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

在过去十年中，在发病率、严重程度和疾病病理生理方面，性别二态性的证据已经积累起来。糖尿病是一种表现出强烈性别差异的代谢性疾病，其特征是由于葡萄糖稳态的丧失而导致的慢性高血糖。了解糖尿病存在性别差异的原因在治疗中很重要；男性和女性对现有疗法的反应可能不同，研究性别差异可能会突出新疗法的目标因素。尽管如此，这方面的研究还很缺乏。最近在伦敦国王学院发现了一种内质网应激诱导的糖尿病小鼠模型（KINGSmouse）。该模型表现出强烈的两性二态性；当雄性在5周时出现明显的糖尿病时，雌性尽管葡萄糖耐量受损，但终生保持正常血糖。研究KINGS小鼠性别差异的驱动因素，雌性KINGS小鼠是否会诱发糖尿病或雄性KINGS小鼠是否会减轻糖尿病，并研究该模型中的性别差异是否可应用于人类胰岛。在项目的第一年，我们将研究b细胞对内质网应激的急性和慢性反应的性别差异。急性反应将通过开发一种离体胰岛试验来研究，其中测量功能适应和对内质网应激的抵抗（急性反应）。慢性反应（增殖、肥大）将通过组织学和分子技术在体内进行分析。该项目的第二个目标将集中在调节体内环境，以确定雌性KINGS小鼠是否会诱发糖尿病，或在雄性KINGS小鼠中是否会减轻糖尿病，因为这将深入了解可能导致性别差异的体内因素。最后，将KINGS小鼠的结果与人类胰岛进行比较，以确定是否存在任何相似性，并确定KINGS小鼠是否代表了研究人类糖尿病性二态性的合适模式。

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.