A Lipotoxic Medium Decreases the Number of Lipid Droplets in β Cells: One Possible Explanation of the β-Cell Failure in Patients With Hyperlipidemia Receiving Tacrolimus.

Abstract

Dyslipidemia is a risk factor for post- transplant diabetes mellitus, especially in patients who are taking tacrolimus. Although lipotoxicity of dyslipidemia leads to β-cell failure, the handling of lipids by β cells is a mystery in molecular endocrinology. Likewise, lipid droplet homeostasis is appreciated as a key component of lipid metabolism in cells like hepatocytes, but its role in β cells remains to be elucidated. To evaluate the morphologic changes in β cells with special focus on lipid droplets, we evaluated electron micrographs under metabolic stress conditions of glucotoxicity, lipotoxicity, and glucolipotoxicity in isolated rat insulinoma INS-1E β cells. Cells were treated with palmitic acid (0.5 mM), glucose (33 mM), or both for 16 hours, after which morphologic changes were observed with an electron microscope. Many lipid droplets were observed in the cytoplasm of healthy β cells in the control group (no treatment). Lipid droplets were also visible in the cytosol, and the cytoplasm was rich in organelles and insulin vesicles under high glucose stimulation. However, after treatment with palmitic acid, almost no lipid droplets were observed. Endocrine vesicles were also depleted, with severe morphologic disruption of other organelles. Under glucolipotoxic conditions, β cells showed a decreased number of lipid droplets and insulin vesicles compared with controls. Lipid droplet dynamics seemed important in the homeostasis of β-cell metabolism. In this preliminary study, healthy β cells appeared rich in lipid droplets under normal conditions. However, lipotoxicity depleted and glucolipotoxicity decreased the number of lipid droplets in β cells. Because dyslipidemia causing lipotoxicity is one of the most frequent metabolic problems in transplant patients and increases risk of posttransplant diabetes mellitus, understanding the mystery of lipid droplets in β cells and the pathophysiology of diabetes in transplant patients is important, especially for those taking tacrolimus.