PDF(Pubmed)
Abstract：
Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release.
摘要：
使用13C6葡萄糖标记与气相色谱-质谱联用和2D1H-13C异核单量子相干NMR光谱，我们已经获得了支持β细胞功能的葡萄糖命运的比较高分辨率图。在小鼠和人类胰岛中，葡萄糖对三羧酸(TCA)循环的贡献是相似的。TCA循环的丙酮酸燃料主要由丙酮酸脱氢酶的活性介导，通过丙酮酸羧化酶的通量较低。虽然丙酮酸通过乳酸脱氢酶（LDH）转化为乳酸可以在两个物种的胰岛中检测到，乳酸的积累是人类胰岛的6倍。人胰岛表达LDH,具有低-中度LDHA表达和β细胞特异性LDHB表达。LDHB抑制放大小鼠和人β细胞中LDHA依赖性乳酸的产生并增加基础胰岛素的释放。最后,顺式仪器孟德尔随机化显示低LDHB表达水平与人空腹胰岛素升高相关。因此，LDHB限制β细胞中的乳酸生成以维持适当的胰岛素释放。
