In Type 2 Diabetes, Rosiglitazone Therapy for Insulin Resistance Ameliorates Endothelial Dysfunction Independent of Glucose Control
Open Access
- 1 February 2004
- journal article
- clinical trial
- Published by American Diabetes Association in Diabetes Care
- Vol. 27 (2), 484-490
- https://doi.org/10.2337/diacare.27.2.484
Abstract
OBJECTIVE—Insulin resistance is an independent risk factor for arteriosclerosis and cardiovascular mortality. However, the mechanism by which insulin resistance contributes to arteriosclerosis is unknown. Conceivably, endothelial dysfunction could be involved. Therefore, we asked whether therapy for insulin resistance ameliorates any endothelial dysfunction. RESEARCH DESIGN AND METHODS—We performed a double-blind cross-over trial of 12 patients with recently diagnosed type 2 diabetes. They received rosiglitazone 4 mg b.i.d. for 12 weeks and nateglinide 60 mg b.i.d. for the same number of weeks in random order. To assess the degree of endothelial dysfunction, we used venous occlusion plethysmography. We studied vasodilation in response to acetylcholine (ACh) with and without exogenous insulin. The agents were infused into the brachial artery. Furthermore, we determined insulin resistance by euglycemic clamp. RESULTS—Glycemic control was comparable under rosiglitazone and nateglinide. Rosiglitazone ameliorated insulin resistance by 60% compared with nateglinide. ACh response was significantly increased after rosiglitazone treatment (maximum forearm blood flow 12.8 ± 1.3 vs. 8.8 ± 1.3 ml/100 ml after rosiglitazone and nateglinide, respectively; P < 0.05) but did not attain the level of healthy control subjects (14.0 ± 0.7 ml/100 ml). Coinfusion of exogenous insulin increased ACh response further in the rosiglitazone group. N-monomethyl-l-arginine-acetate (l-NMMA), an antagonist of nitric oxide synthase, largely prevented the increased vasodilation after rosiglitazone, regardless of the presence or absence of insulin. Insulin sensitivity and blood flow response were found to be correlated (P < 0.01). CONCLUSIONS—Insulin resistance is a major contributor toward endothelial dysfunction in type 2 diabetes. Both endothelial dysfunction and insulin resistance are amenable to treatment by rosiglitazone.Keywords
This publication has 32 references indexed in Scilit:
- Report of the Expert Committee on the Diagnosis and Classification of Diabetes MellitusDiabetes Care, 2003
- Nateglinide, a d-Phenylalanine Derivative Lacking Either a Sulfonylurea or Benzamido Moiety, Specifically Inhibits Pancreatic β-Cell-Type KATP ChannelsJournal of Pharmacology and Experimental Therapeutics, 2002
- Structure, Endothelial Function, Cell Growth, and Inflammation in Blood Vessels of Angiotensin II–Infused RatsCirculation, 2002
- Metabolic and Additional Vascular Effects of ThiazolidinedionesDrugs, 2002
- Quantitative aspects of the inhibition by NG‐monomethyl‐L‐arginine of responses to endothelium‐dependent vasodilators in human forearm vasculatureBritish Journal of Pharmacology, 2001
- Endothelial dysfunction in diabetesBritish Journal of Pharmacology, 2000
- Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.JCI Insight, 1997
- Cyclosporin A Increases Nitric Oxide Activity In VivoHypertension, 1997
- Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.JCI Insight, 1996
- Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitusJournal of the American College of Cardiology, 1996