# Pathogenesis and Impact of Islet Amyloid

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2022 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
 Islet amyloid is a pathological characteristic of type 2 diabetes, contributing to the β-cell loss and secretory
dysfunction that characterize the disease. The unique peptide constituent of these amyloid deposits is the β-
cell secretory product islet amyloid polypeptide (IAPP), which aggregates to form amyloid resulting in β-cell
apoptosis. Human IAPP (hIAPP) aggregation is associated with mitochondrial dysfunction and oxidative stress,
but the mechanism by which formation of islet amyloid results in mitochondrial dysfunction remains unclear.
Cholesterol accumulation in the β-cell is also associated with cellular loss and secretory dysfunction; however,
the mechanism by which cholesterol accumulation is deleterious also remains elusive.
 Steroidogenic Acute Regulatory Protein (StAR) transports cholesterol from the outer to the inner
mitochondrial membrane for subsequent metabolism. In classical steroidogenic tissues, cholesterol
metabolism by cleavage enzymes (CYPs) results in production of glucocorticoids, mineralocorticoids and sex
steroids. In non-classical steroidogenic tissues, StAR is vital to the production of bile acids, glucocorticoids,
neurosteroids and oxysterols that either protect or harm the cell.
 We have established StAR to be present in β-cells and specifically upregulated under conditions of amyloid
formation. This upregulation of StAR in β-cells resulted in increased mitochondrial cholesterol, decreased
mitochondrial function and reduced cell viability. We also found that CYP27A1, which is involved in oxysterol
production, was down regulated with islet amyloid formation, while CYP11A1 and other downstream CYPs
responsible for steroid production were not present in islets. Finally, while expression of StAR is known to be
regulated acutely by the transcription factor CREB (cAMP response element binding protein), we found CREB
activity to be increased chronically along with StAR under amyloid forming conditions.
 Based on our preliminary data, we hypothesize that islet amyloid formation induces StAR expression in a
CREB-dependent manner, resulting in increased transport of cholesterol into mitochondria that in turn leads to
mitochondrial dysfunction, β-cell dysfunction and β-cell loss.
 This hypothesis will be addressed in the following three specific aims, each of which is intended to answer
important questions.
Specific Aim 1: To determine the role of StAR in mediating the toxic effects of increased β-cell cholesterol in
vitro. This aim will answer the following questions: a) Does StAR knockdown under conditions of cholesterol
loading protect hIAPP islets from amyloid-induced toxicity? b) Does StAR overexpression impair mitochondrial
function and result in β-cell dysfunction and loss? c) Can overexpression of CYP27A1 protect islets from the
detrimental effects of StAR on mitochondrial function under amyloid-forming conditions?
Specific Aim 2: To determine whether long-term reduction of StAR expression ...

## Key facts

- **NIH application ID:** 10356070
- **Project number:** 5I01BX001060-10
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Steven Emanuel Kahn
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356070

## Citation

> US National Institutes of Health, RePORTER application 10356070, Pathogenesis and Impact of Islet Amyloid (5I01BX001060-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10356070. Licensed CC0.

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