# Lipid Metabolism and Beta-cell Function

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $342,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Qualitative changes in the American diet have been linked to the development of type 2 diabetes mellitus
(T2DM). An essential component in the development of T2DM is impaired β-cell glucose-stimulated insulin
secretion (GSIS). GSIS is augmented by saturated long-chain fatty acids (FA), but is impaired by both dietary
and infused ω-6 polyunsaturated FAs (PUFA). Intracellular metabolism of FA begins with its thioesterification
by acyl-CoA synthetase (ACSL) with coenzyme A (CoA) to produce an acyl-CoA. We hypothesize that ω-6
PUFA impairs GSIS and disrupts glucose homeostasis by reducing β-cell ACSL isoform 4 (ACSL4) expression
and increasing levels of unesterified epoxyeicosatrienoic acids (EETs). This hypothesis is strongly supported
by several observations: i) exposing INS 832/13 insulinoma β-cells to ω-6 PUFAs (arachidonate or linoleate)
not only impairs GSIS, but also reduces ACSL4 mRNA and protein expression; ii) incubating INS 832/13 cells
with unesterified EETs decreases GSIS by 30%; iii) ACSL4 activates EETs to form EET-CoAs, which are
incorporated into glycerolipids, thereby preventing unesterified EETs from accumulating and impairing GSIS;
and iv) mice that are deficient in β-cell-specific ACSL4 are hypoinsulinemic and hyperglycemic. In this
proposal, we will test the specific hypothesis that unesterified EETs impair GSIS and that ACSL4 activity is
essential in preventing the accumulation of unesterified EETs. In Aim 1, we will determine the mechanism by
which unesterified EETs impair GSIS by evaluating how EETs affect steps in the exocytosis of insulin. In Aim
2, we will determine how dietary ω-6 PUFA increase intracellular unesterified EETs by determining how ω-6
PUFAs regulate ACSL4 expression and activity. In Aim 3, we will determine the role of β-cell ACSL4 in
maintaining whole body glucose homeostasis in the setting of different high FA diets. Using mouse pancreatic
islets, β-cell lines, and animal models, this proposal will examine unique and previously unexplored pathways
in the regulation in insulin secretion. The control of insulin exocytosis by EETs is entirely novel, and should
lead to new understanding of insulin insufficiency in T2DM. Additionally, our β-cell-specific ACSL4 knockout
mouse provides a novel model for T2DM that mimics the insulin secretion defect that is present in the human
disorder. The expected outcome of this proposal is a greater knowledge of how dietary FA impact insulin
secretion and whole body glucose homeostasis. By investigating the metabolism of EETs in β-cells, critical
data will be obtained on the insulin secretory pathway and its regulation by different dietary FAs.
Understanding these mechanisms will enable us to develop targeted dietary therapies to prevent and treat
T2DM.

## Key facts

- **NIH application ID:** 9951026
- **Project number:** 5R01DK107481-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Eric Klett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,000
- **Award type:** 5
- **Project period:** 2016-07-04 → 2022-05-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951026

## Citation

> US National Institutes of Health, RePORTER application 9951026, Lipid Metabolism and Beta-cell Function (5R01DK107481-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9951026. Licensed CC0.

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