# Combining experiments of man and nature to target human insulin resistance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $442,817

## Abstract

Abstract
Insulin resistance is a major cause of chronic diseases including type 2 diabetes (T2D), heart attacks, strokes
and cancer. Only one class of medications, thiazolidinediones (TZDs), specifically targets insulin resistance
primarily by activating the transcription factor PPARG in adipocytes. While TZDs have proven clinically
effective in preventing T2D, heart attacks and strokes, serious side effects have limited their clinical use. New
therapeutic targets to combat insulin resistance are needed. In theory, the gene expression changes caused
by TZD-treatment could be mined for novel insulin-sensitizing effectors, but TZDs alter the expression of
hundreds of genes. These must be sifted by functional investigation for causal effectors versus merely
correlated or toxic bystanders. Standard laboratory-based functional investigation requires invasive
physiological measurements in model systems that are difficult to scale. Even when a potential insulin
sensitizing effector gene is validated in the lab, credentialing its relevance to human insulin sensitivity
necessitates drug development and human trials, another poorly scalable process that usually results in failure
for lack of efficacy. However, the recent accumulation of genome sequences in large, clinically characterized
populations has revealed that nature has performed countless human trials in the form of millions of naturally
occurring, protein-altering genetic variants scattered throughput almost every gene in the genome. The key to
unlocking both these opportunities: 1) identifying novel candidate genes from TZD treatment and 2) leveraging
nature’s clinical trials for assessing therapeutic potential, are high-throughput functional assays. In this
application, we propose to utilize a newly developed massively parallel adipocyte differentiation/ lipid
accumulation assay in an integrative genomic approach to:
Aim 1: Rapidly sort TZD-altered genes for likelihood of being insulin sensitizing effectors and
Aim 2: Credential already identified and novel candidates for therapeutic potential in humans using data from
100,000 sequenced individuals.
This work will produce a systematic dissection of the therapeutic effect of TZDs to identify novel insulin
sensitivity genes and directly assess the therapeutic potential of modulating function in humans for four of
these genes.

## Key facts

- **NIH application ID:** 10102247
- **Project number:** 5R01DK123422-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Amit Majithia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,817
- **Award type:** 5
- **Project period:** 2020-02-10 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102247

## Citation

> US National Institutes of Health, RePORTER application 10102247, Combining experiments of man and nature to target human insulin resistance (5R01DK123422-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102247. Licensed CC0.

---

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