Rountree Austin M, Neal Adam S, Lisowski Mark, Rizzo Norma, Radtke Jared, White Sarah, Luciani Dan S, Kim Francis, Hampe Christiane S, Sweet Ian R
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and.
the Department of Surgery, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
J Biol Chem. 2014 Jul 4;289(27):19110-9. doi: 10.1074/jbc.M114.556050. Epub 2014 May 19.
The aim of the study was to assess the relative control of insulin secretion rate (ISR) by calcium influx and signaling from cytochrome c in islets where, as in diabetes, the metabolic pathways are impaired. This was achieved either by culturing isolated islets at low (3 mm) glucose or by fasting rats prior to the isolation of the islets. Culture in low glucose greatly reduced the glucose response of cytochrome c reduction and translocation and ISR, but did not affect the response to the mitochondrial fuel α-ketoisocaproate. Unexpectedly, glucose-stimulated calcium influx was only slightly reduced in low glucose-cultured islets and was not responsible for the impairment in glucose-stimulated ISR. A glucokinase activator acutely restored cytochrome c reduction and translocation and ISR, independent of effects on calcium influx. Islets from fasted rats had reduced ISR and cytochrome c reduction in response to both glucose and α-ketoisocaproate despite normal responses of calcium. Our data are consistent with the scenario where cytochrome c reduction and translocation are essential signals in the stimulation of ISR, the loss of which can result in impaired ISR even when calcium response is normal.
本研究的目的是评估在胰岛中，钙内流和细胞色素c信号传导对胰岛素分泌率（ISR）的相对控制作用，在糖尿病状态下，胰岛中的代谢途径会受损。这一目的通过在低葡萄糖（3 mM）条件下培养分离的胰岛，或在分离胰岛前对大鼠进行禁食来实现。低葡萄糖培养极大地降低了细胞色素c还原和易位以及ISR的葡萄糖反应，但不影响对线粒体燃料α-酮异己酸的反应。出乎意料的是，在低葡萄糖培养的胰岛中，葡萄糖刺激的钙内流仅略有减少，且不是葡萄糖刺激的ISR受损的原因。一种葡萄糖激酶激活剂能急性恢复细胞色素c还原和易位以及ISR，且与对钙内流的影响无关。尽管钙反应正常，但禁食大鼠的胰岛对葡萄糖和α-酮异己酸的反应中，ISR和细胞色素c还原均降低。我们的数据与以下情况一致：细胞色素c还原和易位是刺激ISR的关键信号，即使钙反应正常，这些信号的缺失也会导致ISR受损。
