Department of Cell Biology and Physiology and Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
Diabetes Obes Metab. 2012 Oct;14 Suppl 3(0 3):129-35. doi: 10.1111/j.1463-1326.2012.01655.x.
Hyperglycaemia has multiple effects on β-cells, some clearly prosecretory, including hyperplasia and elevated insulin content, but eventually, a 'glucotoxic' effect which leads to pancreatic β-cell dysfunction, reduced β-cell mass and insulin deficiency, is an important part of diabetes pathophysiology. Myriad underlying cellular and molecular processes could lead to such dysfunction. High glucose will stimulate glycolysis and oxidative phosphorylation, which will in turn increase β-cell membrane excitability through K(ATP) channel closure. Chronic hyperexcitability will then lead to persistently elevated Ca(2+), a key trigger to insulin secretion. Thus, at least a part of the consequence of 'hyperstimulation' by glucose has been suggested to be a result of 'hyperexcitability' and chronically elevated Ca(2+). This link is lost when the [glucose], K(ATP) -channel activity link is broken, either pharmacologically or genetically. In isolated islets, such studies reveal that hyperexcitability causes a largely reversible chronic loss of insulin content, but in vivo chronic hyperexcitability per se does not lead to β-cell death or loss of insulin content. On the other hand, chronic inexcitability in vivo leads to systemic diabetes and consequential β-cell death, even while Ca(2+) remains low.
高血糖对β细胞有多种影响，一些影响显然是促分泌的，包括增生和胰岛素含量升高，但最终，“糖毒性”作用会导致胰腺β细胞功能障碍、β细胞数量减少和胰岛素缺乏，这是糖尿病病理生理学的重要组成部分。许多潜在的细胞和分子过程都可能导致这种功能障碍。高葡萄糖会刺激糖酵解和氧化磷酸化，这反过来又会通过 K(ATP)通道关闭增加β细胞膜的兴奋性。慢性过度兴奋将导致持续升高的 Ca(2+)，这是胰岛素分泌的关键触发因素。因此，葡萄糖“超刺激”的至少一部分后果被认为是“过度兴奋”和慢性升高的 Ca(2+)的结果。当 [葡萄糖]、K(ATP) -通道活性之间的联系被打破时，无论是通过药理学还是遗传学，这种联系就会丢失。在分离的胰岛中，此类研究表明，过度兴奋会导致胰岛素含量的大量可逆性慢性丧失，但体内慢性过度兴奋本身并不会导致β细胞死亡或胰岛素含量丧失。另一方面，体内慢性兴奋不足会导致全身性糖尿病和随后的β细胞死亡，即使 Ca(2+)仍然较低。
