# Role of RAGE in amyloid-induced pancreatic islet dysfunction in diabetes

> **NIH NIH K08** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $159,936

## Abstract

PROJECT SUMMARY / ABSTRACT
In type 2 diabetes (T2D), amyloid deposits composed of islet amyloid polypeptide (IAPP) are found within
pancreatic islets. T2D islets also have impaired insulin secretion from β cells, dysregulated glucagon secretion
from α cells, increased inflammation, and alterations in vasculature. Among multiple potential mechanisms
linking amyloid deposition and islet dysfunction, the receptor for advanced glycation endproducts (RAGE) was
recently shown to bind IAPP oligomers and mediate β cell toxicity in vitro, which results were also supported
using a transgenic rodent model. But in vitro cell culture models, while valuable, do not fully replicate the
complex environmental, intercellular, or temporal changes in living organisms. Furthermore, human and rodent
islets differ in function, structure, cellular composition, and gene expression. Thus, to fully understand the
pathogenesis of human disease, one must study these processes in human cells and tissues in the in
vivo context. Such studies have been limited by the inability to obtain and manipulate these relatively
inaccessible human tissues and by the lack of in vivo models in which to study them longitudinally. It therefore
remains unknown if endogenously secreted IAPP oligomers act on the RAGE receptor in primary human β
cells, if such signaling occurs in α cells, and what effect IAPP-RAGE signaling in specific cell types has on islet
function. I hypothesize that IAPP oligomer-induced activation of RAGE receptors on β and α cells impairs
human islet function and health in vitro and in vivo. To test my hypothesis using human islets, I will employ
four novel techniques and reagents. 1) Our recently reported pseudoislet method will enable efficient genetic
manipulation of specific islet cell types prior to reaggregation into functional cell clusters. 2) New intravital
imaging techniques will allow longitudinal monitoring of amyloid formation in human pseudoislets transplanted
into the mouse anterior chamber of the eye. 3) Transplantation of pseudoislets into a recently developed
glucagon knockout mouse will permit accurate measurement of human glucagon secretion in vivo. 4)
Application of single nuclear RNA sequencing approaches will permit assessment of transcriptional effects on
specific cell types in transplanted 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.
Completion of these aims will elucidate key mechanisms responsible for pathogenesis of T2D, opening
avenues for study into new preventive and therapeutic approaches. I will benefit from the outstanding
environment, collaboration, and mentorship at the Vanderbilt Diabetes Research and Training Center as I
transition to independence as a physician-scientist.

## Key facts

- **NIH application ID:** 10506592
- **Project number:** 1K08DK133691-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jordan James Wright
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $159,936
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10506592

## Citation

> US National Institutes of Health, RePORTER application 10506592, Role of RAGE in amyloid-induced pancreatic islet dysfunction in diabetes (1K08DK133691-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10506592. Licensed CC0.

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