ESPE Abstracts (2016) 86 S5.1

Wolfram Syndrome, a Prototype of ER Stress-Induced Beta Cell Death

Fumihiko Urano


MO, USA


Background: Endoplasmic reticulum (ER) participates in so many cellular tasks that trouble can ensue when it stops working properly, including β cell death in type 1 and type 2 diabetes mellitus. Despite the underlying importance of ER dysfunction in β cell death during the progression of diabetes, there is no effective treatment targeting the ER due to the complex etiologies of type 1 and type 2 diabetes.

Objective and hypotheses: Our strategy for overcoming this challenge is to focus on genetic forms of diabetes in which mutations in single genes are involved in ER dysfunction and disease manifestations.

Method: Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by juvenile-onset diabetes, optic nerve atrophy, hearing loss, and neurodegeneration. The prevalence is estimated at 1:200,000-1:700,000. Caused by mutations in the WFS1 gene, Wolfram syndrome is considered a prototype of human ER disease. Diabetes mellitus is typically the first manifestation, usually diagnosed around age 6. We have recently shown that ER calcium depletion, followed by subsequent increase in cytoplasmic calcium levels, is a common molecular pathway altered in β cell models of type 1 and type 2 diabetes, as well as Wolfram syndrome.

Results: We have recently shown that ER calcium depletion, followed by subsequent increase in cytoplasmic calcium levels, is a common molecular pathway altered in β cell models of type 1 and type 2 diabetes, as well as Wolfram syndrome.

Conclusion: In this lecture, I will articulate the role of ER stress in β cell dysfunction and death in Wolfram syndrome and its relevance to type 1 and type 2 diabetes, and discuss a therapeutic strategy targeting the ER for diabetes.

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