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Pathological ER Stress in β Cells

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Endoplasmic Reticulum Stress in Health and Disease

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Abstract

Diabetes mellitus is a global chronic disease, major cause of morbidity and mortality, and significantly decreases both quality of life and life expectancy. The reduction in functional β cell mass due to increased β cell apoptosis and decreased β cell proliferation is a crucial factor in the pathogenesis of diabetes mellitus. Mounting clinical and experimental research findings suggest that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) play fundamental roles in the diminution of functional β cell mass during the prediabetic phase. In this chapter, the physiological purpose of ER stress in the pancreatic β cell is reviewed and the pathological features of chronic ER stress and unwarranted UPR activation in the progression to β cell dysfunction and diabetes progression are described. The molecular pathways activated during the transition from physiological to pathological UPR and proapoptotic signaling in a variety of environmental and genetic diabetic conditions are addressed. In addition, therapeutic approaches to modulate the level of β cell ER stress and mitigate UPR activation are discussed. Finally, we propose that the identification of clinical biomarkers for detection of overt ER stress and UPR activation would herald ER stress and the UPR as viable targets in the prevention of diabetes progression or treatment of established diabetes.

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Abbreviations

ADA:

American Diabetes Association

ATF4/6:

Activating Transcription Factor 4/6

ATP/ADP:

Adenosine Triphosphate/Adenosine Diphosphate

BMI:

Body Mass Index

CHOP:

C/EBP Homologous Protein

CREBH:

cyclic AMP response element-binding protein H

eIF2α:

eukaryotic Initiation Factor-2α

ER:

Endoplasmic Reticulum

FAD:

flavin adenine dinucleotide

FBG:

Fasting Blood Glucose

FFAs:

Free Fatty Acids

GRP78:

Glucose Regulated protein 78

GSK3β:

glycogen synthase kinase 3β

GWAS:

genome-wide association studies

IAPP:

islet amyloid polypeptide

IFN-γ:

interferon-γ

IKK:

inhibitor of κB

IL-1β:

interleukin-1β

IRE1:

Inositol Requiring Enzyme 1

JNK:

c-Jun N-terminal Kinase

K+:

Potassium

MIDYyouth:

mutant INS-gene-induced diabetes of

NF-κB:

Nuclear Factor κ-light-chain enhancer of activated B cells

Nrf2:

Nuclear factor-E2-related factor 2

OGTT:

oral glucose tolerance test

PDI:

Protein Disulphide Isomerase

PERK:

double stranded RNA-activated protein kinase (PKR)–like ER Kinase

PND:

Permanent Neonatal Diabetes

RIDD:

Regulated IRE1 Dependent Decay

ROS:

Reactive Oxygen Species

SERCA:

Sarco/Endoplasmic Reticulum Ca2+ ATPase

TRAF2:

Tumor necrosis factor receptor (TNFR) Associated Factor 2

TUDCA:

tauro-ursodeoxycholic acid

UPR:

Unfolded Protein Response

WFS1:

Wolframin 1

WHO:

World Health Organization

XBP1:

X-box Binding Protein 1

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Acknowledgements

Work in the laboratory of F. Urano is supported by grants from NIH-NIDDK (R01DK067493), the Diabetes and Endocrinology Research Center at the University of Massachusetts Medical School (5 P30 DK32520), and the Juvenile Diabetes Research Foundation International (1-2008-593 and 40-2011-14).

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Authors and Affiliations

  1. Program in Molecular Medicine and Program in Gene Function and Expression, University of Massachusetts Medical School, 01605, Worcester, MA, USA

    Fumihiko Urano & Bryan O’Sullivan-Murphy

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  1. Fumihiko Urano
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  2. Bryan O’Sullivan-Murphy
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Correspondence to Fumihiko Urano .

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  1. Dept Molec Cell Bio, K.U. Leuven, Harestraat/Gasthuisberg, B-3000 Leuven, 3000, Belgium

    Patrizia Agostinis

  2. School of Natural Science, Department of Biochemistry, NUI Galway, University Road, Galway, Ireland

    Samali Afshin

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Urano, F., O’Sullivan-Murphy, B. (2012). Pathological ER Stress in β Cells. In: Agostinis, P., Afshin, S. (eds) Endoplasmic Reticulum Stress in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4351-9_9

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