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

Biochemistry, Medical School, University of Tasmania, Hobart, Australia

Submitted 9 August 2006 ; accepted in final form 11 November 2006

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 µg·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 (10 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 P-Akt/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 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.

glucose uptake; blood flow; microvasculature; insulin action

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