title: Melatonin prevents pancreatic β-cell loss due to glucotoxicity: the relationship between oxidative stress and endoplasmic reticulum stress.
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.
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Park
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Shim
authors.forename: Ann-Yae
authors.initials: AY
authors.lastname: Na
authors.forename: Ki-Cheor
authors.initials: KC
authors.lastname: Bae
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Bae
authors.forename: Seung-Soon
authors.initials: SS
authors.lastname: Im
authors.forename: Ho-Chan
authors.initials: HC
authors.lastname: Cho
authors.forename: Dae-Kyu
authors.initials: DK
authors.lastname: Song
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010179:Pancreas; D051381:Rats; D017207:Rats, Sprague-Dawley; D014363:Tryptamines / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D007328:Insulin; D014363:Tryptamines; C057154:luzindole; D005947:Glucose; D008550:Melatonin
keywords: diabetes; endoplasmic reticulum stress; glucotoxicity; insulin secretion; melatonin; oxidative stress; pancreatic β-cell