Metallothionein 1E as a Central Regulator of Human Pancreatic Beta Cell Function and Survival

大量证据表明胰腺β细胞功能障碍和死亡在2型糖尿病（T2DM）发病机制中起核心作用。据推测，胰腺β细胞功能和质量的下降可能是由遗传变异引起的，这是代谢损伤向疾病状态发展的关键步骤。事实上，全基因组关联研究（GWAS）已经确定了大约100个与2型糖尿病相关的基因，其中大多数都指向β细胞。然而，阐明从GWAS中鉴定的T2DM基因的生物学功能和机制仍然具有挑战性，因为缺乏一个强大的系统来系统地评估与疾病相关的人类胰腺β细胞中的这些变异。了解T2DM相关基因的功能和下游通路将为控制T2DM进展的机制提供新的见解。我们建立了一个强大的平台，利用等基因人胚胎干细胞（hESCs）研究T2DM相关基因在人胰腺β细胞功能和存活中的作用，发现CDKAL1的缺失通过下调金属硫蛋白1E （MT1E）导致人胰腺β细胞功能障碍和细胞死亡增加。此外，我们的初步研究表明，另一种T2DM相关基因SLC30A8的缺失也会导致人类胰腺β细胞功能障碍并下调MT1E。此外，MT1E的强制表达保护hesc来源的β样细胞免受高糖和高脂肪酸诱导的β细胞功能障碍。最后，MT1E的强制表达恢复了T2DM胰岛的功能。在这里，我们将验证MT1E在控制人类胰腺β细胞功能和存活中起核心作用的假设。最后，MT1E将在T2DM胰岛中被迫表达，以挽救功能障碍和死亡。总之，这一提议不仅将确定一种新的生物标志物来研究人类胰腺β细胞的异质性，而且还将导致发现T2DM药物开发的新靶点。

Significantly amount of evidence suggested the central role of pancreatic beta cell dysfunction and death in the pathogenesis of type 2 diabetes mellitus (T2DM). It is hypothesized that the decreased pancreatic beta cell function and mass, a key step in the progression from metabolic impairments to a disease state, might be resulted from genetic variants. Indeed, genome-wide association studies (GWAS) have identified around 100 genes associated with T2DM, most of which pointed to beta cells. However, clarifying the biological functions and mechanism of T2DM genes identified from GWAS remains challenging, due to lacking of a robust system to systematically evaluate these variants in disease-relevant human pancreatic beta cells. Understanding the function and downstream pathways of T2DM associated genes will provide novel insight of the mechanism controlling T2DM progression. We have established a robust platform to use isogenic human embryonic stem cells (hESCs) to study the role of T2DM associated genes in human pancreatic beta cell function and survival and found that loss of CDKAL1 causes human pancreatic beta cell dysfunction and increased cell death by downregulating Metallothionein 1E (MT1E). In addition, our preliminary studies suggested that loss of SLC30A8, another T2DM associated gene, also causes human pancreatic beta cell dysfunction and downregulates MT1E. Furthermore, the forced expression of MT1E protects hESC-derived beta-like cells from high glucose and high fatty acid-induced beta cell dysfunction. Finally, the forced expression of MT1E rescues function of T2DM islets. Here, we will test the hypothesis that MT1E plays a central role to control human pancreatic beta cell function and survival. Finally, MT1E will be forced expressed in T2DM islets to rescue dysfunction and death. Together, this proposal will not only identify a novel biomarker to study the heterogeneity of human pancreatic beta cells, but also lead to the discovery of a novel target of T2DM drug development.