Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone.
Insulin resistance is associated with a decreased vasodilator response to insulin. Because insulin's vasodilator effect is nitric oxide dependent, this impairment may reflect endothelial dysfunction. Troglitazone, an insulin-sensitiser, might thus improve insulin-dependent and/or endothelium-dependent vascular function in insulin resistant obese subjects. For 8 weeks, fifteen obese subjects were treated with either 400 mg troglitazone once daily or placebo, in a randomised, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses (plethysmography) to intra-arterial administered acetylcholine and sodium nitroprusside; insulin sensitivity and insulin-induced vascular and neurohumoral responses (clamp); vasoconstrictor responses to NC-monomethyl-L-arginine (L-NMMA) during hyperinsulinaemia; and ambulatory 24-h blood pressure (ABPM). Baseline data (placebo) of obese subjects were compared with those obtained in lean control subjects. Obese subjects were insulin resistant compared with leans (whole-body glucose uptake: 26.8+/-3.0 vs. 53.9+/-4.3 [tmol kgl min-, p < 0.001). Troglitazone improved whole-body glucose uptake (to 31.9+/-3.3 micromol x kg(-1) x min(-1) , p=0.028), and forearm glucose uptake (from 1.09+/-0.54 to 2.31+/-0.69 micromol dL(-1) x min(-1), p=0.006). Insulin-induced vasodilatation was blunted in obese subjects (percent increase in forearm blood flow (FBF) in lean 66.5+/-23.0%, vs. 10.1+/-11.3% in obese, p=0.04), but did not improve during troglitazone. Vascular responses to acetylcholine, sodium nitroprusside and L-NMMA did not differ between the obese and lean group, nor between both treatment periods in the obese individuals. In conclusion, in insulin resistant obese subjects, endothelial vascular function is normal despite impaired vasodilator responses to insulin. Troglitazone improved insulin sensitivity but it had no effects on endothelium-dependent and -independent vascular responses. These data do not support an association between insulin resistance and endothelial function.
Tack
C J
CJ
Department of Internal Medicine, University Hospital Nijmegen, The Netherlands. c.tackdaig.azn.nz.
Ong
M K
MK
Lutterman
J A
JA
Smits
P
P
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000328:Adult; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects; D016022:Case-Control Studies; D002839:Chromans / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005215:Fasting; D005260:Female; D005542:Forearm; D015309:Glucose Clamp Technique; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000627:therapeutic use*; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D009765:Obesity / Q000188:drug therapy*; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D000077288:Troglitazone; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use; D019323:omega-N-Methylarginine / Q000494:pharmacology
D015415:Biomarkers; D001786:Blood Glucose; D002839:Chromans; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D013844:Thiazoles; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D000077288:Troglitazone; D000109:Acetylcholine