# The role of hyaluronan in hIAPP-induced beta cell toxicity

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2021 · —

## Abstract

The pathophysiology of type 2 diabetes (T2D) requires islet β-cell dysfunction in the presence of insulin
resistance. Islet amyloid is a pathological feature which occurs in the vast majority of individuals with type 2
diabetes (T2D) and contributes to the β-cell dysfunction and loss that characterizes the disease. Islet amyloid
arises due to aggregation of the β-cell peptide islet amyloid polypeptide (IAPP), which is deposited in the islet
extracellular matrix (ECM), between β cells and endothelial cells; the latter being the major cell type of the islet
capillary network. Despite decades of work in the field of islet amyloid, no studies have examined whether (i)
islet amyloid is toxic to islet endothelial cells or (ii) whether islet endothelial cells contribute to the toxic effects
of islet amyloid. Our preliminary data suggest that both occur, and that the ECM molecule hyaluronan (HA)
produced by the islet endothelial cell is a major mediator of amyloid-induced toxicity.
 Specifically, we have found that islet amyloid deposition in vivo is detrimental to islet endothelial cells, while
treatment of isolated primary islet endothelial cells in vitro with amyloidogenic human IAPP (hIAPP) peptide is
cytotoxic and results in HA production. Our preliminary data also show that HA enhances hIAPP fibril formation
in vitro, which is in line with our observation that HA deposition is also present in in vivo amyloid deposits in
islets from hIAPP transgenic mice and human T2D.
 We and others have shown that IAPP aggregation is proinflammatory, activating macrophages, and
resulting in IL-1β production. However, the mechanism by which recruitment and priming of these
macrophages occurs has not been established. Based on the literature, we propose that islet endothelial-
derived HA provides this missing link and mediates macrophage chemotaxis, adhesion and priming.
 Based on these data, we hypothesize that hIAPP aggregation induces HA production from islet
endothelial cells, which exacerbates hIAPP fibril formation and cytotoxicity, and acts to recruit and
prime macrophages.
 We will address this hypothesis in the following specific aims:
Specific Aim 1: To determine the mechanism by which HA exacerbates hIAPP aggregation, and thereby β-cell
toxicity, in vitro. In this aim, we will determine how HA alters hIAPP peptide conformation, increases hIAPP
fibril formation and whether hIAPP fibrils formed in the presence of HA show increased β-cell cytotoxicity.
Specific Aim 2: To determine whether islet endothelial cell-derived HA is necessary for migration, adhesion and
priming of monocytes/macrophages under conditions of islet amyloid formation. We will determine whether HA
produced by hIAPP-treated islet endothelial cells results in monocyte chemotaxis, macrophage adhesion,
priming of the NLRP3 inflammasome and fragmentation of HA. We will also determine if cytokines produced by
macrophages or endothelial cells in response to hIAPP treatment, are necessary for HA ...

## Key facts

- **NIH application ID:** 10265348
- **Project number:** 5I01BX004063-03
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** REBECCA LUCY HULL-MEICHLE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265348

## Citation

> US National Institutes of Health, RePORTER application 10265348, The role of hyaluronan in hIAPP-induced beta cell toxicity (5I01BX004063-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10265348. Licensed CC0.

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