In Type 2 Diabetes, Rosiglitazone Therapy for Insulin Resistance Ameliorates Endothelial Dysfunction Independent of Glucose Control
- Frank Pistrosch, MD1,
- Jens Passauer, MD1,
- Sabine Fischer, MD2,
- Katja Fuecker2,
- Markolf Hanefeld, MD3 and
- Peter Gross, MD1
- 1Nephrology, Department of Medicine, University Hospital Dresden, Dresden, Germany
- 2Endocrinology and Diabetes, Department of Medicine, University Hospital Dresden, Dresden, Germany
- 3Center of Clinical Studies, Technical University Dresden, Dresden, Germany
- Address correspondence and reprint requests to Dr. Frank Pistrosch, University Hospital Dresden, Nephrology, Department of Medicine, Fetscherstrasse 74, 01307 Dresden, Germany. E-mail: frankpistrosch{at}hotmail.com
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.
- ACh, acetylcholine
- AUC, area under the curve
- FBF, forearm blood flow
- FFA, free fatty acids
- FPG, fasting plasma glucose
- l-NMMA, N-monomethyl-l-arginine-acetate
- NO, nitric oxide
- PGI2, prostacyclin
- SNP, sodium nitroprusside
Footnotes
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A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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- Accepted October 16, 2003.
- Received May 9, 2003.
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