# High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes

> **NIH NIH R01** · ICAGEN-T, INC. · 2020 · $625,517

## Abstract

PROJECT SUMMARY / ABSTRACT
Insulin resistance (IR) in skeletal muscle and other tissues is obligatory for the development of type 2 diabetes.
Excess accumulation of incompletely oxidized non-esterified fatty acids (FAs) in muscle cells, i.e., lipotoxicity,
is increasingly appreciated to underlie the development of IR. In parallel, branched chain amino acids (BCAAs)
have recently moved front and center in the field of diabetes, as unbiased metabolomic profiling in large
prospective epidemiological studies has shown that serum elevations of BCAAs predict IR and diabetes as
much as 20 years prior to clinical presentation. We have now uncovered a novel molecular pathway that links
these two observations. Active catabolism of the BCAA valine in skeletal muscle causes the paracrine
secretion of a metabolite, 3-hydroxyisobutyrate (3-HIB), which promotes entry of FAs into skeletal muscle, and
subsequent lipotoxicity.
The identification of this pathway provides a novel entry point for the potential treatment of insulin resistance,
orthogonal to most current insulin-based or insulin secretogenic therapies. The proposed project responds to
PA-16-374 (Assay Development and Screening to Discover Therapeutic or Imaging Agents for Diseases of
Interest to the NIDDK) and will identify lead-enabling small molecules that target this newly discovered
pathway. Aim 1 use in silico and high-throughput screening to identify molecules that block production of 3HIB.
Identified hits will be taken through a robust workflow of secondary counterscreens. In Aim 2, the molecules
identified in Aim 1 will be tested for efficacy and safety in intact cells. In Aim 3, validated hits from Aims 1 and 2
will first be submitted to in vivo pharmacokinetic and pharmacodynamic studies. Viable candidates will then be
tested for their ability to block lipid accumulation and insulin resistance in 3HIB-treated mice as well as in a pre-
clinical high-fat fed model of insulin resistance.
The proposed work represents a close collaboration between academia and a strong private sector team with
a long history of successes. We propose a novel and provocative hypothesis, and a previously unexplored
approach to understand and target lipotoxicity. Success would yield novel targets and potential lead
compounds for the development of new therapeutics that address the root of insulin resistance.

## Key facts

- **NIH application ID:** 9882262
- **Project number:** 5R01DK119656-02
- **Recipient organization:** ICAGEN-T, INC.
- **Principal Investigator:** Zoltan P Arany
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $625,517
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882262

## Citation

> US National Institutes of Health, RePORTER application 9882262, High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes (5R01DK119656-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9882262. Licensed CC0.

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