Pancreatic stone protein/regenerating protein is a potential biomarker for endoplasmic reticulum stress in beta cells

Stephen Stone,Tamara Hershey,Rie Asada,Bess A Marshall,Rolf Graf,Fumihiko Urano,Damien Abreu,Jana Mahadevan,Kelly Kries

doi:10.1038/s41598-019-41604-4

Abstract

Endoplasmic reticulum (ER) stress in beta cells is an important pathogenic component of both type 1 and type 2 diabetes mellitus, as well as genetic forms of diabetes, especially Wolfram syndrome. However, there are currently no convenient ways to assess ER stress in beta cells, raising the need for circulating ER stress markers indicative of beta cell health. Here we show that pancreatic stone protein/regenerating protein (PSP/reg) is a potential biomarker for ER stressed beta cells. PSP/reg levels are elevated in cell culture and mouse models of Wolfram syndrome, a prototype of ER stress-induced diabetes. Moreover, PSP/reg expression is induced by the canonical chemical inducers of ER stress, tunicamycin and thapsigargin. Circulating PSP/reg levels are also increased in some patients with Wolfram syndrome. Our results therefore reveal PSP/reg as a potential biomarker for beta cells under chronic ER stress, as is the case in Wolfram syndrome.

Highlights

Endoplasmic reticulum (ER) stress in beta cells is an important pathogenic component of both type 1 and type 2 diabetes mellitus, as well as genetic forms of diabetes, especially Wolfram syndrome
We hypothesized that beta cells in Wolfram syndrome would activate signaling pathways that could be utilized as clinical biomarkers of beta cell ER stress
ER stress is increasingly recognized as a significant pathologic component of beta cell dysfunction and beta cell death in diabetes[5,6,7,8]

Summary

Introduction

Endoplasmic reticulum (ER) stress in beta cells is an important pathogenic component of both type 1 and type 2 diabetes mellitus, as well as genetic forms of diabetes, especially Wolfram syndrome. PSP/reg levels are elevated in cell culture and mouse models of Wolfram syndrome, a prototype of ER stressinduced diabetes. Our results reveal PSP/reg as a potential biomarker for beta cells under chronic ER stress, as is the case in Wolfram syndrome. ER dysfunction, or ER stress, is directly involved in the beta cell pathogenesis of both type 1 (T1DM) and type 2 diabetes (T2DM)[5,6,7,8,9] In both forms of diabetes, a combination of genetic and metabolic insults to ER homeostasis result in a complex cellular response that drives calcium efflux from the ER and activates the unfolded protein response[4]. Depending on the severity and duration of the stress, these responses by the ER can culminate in beta cell death[4,10,11]

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