# Structural Investigation of Amylin Oligomers Associated to Type-2 Diabetes

> **NIH NIH R01** · FLORIDA STATE UNIVERSITY · 2024 · $354,275

## Abstract

The accumulation of particular proteins into long fibrillar aggregates known as amyloids is a common feature of
many devastating aging-related pathologies. In type II diabetes mellitus, the main constituent of these
aggregates is Islet Amyloid Polypeptide (IAPP, also known as amylin). Like many other amyloidogenic
proteins, the aggregation of IAPP has been linked to cellular dysfunction and death. However, the mechanism
by which IAPP aggregates form and how this aggregation is linked to cell death remain mysterious. To help
reduce this gap, we propose to characterize the oligomeric intermediates of human-IAPP formed in solution, in
presence of metals (such as zinc and copper), and in lipid-membrane via three specific aims. 1) In Aim 1, we
propose to characterize the intermediates formed by human-IAPP at atomic resolution by NMR spectroscopy.
The identified oligomeric intermediates will be tested for cell toxicity and the structural models derived from
NMR constraints will be used to evaluate the mechanism and efficiency of amyloid inhibitors. 2) Since a
possible genetic link between zinc regulation and type II diabetes has been discovered, we will characterize
zinc-IAPP adducts by cell toxicity, NMR and other biophysical experiments in Aim 2. Mutants of oxidized and
reduced forms of human-IAPP will be used to probe the metal binding sites, and isothermal titration
experiments will be used to measure the metal binding affinities to different amyloid species. In addition, the
non-fibril forming and non-toxic rat-IAPP and pramlintide (trade name symlin approved by FDA for use by both
type 1 and type 2 diabetic patients) will be used as controls. 3) To gain insight into the lipid-membrane assisted
hIAPP aggregation and the mechanism by which hIAPP disrupts the lipid-membrane, we propose to
characterize the role of lipid membrane by a variety of biophysical techniques (including high-speed atomic
force microscopy), and stabilize hIAPP oligomeric intermediates using lipid-nanodisc technology and solve the
high-resolution structure of oligomers by a combination of solid-state and solution NMR techniques. These
high-resolution structures will aid in the development of drugs to stop beta-cell death.

## Key facts

- **NIH application ID:** 10814774
- **Project number:** 5R01DK132214-04
- **Recipient organization:** FLORIDA STATE UNIVERSITY
- **Principal Investigator:** Ayyalusamy Ramamoorthy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $354,275
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814774

## Citation

> US National Institutes of Health, RePORTER application 10814774, Structural Investigation of Amylin Oligomers Associated to Type-2 Diabetes (5R01DK132214-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10814774. Licensed CC0.

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