# Development of an innovative diabetes therapeutic via GPER targeting

> **NIH NIH R41** · GPER G-1 DEVELOPMENT GROUP LLC · 2020 · $299,952

## Abstract

PROJECT SUMMARY
Diabetes mellitus is a group of metabolic disorders characterized by high blood sugar, which is caused by
deficiencies in insulin secretion and/or insulin action. Chronic diabetes can result in complications such as
heart and peripheral vascular disease, kidney failure, limb amputation, and blindness and can even contribute
to carcinogenesis. Diabetes represents a significant health and economic concern in the US: Nearly half of
the US population is either diabetic or pre-diabetic, and the estimated economic burden of diabetes in the
US in 2017 was over $300 billion, including $237 billion in direct medical costs and $90 billion in lost
productivity. Most patients with diabetes have Type 2 diabetes (T2D), which typically begins with insulin
resistance. Estrogen (E2) is known to protect against the development of diabetes, but is not a preferred
treatment, especially in men and in post-menopausal women. The actions of E2 are widely assumed to occur
through the classical nuclear estrogen receptors (ERs). However, recent studies have implicated the
involvement of a novel G protein-coupled estrogen receptor (GPER), distinct from the classical ERs. GPER
and its selective agonist G-1 mediate only a subset of the actions of E2 in vitro and in vivo, and in particular
do not activate classical ER/ERE-mediated transcriptional activity (largely responsible for the feminizing
effects of E2). Thus, GPER-selective activation via G-1 represents an innovative approach to the treatment
of T2D, particularly in post-menopausal women as well as in men. In addition to stimulating insulin secretion,
GPER activation limits β-cell apoptosis and may reduce or even reverse insulin resistance in peripheral
tissues. G-1 therefore has the potential to act as a multi-pronged approach to the treatment of T2D. GPER
G-1 Development Group intends to develop the GPER agonist G-1 as a novel diabetes treatment based on
the documented beneficial effects of E2 on disease progression and severity. In this Phase I STTR project,
racemic G-1 will be resolved into its enantiomers and the active enantiomer determined in vivo (Aim 1). Next,
for the active enantiomer, the in vitro toxicity will be assessed via AMES mutagenicity and hERG assays,
and the in vivo toxicity and pharmacokinetics of G-1 will be examined using acute dose-escalation and repeat
dose-range finding toxicology studies in male and female Sprague Dawley rats (Aim 2). This Phase I work
will lay the foundation for more extensive, IND-enabling studies in Phase II.

## Key facts

- **NIH application ID:** 10008343
- **Project number:** 1R41DK122856-01A1
- **Recipient organization:** GPER G-1 DEVELOPMENT GROUP LLC
- **Principal Investigator:** John Elling
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $299,952
- **Award type:** 1
- **Project period:** 2020-07-10 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10008343

## Citation

> US National Institutes of Health, RePORTER application 10008343, Development of an innovative diabetes therapeutic via GPER targeting (1R41DK122856-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10008343. Licensed CC0.

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