# Mechanisms and Impact of Islet Vascular Inflammation in Diabetes

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2024 · —

## Abstract

Insufficient release of insulin from the pancreatic islet β cell is a critical defect in type 2 diabetes (T2D).
Pancreatic islets are highly vascularized, and this vasculature is essential for nutrient supply to islet cells,
insulin delivery to peripheral tissues and as a rich source of signals that support β-cell function. In human T2D
and animal models, islet vasculopathy manifests as endothelial inflammation and capillary dilation and
fragmentation. Moreover, induction of these islet vascular abnormalities in vitro is sufficient to impair insulin
release and/or induce β-cell death.
 We have identified human islet amyloid polypeptide (hIAPP) aggregation as a mediator of islet
vasculopathy. hIAPP-derived amyloid deposits accumulate in the extracellular matrix between β cells and islet
capillaries in almost all patients with T2D. We now show that hIAPP aggregation results in islet endothelial cell
cytotoxicity and inflammation, capillary dilation and loss. Using, RNA-Seq we identified Clec14a as a potential
molecular mediator of hIAPP-induced islet endothelial damage. Clec14a is a member of the vascular C-type
lectin family, whose pancreatic expression is restricted to endothelial cells. Clec14a deficiency has been shown
to result in microvascular destabilization, inflammation and cell death in several tissues but has never been
studied in the pancreas. We will now determine if loss of Clec14a exacerbates the islet endothelial response to
hIAPP in vitro and increases susceptibility to hIAPP-induced islet vasculopathy and exacerbates β-cell
dysfunction in vivo.
 Capillary-associated pericytes play a critical role in normal microvascular homeostasis. In several tissues,
including islets, pericytes regulate capillary tone and blood flow. Pericyte coverage is also necessary for
endothelial integrity, pericyte-endothelial interactions prevent endothelial inflammation and vessel leakage.
This interaction, in non-islet tissues, is governed both by paracrine signals and cell-cell contact, of which
Clec14a is just one mediator. Disruption of endothelial-pericyte interactions underlies the vascular instability
and inflammation that drives development of diabetic retinopathy and renal fibrosis. Pericyte detachment/loss
also occurs in T2D islets. However, the mechanisms that govern islet endothelial-pericyte attachment, how
these are disrupted in T2D and the consequent impact on β-cell function have not been studied. This proposal
will address this major knowledge gap. Our preliminary data show that hIAPP aggregation leads to islet
pericyte detachment and degeneration. Our data and others’ show this includes a direct toxic effect of hIAPP
on microvascular pericytes, resulting in loss of key signals that govern endothelial cell-pericyte cross-talk. This
proposal will address the hypothesis that disruption of islet endothelial cell-pericyte interactions,
mediated in part by Clec14a deficiency, underlies hIAPP-induced islet vasculopathy and contributes to
β-cel...

## Key facts

- **NIH application ID:** 10781944
- **Project number:** 5I01BX004063-06
- **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:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10781944

## Citation

> US National Institutes of Health, RePORTER application 10781944, Mechanisms and Impact of Islet Vascular Inflammation in Diabetes (5I01BX004063-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10781944. Licensed CC0.

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