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 microg.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 (Ra), 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 approximately 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.
Bradley
Eloise A
EA
Biochemistry, Medical School, University of Tasmania, Hobart, 7001 TAS, Australia.
Clark
Michael G
MG
Rattigan
Stephen
S
D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D001775:Blood Circulation / Q000187:drug effects*; D001786:Blood Glucose / Q000032:analysis; D005269:Femur / Q000098:blood supply / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008660:Metabolism / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors; D000077191:Wortmannin
D000730:Androstadienes; D001786:Blood Glucose; D007328:Insulin; D051058:Oncogene Protein v-akt; D005947:Glucose; D000077191:Wortmannin