and plasma insulin concentrations were determined. Plasma insulin increased from 410 +/- 49 to 1,680 +/- 430 and 5,060 +/- 230 pM with 10 and 20 mU . min(-1) . kg(-1) insulin, respectively. Insulin ( and 20 mU . min(-1) . kg(-1)) increased FBF, MXD, GIR, R-d, and HLGU as well as liver, muscle, and aorta P- Akt/ Akt and decreased R-a ( all P < 0.05). Wortmannin alone increased plasma insulin to 5,450 +/- 770 pM and increased R-a, R-d, HLGU, and muscle P- Akt/ Akt without effect on blood glucose, FBF, MXD liver, or aorta P- Akt/ Akt. Wortmannin blocked FBF, MXD, and liver PAkt/ Akt increases from 10 mU . min(-1) . kg(-1) insulin. Comparison of wortmannin + 10 mU . min(-1) . kg(-1) insulin and 20 mU . min(-1) . kg(-1) insulin alone ( both at similar to 5,000 pM PI) showed that wortmannin fully blocked the changes in FBF and R-a and partly those of GIR, R-a, R-d, HLGU, and muscle P- AKT/ Akt. In summary, wortmannin in vivo increases plasma insulin and fully inhibits insulin- mediated effects in liver and aorta and partially those of muscle, where the latter may result from inhibition of insulin- mediated increases in blood flow and capillary recruitment.