Are metabolic oscillations responsible for normal oscillatory insulin secretion?
Are metabolic oscillations responsible for normal oscillatory insulin secretion?
复制标题
DOI：
10.2337/diabetes.46.9.1375
复制
发表时间：
1997-09-01
期刊：
影响因子：
7.7
通讯作者：
Tornheim, K
中科院分区：
文献类型：
--
作者：
Tornheim, K
正常的胰岛素分泌在体内和体外是振荡的，周期大约为5-10分钟。产生这些振荡的机制尚未确定，但代谢基础似乎最有可能是葡萄糖刺激的分泌。基本原理是 I) 糖酵解的自发振荡操作是一种公认的现象； 2) 糖酵解的振荡行为涉及 ATP/ADP 比率的振荡，这会导致 ATP 敏感的 K+ 通道交替打开和关闭，导致观察到的膜电位振荡和胰腺 β 细胞中 Ca2+ 内流，并且还可能对胞吐作用产生下游影响； 3) 在这种情况下，自发的 Ca2+ 振荡不太可能是基础，因为细胞内储存在刺激-分泌耦合中并不是最重要的，而且，胰岛素振荡是在细胞内 Ca2+ 水平不发生变化的情况下发生的； 4) 神经基础无法解释来自灌注胰岛和克隆β细胞或体内移植胰岛或胰腺的胰岛素振荡； 5) 观察到的代谢物水平和通量的振荡进一步支持了代谢基础，β 细胞中磷酸果糖激酶 (PFK-M) 振荡亚型的存在也是如此。 NIDDM 患者及其近亲的正常振荡分泌受损这一事实表明，这种紊乱可能与疾病的发展有关；此外，这可能反映了胰腺β细胞燃料代谢/传感途径的调节和操作的早期缺陷。
Normal insulin secretion is oscillatory in vivo and in vitro, with a period of similar to 5-10 min. The mechanism of generating these oscillations is not yet established, but a metabolic basis seems most likely for glucose-stimulated secretion. The rationale is that I)spontaneous oscillatory operation of glycolysis is a well-established phenomenon; 2) oscillatory behavior of glycolysis involves oscillations in the ATP/ADP ratio, which can cause alternating opening and closing of ATP-sensitive K+ channels, leading to the observed oscillations in membrane potential and Ca2+ influx in pancreatic beta-cells, and may also have downstream effects on exocytosis; 3) spontaneous Ca2+ oscillations are an unlikely basis in this case, since intracellular stores are not of primary importance in the stimulus-secretion coupling, and furthermore, insulin oscillations occur under conditions when intracellular Ca2+ levels are not changing; 4) a neural basis cannot account for insulin oscillations from perifused islets and clonal beta-cells or from transplanted islets or pancreas in vivo; 5) observed oscillations in metabolite levels and fluxes further support a metabolic basis, as does the presence in beta-cells of the oscillatory isoform of phosphofructokinase (PFK-M). The fact that normal oscillatory secretion is impaired in patients with NIDDM: and in their near relatives suggests that such derangement may be involved in the development of the disease; furthermore, this probably reflects an early defect in the regulation and operation of the fuel metabolizing/sensing pathways of the pancreatic beta-cell.