title: Effects of losartan on whole body, skeletal muscle and vascular insulin responses in obesity/insulin resistance without hypertension.
abstract: OBJECTIVE
  Renin-angiotensin system antagonists have been found to improve glucose metabolism in obese hypertensive and type 2 diabetic subjects. The mechanism of these effects is not well understood. We hypothesized that the angiotensin receptor antagonist losartan would improve insulin-mediated vasodilation, and thereby improve insulin-stimulated glucose uptake in skeletal muscle of insulin-resistant subjects.
  
  
  METHODS
  We studied subjects with obesity and insulin resistance but without hypertension, hypercholesterolaemia or dysglycaemia [age 39.0 ± 9.6 yr (mean ± SD), body mass index (BMI) 33.2 ± 5.9 kg/m(2) , BP 115.8 ± 12.2/70.9 ± 7.2 mmHg, LDL 2.1 ± 0.5 mmol/l]. Subjects were randomized to 12 weeks' double-blind treatment with losartan 100 mg once daily (n = 9) or matching placebo (n = 8). Before and after treatment, under hyperinsulinaemic euglycaemic clamp conditions we measured whole-body insulin-stimulated glucose disposal, insulin-mediated vasodilation, and insulin-stimulated leg glucose uptake by the limb balance technique.
  
  
  RESULTS
  Whole-body insulin-stimulated glucose disposal was not significantly increased by losartan. Insulin-mediated vasodilation was augmented following both treatments [increase in leg vascular conductance: pretreatment 0.7 ± 0.3 l/min/mmHg (losartan, mean ± SEM) and 0.9 ± 0.3 (placebo), posttreatment 1.0 ± 0.4 (losartan) and 1.3 ± 0.6 (placebo)] but not different between treatment groups (p = 0.53). Insulin's action to augment nitric oxide (NO) production and to augment endothelium-dependent vasodilation was also not improved. Leg glucose uptake was not significantly changed by treatments, and not different between groups (p = 0.11).
  
  
  CONCLUSIONS
  These findings argue against the hypothesis that losartan might improve skeletal muscle glucose metabolism by improving insulin-mediated vasodilation in normotensive insulin-resistant obese subjects. The metabolic benefits of angiotensin receptor blockers may require the presence of hypertension in addition to obesity-associated insulin resistance.
authors: Department of Medicine, Division of Endocrinology & Metabolism, Indiana University School of Medicine, 541 North Clinical Drive, Indianapolis, IN, USA.
authors: A A
authors: AA
authors: Lteif
authors: R L
authors: RL
authors: Chisholm
authors: K
authors: K
authors: Gilbert
authors: R V
authors: RV
authors: Considine
authors: K J
authors: KJ
authors: Mather
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D017211:Treatment Failure; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D014665:Vasodilator Agents; D019808:Losartan