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Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease

Department of Internal Medicine, Karolinska Institute, Stockholm South Hospital, Stockholm SE-118 83, Sweden

Submitted 2 February 2004 ; accepted in final form 17 July 2004

Tetrahydrobiopterin (BH₄) is an essential cofactor of nitric oxide synthase that improves endothelial function in diabetics, smokers, and patients with hypercholesterolemia. Insulin resistance has been suggested as a contributing factor in the development of endothelial dysfunction via an abnormal pteridine metabolism. We hypothesized that BH₄ would restore flow-mediated vasodilation (FMD, endothelial-dependent vasodilation), which may affect insulin resistance in type 2 diabetic patients. Thirty-two subjects (12 type 2 diabetic subjects, 10 matched nondiabetic subjects, and 10 healthy unmatched subjects) underwent infusion of BH₄ or saline in a random crossover study. Insulin sensitivity index (S_I) was measured by hyperinsulinemic isoglycemic clamp. FMD was measured using ultrasonography. BH₄ significantly increased S_I in the type 2 diabetics [3.6 ± 0.6 vs. 4.9 ± 0.7 x 10^–4 dl·kg^–1·min^–1/(µU/ml), P < 0.05], while having no effects in nondiabetics [8.9 ± 1.1 vs. 9.0 ± 0.9 x 10^–4 dl·kg^–1·min^–1/(µU/ml), P = 0.92] or in healthy subjects [17.5 ± 1.6 vs. 18 ± 1.8 x 10^–4 dl·kg^–1·min^–1/(µU/ml), P = 0.87]. BH₄ did not affect the relative changes in brachial artery diameter from baseline FMD (%) in type 2 diabetic subjects (2.3 ± 0.8 vs. 1.8 ± 1.0%, P = 0.42), nondiabetic subjects (5.3 ± 1.1 vs. 6.6 ± 0.9%, P = 0.32), or healthy subjects (11.9 ± 0.6 vs. 11.0 ± 1.0%, P = 0.48). In conclusion, BH₄ significantly increases insulin sensitivity in type 2 diabetic patients without any discernible improvement in endothelial function.

endothelial dysfunction; nitric oxide; insulin resistance

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