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 ??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 ?-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 ?-cells (?ARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS) and develop ?-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 ?-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 ?-cells and 2) To elucidate the molecular determinants that maintain AR in an extranuclear compartment of ?-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.

Public Health Relevance

The research proposed in this grant will have a significant impact because when successfully completed it will fill key gaps in our understanding of the basic mechanism of insulin deficiency and type 2 diabetes in a large segment of the aging and androgen-deficient male population of the Veterans Healthcare system. This information will provide the foundation for development of approaches to modulate the androgen receptor (AR) to prevent diabetes without prostate or cardiovascular side effects. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX003725-01A1
Application #
9349732
Study Section
Endocriniology A (ENDA)
Project Start
2017-10-01
Project End
2021-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Southeast Louisiana Veterans Health Care
Department
Type
DUNS #
828108790
City
New Orleans
State
LA
Country
United States
Zip Code
70161
Morford, Jamie J; Wu, Sheng; Mauvais-Jarvis, Franck (2018) The impact of androgen actions in neurons on metabolic health and disease. Mol Cell Endocrinol 465:92-102
Li, Jianzhuo; Fu, Xueqi; Cao, Subing et al. (2018) Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27). J Biol Chem 293:12719-12729
Zhou, Zhenqi; Ribas, Vicent; Rajbhandari, Prashant et al. (2018) Estrogen receptor ? protects pancreatic ?-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. J Biol Chem 293:4735-4751
Xu, Beibei; Allard, Camille; Alvarez-Mercado, Ana I et al. (2018) Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes. Cell Rep 24:181-196
Gautier, Jean-Fran├žois; Fetita, Lila Sabrina; Riveline, Jean-Pierre et al. (2018) Sex Difference In the Effect of Fetal Exposure to Maternal Diabetes on Insulin Secretion. J Endocr Soc 2:391-397
Mauvais-Jarvis, Franck (2018) Gender differences in glucose homeostasis and diabetes. Physiol Behav 187:20-23
Mauvais-Jarvis, Franck (2017) New Insights Into Estrogens Inactivation and Prevention of Systemic Inflammation in Male Subjects. Endocrinology 158:3711-3712