Journal
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 81
Volume 81, Issue -, Pages 767-793Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-biochem-072909-095555
Keywords
unfolded protein response; ER stress; free fatty acid; glucose; pancreatic beta-cell
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Funding
- NHLBI NIH HHS [HL057346, P01 HL057346, HL052173, R01 HL052173] Funding Source: Medline
- NIAID NIH HHS [R01 AI042394] Funding Source: Medline
- NIDDK NIH HHS [R01 DK042394, R37 DK042394, DK88227, R01 DK088227, DK042394, R24 DK093074, DK093074] Funding Source: Medline
- National Research Foundation of Korea [과06B1212] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Given the functional importance of the endoplasmic reticulum (ER), an organelle that performs folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, the maintenance of ER homeostasis in insulin-secreting beta-cells is very important. When ER homeostasis is disrupted, the ER generates adaptive signaling pathways, called the unfolded protein response (UPR), to maintain homeostasis of this organelle. However, if homeostasis fails to be restored, the ER initiates death signaling pathways. New observations suggest that both chronic hyperglycemia and hyperlipidemia, known as important causative factors of type 2 diabetes (T2D), disrupt ER homeostasis to induce unresolvable UPR activation and beta-cell death. This review examines how the UPR pathways, induced by high glucose and free fatty acids (FFAs), interact to disrupt ER function and cause beta-cell dysfunction and death.
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