Melatonin protects INS-1 pancreatic β-cells from apoptosis and senescence induced by glucotoxicity and glucolipotoxicity

Abstract

Introduction: Melatonin is a hormone known as having very strong anti-oxidant property. Senescence is a biological state characterized by the loss of cell replication and the changes consisting of a pro-inflammatory phenotype, leading to Senescence Associated Secretory Phenotype (SASP) which is now regarded as one of the fundamental processes of many degenerative diseases. Increased cell division count induces cell senescence via DNA damage in response to elevated Reactive Oxygen Species (ROS). We wanted to test whether melatonin could reduce apoptosis and stress induced premature pancreatic β-cell senescence induced by glucotoxicity and glucolipotoxicity. Materials and method: Cultured rodent pancreatic β-cell line (INS-1 cell) was used. Glucotoxicity (HG: hyperglycemia) and glucolipotoxicity (HGP: hyperglycemia with palmitate) were induced by hyperglycemia and the addition of palmitate. The degrees of the senescence were measured by SAβ-Gal and P16 lnk4A staining along with the changes of cell viabilities, cell cycle-related protein and gene expressions, endogenous anti-oxidant defense enzymes, and Glucose Stimulated Insulin Secretion (GSIS), before and after melatonin treatment. Results: Cultured INS-1 cells in HG and HGP conditions revealed accelerated senescence, increased apoptosis, cell cycle arrest, compromised endogenous anti-oxidant defense, and impaired glucosestimulated insulin secretion. Melatonin decreased apoptosis and expressions of proteins related to senescence, increase the endogenous anti-oxidant defense, and improved glucose-stimulated insulin secretion. Conclusion:Melatonin protected pancreatic β-cell from apoptosis, decreased expressions of the markers related to the accelerated senescence, and improved the biological deteriorations induced by glucotoxicity and glucolipotoxicity.

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

“…This paradox may be resolved if we assume that the inhibition of insulin secretion by β-cells may preserve these cells from becoming exhausted under continuous stimulation by high glucose and may also reduce insulin resistance. This is consistent with the fact that melatonin treatment prevents β-cell damage induced by chemicals and glucotoxicity under in vivo and in vitro conditions [ 211 , 212 , 213 ]. Clinical studies also show that the serum melatonin levels are inversely correlated to insulin resistance [ 214 ].…”

CD36 regulates β cell differentiation and influences type 2 diabetic sepsis

“…CD36 could manage T2DM by negatively regulating insulin secretion [53]. CD36 participates in multiple homeostatic and pathological processes.…”

Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites

“…Pancreatic β-cells incubated in HG medium undergo premature senescence which is associated with reduced expression of antioxidant enzymes and increased ROS [ 78 ]. HG-treated cells exhibit impaired insulin secretion.…”

“…HG-treated cells exhibit impaired insulin secretion. Melatonin attenuates HG-induced senescence and improves insulin secretory activity by restoring expression of antioxidant enzymes and suppressing ROS generation [ 78 ]. Melatonin was reported to protect MSC from oxidant-stress-induced senescence by scavenging ROS generation [ 79 ].…”

“…Melatonin is also effective in antagonizing the action of a uremic toxin, p-cresol, on MSC senescence [ 80 ]. Melatonin blocks HG- and oxidant-induced senescence in diverse cell types by scavenging ROS generation through upregulation of MnSOD and catalase activities [ 78 , 80 ] in a manner analogous to 5-MTP.…”