ICA69的表达调控对胰岛β细胞能量代谢的影响机制

糖尿病是威胁人类健康的最重要慢性疾病之一,胰岛素是唯一降血糖激素,仅从胰岛β细胞中分泌，胰岛β细胞功能是糖尿病研究的重要领域。有报道胰岛β细胞中ICA69参与胰岛素囊泡运输,ICA69的缺失导致胰岛素分泌下降;胰岛素原分泌增加,但ICA69在胰岛中的表达调控、影响机制尚不明确。此外ICA69具有BAR结构域可与磷脂膜结合，提示ICA69可能与具有双层膜的线粒体存在相互作用。课题组研究发现高糖可甲基转移酶依赖性下调胰岛细胞ICA69表达;ICA69敲低使线粒体膜电位下调,有氧呼吸和ATP产量下降。结果提示糖尿病可能通过表观遗传学调控β细胞ICA69的表达继而影响细胞能量代谢。为此本课题拟利用细胞、糖尿病动物和ICA69-/-小鼠进一步探索糖尿病内环境对胰岛ICA69表达的调控机制;阐明ICA69及其BAR结构域影响胰岛细胞线粒体功能和能量代谢的具体机制,为探索糖尿病的发病机制提供科学依据。

Diabetes is the one of the most serious chronic diseases. Insulin, the unique hypoglycemic hormone, is only secreted from pancreatic islets β cells, and the islets function is the important research field in diabetes. It has been reported that Islet cell autoantigen of 69 kDa (ICA69) was involved in vesicular transport of insulin. Deficient of ICA69 decreased insulin secretion but increased the ration of proinsulin. However, the alternation of ICA69 expression and its influence in diabetic islets have not been clearly addressed. Otherwise, ICA69 has a BAR domain with the membrane-binding capability, which infer ICA69 may cross-talk with mitochondria. Our previous data showed that high glucose reduced ICA69 mRNA depended on methyltransferase in INS-1 cell line. Low expression of ICA69 suppressed the mitochondrial member potential, aerobic respiration and ATP production. These results suggested that diabetes may disrupt cell metabolism via epigenetic regulation of ICA69 expression in islets β cells. Based on this, using cell line, diabetes model and ICA69-/- mice ,we sought to explore the underlying mechanisms involved in ICA69 down-regulation in diabetic islets, address the mechanism of ICA69 and its BAR domain on mitochondrial function and energy metabolism in islets β cells. Giving scientific supporting for the pathogenesis diagnosis of diabetes.