Potentiation of Lipotoxicity in Human EndoC‐βH1 β‐Cells by Glucose is Dependent on the Structure of Free Fatty Acids

Scope Lipotoxicity is a significant element in the development of type 2 diabetes mellitus (T2DM). Since pro‐diabetic nutritional patterns are associated with hyperglycemia as well as hyperlipidemia, the study analyzes the effects of combining these lipid and carbohydrate components with a special focus on the structural fatty acid properties such as increasing chain length (C16–C20) and degree of saturation with regard to the role of glucolipotoxicity in human EndoC‐βH1 β‐cells. Methods and results β‐cell death induced by saturated FFAs is potentiated by high concentrations of glucose in a chain length‐dependent manner starting with stearic acid (C18:0), whereas toxicity remains unchanged in the case of monounsaturated FFAs. Interference with FFA desaturation by overexpression and inhibition of stearoyl‐CoA‐desaturase, which catalyzes the rate‐limiting step in the conversion of long‐chain saturated into corresponding monounsaturated FFAs, does not affect the potentiating effect of glucose, but FFA desaturation reduces lipotoxicity and plays an important role in the formation of lipid droplets. Crucial elements underlying glucolipotoxicity are ER stress induction and cardiolipin peroxidation in the mitochondria. Conclusion In the context of nutrition, the data emphasize the importance of the lipid component in glucolipotoxicity related to the development of β‐cell dysfunction and death in the manifestation of T2DM. Toxicity of saturated free fatty acids (FFAs) (≥C18) but not of monounsaturated FFAs is potentiated by high glucose concentrations inhuman β‐cells. Crucial elements are enhanced ER‐stress and mitochondrial damage. Interference with FFA desaturation does not affect the potentiation of glucose, but reduces lipotoxicity and influences lipid droplet formation emphasizing the importance of the lipid component in glucolipotoxicity.