ER stress attenuation by Aloe-derived polysaccharides in the protection of pancreatic ß-cells from free fatty acid-induced lipotoxicity.

ABSTRACT

Insulin resistance, a pathophysiology of type 2 diabetes, is associated with obesity. Lipotoxicity in obesity leads to the dysfunction and death of pancreatic ß-cells and inadequate insulin production, thereby aggravating type 2 diabetes. The present study was conducted to determine the effect of Aloe vera polysaccharides (APs) as an anti-hyperglycemic agent and their mechanisms of action. Gel polysaccharides from Aloe extracts were separated using ultrafiltration devices with molecular weight-cutoff membranes, and the protective effect of APs on pancreatic ß-cells in response to free fatty acids (FFAs) was determined. Hamster pancreatic ß-cell line HIT-T15 was treated with palmitate and APs to analyze cellular responses. We observed a large number of apoptotic ß-cell death after treatment with high levels of palmitate, but this was efficiently prevented by the addition of APs in a dose-dependent manner. It was found that the anti-apoptotic properties of APs were largely due to the relief of endoplasmic reticulum (ER) stress signaling. APs were effective in interfering with the FFA-induced activation of the PERK and IRE1 pathways as well as ROS generation, thereby protecting pancreatic ß-cells from lipotoxicity. Although variation in the chain length of APs can influence the activity of FFA-mediated ER stress signaling in different ways, polysaccharide mixtures with molecular weights higher than 50 kDa showed greater antiapoptotic and antioxidant activity in ß-cells. After oral administration of APs, markedly lowering fasting blood glucose levels were observed in db/db mice, providing evidence of the potential of APs as an alternative insulin sensitizer. Therefore, it was concluded that APs have a protective effect against type 2 diabetes by modulating obesity-induced ER stress in pancreatic ß-cells.