Insulin Secretion in Response to L-Arginine under Decreasing Tetrahydrobiopterin Content

Tetrahydrobiopterin (BH 4 ) content in the pancreas from GK (Goto-Kakizaki) rats as a type II diabetic model was markedly decreased compared to Wistar rats as a healthy control. Moreover, insulin stimulated BH 4 synthesis in a hamster pancreatic β-cell line, HIT-T15 cells. Therefore, in diabetic condition, the reduction of insulin action is likely to lead to the low levels of BH 4 content in pancreatic β-cells. In this study, we examined the effects of the decrease in BH 4 content on insulin secretion by L-arginine (L-Arg) or glucose using HIT-T15 cells. Cytosolic calcium concentration ([Ca 2+ ] i ) in HIT-T15 cells was increased by L-Arg. Under the low BH 4 content using 2,4- diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of BH 4 synthesis, L-Arg-induced both Ca 2+ response and insulin secretion were stimulated. These stimulating effects were recovered by BH 4 content recovering, using sepiapterin, a precursor of BH 4 biosynthesis. By contrast, glucose-induced Ca 2+ response was not affected by the BH 4 content. These results suggest that the decrease of BH 4 content in β-cells may stimulate insulin secretion by L-Arg, but not by glucose, under diabetic conditions.