Melatonin prevents pancreatic β-cell loss due to glucotoxicity: the relationship between oxidative stress and endoplasmic reticulum stress

Authors
Jae-Hyung ParkHye-Min ShimAnn-Yae NaKi-Cheor BaeJae-Hoon BaeSeung-Soon ImHo-Chan ChoDae-Kyu Song
Department
Dept. of Physiology (생리학); Dept. of Orthopedic Surgery (정형외과학); Dept. of Internal Medicine (내과학)
Issue Date
2014
Citation
Journal of Pineal Research, Vol.56(2) : 143-153, 2014
ISSN
0742-3098
Abstract
Prolonged hyperglycemia results in pancreatic β-cell dysfunction and apoptosis, referred to as glucotoxicity. Although both oxidative and endoplasmic reticulum (ER) stresses have been implicated as major causative mechanisms of β-cell glucotoxicity, the reciprocal importance between the two remains to be elucidated. The aim of this study was to evaluate the differential effect of oxidative stress and ER stress on β-cell glucotoxicity, by employing melatonin which has free radical-scavenging and antioxidant properties. As expected, in β-cells exposed to prolonged high glucose levels, cell viability and glucose-stimulated insulin secretion (GSIS) were significantly impaired. Melatonin treatment markedly attenuated cellular apoptosis by scavenging reactive oxygen species via its plasmalemmal receptor-independent increase in antioxidant enzyme activity. However, treatments with antioxidants alone were insufficient to recover the impaired GSIS. Interestingly, 4-phenylbutyric acid (4-PBA), a chemical chaperone that attenuate ER stress by stabilizing protein structure, alleviated the impaired GSIS, but not apoptosis, suggesting that glucotoxicity induces oxidative and ER stress independently. We found that cotreatment of glucotoxic β-cells with melatonin and 4-PBA dramatically improved both their survival and insulin secretion. Taken together, these results suggest that ER stress may be the more critical mechanism for prolonged high-glucose-induced GSIS impairment, whereas oxidative stress appears to be more critical for the impaired β-cell viability. Therefore, combinatorial therapy of melatonin with an ER stress modifier may help recover pancreatic β-cells under glucotoxic conditions in type 2 diabetes.
Keywords
diabetesendoplasmic reticulum stressglucotoxicity, insulin secretionmelatoninoxidative stresspancreatic β-cell
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/33878
Appears in Collections:
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
Keimyung Author(s)
박재형; 배재훈; 임승순; 송대규; 배기철; 조호찬
Full Text
http://lps3.onlinelibrary.wiley.com.proxy.dsmc.or.kr/doi/abs/10.1111/jpi.12106
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