# The role of the androgen receptor in insulin secretion

> **NIH VA I01** · SOUTHEAST LOUISIANA VETERANS HEALTH CARE · 2020 · —

## Abstract

In the Veterans Healthcare System, aging men with testosterone deficiency and men on androgen depletion
therapy for prostate cancer are at increased risk of developing type 2 diabetes (T2D). Although studies
examining this issue have focused on the role of testosterone deficiency as a risk factor for insulin
resistance, this approach ignores the role of testosterone deficiency as a potential cause of pancreatic β–cell
dysfunction in men. Although it has been established that testosterone action is mediated via the androgen
receptor (AR) -a ligand-activated transcription factor- the role of the AR in β-cell dysfunction in T2D is
unknown. There is tremendous potential for therapeutic application of novel work that addresses androgen
deficiency in the context of T2D in large segments of aging men. The new far-reaching preliminary data from
our laboratory show that 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 compensate for high fat diet-
induced insulin resistance. The insulinotropic function of the testosterone-AR axis is present in cultured
male human islets. Most importantly, in β-cells, the AR is extranuclear, and the stimulatory effect of AR on
GSIS involves cAMP generation and protein kinase A (PKA) activation. Finally, testosterone amplifies
glucagon-like peptide-1 (GLP-1) enhancement of GSIS in rodent islets. Accordingly, the aims of this
application are: 1) To explore a novel paradigm in which testosterone action on AR enhances GLP-1 action
in β-cells and 2) To elucidate the molecular determinants that maintain AR in an extranuclear compartment
of β-cells that amplify GLP-1 receptor action. The knowledge that will be generated by this grant will fill key
gaps in our understanding of the fundamental mechanism of -cell dysfunction in men. This information will
provide the foundation for development of approaches to modulate AR in a tissue-specific manner to prevent
diabetes without prostate or cardiovascular side effects. Thus, the proposed work will have major scientific
impact and open clinically relevant avenues for the Veterans Healthcare System population.

## Key facts

- **NIH application ID:** 9815440
- **Project number:** 5I01BX003725-03
- **Recipient organization:** SOUTHEAST LOUISIANA VETERANS HEALTH CARE
- **Principal Investigator:** Franck Mauvais-Jarvis
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815440

## Citation

> US National Institutes of Health, RePORTER application 9815440, The role of the androgen receptor in insulin secretion (5I01BX003725-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815440. Licensed CC0.

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