Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes
Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes
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DOI：
10.1172/jci142365
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发表时间：
2021-01-01
影响因子：
15.9
通讯作者：
Matveyenko, Aleksey, V
中科院分区：
文献类型：
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作者：
Brown, Matthew R.;Holmes, Heather;Matveyenko, Aleksey, V
2型糖尿病（T2 DM）中的胰腺β细胞衰竭归因于β细胞转录景观的扰动，导致葡萄糖刺激的胰岛素分泌受损。最近的研究发现SLC 4A 4（一种编码产电Na+偶联HCO 3协同转运蛋白和细胞内pH调节剂NBCe 1的基因）是T2 DM患者β细胞中错误表达的基因之一。因此，在目前的研究中，我们着手检验T2 DM β细胞中SLC 4A 4/NBCe 1的错误表达导致β细胞功能障碍和葡萄糖稳态受损的假设。为了解决这一假设，我们首先证实了T2 DM患者β细胞中SLC 4A 4/NBCe 1表达的诱导，并证明其表达与β细胞转录特性的丧失、细胞内碱化和β细胞功能障碍相关。此外，我们产生了β细胞选择性Slc 4a 4/NBCe 1-KO小鼠模型，并发现这些小鼠免受饮食诱导的代谢应激和β细胞功能障碍的影响。重要的是，Slc 4a 4/NBCe 1缺陷小鼠中葡萄糖耐量的改善和β细胞功能的增强是由于线粒体功能的增强和调节β细胞身份和功能的基因表达的增加。这些结果表明，在T2 DM中增加的SLC 4A 4/NBCe 1的β细胞表达在促进β细胞衰竭中起贡献作用，并且应该被认为是潜在的治疗靶点。
Pancreatic beta cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the beta cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in beta cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM beta cells contributes to beta cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in beta cells of patients with T2DM and demonstrated that its expression was associated with loss of beta cell transcriptional identity, intracellular alkalinization, and beta cell dysfunction. In addition, we generated a beta cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and beta cell dysfunction. Importantly, improved glucose tolerance and enhanced beta cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating beta cell identity and function. These results suggest that increased beta cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of beta cell failure and should be considered as a potential therapeutic target.