# Structural Insights to Insulin Receptor Ligand Interactions

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $397,075

## Abstract

ABSTRACT
Insulin treatment dramatically improves the health of people with diabetes, and is usually administered as a daily
long-acting insulin and a prandial fast-acting insulin. Despite considerable success, a number of important
challenges remain, including three major limitations that are addressed in this proposal. First, even the best
clinically-available fast-acting insulins are too slow and last too long to provide tight control of serum glucose
within the physiological range, resulting in substantial excursions outside of this range and chronic hyperglycemia
or acute hypoglycemic complications. Second, currently available insulins require continual refrigeration to avoid
aggregation, whereas therapeutic insulins that do not require cold-chain delivery would offer considerable
advantages, especially for use in long-term insulin pumps and in circumstances where electrical power is
unreliable. Third, because insulin stimulates two signals, one therapeutically advantageous for metabolic control
(Akt pathway) and one therapeutically concerning for mitogenic growth (Erk pathway), there is interest in
developing analogs that preferentially stimulate the Akt pathway. This proposal takes a biochemical and
structure-based approach to gain mechanistic insight to each of these concerns, including cryo-EM structure
determination of receptor-ligand complexes complemented by a variety of approaches, including cell signaling
and mouse glucose-responsiveness studies. Aim 1 focusses on two humanized variants of cone snail venom
insulins, which lack residues that make native insulin dimeric and inherently slow acting upon subcutaneous
injection, and have been engineered to provide fast response, short duration of action, and high potency. Aim 2
focusses on approaches to render insulins resistant to aggregation/fibrillation, including following up on the
surprising finding that one of the humanized venom insulins is highly resistant to aggregation. Aim 3 explores
the remarkable property of some receptor ligands to elicit biased signaling that emphasizes either the Akt or the
Erk pathways, and offers potential to understand the structural basis for these effects. Completion of these aims
will provide fundamental mechanistic insights and inform efforts to develop improved therapeutics.

## Key facts

- **NIH application ID:** 10367480
- **Project number:** 1R01DK127268-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** CHRISTOPHER P. HILL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,075
- **Award type:** 1
- **Project period:** 2021-09-25 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367480

## Citation

> US National Institutes of Health, RePORTER application 10367480, Structural Insights to Insulin Receptor Ligand Interactions (1R01DK127268-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10367480. Licensed CC0.

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