# Determination of the mechanistic targets of metformin

> **NIH NIH DP1** · UNIVERSITY OF PENNSYLVANIA · 2020 · $810,000

## Abstract

PROJECT SUMMARY
Diabetes affects over 30 million Americans, which represents a staggering 9.4% of the population.
Diabetes causes an elevated blood glucose level. Over time, the presence of high glucose in the body
results in damage to various tissues. Metformin is an FDA drug commonly used as a first line therapy for
the treatment of Type 2 Diabetes. It mainly acts to make tissues more sensitive to insulin, thereby
enhancing the effects of insulin produced by the pancreas to homeostatically lower blood glucose levels.
Importantly, however, Metformin also prolongs lifespan and delays the onset of aging from yeast to
mammals. In higher organisms, it additionally reduces the risk of cardiovascular disease and inhibits
tumor growth. Astoundingly, given its clinical use in humans since 1958, the exact molecular mechanisms
underlying its wide-ranging health benefits are unknown. This Catalyst project is directed towards
elucidating the direct cellular protein targets of Metformin for the first time. Our encouraging preliminary
data shows that we can apply cutting-edge proteomics approaches to such binding events in an unbiased
way. In this project, we wish to extend this extremely promising approach to a diverse range of organisms.
By identifying molecular targets of Metformin in a variety of phylogenetically different model organisms
(yeast, worms, flies, mouse, and humans), we will be able to home in on proteins of crucial importance,
while simultaneously screening out non-specific binders. We will mechanistically test discovered targets
by loss- and gain-of-function experiments using various assays, which will be adapted as the project
advances. After validation of a small number of strong candidate Metformin binding proteins, we will test
these promising candidates in mammals by making transgenic mice harboring deletions in the relevant
genes coding for these proteins. We anticipate that the identification of specific mechanistic Metformin
targets will facilitate the development of novel therapeutics to treat diabetes and promote healthy aging.
Both of these goals are closely aligned with the core missions of NIDDK, and the wider NIH.

## Key facts

- **NIH application ID:** 10064481
- **Project number:** 1DP1DK126167-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Akhilesh Basi Reddy
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $810,000
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064481

## Citation

> US National Institutes of Health, RePORTER application 10064481, Determination of the mechanistic targets of metformin (1DP1DK126167-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10064481. Licensed CC0.

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