# Genetic analysis of a truncated insulin receptor.

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $387,242

## Abstract

PROJECT SUMMARY
The molecular mechanisms that underpin the development of insulin resistance remain poorly defined, yet a
better understanding of this process is critical, given the fact that obesity, metabolic disease and diabetes have
reached epidemic status in the US. We discovered that alternative splicing of the insulin receptor, in worms,
mice and humans, generates truncated isoforms that are able to attenuate insulin signaling, by inhibiting
signaling through the full length receptor. Determination of the physiological significance of these new isoforms
is critical in establishing their role in the pathophysiology of insulin resistance. However, such studies in
mammals are expensive, time consuming and risky. In contrast, the nematode C. elegans provides an
economical system in which to rapidly determine their physiological relevance. To this end, we have started to
characterize the truncated isoform of the insulin receptor in the nematode C. elegans, termed DAF-2B, that is
directly analogous to mammalian truncated receptors, termed IR-C and IR-D.
 Preliminary analysis indicates that daf-2b expression varies across tissues and through development.
Importantly, we find that genetic deletion of the truncated daf-2b isoform confers insulin sensitivity, while over-
expression of a daf-2b cDNA in worms produces phenotypes consistent with attenuated insulin signaling. We
are now focused on determining the mechanism(s) by which daf-2b mediates its effects on insulin sensitivity,
using a combination of novel reporters that inform on daf-2b dynamics, as well as tissue-specific genetic
manipulation of daf-2b. Using a novel reporter strain that permits visualization of differential splicing between
the full length and truncated daf-2 isoforms in vivo, we identified specific splicing factors that alter the
expression of daf-2b. Exploration of the mechanism by which splicing factor activity regulates the expression
of daf-2b will identify novel points of regulation and intervention in this pathway. These discoveries in C.
elegans are now guiding studies of the mammalian truncated IRs, including characterization the mode of action
of IR-C and IR-D, as well as examining the regulatory factors that lead to expression of these truncated
receptors in mammals. Finally, a comprehensive survey of the expression of murine IR-C and IR-D in vivo,
relative to full length insulin receptors, will establish their physiological and pathophysiological regulation.
 We hypothesize that aberrant or mis-regulated expression of truncated IR-C and IR-D isoforms in
mammals could be causally involved in the pathogenesis of insulin resistance, diabetes and other forms of
metabolic disease. In this respect, the identification of genetic targets and regulatory mechanisms that
influence expression of truncated insulin receptor isoforms will expedite the discovery of therapeutic strategies
that target this novel insulin regulatory mechanism.

## Key facts

- **NIH application ID:** 10415470
- **Project number:** 7R01DK108801-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** MATTHEW SIMON GILL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,242
- **Award type:** 7
- **Project period:** 2018-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415470

## Citation

> US National Institutes of Health, RePORTER application 10415470, Genetic analysis of a truncated insulin receptor. (7R01DK108801-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10415470. Licensed CC0.

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