# Mechanism of Integrative Metabolic Regulation by Iron and Hypoxia

> **NIH VA I01** · W G HEFNER VA MEDICAL CENTER · 2022 · —

## Abstract

PROJECT SUMMARY
 Insulin resistance, excess hepatic glucose production, and impaired insulin secretion are the hallmarks
of type 2 diabetes mellitus (T2DM), and tissue iron levels significantly affect all three. In mice and humans, we
have shown that high iron impairs insulin secretion and down regulates leptin and adiponectin. Our preliminary
data show further that these effects of iron are fuel-dependent, with much of this difference based on higher
iron levels supporting higher levels of fat oxidation. Our mechanistic work on these effects of iron has revealed
the involvement of numerous pathways, including transcriptional regulation (notably by CREB, FoxO1, and
PGC1α) and nutrient/metabolite signaling (AMPK, sirtuins, and mTOR). Thus, the effects of iron are complex,
pleiotropic, and cannot be explained by invoking a single linear signal transduction pathway.
 Recently our work on the mechanism by which iron regulates leptin secretion has revealed a unifying
concept for these pleiotropic effects: High tissue iron down-regulates a central integrator of nutrient and redox
status, the O-linked N-acetyl glucosamine (O-GlcNAc) pathway. This pathway results in the O-GlcNAc
modification of most transcription factors and numerous enzymes that regulate metabolism. Activation of the
pathway is often a direct readout of cellular nutrient fluxes, and we have shown it to be sufficient to induce
changes in insulin sensitivity, insulin secretion, and hepatic glucose metabolism in ways that recapitulate
T2DM. A second pathway that responds to both nutrient and oxidative stresses is the hypoxia-sensing
pathway. Like the O-GlcNAc pathway, it functions at both ends of two metabolic spectra—low glucose and low
oxygen as well as high glucose and oxidative stress. The pathways regulate one another and interact in
determining hepatic glucose production, insulin sensitivity, and insulin secretion. Importantly, both the O-
GlcNAc and hypoxia pathways are not only relevant to pathologic iron overload and hypoxia, but regulate
metabolism in normal physiology, across the very broad range of “normal” iron and in individuals at sea level.
 In sum, the O-GlcNAc and hypoxia pathways cooperate to sense the availability or excess of two
essential elements required for oxidative metabolism, iron and oxygen. Based on the above, our published
work, and Preliminary Data, we therefore hypothesize that these two pathways integrate these signals to
regulate several metabolic pathways involved in the pathogenesis of T2DM. Modulation of the O-GlcNAc
pathway by iron affects numerous signal transduction pathways, leading to broad-based changes in
metabolism that globally alter fuel utilization to confer adaptive responses to either a lack or excess of iron. In
parallel, the hypoxia pathway performs a parallel function based on oxygen availability or excess oxidant
stress. Crosstalk between the two pathways can amplify their effects, resulting in integration and a “fine-tuning”
of metabo...

## Key facts

- **NIH application ID:** 10293553
- **Project number:** 5I01BX005109-02
- **Recipient organization:** W G HEFNER VA MEDICAL CENTER
- **Principal Investigator:** DONALD A. MCCLAIN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293553

## Citation

> US National Institutes of Health, RePORTER application 10293553, Mechanism of Integrative Metabolic Regulation by Iron and Hypoxia (5I01BX005109-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10293553. Licensed CC0.

---

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