# Mouse Models of Insulin Resistance

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $490,026

## Abstract

ABSTRACT
Insulin resistance stands as a significant threat to public health worldwide, and a largely unmet medical
need. To unravel the complex biology of this protean syndrome, we endeavored to apply genetic
techniques to probe gene function and tissue interactions related to metabolism, and identify tractable
targets for pharmacological intervention in type 2 diabetes. Over the ten years of the MERIT award,
notable contributions of this grant to our knowledge of the insulin resistance syndrome have included: (i)
mapping the tissue-specific contributions of insulin resistance to the onset and progression of diabetes;
(ii) identification and molecular characterization of distinct cell types in the central nervous system that
mediate different effects of insulin and counterregulatory hormones on plasma glucose levels, satiety,
and energy balance; (iii) discovery and molecular characterization of Gpr17, an orphan receptor that
mediates the anorexigenic effects of insulin in the hypothalamus; (iv) demonstration of the remarkable
property of enteroendocrine cells to undergo conversion into glucose-responsive insulin-producing cells
in experimental animals as well as human organoid cultures. Building on this foundation, the focus of this
renewal application is to understand the divergence of insulin signaling pathways regulating hepatic
glucose and lipid production, while bringing to the fore FoxO-independent mechanisms of transcriptional
regulation by insulin. To that end, the PI presents preliminary data identifying a broad set of hormone-
responsive hepatic transcription factors, and outlines two aims to characterize their contribution to insulin
resistance. Aim 1 will delve into the role of transcription factors FoxK1 and FoxK2 in mediating the
paradoxical admixture of increased glucose production and triglyceride synthesis that characterizes the
diabetic liver. Specifically, experiments will test whether differential phosphorylation at Akt and mTOR
sites on these proteins affects their transcriptional output. Aim 2 will analyze the contribution of the high
mobility group transcription factor TOX4 to gluconeogenesis and de novo triglyceride synthesis. In both
aims, extensive epistasis with existing models of insulin resistance will be employed to answer the
question of whether the newly identified factors are independent of or overlapping with known insulin
signaling modalities. The proposed body of work will advance our understanding of the insulin-resistant
syndrome at the biochemical, genetic, and integrated physiological levels, with the ultimate goal of
translating newly acquired information into innovative approaches to treatment.

## Key facts

- **NIH application ID:** 10207591
- **Project number:** 5R01DK058282-22
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** DOMENICO ACCILI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $490,026
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207591

## Citation

> US National Institutes of Health, RePORTER application 10207591, Mouse Models of Insulin Resistance (5R01DK058282-22). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10207591. Licensed CC0.

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