# Microbiome origins and insulin regulatory responses of the short chain fatty acid acetate

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $607,517

## Abstract

Project Summary
Obesity, which affects one in three Americans, is a major risk factor for hyperlipidemia, hypertension, insulin
resistance, type 2 diabetes (T2D), cardiovascular disease, and certain types of cancer. Recent studies have
suggested that alterations in the gut microbiota may be a major contributor to this increased prevalence of
obesity, however the mechanism by which this occurs is unknown.
The Overarching Hypothesis guiding the aims of this grant, based on our recent studies, is that a high-fat diet
(HFD) increases net production of acetate by the gut microbiota, leading to activation of the parasympathetic
nervous system, which in turn promotes increased glucose-stimulated insulin secretion (GSIS), increased
ghrelin secretion, hyperphagia, obesity and its related sequelae of hypertriglyceridemia, non-alcoholic fatty liver
disease (NAFLD) and insulin resistance. These findings open the door to new therapeutic interventions, but the
current lack of understanding of the underlying mechanisms, risk factors, and effect of existing T2D drugs is a
significant roadblock.
In this proposal, we present a plan to first determine how HFD increases net acetate production by the
microbiota. Second, we will assess whether human gut microbiomes, which vary broadly between individuals,
are differentially susceptible or resistant to HFD-induced acetate production. Finally, we will determine whether
changes in the microbiota with metformin therapy may contribute to its efficacy for the control of hyperglycemia
in T2DM patients. Specifically, we will test the hypothesis that metformin causes changes in the intestinal
microbiome that contribute to reduced postprandial hyperglycemia via altered acetate production.

## Key facts

- **NIH application ID:** 9891053
- **Project number:** 5R01DK114793-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** GARY W CLINE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $607,517
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891053

## Citation

> US National Institutes of Health, RePORTER application 9891053, Microbiome origins and insulin regulatory responses of the short chain fatty acid acetate (5R01DK114793-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891053. Licensed CC0.

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