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 (Rd), 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, Rd, and HLGU as well as liver, muscle, and aorta P-Akt/Akt and decreased Ra (all P < 0.05). Wortmannin alone increased plasma insulin to 5,450 ± 770 pM and increased Ra, Rd, 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 Ra and partly those of GIR, Ra, Rd, 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. Copyright © 2007 the American Physiological Society.

Item Type:	Refereed Article
Research Division:	Medical and Health Sciences
Research Group:	Clinical Sciences
Research Field:	Endocrinology
Objective Division:	Health
Objective Group:	Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:	Diabetes
Author:	Bradley, EA (Miss Eloise Bradley)
Author:	Clark, MG (Professor Michael Clark)
Author:	Rattigan, S (Professor Stephen Rattigan)
ID Code:	49791
Year Published:	2007
Web of Science® Times Cited:	10
Deposited By:	Biochemistry
Deposited On:	2007-08-01
Last Modified:	2010-04-14
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