Tong Xin, Kono Tatsuyoshi, Anderson-Baucum Emily K, Yamamoto Wataru, Gilon Patrick, Lebeche Djamel, Day Richard N, Shull Gary E, Evans-Molina Carmella
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
Diabetes. 2016 Oct;65(10):3039-52. doi: 10.2337/db16-0084. Epub 2016 Aug 3.
The sarcoendoplasmic reticulum (ER) Ca(2+) ATPase 2 (SERCA2) pump is a P-type ATPase tasked with the maintenance of ER Ca(2+) stores. Whereas β-cell SERCA2 expression is reduced in diabetes, the role of SERCA2 in the regulation of whole-body glucose homeostasis has remained uncharacterized. To this end, SERCA2 heterozygous mice (S2HET) were challenged with a high-fat diet (HFD) containing 45% of kilocalories from fat. After 16 weeks of the HFD, S2HET mice were hyperglycemic and glucose intolerant, but adiposity and insulin sensitivity were not different between HFD-fed S2HET mice and HFD-fed wild-type controls. Consistent with a defect in β-cell function, insulin secretion, glucose-induced cytosolic Ca(2+) mobilization, and the onset of steady-state glucose-induced Ca(2+) oscillations were impaired in HFD-fed S2HET islets. Moreover, HFD-fed S2HET mice exhibited reduced β-cell mass and proliferation, altered insulin production and proinsulin processing, and increased islet ER stress and death. In contrast, SERCA2 activation with a small molecule allosteric activator increased ER Ca(2+) storage and rescued tunicamycin-induced β-cell death. In aggregate, these data suggest a critical role for SERCA2 and the regulation of ER Ca(2+) homeostasis in the β-cell compensatory response to diet-induced obesity.
肌浆网（ER）Ca(2+) ATP酶2（SERCA2）泵是一种P型ATP酶，负责维持内质网Ca(2+)储存。虽然糖尿病患者的β细胞SERCA2表达降低，但SERCA2在全身葡萄糖稳态调节中的作用仍未明确。为此，用含45%千卡脂肪的高脂饮食（HFD）对SERCA2杂合小鼠（S2HET）进行挑战。高脂饮食16周后，S2HET小鼠出现高血糖和葡萄糖不耐受，但高脂饮食喂养的S2HET小鼠与高脂饮食喂养的野生型对照之间的肥胖和胰岛素敏感性并无差异。与β细胞功能缺陷一致，高脂饮食喂养的S2HET胰岛中的胰岛素分泌、葡萄糖诱导的胞质Ca(2+)动员以及稳态葡萄糖诱导的Ca(2+)振荡的起始均受损。此外，高脂饮食喂养的S2HET小鼠表现出β细胞质量和增殖减少、胰岛素产生和胰岛素原加工改变，以及胰岛内质网应激和死亡增加。相比之下，用小分子变构激活剂激活SERCA2可增加内质网Ca(2+)储存，并挽救衣霉素诱导的β细胞死亡。总体而言，这些数据表明SERCA2以及内质网Ca(2+)稳态调节在β细胞对饮食诱导肥胖的代偿反应中起关键作用。
