Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic β-cells.
Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic β-cells.
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DOI：
10.1016/j.cellsig.2018.03.001
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发表时间：
2018-06
影响因子：
4.8
通讯作者：
Berggren PO
中科院分区：
文献类型：
--
作者：
Rajasekaran SS;Kim J;Gaboardi GC;Gromada J;Shears SB;Dos Santos KT;Nolasco EL;Ferreira SS;Illies C;Köhler M;Gu C;Ryu SH;Martins JO;Darè E;Barker CJ;Berggren PO
二磷酸肌醇五磷酸（IP7）对于胰腺β细胞的胞吐能力至关重要，但β细胞胞吐的主要引发剂葡萄糖对其的调节尚不清楚。产生IP7的酶，肌醇六磷酸激酶（IP6K1和2）的ATP的高Km表明这些酶可能在胰岛素分泌β细胞中充当代谢传感器，并在糖尿病中充当破坏的代谢的翻译器。我们研究了这一假设，现在表明，葡萄糖刺激，增加ATP/ADP的比例，导致早期上升的IP 7浓度在β细胞。RNAi介导的IP6K1同种型的敲低抑制葡萄糖介导的IP7和第一时相胰岛素分泌的增加，表明IP6K1整合了葡萄糖代谢和胰岛素胞吐。在糖尿病小鼠胰岛中，基础和葡萄糖刺激条件下的ATP/ADP水平紊乱反映在IP7生成和胰岛素释放中断中。因此，IP6K1独特的代谢传感特性保证了IP7的适当浓度，从而保证了正确的基础胰岛素分泌和完整的第一阶段胰岛素释放。此外，我们的数据表明，一个特定的细胞信号传导缺陷，即，不适当的IP7生成可能是一个重要的汇聚点，将多种代谢缺陷整合到糖尿病中常见的表型中。葡萄糖通过胰腺β细胞中的IP6K1瞬时增加IP7水平。IP6K1将葡萄糖驱动的ATP/ADP比率增加解码为第一时相胰岛素释放。IP7的产生和胰岛素的释放反映了糖尿病胰岛的代谢紊乱。IP6K1在正常和病理条件下充当β细胞代谢传感器。
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 Km 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. Glucose increases IP7 levels transiently through IP6K1 in pancreatic β-cells. IP6K1 decodes glucose-driven increases in ATP/ADP ratio into 1st phase insulin release. IP7 production and insulin release mirror perturbed metabolism in diabetic islets. IP6K1 acts as a β-cell metabolic sensor under normal and pathological conditions.
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影响因子：
4.8
作者：
Kennedy, HJ;Pouli, AE;Rutter, GA
通讯作者：
Rutter, GA
影响因子：
7.3
作者：
Chakraborty A;Kim S;Snyder SH
通讯作者：
Snyder SH
影响因子：
64.5
作者：
Chakraborty A;Koldobskiy MA;Bello NT;Maxwell M;Potter JJ;Juluri KR;Maag D;Kim S;Huang AS;Dailey MJ;Saleh M;Snowman AM;Moran TH;Mezey E;Snyder SH
通讯作者：
Snyder SH
影响因子：
--
作者：
Chakraborty A
通讯作者：
Chakraborty A
影响因子：
8.2
作者：
Anello, M;Lupi, R;Marchetti, P
通讯作者：
Marchetti, P