TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells.
TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells.
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作者：
da Silva Xavier G;Loder MK;McDonald A;Tarasov AI;Carzaniga R;Kronenberger K;Barg S;Rutter GA
人类 TCF7L2 基因的多态性与胰岛素分泌减少和 2 型糖尿病风险增加有关。然而，TCF7L2影响胰岛素分泌的机制仍不清楚。我们定义了 TCF7L2 表达水平对成熟 β 细胞功能的影响，并提出了其作用的潜在机制。使用 RNAi 或腺病毒转导改变啮齿动物胰岛和 β 细胞系中的 TCF7L2 表达。通过实时定量 PCR 测量 β 细胞基因谱，并通过活细胞成像、电子显微镜和膜片钳电生理学测量对细胞内信号传导和胞吐作用的影响。通过 RNAi 降低 TCF7L2 表达水平会减少葡萄糖诱导的胰岛素分泌，但不会减少 KCl 诱导的胰岛素分泌。与对照组相比，葡萄糖诱导的 ATP/ADP 比值和胞质游离 Ca2+ 浓度 ([Ca2+]i) 增加均有所增加。 TCF7L2 的过度表达对 [Ca2+]i 的葡萄糖调节变化和胰岛素释放产生轻微的抑制作用。 TCF7L2 沉默细胞中的基因表达谱显示，编码突触蛋白 1A 的 mRNA 水平升高，但 Munc18-1 和 ZnT8 mRNA 水平降低。尽管 TCF7L2 抑制导致形态上对接的囊泡数量没有变化，但分泌颗粒运动增加且电容变化减少，表明囊泡融合有缺陷。结论：TCF7L2 参与维持调节分泌颗粒融合的 β 细胞基因的表达。因此，胰岛素胞吐作用缺陷可能是高危 TCF7L2 等位基因携带者糖尿病发病率增加的原因。
Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature β-cell function and suggest a potential mechanism for its actions. TCF7L2 expression in rodent islets and β-cell lines was altered using RNAi or adenoviral transduction. β-Cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology. Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca2+ concentration ([Ca2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+]i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18–1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion. CONCLUSION—TCF7L2 is involved in maintaining expression of β-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles.
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