Temporal Transcriptomic and Proteomic Landscapes of Deteriorating Pancreatic Islets in Type 2 Diabetic Rats

Progressive reductions in β-cell mass and function comprise the core of the pathogenesis mechanism leading to type 2 diabetes (T2D). To understand the molecular events in this process, we quantified the temporal transcriptome and proteome of pancreatic islets from Goto-Kakizaki (GK) rats at different stages of diabetes. Integrated omics analysis allowed us to unravel the chronological order of T2D-related molecular events during GK islet deterioration. Two major events occur early in the disease, specifically, a reduction in β-cell mass caused by defective neogenesis and senescence-related low proliferation, and metabolic shift caused by mitochondrial dysfunction. Furthermore, our data revealed the evolution of compensation failure in GK islets and two distinct stages of islet inflammation: priming and amplification. Our study offers a valuable resource for the diabetes research community and will facilitate further studies aimed at protecting β-cell mass and function.β细胞质量与功能的进行性减退，是驱动2型糖尿病（type 2 diabetes, T2D）发生的核心致病机制。为解析该进程中的分子事件，我们对不同糖尿病病程阶段的Goto-Kakizaki（GK）大鼠胰岛的时序转录组与蛋白质组进行了定量分析。通过整合多组学分析，我们明确了GK大鼠胰岛退变过程中与2型糖尿病相关的分子事件的发生时序。疾病早期存在两大核心事件：其一为β细胞新生缺陷与衰老相关增殖不足所导致的β细胞质量减退；其二为线粒体功能异常引发的代谢重编程。此外，本研究数据还揭示了GK大鼠胰岛代偿功能衰竭的动态演变，以及胰岛炎症的两个截然不同的阶段：致敏（priming）与扩增（amplification）。本研究为糖尿病研究领域提供了宝贵的研究资源，同时将助力后续旨在保护β细胞质量与功能的相关研究。