# Targeting Insulin Resistance by Estrogen Receptor in Control of Type 2 Diabetes Mellitus

> **NIH NIH R01** · TEXAS A&M AGRILIFE RESEARCH · 2021 · $357,820

## Abstract

Project Summary
 This proposal “Targeting Insulin Resistance by Estrogen Receptor in Control of Type 2 Diabetes Mellitus”
addresses a fundamental mechanism based on the gender difference in control of type 2 diabetes. The gender
difference exists for the incidence of T2D, with improved insulin sensitivity and survival in females, but the
mechanism is unclear. Sex hormone estrogen and its receptor system have shown benefit to metabolic
function. This proposal will address the molecular and physiological mechanism by which estrogen and insulin
signaling crosstalk at the level of IRS1 and IRS2 proteins and downstream protein kinase Akt and forkhead
transcription factor Foxo1 that controls mitochondrial biogenesis and function through the heme oxygenase 1
(HO1) gene.
 The O-class of the forkhead transcription factor Foxo1 is a key downstream target of the
insulin→PI3K→protein kinase B (Akt) signaling pathway, governing multiple physiological functions. Our
previous studies have demonstrated Foxo1 is a key substrate of Akt downstream from both insulin and
estrogen signaling that controls glucose homeostasis via glucose-6-phosphatase gene expression. Foxo1 also
stimulates expression of heme-oxygenase-1 (HO1) that catalyzes degradation of heme, a key component of
mitochondrial electron transport chains, then reducing mitochondrial biogenesis and function.
 In this proposal, we hypothesize that insulin and 17-beta-estradiol (E2) play important roles in activation of
PI3K-Akt and suppressing Foxo1-HO1 in control of mitochondrial function, while loss of IRS1/2 and estrogen
receptor-alpha (ERα) signaling and resultant HO1 overexpression are fundamental and unifying mechanisms
for mitochondrial dysfunction that promotes meta-inflammation. In Aim 1, we use the liver-specific ER-alpha
gene knockout mice in insulin resistant mice and examine whether ERα gene is required for IRS1, 2 and
associated PI3K-AKT activation and suppression of Foxo1 and HO1 in the liver. In Aim2, we will use protein-
protein interaction assays to map out the key domain of ERα for interaction with IRS1 and IRS2, activating
PI3K-Akt and inhibiting Foxo1-HO1 in cells. We test the hypothesis that either N-terminal ERα without DNA
binding domain (DBD) interacts with IRS1/2, preventing IRS1/2 serine phosphorylation coupled degradation,
suppressing Foxo1 and HO1 in cells. In Aim 3, we will use adenovirus-mediated gene expression of N-terminal
domain ERα in HFD-fed mice to examine whether there is achievable hepatic protection by activation of IRS-
associated PI3K and suppression of Foxo1 and HO1. Moreover, we will target HO1 with nanoparticle-mediated
HO1 inhibitor (Zn2+-protoporphyrin) in the liver of mice lacking IRS1/2 and ERα or high fat-diet (HFD)-induced
insulin resistance. We will examine whether HO1 inhibition sufficiently protects hepatic mitochondrial
dysfunction and inflammation in insulin resistant mice. Therefore, this proposal will provide novel mechanisms
of ERα and HO1 in insul...

## Key facts

- **NIH application ID:** 10169433
- **Project number:** 5R01DK120968-03
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** Shaodong Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,820
- **Award type:** 5
- **Project period:** 2019-09-12 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169433

## Citation

> US National Institutes of Health, RePORTER application 10169433, Targeting Insulin Resistance by Estrogen Receptor in Control of Type 2 Diabetes Mellitus (5R01DK120968-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10169433. Licensed CC0.

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