The goal of this project is to elucidate the basic mechanisms by which gonadal and/or genetic sex program the sex-specific response to the selective estrogen receptor modulator (SERM) bazedoxifene to protect pancreatic islet β cells. Type 2 diabetes (T2D) is a heterogeneous disease affecting the function of pancreatic islet β cells. Evidence has shown that sex affects T2D pathogenesis, including β cell failure. The mechanisms that drive this male predominance in β cell failure are unknown. Sex differences in biology and disease are due to either sex chromosome X Y gene dosage, the developmental epigenetic programming by testicular testosterone in the male and/or the acute and reversible effect of circulating sex hormones after puberty. The study of sex differences in human islet biology and dysfunction represents a unique avenue to fully understanding sex-based pathogenesis of T2D. The associated study of islets from genetic mouse models will also open avenues that can be translated to other tissues. However, sex differences in human islet have yet to be adequately studied and understood. Our overarching hypothesis is that sex differences in islet biology (and in response to drugs) result from a combination of acute sex hormone effects observed only in the in vivo environment and cell autonomous (sex chromosome or developmental testosterone epigenetic programming) effects that are still present in vitro in the absence of hormones. We have based this hypothesis on previous research and the new and recently published far-reaching preliminary data from our laboratory showing that the SERM bazedoxifene acts as an ER agonist to protect β cells in females but not in males, where it behaves as an ER antagonist. We believe that the cell autonomous and sex-specific genetic and molecular architecture of female and male β cells (sex chromosomes) underly these sex-specific effects. The goals of the proposed work are to elucidate the genetic and molecular bases by which bazedoxifene exhibits sex-specific beneficial actions. This paradigm is broadly relevant to the mechanism of sex-specific activation of other ligand-activated steroid receptors. Accordingly, the specific aims of this application are to 1) Determine the molecular bases by which bazedoxifene acts as an ERα agonist selectively in β cells of females but not males combining human islets and genetic mouse models and 2) Determine to what extent bazedoxifene sex-specific actions on ERα are programmed by sex chromosomes combining human islets and genetic mouse models. The proposed work will fill key gaps in our understanding of the fundamental genetic modifiers of sex-specific β cell function and failure. It will also have a lasting scientific impact by opening clinically relevant avenues for sex-based precision medicine.

The role of testosterone deficiency as a cause of pancreatic beta–cell dysfunction predisposing to type 2 diabetes (T2D) in men is poorly studied. While it is established that testosterone action is mediated via the AR, a ligand-activated transcription factor, the role of the AR in beta-cell function is still poorly understood. Our published far-reaching preliminary data demonstrated that testosterone action on the androgen receptor (AR) in male insulin-producing pancreatic beta-cells enhances insulin secretion by amplifying glucagon-like peptide-1 (GLP-1) actions. The goal of this project is to further elucidate the molecular bases by which DHT-activated AR stimulates cAMP production and enhances GLP-1 signaling at the plasma membrane and endosomes to increase insulin secretion in males. This study will fill key gaps in our understanding of the fundamental mechanisms of beta-cell function and will have a lasting scientific impact and open clinically relevant avenues for androgen-deficient male with diabetes.