Diphosphoinositol pentakisphosphate (IP₇) is critical for the exocytotic capacity of the pancreatic β-cell, but its regulation by the primary instigator of β-cell exocytosis, glucose, is unknown. The high K_m for ATP of the IP₇-generating enzymes, the inositol hexakisphosphate kinases (IP6K1 and 2) suggests that these enzymes might serve as metabolic sensors in insulin secreting β-cells and act as translators of disrupted metabolism in diabetes. We investigated this hypothesis and now show that glucose stimulation, which increases the ATP/ADP ratio, leads to an early rise in IP₇ concentration in β-cells. RNAi mediated knock down of the IP6K1 isoform inhibits both glucose-mediated increase in IP₇ and first phase insulin secretion, demonstrating that IP6K1 integrates glucose metabolism and insulin exocytosis. In diabetic mouse islets the deranged ATP/ADP levels under both basal and glucose-stimulated conditions are mirrored in both disrupted IP₇ generation and insulin release. Thus the unique metabolic sensing properties of IP6K1 guarantees appropriate concentrations of IP₇ and thereby both correct basal insulin secretion and intact first phase insulin release. In addition, our data suggest that a specific cell signaling defect, namely, inappropriate IP₇ generation may be an essential convergence point integrating multiple metabolic defects into the commonly observed phenotype in diabetes.

二磷酸肌醇五磷酸酯（IP ₇）对于胰腺β细胞的胞吐能力至关重要，但尚不清楚它是由β细胞胞吐的主要诱因即葡萄糖调节的。产生IP _7的酶（肌醇六磷酸激酶（IP6K1和2））的ATP具有很高的K _m，表明这些酶可能在分泌胰岛素的β细胞中充当代谢传感器，并充当糖尿病中新陈代谢破坏的翻译器。我们研究了这一假设，现在表明，葡萄糖刺激会增加ATP / ADP比率，从而导致β细胞中IP ₇浓度提前升高。RNAi介导的IP6K1亚型的抑制同时抑制葡萄糖介导的IP ₇升高第一阶段胰岛素分泌，表明IP6K1整合了葡萄糖代谢和胰岛素胞吐作用。在糖尿病小鼠胰岛中，在基础和葡萄糖刺激的条件下，ATP / ADP的水平紊乱都反映了IP _7的产生中断和胰岛素释放。因此，IP6K1独特的代谢感应特性可确保IP _7的浓度适中，从而既可校正基础胰岛素分泌，又可维持完整的第一阶段胰岛素释放。此外，我们的数据表明，特定的细胞信号缺陷，即不适当的IP ₇产生，可能是将多种代谢缺陷整合到糖尿病患者常见表型中的必不可少的收敛点。