Metformin promotes lipid droplet-mitochondria coupling and improves insulin secretion in pancreatic β-cells exposed to lipotoxicity
Abstract
Lipotoxicity that is caused by excess lipid accumulation is a major factor that contributes to gradual impairments of β-cell function and the development of type 2 diabetes. Metformin has shown protective effects against lipid-induced damage in β-cells, but its specific mechanisms of action within pancreatic islets remain unclear. The present study comprehensively examined direct effects of metformin on lipid metabolism pathways in INS-1E β-cells that were exposed to lipotoxic stress. Our results showed that metformin reduced both the number and size of lipid droplets in palmitate-treated INS-1E cells. This was followed by an increase in fatty acid utilization and the enhanced association between mitochondria and lipid droplets. Under conditions of palmitate overexposure, metformin limited the activity of adipose triglyceride lipase and lipogenic regulators, such as stearoyl-CoA desaturase, and suppressed fatty acid uptake into cells. Additionally, metformin alleviated triglyceride and free fatty acid accumulation and partially reversed palmitate-induced impairments in insulin secretion in INS-1E cells that were subjected to lipotoxicity. Notably, this beneficial effect of metformin on insulin secretion in INS-1E cells exposed to lipotoxic stress was less pronounced when the balance between mitochondrial fusion and fission was disturbed. These findings provide additional mechanistic insights into pleiotropic effects of metformin and its role in regulating β-cell function.
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