Using the KINGS diabetic mouse model to investigate sex differences underlying pancreatic islet biology and its dysfunction

在过去的十年里，在疾病的发病率、严重性和病理生理学方面，已经积累了性别二态的证据。一种表现出强烈性别差异的代谢性疾病是糖尿病，其特征是由于葡萄糖代谢紊乱而导致的慢性高血糖。了解糖尿病中存在性别差异的原因在治疗背景下是重要的；男性和女性对现有治疗方法的反应可能不同，研究性别差异可能会突出可以作为新疗法目标的因素。尽管如此，这一领域的研究还很匮乏。伦敦国王学院最近发现了一种内质网应激诱导的糖尿病小鼠模型(KINGS小鼠)。这个模型表现出强烈的性二态糖尿病表型；而雄性在5周时出现明显的糖尿病，而雌性在他们的一生中保持正常的血糖水平，尽管糖耐量受损。为了研究是什么因素导致了Kings小鼠的性别差异，是否可以在雌性KINGS小鼠中诱导糖尿病或缓解雄性Kings小鼠的糖尿病，并研究该模型中的性别差异是否可以应用于人类岛屿。在项目的第一年，我们将调查B细胞对ER应激的急性和慢性反应的性别差异。急性反应将通过建立体外胰岛试验来研究，其中测量对ER应激的功能适应和抵抗(急性反应)。慢性反应(增殖、肥大)将通过组织学和分子技术进行活体分析。该项目的第二个目标将集中在调节体内环境，以确定糖尿病是否可以在雌性Kings小鼠身上诱发或在雄性小鼠身上得到缓解，因为这将深入了解可能导致性别差异的体内因素。最后，来自Kings小鼠的结果将与人类胰岛进行比较，以确定是否存在任何相似之处，并确定Kings小鼠是否代表了研究人类糖尿病性二型的合适模式。

Evidence for sexual dimorphisms in incidence, severity and pathophysiology of disease has accumulated in the lastdecade. A metabolic disease showing strong sex differences is diabetes mellitus, which is characterised by chronichyperglycaemia resulting from loss of glucose homeostasis.Understanding why sex differences exist in diabetes is important in the context of treatment; males and females mayrespond differently to existing therapies and studying sex differences may highlight factors that can be targeted for noveltherapies. Despite this, research in this area is lacking. An ER-stress-induced murine model of diabetes (the KINGSmouse) has recently been discovered at Kings College London. This model exhibits strong sexual dimorphisms indiabetic phenotype; whilst males develop overt diabetes at 5-weeks, females remain normoglycemic throughout theirlives despite having impaired glucose tolerance.To investigate what factors drive sex differences in the KINGS mouse, whether diabetes can be induced in femaleKINGS mice or alleviated in male KINGS mice, and to investigate whether sex differences in this model can beapplied to human islets.In the first year of the project we will investigate sex differences in acute and chronic responses of B-cells to ER-stress.Acute responses will be investigated by developing an ex vivo islet assay where functional adaptation and resistance(acute responses) to ER-stress are measured. Chronic responses (proliferation, hypertrophy) will be analysed in vivothrough histology and molecular techniques. The second aim of the project will focus around modulating the in vivoenvironment to establish whether diabetes can be induced in female KINGS mice or alleviated in males since this willgive insight into in vivo factors that may drive sex differences. Finally, results from the KINGS mice will becompared to human islets to establish whether any similarities exist and determine whether the KINGS mouserepresents a suitable mode for studying diabetic sexual dimorphisms in humans.