Blocking Ca(2+) Channel β(3) Subunit Reverses Diabetes.
Blocking Ca(2+) Channel β(3) Subunit Reverses Diabetes.
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DOI：
10.1016/j.celrep.2018.06.086
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发表时间：
2018-07-24
期刊：
影响因子：
8.8
通讯作者：
Berggren PO
中科院分区：
文献类型：
--
作者：
Lee K;Kim J;Köhler M;Yu J;Shi Y;Yang SN;Ryu SH;Berggren PO
电压门控Ca 2+通道（Cav）是胰腺β细胞功能所必需的，因为它们介导Ca 2+内流，这导致胰岛素胞吐。Cav β3亚基（Cavβ3）被认为在生理条件下调节胞浆Ca 2+（[Ca 2 +]i）振荡频率和胰岛素分泌，但其在糖尿病中的作用尚不清楚。在这里，我们报告糖尿病小鼠的胰岛显示Cavβ3过表达，[Ca 2 +]i动力学改变，葡萄糖刺激后胰岛素分泌受损。因此，在高脂饮食（HFD）诱导的糖尿病中，Cavβ3缺陷（Cavβ3−/−）小鼠显示出改善的胰岛功能和增强的葡萄糖耐量。通过反义寡核苷酸使ob/ob胰岛中Cavβ3表达正常化可挽救[Ca 2 +]i动力学改变和胰岛素分泌受损。重要的是，将Cavβ3−/−胰岛移植到眼前房中可以改善HFD喂养小鼠的葡萄糖耐量。Cavβ3在人胰岛中的过表达也损害胰岛素分泌。因此，我们建议Cavβ3可以作为糖尿病治疗的药物靶点。糖尿病小鼠胰岛Cav β3水平增加Cavβ3在胰岛中的过表达改变了Ca 2+动力学并损害胰岛素分泌Cav β3的缺乏可预防糖尿病中的胰岛功能障碍和葡萄糖耐受不良封闭Cavβ3可改善糖尿病发病后的胰岛功能和葡萄糖耐受。报道糖尿病小鼠的胰岛过度表达Cavβ3，导致[Ca 2 +]i动力学改变和胰岛素分泌受损。减少Cavβ3表达可恢复胰岛功能障碍和葡萄糖稳态。人类胰岛实验表明Cavβ3可能构成糖尿病治疗中的药物靶点。
Voltage-gated Ca2+ channels (Cav) are essential for pancreatic beta cell function as they mediate Ca2+ influx, which leads to insulin exocytosis. The β3 subunit of Cav (Cavβ3) has been suggested to regulate cytosolic Ca2+ ([Ca2+]i) oscillation frequency and insulin secretion under physiological conditions, but its role in diabetes is unclear. Here, we report that islets from diabetic mice show Cavβ3 overexpression, altered [Ca2+]i dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Cavβ3-deficient (Cavβ3−/−) mice showed improved islet function and enhanced glucose tolerance. Normalization of Cavβ3 expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca2+]i dynamics and impaired insulin secretion. Importantly, transplantation of Cavβ3−/− islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Cavβ3 overexpression in human islets also impaired insulin secretion. We thus suggest that Cavβ3 may serve as a druggable target for diabetes treatment. Pancreatic islets from diabetic mice have increased level of Cavβ3 Overexpression of Cavβ3 in islets alters Ca2+ dynamics and impairs insulin secretion Deficiency of Cavβ3 prevents islet dysfunction and glucose intolerance in diabetes Blocking Cavβ3 improves islet function and glucose tolerance after onset of diabetes Lee et al. report that pancreatic islets from diabetic mice overexpress Cavβ3, resulting in altered [Ca2+]i dynamics and impaired insulin secretion. Reducing Cavβ3 expression recovers islet dysfunction and glucose homeostasis. Experiments with human islets suggest that Cavβ3 may constitute a druggable target in diabetes treatment.
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影响因子：
3.4
作者：
Flanagan SE;Vairo F;Johnson MB;Caswell R;Laver TW;Lango Allen H;Hussain K;Ellard S
通讯作者：
Ellard S
影响因子：
4
作者：
Ramadan JW;Steiner SR;O'Neill CM;Nunemaker CS
通讯作者：
Nunemaker CS
DOI：
10.1016/j.tig.2017.01.010
发表时间：
2017-04
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Lawlor N;Khetan S;Ucar D;Stitzel ML
通讯作者：
Stitzel ML
影响因子：
2.1
作者：
Bernardo, Jose F.;Magyar, Clara E.;Friedman, Peter A.
通讯作者：
Friedman, Peter A.
影响因子：
4.8
作者：
Jeon, Daejong;Song, Inseon;Shin, Hee-Sup
通讯作者：
Shin, Hee-Sup