Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany.
German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany.
Int J Mol Sci. 2022 Mar 16;23(6):3205. doi: 10.3390/ijms23063205.
Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options. Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) , a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls. Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis. Finally, of the five genes (, , , , and ) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein gene to affect islet cell proliferation as well as apoptosis when overexpressed in MIN6 cells. In summary, we define as the most striking gene to be causal for the diabetes QTL by affecting β-cell proliferation and apoptosis. Thus, is an entirely novel diabetes gene regulating islet cell function.
目前预防和治疗 2 型糖尿病的尝试已经取得了一定的效果，而深入了解这种复杂疾病的分子根源对于开发更成功和精确的治疗方法非常重要。最近，我们启动了糖尿病的集体交叉研究，将四个在糖尿病易感性上存在差异的近交系小鼠与肥胖且易患糖尿病的 NZO 品系杂交，并确定了与 NZO 等位基因携带者的高血糖相关的数量性状基因座（QTL），该基因座位于染色体 13 上。随后对包含 644 个基因的关键区域进行了分析，包括对同源系小鼠胰岛的表达研究、整合来自亲本 NZO 和 B6 胰岛的单细胞数据以及单倍型分析。最后，在 B6 与 NZO 小鼠胰岛中表达不同的多态性单倍型块内的五个基因（、、、、和）中，我们确定钙结合蛋白 基因会影响 MIN6 细胞中的胰岛细胞增殖和凋亡。综上所述，我们确定 是影响β细胞增殖和凋亡从而导致糖尿病 QTL 的最显著基因，因此， 是一个全新的调节胰岛细胞功能的糖尿病基因。
