Grant: Team Grant: Diabetes Mechanisms and Translational Solutions - General Pool

T2D in childhood continues to increase worldwide and affects Indigenous children and families more than non-Indigenous populations. Childhood onset T2D is associated with high rates of early onset rapidly progressive kidney disease. As more children are diagnosed with T2D, more babies are being born having been exposed to diabetes in the womb (in utero). Consequently, we now know that diabetes exposure in utero is a potent risk factor for the exposed child to develop childhood-onset T2D; however, it is not yet known how diabetes exposure increases the risk or if it increases risk of associated renal complications. Recent scientific advances have revealed that the environment in the womb can alter the expression of genes in the offspring via a process called "epigenetic regulation", which can impact important metabolic pathways needed to maintain health. In addition, a specific change in the DNA sequence (HNF1a gene variant) also imparts a risk of T2D development in the offspring. In this study, we aim to define the epigenetic signature of babies born to mothers with diabetes so that we can determine which genes and pathways are affected by this exposure. Subsequently, we aim to use mouse and cell models to examine how these epigenetic changes impact function of important metabolic tissues, including the pancreas. Finally, we will examine how the HNF1a variant results in T2D risk for children and if it also impacts renal development, function and risk. Upon completion of this study, we hope to better understand how maternal diabetes exposure and the HNF1a gene variant impacts offspring health, to identify biomarkers at birth that can be used to determine which children are at highest risk of developing T2D, and to inform the development of new treatments to prevent T2D and renal complications in exposed children.