We studied whether the rapid hypoglycemic action of nateglinide is associated with an increase in islet blood flow. Islet blood flow was measured using the two-colour microsphere method. Orally administered nateglinide with glucose acutely increased islet blood flow to levels greater than those after glucose alone or tolbutamide with glucose in conscious Sprague-Dawley rats (percent increase at 10 min after oral administration; nateglinide + glucose, 125 ± 25%; glucose, 33 ± 11%, p < 0.001; tolbutamide + glucose, 42 ± 23%, p < 0.01). Nateglinide administered with non-metabolisable 3-O-methylglucose also increased islet blood flow (61 ± 17%). The stimulated islet blood flow significantly correlated with serum insulin levels. NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, completely inhibited the increase in islet blood flow induced by nateglinide with glucose. Intravenously administered nateglinide did not significantly affect the already increased islet blood flow in diabetic Otsuka Long-Evans Tokushima Fatty rats. Our results indicated that nateglinide acutely increased islet blood flow at least in part through a nitric oxide-dependent mechanism.
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