Diabetes afflicts approximately 29 million adult Americans (9.3% of the total population), 90-95% of whom have type 2 diabetes (T2D). T2D is a complex disease with both genetic and environmental components and ultimately manifests when pancreatic islets fail to secrete sufficient insulin to compensate for increased insulin resistance. Despite the success of genome-wide association studies (GWAS) in linking >100 loci to islet dysfunction and T2D, we still lack the mechanistic insights necessary to develop novel treatments and preventions. Detailed molecular and phenotypic analyses of each T2D-associated GWAS locus are thus essential to determine how they contribute to islet dysfunction and diabetes. We have recently linked altered C2CD4A/B expression to genetic risk of islet dysfunction and T2D. Our overall objective is to understand the islet/beta cell regulation and function of the C2CD4A/B locus in physiologic and diabetogenic states. We hypothesize that these genes regulate stimulus-secretion coupling and that chronic activation of C2CD4A/B by genetic and/or environmental risk factors contributes to the declines in first-phase insulin secretion that are hallmarks of the early stages of T2D. To test this hypothesis, we will determine the regulatory circuitry controlling C2CD4A/B responses to inflammatory stressors and determine the effect of T2D-associated GWAS variants on C2CD4A/B activity (Aim 1). In parallel, we will dissect the beta cell functions of C2CD4A and C2CD4B in glucose-stimulated insulin secretion (Aim 2). Finally, we will assess the in vivo effects of deleting these genes in a polygenic T2D mouse model (Aim 3). Together, these aims will provide fundamental, mechanistic insights into the regulation and function of the C2CD4A/B locus and will delineate the roles of these genes in islet function and T2D pathogenesis. More broadly, we anticipate the study of this locus will provide new perspectives/insights into the mechanics of insulin secretion and beta cell compensation. The cellular and mouse models that we will create to dissect the regulation and function of the C2CD4A/B locus in diabetes pathogenesis will empower future analyses of novel therapeutic molecules and approaches to target this locus to prevent and treat diabetes.

Public Health Relevance

/ RELEVANCE TO PUBLIC HEALTH Type 2 diabetes (T2D) is a complex disorder influenced by both genetics and lifestyle that places substantial burden on the medical and public health systems. Dysfunction and failure of the pancreatic islets are central to type 2 diabetes. In this project, we will investigate how the C2CD4A/B locus, which we have recently linked to islet dysfunction and T2D susceptibility, is involved in regulating the pancreatic islets?knowledge that will open up new avenues for diabetes treatments.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Sato, Sheryl M
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Jackson Laboratory
Bar Harbor
United States
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