Fatty Acid and Lipopolysaccharide Effect on Beta Cells Proteostasis and its Impact on Insulin Secretion.

Metabolic overload by saturated fatty acids (SFA), which comprises ß-cell function, and impaired glucose-stimulated insulin secretion are frequently observed in patients suffering from obesity and type 2 diabetes mellitus. The increase of intracellular Ca2+ triggers insulin granule release, therefore several mechanisms regulate Ca2+ efflux within the ß-cells, among others, the plasma membrane Ca2+-ATPase (PMCA). In this work, we describe that lipotoxicity mediated mainly by the saturated palmitic acid (PA) (16C) is associated with loss of protein homeostasis (proteostasis) and potentially cell viability, a phenomenon that was induced to a lesser extent by stearic (18C), myristic (14C) and lauric (12C) acids. PA was localized on endoplasmic reticulum, activating arms of the unfolded protein response (UPR), as also promoted by lipopolysaccharides (LPS)-endotoxins. In particular, our findings demonstrate an alteration in PMCA1/4 expression caused by PA and LPS which trigger the UPR, affecting not only insulin release and contributing to ß-cell mass reduction, but also increasing reactive nitrogen species. Nonetheless, stearic acid (SA) did not show these effects. Remarkably, the proteolytic degradation of PMCA1/4 prompted by PA and LPS was avoided by the action of monounsaturated fatty acids such as oleic and palmitoleic acid. Oleic acid recovered cell viability after treatment with PA/LPS and, more interestingly, relieved endoplasmic reticulum (ER) stress. While palmitoleic acid improved the insulin release, this fatty acid seems to have more relevant effects upon the expression of regulatory pumps of intracellular Ca2+. Therefore, chain length and unsaturation of fatty acids are determinant cues in proteostasis of ß-cells and, consequently, on the regulation of calcium and insulin secretion.

Effects of Dietary Fatty Acids in Pancreatic Beta Cell Metabolism, Implications in Homeostasis.

Fatty acids are involved in several metabolic processes, including the development of metabolic and cardiovascular diseases. In recent years a disease that has received escalated interest is type 2 diabetes (T2D). Many contributing factors including a high-caloric diet rich in dietary saturated fats have been broadly characterized as triggers of T2D. Insulin resistance resulting from a high saturated fat diet leads to alterations in lipid cellular intake and accumulation which generate lipotoxic conditions, a key phenomenon in the metabolism of ß-cells. Alternatively, unsaturated fatty acids have been described to show opposite effects in pancreatic ß-cells. The purpose of this work is to perform a critical analysis of the complex role of saturated and unsaturated fatty acids in ß-cell metabolism. We discuss the diverse effects main dietary fatty acids have upon pancreatic ß-cell metabolism as a key factor to maintain homeostasis by focusing in the cellular and molecular mechanisms involved in the development and progression of T2D. For instance, modifications in protein homeostasis as well as the intracellular management of lipid metabolism which are associated with inflammatory pathways. These conditions initiate critical metabolic rearrangements, that in turn have repercussions on insulin ß-cell metabolism. This review allows an integral and broad understanding of different functions of fatty acids inside ß-cells, being important metabolites for novel therapeutic targets in T2D treatment.