title: Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease.
abstract: Tetrahydrobiopterin (BH(4)) 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 BH(4) 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 BH(4) or saline in a random crossover study. Insulin sensitivity index (S(I)) was measured by hyperinsulinemic isoglycemic clamp. FMD was measured using ultrasonography. BH(4) 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)/(microU/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)/(microU/ml), P = 0.92] or in healthy subjects [17.5 +/- 1.6 vs. 18 +/- 1.8 x 10(-4) dl.kg(-1).min(-1)/(microU/ml), P = 0.87]. BH(4) 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, BH(4) significantly increases insulin sensitivity in type 2 diabetic patients without any discernible improvement in endothelial function.
authors.affiliation: Dept. of Internal Medicine, Karolinska Institute, Stockholm South Hospital, Södersjukhuset, Stockholm SE-118 83, Sweden. thomas.nystrom@sos.sll.se
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
authors.forename: Arne
authors.initials: A
authors.lastname: Nygren
authors.forename: Ake
authors.initials: A
authors.lastname: Sjöholm
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism*; D003067:Coenzymes / Q000494:pharmacology / Q000502:physiology; D003327:Coronary Disease / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D016555:Matched-Pair Analysis; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D012016:Reference Values; D014664:Vasodilation / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D003067:Coenzymes; D007328:Insulin; D001708:Biopterins; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin