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 ? 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 ? cells in two diabetic mouse models caused by ER stress-induced ? 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 ? 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 ? cell function and survival in Akita diabetic mice. The effect of Khellin on ER stress/UPR in ? 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 ? cell function, insulin sensitivity, and overall diabetic and obese conditions in animals by inhibiting ER stress-induced IRE1a hyperactivation, thus establishing the foundation for the clinical development of Khellin as a novel dietary supplement for ER stress-related diseases.
It is estimated that there are over three hundred million of diabetes patients globally. ER stress-associated beta cell dysfunction and death play an important role in the onset and progression of diabetes. The proposed research is directly relevant to public health because our work on chemicals that protect function and survival of insulin-producing pancreatic beta cell and other cell type has the potential to develop them into drugs to treat diabetes and other ER stress-related diseases.