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

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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.