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, we analyzed 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 was potentiated by high concentrations of glucose in a chain length-dependent manner starting with stearic acid (C18:0), whereas toxicity remained unchanged in the case of the 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, did not affect the potentiating effect of glucose, but FFA desaturation reduced lipotoxicity and played an important role in the formation of lipid droplets. Crucial elements underlying glucolipotoxicity were ER stress induction and cardiolipin peroxidation in the mitochondria. CONCLUSION In the context of nutrition, our 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. This article is protected by copyright. All rights reserved.