Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil.
Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany.
Sci Rep. 2018 Aug 30;8(1):13061. doi: 10.1038/s41598-018-31325-5.
The exposure of pancreatic islets to high glucose is believed to be one of the causal factors of the progressive lowering of insulin secretion in the development of type 2 diabetes. The progression of beta cell failure to type 2 diabetes is preceded by an early positive increase in the insulin secretory response to glucose, which is only later followed by a loss in the secretion capacity of pancreatic islets. Here we have investigated the electrophysiological mechanisms underlying the early glucose-mediated gain of function. Rodent pancreatic islets or dispersed islet cells were cultured in medium containing either 5.6 (control) or 16.7 (high-glucose) mM glucose for 24 h after isolation. Glucose-stimulated insulin secretion was enhanced in a concentration-dependent manner in high glucose-cultured islets. This was associated with a positive effect on beta cell exocytotic capacity, a lower basal K conductance and a higher glucose sensitivity to fire action potentials. Despite no changes in voltage-gated Ca currents were observed in voltage-clamp experiments, the [Ca] responses to glucose were drastically increased in high glucose-cultured cells. Of note, voltage-dependent K currents were decreased and their activation was shifted to more depolarized potentials by high-glucose culture. This decrease in voltage-dependent K channel (Kv) current may be responsible for the elevated [Ca] response to metabolism-dependent and independent stimuli, associated with more depolarized membrane potentials with lower amplitude oscillations in high glucose-cultured beta cells. Overall these results show that beta cells improve their response to acute challenges after short-term culture with high glucose by a mechanism that involves modulation not only of metabolism but also of ion fluxes and exocytosis, in which Kv activity appears as an important regulator.
胰岛暴露于高葡萄糖被认为是 2 型糖尿病发展中胰岛素分泌逐渐降低的一个因果因素。β 细胞衰竭向 2 型糖尿病的进展先于葡萄糖介导的早期胰岛素分泌反应的正向增加，随后才是胰岛分泌能力的丧失。在这里，我们研究了早期葡萄糖介导的功能获得的电生理机制。在分离后，将啮齿动物胰岛或分散的胰岛细胞在含有 5.6（对照）或 16.7（高葡萄糖）mM 葡萄糖的培养基中培养 24 小时。在高葡萄糖培养的胰岛中，葡萄糖刺激的胰岛素分泌呈浓度依赖性增强。这与β细胞胞吐能力的正向作用、基础 K 电导降低以及对动作电位放电的葡萄糖敏感性增加有关。尽管在电压钳实验中未观察到电压门控 Ca 电流的变化，但在高葡萄糖培养的细胞中，葡萄糖引起的[Ca]反应明显增加。值得注意的是，高葡萄糖培养降低了电压依赖性 K 电流（Kv），并将其激活移向更去极化的电位。这种电压依赖性 K 通道（Kv）电流的减少可能是导致代谢依赖性和非依赖性刺激的[Ca]反应升高的原因，与高葡萄糖培养的β 细胞中膜电位更去极化和幅度较小的振荡有关。总的来说，这些结果表明，β 细胞通过一种不仅涉及代谢调节，还涉及离子通量和胞吐作用调节的机制，在短期高葡萄糖培养后提高了对急性挑战的反应，其中 Kv 活性似乎是一个重要的调节因子。
