# In vivo mechanisms of amyloid-induced pancreatic islet dysfunction in type 2 diabetes

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

PROJECT SUMMARY / ABSTRACT
Type 2 diabetes (T2D) affects 20% of veterans and costs the VA almost $1.5 billion annually. In addition to
insulin resistance, the hyperglycemia that defines T2D is caused by insufficient insulin secretion and
dysregulated glucagon secretion from the β and α cells of pancreatic islets. T2D islets are also characterized
by changes in vasculature, increased inflammation, and deposition of insoluble amyloid, composed primarily of
islet amyloid polypeptide (IAPP). Soluble IAPP oligomers, rather than the amyloid itself, are toxic to β cells,
through various postulated mechanisms including ER stress, oxidative stress, membrane permeabilization, and
receptor-mediated signaling. The receptor for advanced glycation endproducts (RAGE), which binds several
extracellular ligands and activates intracellular inflammatory signaling pathways, was recently shown to bind
IAPP oligomers and mediate IAPP oligomer-induced toxicity in β cells using cell and islet culture models and
transgenic mouse models. However, it is unknown if IAPP-RAGE signaling occurs in human islets, if such
signaling occurs in non-β islet cells including α cells, what effect IAPP-RAGE signaling in specific cell types
has on human islet function, and what specific RAGE signaling pathways are activated in human islet cells. I
hypothesize that IAPP oligomer-induced activation of RAGE receptors on β and ⍺ cells modulates
human islet function and health in vitro and in vivo. To test my hypothesis and fill these knowledge gaps, I
will leverage four new experimental techniques to study primary human islet cells: 1) recently developed
pseudoislet methodology that allows efficient cell-specific genetic manipulation of human islets; 2)
transplantation of human pseudoislets into mice to enable longitudinal analysis of structure and function in
vivo; 3) modified intravital imaging techniques to visualize amyloid formation and cell death longitudinally; 4)
single nuclear isolation and sequencing technologies to detect changes in gene expression in transduced
pseudoislets. In Aim 1, I will test the hypothesis that RAGE mediates IAPP oligomer-induced β cell
dysfunction in human islets in vitro and in vivo. In Aim 2, I will test the hypothesis that IAPP-RAGE signaling in
⍺ cells causes dysregulated glucagon secretion in human islets in vitro and in vivo. These experiments will
clarify fundamental processes in T2D pathogenesis and help identify novel targets to treat and prevent T2D. I
will complete these aims as part of an intensive supervised career development plan with oversight and
guidance from an expert multi-disciplinary mentoring committee. I will receive formal and informal training in
five fundamental areas: 1) new and emerging experimental techniques; 2) scientific education; 3) presentation
and communication skills; 4) professional development; and 5) laboratory management. These skills and the
results of my proposed experiments will form a strong foundation for my ind...

## Key facts

- **NIH application ID:** 10828301
- **Project number:** 5IK2BX005910-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Jordan James Wright
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828301

## Citation

> US National Institutes of Health, RePORTER application 10828301, In vivo mechanisms of amyloid-induced pancreatic islet dysfunction in type 2 diabetes (5IK2BX005910-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10828301. Licensed CC0.

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