# Cytoprotection and the mechanism of action of a natural product Khellin against ER stress

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2021 · $145,000

## Abstract

Abstract
 Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of a growing list of human
diseases, including diabetes, obesity, atherosclerosis, and neurodegenerative diseases. In diabetes, ER stress
plays important roles in the pathogenesis of all types of diabetes; it is involved in β cell defects and in the
development of insulin resistance in adipose tissue, liver, and skeletal muscles. Chronic ER stress leads to cell
dysfunction and death through the hyperactivation of the unfolded protein response (UPR), and ER stress/UPR
hyperactivation has therefore been proposed as a therapeutic target for the treatment of ER stress-associated
diseases. However, no drugs on the market have been approved for targeting ER stress/UPR-induced cell
dysfunction and death as their mode of action. In our parent R01 award, we have identified a natural product
Khellin as a molecule of cytoprotection against ER stress in a high throughput screen. Khellin treatment via the
intraperitoneal (i.p.) injection significantly ameliorates hyperglycemia and protects the function and survival of β
cells in two diabetic mouse models caused by ER stress-induced β cell death. Furthermore, Khellin injection
also significantly improved insulin sensitivity and reduced body weight in obese animal model. Importantly, we
discovered that Khellin selectively inhibits the ER stress-induced activation of one of three UPR pathways, the
IRE1a pathway, but with no effect on the other two UPR pathways: PERK and ATF6. These findings revealed
for the first time that the natural product Khellin increases functional β cell mass, improves insulin resistance,
and ameliorates diabetes and obesity by inhibiting ER stress-induced IRE1a hyperactivation. So far, in our
parent R01 award, we have achieved these exciting results in animal models with Khellin treatment via the i.p.
injection. In a pilot study, we have treated the Akita diabetic mice with Khellin added to diet and observed that
similar to the i.p. injection, the oral treatment of Khellin also significantly lowered blood glucose levels in Akita
mice. As a natural extension, in the Dietary Supplements application, we will test the hypothesis that oral
Khellin improves diabetic and obese conditions by inhibiting IRE1a activation. We will test this hypothesis with
two aims. In Aim 1, we will determine the effect of Khellin orally taken from diet on β cell function and survival
in Akita diabetic mice. The effect of Khellin on ER stress/UPR in β cells will be examined. In Aim 2, we will
determine the effect of orally taken Khellin in insulin sensitivity and obesity in diet-induced insulin resistant and
obesity mouse model. The effect of Khellin on ER stress/UPR in adipose tissue, liver, and skeletal muscles will
be examined. Together, this work will reveal that orally taken Khellin improves β cell function, insulin
sensitivity, and overall diabetic and obese conditions in animals by inhibiting ER stress-induced IRE1a
hype...

## Key facts

- **NIH application ID:** 10285537
- **Project number:** 3R01DK116017-03S1
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Weidong Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $145,000
- **Award type:** 3
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285537

## Citation

> US National Institutes of Health, RePORTER application 10285537, Cytoprotection and the mechanism of action of a natural product Khellin against ER stress (3R01DK116017-03S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10285537. Licensed CC0.

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