# Genetic and molecular architecture of sex-specific drug response in human islets

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2024 · $623,472

## Abstract

The goal of this application 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.

## Key facts

- **NIH application ID:** 10975212
- **Project number:** 2R01DK074970-13
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Franck Mauvais-Jarvis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $623,472
- **Award type:** 2
- **Project period:** 2007-04-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975212

## Citation

> US National Institutes of Health, RePORTER application 10975212, Genetic and molecular architecture of sex-specific drug response in human islets (2R01DK074970-13). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10975212. Licensed CC0.

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