# Role of the Androgen Receptor in Insulin Secretion in the Male

> **NIH VA I01** · SOUTHEAST LOUISIANA VETERANS HEALTH CARE · 2024 · —

## Abstract

The goal of this renewal application is to further elucidate the mechanisms by which testosterone action on the
androgen receptor (AR) in male insulin-producing pancreatic β-cells enhances insulin secretion by amplifying
glucagon-like peptide-1 (GLP-1) actions. The role of testosterone deficiency as a cause of pancreatic β–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 β-cell
function is still poorly understood. Funded by this Merit Award I01BX003725, the new and recently published
far-reaching preliminary data from our laboratory investigating the role of the AR in β-cell function provides the
following information: 1) male mice with conditional deletion of the AR in β-cells (βARKO) exhibit decreased
glucose-stimulated insulin secretion (GSIS) and develop β-cell failure to produce enough insulin, leading to
T2D; 2) the insulinotropic function of AR is recapitulated in islets from male human donors that have the
enzymatic machinery to convert circulating testosterone to the potent AR agonist dihydrotestosterone (DHT);
3) DHT activates an extranuclear AR in mouse and human β-cells that enhances GSIS by amplifying the
actions of glucagon-like peptide-1 (GLP-1) on the GLP-1 receptor, increasing cAMP production at the plasma
membrane and endosomes; 4) DHT selectively enhances GLP-1-mediated cAMP production and GSIS but not
that of glucose-insulinotropic polypeptide (GIP) or glucagon (GCN); 5) DHT amplification of GSIS from islets
requires the tyrosine kinase SRC, the mammalian target of rapamycin complex 2 (mTORC2), and the activities
of transmembrane (tmAC) and soluble (sAC) adenylate cyclases. Based on this extensive preliminary data and
the scientific rigor of previous research presented in the application, our overarching hypothesis is that in male
β-cells, DHT action on AR in the vicinity of the plasma membrane binds SRC and phosphoinositide 3-kinase
(PI3K), thus recruiting mTORC2 and increasing the activities of tmAC and sAC at the plasma membrane and
endosomes. This enhances GLP-1 receptor (GLP-1R) production of cAMP and GSIS. DHT-activated AR is
selectively biased toward the GLP-1R, because AR and GLP-1R uniquely converge on mTORC2 signaling to
activate tmAC and sAC to produce cAMP in similar microdomains. The proposed work uses genetic,
physiological and pharmacological tools in genetically modified mice, as well as in human islets and β-cells.
This work is particularly relevant against to the aging and androgen-deficient male Veterans and the T2D
epidemic, because the AR is a well-characterized drug target. The goal of the work proposed in this application
is to 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. Accordingly,
the specific ...

## Key facts

- **NIH application ID:** 10867257
- **Project number:** 5I01BX005812-02
- **Recipient organization:** SOUTHEAST LOUISIANA VETERANS HEALTH CARE
- **Principal Investigator:** Franck Mauvais-Jarvis
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867257

## Citation

> US National Institutes of Health, RePORTER application 10867257, Role of the Androgen Receptor in Insulin Secretion in the Male (5I01BX005812-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10867257. Licensed CC0.

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