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-beta H1 beta-cells.Methods and results: beta-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 beta -cell dysfunction and death in the manifestation of T2DM.

Automated summary

Lipotoxicity is a significant factor in the development of type 2 diabetes mellitus (T2DM). This study analyzes the effects of combining carbohydrate and lipid components on the structural properties of fatty acids, with a focus on chain length and saturation degree, in relation to glucolipotoxicity in human EndoC-beta H1 beta-cells.