# Using a Rare Disease Model to Explore the Role of FGF21 in Insulin Resistance

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2024 · $160,804

## Abstract

Project Summary/Abstract
 Insulin-mediated pseudoacromegaly (IMPA) is a rare insulin resistance syndrome that is distinct from other
insulin resistance syndromes, as it leads to overgrowth and tall stature. Despite the handful of reported cases in
the literature, there is no molecular or genetic explanation for this disease. Exome sequencing on an adolescent
female with IMPA and her sibling and parents revealed that she carries two rare, potentially deleterious, variants
in Fibroblast Growth Factor Receptor 1 (FGFR1) and 𝛽𝛽-Klotho (KLB), which form the receptor complex for
Fibroblast Growth Factor 21 (FGF21). We hypothesize that these mutations explain the extreme insulin
resistance, tall stature, and lipodystrophy-like phenotype seen in IMPA. To test the function of these FGFR1 and
KLB variants in vivo, we used CRISPR/Cas9 genome editing to create a transgenic knock-in mouse line with
these variants and corrected the FGFR1 and KLB mutations in an induced pluripotent stem cell (iPSC) line
isolated from our proband with IMPA. In this study, we are proposing the following specific aims. In Aim 1, we
will determine whether the metabolic and physical phenotype of IMPA mice (with mutations in Fgfr1/Klb) is a
consequence of impaired FGF21 signaling. In Aim 2, we will determine if the insulin resistance seen in IMPA is
due to impaired adipocyte function. In Aim 3, we will determine the mechanism of fatty liver disease in IMPA
mutant mice.
 In addition to forming a functional genetic approach toward defining a novel insulin resistance syndrome, this
four-year proposal outlines a comprehensive strategy for the principal investigator's career development in
academic pediatric endocrinology. This strategy logically builds on the principal investigator's previous research
experience and clinical training. After obtaining his MD, the principal investigator completed his residency training
in general pediatrics, and fellowship in pediatric endocrinology. This proposal now focuses on expanding his
scientific skills by attaining additional knowledge and practical research experience in studying a transgenic
mouse model of a rare human insulin resistance syndrome. The career development goals will be achieved
through a multi-faceted approach involving mentoring by Dr. David Ornitz (fibroblast growth factors and
transgenic mouse models) and Dr. Fumihiko Urano (metabolic testing in mice), hands-on laboratory experience,
scientific investigation, and training in genetics/genomics, biostatistics, scientific communication, and research
ethics. This work will take place in a unique training environment comprised of complementary experiences at
Washington University and St. Louis Children's Hospital. Successful completion of this career development
award will result in the principal investigator's transition to an independent physician-scientist. Additionally, this
work will contribute to a better understanding of the role that FGF21 plays in human insulin resistance, w...

## Key facts

- **NIH application ID:** 10754536
- **Project number:** 5K08DK124574-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Stephen Isaac Stone
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $160,804
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754536

## Citation

> US National Institutes of Health, RePORTER application 10754536, Using a Rare Disease Model to Explore the Role of FGF21 in Insulin Resistance (5K08DK124574-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10754536. Licensed CC0.

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