Gaspar Tiago Bordeira, Jesus Tito Teles, Azevedo Maria Teresa, Macedo Sofia, Soares Mariana Alves, Martins Rui Sousa, Leite Rúben, Rodrigues Lia, Rodrigues Daniela Ferreira, Cardoso Luís, Borges Inês, Canberk Sule, Gärtner Fátima, Miranda-Alves Leandro, Lopes José Manuel, Soares Paula, Vinagre João
Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal.
Cancers (Basel). 2023 Jun 1;15(11):3018. doi: 10.3390/cancers15113018.
Atrx loss was recently ascertained as insufficient to drive pancreatic neuroendocrine tumour (PanNET) formation in mice islets. We have identified a preponderant role of Atrx in the endocrine dysfunction in a genetically engineered mouse model (GEMM). To validate the impact of a different -driver line, we used similar methodologies and characterised the () GEMM to search for PanNET formation and endocrine fitness disruption for a period of up to 24 months. Male and female mice presented different phenotypes. Compared to , males were heavier during the entire study period, hyperglycaemic between 3 and 12 mo., and glucose intolerant only from 6 mo.; in contrast, females started exhibiting increased weight gains later (after 6 mo.), but diabetes or glucose intolerance was detected by 3 mo. Overall, all studied mice were overweight or obese from early ages, which challenged the histopathological evaluation of the pancreas and liver, especially after 12 mo. Noteworthily, losing predisposed mice to an increase in intrapancreatic fatty infiltration (FI), peripancreatic fat deposition, and macrovesicular steatosis. As expected, no animal developed PanNETs. An obese diabetic GEMM of disrupted is presented as potentially useful for metabolic studies and as a putative candidate for inserting additional tumourigenic genetic events.
最近确定Atrx缺失不足以驱动小鼠胰岛中胰腺神经内分泌肿瘤（PanNET）的形成。我们在一个基因工程小鼠模型（GEMM）中发现了Atrx在内分泌功能障碍中的主要作用。为了验证不同驱动系的影响，我们使用了类似的方法，并对（）GEMM进行了表征，以寻找长达24个月的PanNET形成和内分泌适应性破坏情况。雄性和雌性小鼠表现出不同的表型。与相比，雄性在整个研究期间体重更重，在3至12个月时血糖升高，仅从6个月起出现葡萄糖不耐受；相比之下，雌性小鼠后来（6个月后）开始出现体重增加，但在3个月时检测到糖尿病或葡萄糖不耐受。总体而言，所有研究的小鼠从幼年起就超重或肥胖，这对胰腺和肝脏的组织病理学评估提出了挑战，尤其是在12个月后。值得注意的是，缺失使小鼠易发生胰腺内脂肪浸润（FI）增加、胰腺周围脂肪沉积和大泡性脂肪变性。正如预期的那样，没有动物发生PanNETs。一种破坏的肥胖糖尿病GEMM被认为可能对代谢研究有用，并且是插入额外致瘤基因事件的推定候选者。
