# Novel effectors of insulin action in the liver

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $533,354

## Abstract

Project Summary/Abstract:
Type 2 diabetes is an epidemic health problem, but in part due to the incomplete understanding on the
underlying mechanisms, the current treatments or preventive options are limited. A central paradox in the
pathogenesis of type 2 diabetes is the selective mode of hepatic insulin resistance, in which insulin fails to
suppress hepatic gluconeogenesis but continues to stimulate lipogenesis, resulting in hyperglycemia and
hypertriglyceridemia. Although the acute regulation of glucose and lipid metabolism is largely through
changes in metabolite flux and allosteric modulation of key enzyme activities, the chronic regulation of
metabolism requires gene transcription. As a cofactor that links multiple transcription factors to RNA
polymerase II, the Mediator complex has merged as an important regulator of metabolism. The mammalian
Mediator complex is composed of up to 30 subunits. Our central hypothesis is that the Mediator
complex integrates hormonal and/or nutritional signals with metabolic gene expression by
connecting relevant transcription factors to RNA polymerase II through specific binding domains
within particular Mediator subunits.
 This proposal is focused on a novel interaction between the Mediator subunit MED15 and GATA4
transcription factor. In addition to our previous work showing that MED15 stimulates lipogenesis by co-
activating SREBP-1c transcription factor, our preliminary studies support a role of hepatic GATA4/MED15
complex in activating gluconeogenesis and in the development of insulin resistance. Interestingly, although
the molecular mechanisms are unknown, human genetic studies indicate that mutations in Gata4 gene
(likely gain of function) among all reported genetic variations display the strongest correlation with
hypertriglyceridemia. Our hypothesis will be tested in two Specific Aims: Aim 1 will study insulin regulation
of hepatic GATA4 in glucose metabolism, and Aim 2 will study the role of hepatic MED15 coactivating
SREBP-1c and GATA4 in insulin resistance. A combined genetic and gene delivery approaches together
with metabolic, biochemical and molecular analyses will be used to carry out these Aims. All key animal
models, reagents and techniques have been established, and supportive preliminary results have been
obtained. Overall, successful completion of the proposed studies will yield a novel insight into the
mechanisms underlying selective hepatic insulin resistance, and may also aid the development of novel
interventional strategies against type 2 diabetes.

## Key facts

- **NIH application ID:** 10101601
- **Project number:** 5R01DK117417-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Fajun James Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $533,354
- **Award type:** 5
- **Project period:** 2020-01-03 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101601

## Citation

> US National Institutes of Health, RePORTER application 10101601, Novel effectors of insulin action in the liver (5R01DK117417-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10101601. Licensed CC0.

---

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