Type 2 diabetes (T2D) has a strong genetic component. Most of the gene variants driving the pathogenesis of T2D seem to target pancreatic β-cell function. To identify novel gene variants acting at early stage of the disease, we analyzed whole transcriptome data to identify differential expression (DE) and alternative exon splicing (AS) transcripts in pancreatic islets collected from two metabolically diverse mouse strains at 6 weeks of age after three weeks of high-fat-diet intervention. Our analysis revealed 1218 DE and 436 AS genes in islets from NZO/Hl vs C3HeB/FeJ. Whereas some of the revealed genes present well-established markers for β-cell failure, such as Cd36 or Aldh1a3, we identified numerous DE/AS genes that have not been described in context with β-cell function before. The gene Lgals2, previously associated with human T2D development, was DE as well as AS and localizes in a quantitative trait locus (QTL) for blood glucose on Chr.15 that we reported recently in our N₂(NZOxC3H) population. In addition, pathway enrichment analysis of DE and AS genes showed an overlap of only half of the revealed pathways, indicating that DE and AS in large parts influence different pathways in T2D development. PPARG and adipogenesis pathways, two well-established metabolic pathways, were overrepresented for both DE and AS genes, probably as an adaptive mechanism to cope for increased cellular stress. Our results provide guidance for the identification of novel T2D candidate genes and demonstrate the presence of numerous AS transcripts possibly involved in islet function and maintenance of glucose homeostasis.

2 型糖尿病 (T2D) 具有很强的遗传成分。大多数驱动 T2D 发病机制的基因变异似乎都针对胰腺 β 细胞功能。为了鉴定在疾病早期起作用的新基因变体，我们分析了全转录组数据以鉴定胰岛中的差异表达 (DE) 和选择性外显子剪接 (AS) 转录物，这些转录物是从 6 周龄的两个代谢多样化的小鼠品系中收集的，三岁后数周的高脂肪饮食干预。我们的分析揭示了 NZO/H1 与 C3HeB/FeJ 的胰岛中有 1218 个 DE 和 436 个 AS 基因。而一些揭示的基因呈现出成熟的 β 细胞衰竭标志物，例如Cd36或Aldh1a3，我们鉴定了许多以前没有在 β 细胞功能的背景下描述的 DE/AS 基因。先前与人类 T2D 发育相关的基因Lgals2是 DE 和 AS，并定位于 Chr.15 上血糖的数量性状基因座 (QTL)，我们最近在 N _{2 中}报道了这一点(NZOxC3H) 种群。此外，DE和AS基因的通路富集分析显示，只有一半的揭示通路重叠，表明DE和AS在很大程度上影响了T2D发展中的不同通路。PPARG 和脂肪生成途径，两种成熟的代谢途径，在 DE 和 AS 基因中的比例过高，可能是一种适应机制来应对增加的细胞压力。我们的结果为新的 T2D 候选基因的鉴定提供了指导，并证明了许多 AS 转录物的存在可能与胰岛功能和维持葡萄糖稳态有关。