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.

Cytoprotective effect of melatonin against hypoxia/serum deprivation-induced cell death of bone marrow mesenchymal stem cells in vitro

“…And melatonin has been illustrated to have the antioxidant and anti-apoptosis properties in various cell types (Carpentieri et al, 2014;Park et al, 2013;Wang et al,2013). In the present study, we demonstrated that the preadministration of melatonin markedly attenuated Hy/SDinduced MSC early apoptosis/necroptosis supported by changes in cell viability and Annexin V/PI double staining assay, as well as the morphological changes.…”

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…Together, these data suggest that melatonin can have both stimulatory and inhibitory influences on insulin secretion. Notably, in vitro melatonin administration protects beta cells from the deleterious effects of glucose toxicity, improving beta cell survival, and reducing oxidative stress responses in both INS-1 832/13 rodent beta cells and isolated human islets from individuals with type 2 diabetes [115,116]. In vivo, chronic treatment with melatonin (10 mg kg −1 day −1 ) was also able to partially restore beta cell mass in a rat model of streptozotocin (STZ)-induced diabetes [117].…”

Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis

“…Park et al. induced glucotoxicity in rat insulinoma INS‐1 cells to explore the protective mechanisms of melatonin. They observed that melatonin restored cell survival, decreased ROS production, and downregulated pro‐apoptotic protein expression (p38, JNK) and markers of apoptosis including caspase‐3 under high glucose conditions; moreover, the glucotoxic state caused a significantly reduction in the antioxidant defense system, but the addition of melatonin re‐instated this machinery.…”