# A Novel Neural Mechanism that Mediates the Therapeutic Effects of Metformin

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $419,719

## Abstract

Metformin is the most prescribed first-line anti-diabetic drug. It has been widely accepted that metformin
lowers blood glucose primarily by reducing glucose output in the liver, and to a lesser extent by increasing
peripheral glucose uptake. However, exactly how metformin can do so remains controversial and debated.
The brain has (re)emerged as an important regulator of whole-body glucose metabolism. The central nervous
system (CNS) is known to regulate glucose output and glucose uptake in the peripheral tissues, thereby
changing whole-body glucose balance. We previously found that the small GTPase Rap1 in the brain or in the
hypothalamus strongly influences glucose balance without affecting energy balance. Remarkably, we
have further revealed that forebrain-specific Rap1 deficient mice are selectively resistant to metformin's
glucose-lowering action, but retain sensitivity to other classes of anti-diabetic drugs. This preliminary
discovery suggests a previously completely unrecognized CNS process potentially accounting for the anti-
diabetic mechanism of metformin. To elucidate the neural mechanisms by which metformin lowers blood
glucose, we will test the hypothesis that metformin acts centrally to lower hyperglycemia via inhibition of Rap1
in the ventromedial hypothalamic nucleus (VMH), a well-established site for glycemic control. This hypothesis
is formulated on the basis of our exciting, solid preliminary data through genetic, anatomical, pharmacological
and electrophysiology studies, which are for the first time presented here. The following three Specific Aims
will be addressed to test our hypothesis: 1) using state-of-the-art in vivo methodologies such as euglycemic
clamp and stable-isotope tracer techniques, we will investigate exactly how metformin in the brain
regulates systemic glucose metabolism, 2) using in vivo GCaMP and chemogenetic tools, we will
establish the importance of VMH SF1 neurons for the therapeutic action of metformin; and 3)
experiments in Aim 3 will use loss-of-function and gain-of-function studies to conclusively determine the role
of Rap1 in the VMH for metformin's anti-diabetic action. Together, these Aims will uncover an entirely novel
site(s) and molecular mechanism(s) of action of metformin. This proposal will uncover a long-speculated
mechanism explaining how metformin exerts its anti-diabetic actions by establishing a previously unknown
connection between metformin, the brain (VMH) and the small GTPase Rap1. Lastly, the outcomes are thus
likely to open a new area of pathophysiological and therapeutic discovery of type 2 diabetes.

## Key facts

- **NIH application ID:** 10352376
- **Project number:** 5R01DK126655-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Makoto Fukuda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $419,719
- **Award type:** 5
- **Project period:** 2021-02-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352376

## Citation

> US National Institutes of Health, RePORTER application 10352376, A Novel Neural Mechanism that Mediates the Therapeutic Effects of Metformin (5R01DK126655-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10352376. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*