Proteomics on am mouse model reveals phenotypic divergence from human disease

Introduction: Maturity-onset Diabetes of the Young (MODY) is a rare form of diabetes and arises from mutations in key regulatory genes of the pancreatic beta-cell, leading to their functional impairment and early-onset diabetes. Research into PDX1-MODY, a form of MODY caused by mutations in the PDX1 gene, enhances understanding of gene-specific mechanisms underlying glucose dysregulation and provides insights into possible approaches to restore normal metabolic function. However, no currently published mouse model accurately depicts the genetic cause of PDX1-MODY in human patients. Methods: Using CRISPR-Cas9 technology, we generated the first mouse model carrying one of the most prevalent pathological PDX1 point mutation found in human patients, P33T, and conducted an 18-week in vivo phenotyping experiment assessing homozygous PDX1P33T and wild type littermates on both chow and high fat diet (HFD). Additionally, transcriptomic and proteomic analyses were performed on isolated pancreatic islets. Islet architecture was investigated via fluorescent microscopy. Result: Contrary to expectations, our comprehensive phenotypic analysis of the mouse model carrying the homozygous PDX1P33T point mutation revealed no significant differences in metabolic parameters compared to wild-type controls, and no pathological outcomes were observed as seen in human patients. Notably, male PDX1P33T mice exhibited an increase in islet size and number on chow diet but failed to adapt respectively on HFD. Discussion: Our work indicates substantial differences between mouse and human PDX1 function in the pancreas. Further refinement of animal models is necessary to better elucidate the pathophysiology of PDX1-MODY. Ultimately, this study emphasizes the complexities involved in translating human pathologies to animal models, serving as a reminder that findings generated in mice may not always be easily translated to humans.

引言：青少年发病的成年型糖尿病（Maturity-onset Diabetes of the Young, MODY）是一类罕见糖尿病亚型，其发病机制为胰腺β细胞关键调控基因突变，导致β细胞功能受损并引发早发性糖尿病。针对PDX1-MODY——一种由PDX1基因突变导致的MODY亚型——开展研究，有助于深化对葡萄糖代谢失调相关基因特异性机制的理解，并为恢复正常代谢功能的潜在干预策略提供理论参考。然而，目前尚无已发表的小鼠模型能够准确模拟人类患者PDX1-MODY的遗传致病机制。
方法：本研究借助CRISPR-Cas9基因编辑技术，构建了首个携带人类患者中最常见致病性PDX1点突变P33T的小鼠模型；随后开展了为期18周的体内表型分析实验，分别在普通饲料与高脂饮食（high fat diet, HFD）条件下，对纯合子PDX1P33T小鼠及其野生型同窝仔鼠进行系统评估。此外，本研究还对分离获取的胰腺胰岛进行了转录组学与蛋白质组学分析，并通过荧光显微镜观察胰岛组织结构。
结果：与预期相悖的是，本研究对携带纯合子PDX1P33T点突变的小鼠模型开展的全面表型分析显示，其代谢参数与野生型对照组无显著差异，且未观察到人类患者中出现的病理特征。值得注意的是，在普通饲料喂养条件下，雄性PDX1P33T小鼠的胰岛体积与数量均有所增加，但在高脂饮食条件下这一表型优势并未得以维持。
讨论：本研究结果表明，小鼠与人类胰腺中PDX1的功能存在显著差异。未来需进一步优化动物模型，以更清晰地阐明PDX1-MODY的病理生理学机制。本研究最终强调了将人类疾病病理转化为动物模型研究时所涉及的复杂性，提醒学界小鼠实验的研究结果未必可直接外推至人类。