Fatty acidity (FA)-activated insulin secretion (FASIS) is definitely reviewed here in contrast to type 2 diabetes etiology, resulting from FA overload, oxidative stress, intermediate hyperinsulinemia, and inflammation, most converging into insulin resistance. diabetic hyperinsulinemia. With overnutrition Mbp and obesity, the FA overload causes impaired GSIS by metabolic dysbalance, paralleled by oxidative and metabolic pressure, endoplasmic reticulum pressure and several pro-apoptotic signaling, all leading to decreased -cell survival. Lipotoxicity is definitely exerted by saturated FAs, whereas -3 polyunsaturated FAs regularly exert antilipotoxic effects. FA-facilitated swelling upon the recruitment of excessive M1 macrophages into islets (over resolving M2 type), amplified by cytokine and chemokine secretion by -cells, leads to an inevitable failure of pancreatic -cells. launch from mitochondria followed by the activation of downstream caspases . Elevated ROSs are mediators of cytokine-induced cell death, since the overexpression of antioxidant enzymes prevented the -cells from cytokine-induced death . Cytokines also induce ER stress by several mechanisms . 3.3. Native Antilipotoxic Factors Finally, phylogenesis has developed factors counteracting lipotoxicity, having a mission to protect pancreatic -cells. Let us briefly describe several of them in the following sub-sections. 3.3.1. Incretins GLP-1 helps prevent -cell death by increasing autophagic flux, which enhances lysosomal function that would be normally impaired by lipotoxic and glutotoxic stimuli. These stimuli lead to the build up of defective lysosomes and cathepsin D launch, which contributes to cell death . The beneficial effects of incretins have been described PF 4708671 elsewhere [13,14]. 3.3.2. Irisin Recently, myokine irisin has been recognized as another pancreatic -cell secretagogue and as a survival factor . Irisin potentiates PF 4708671 GSIS via the PKA pathway. As a pro-survival factor, irisin counteracts the LCFA-induced -cell apoptosis via AKt/Bcl2 signaling, and increases -cell proliferation. 3.3.3. Neutral Ceramidase Neutral ceramidase-degradating ceramides are suppressed by saturated FAs; thus, when there is an excess of saturated FAs, ceramides are accumulated in -cells . This leads to the facilitation of apoptosis that is promoted by saturated FAs. In conclusion, sufficient neutral ceramidase activity is required to defend lipotoxicity. 3.3.4. Other Native Antilipotoxic Factors The ER-localized protein thrombospondin 1 (THBS1) has also been identified as a pro-survival factor upon PF 4708671 lipotoxic stress of -cells. THBS1 has been found to be cytoprotective to rat, mouse, and human PF 4708671 -cells during cytokine- or thapsigargin-induced ER stress. The mechanism involves the expression maintenance of the mesencephalic astrocyte-derived neutrotrophic factor (MANF) in -cells. MANF prevents the pro-apoptotic BH3-only protein BIM from triggering apoptosis . Acknowledgments An excellent technical assistance of Jana Vaicov and Ludmila ?ime?kov is acknowledged. Author Contributions L.P.-H. and M.J. contributed to several chapters; B.H. conducted the experiments, as shown in Figure 1a,b; M.J. handled the references; and P.J. wrote the paper, designed the figures, and plotted them. Funding This research was funded by the Grant Agency of the Czech Republic, grant No. 16-06700S. Conflicts of Interest The authors declare no PF 4708671 conflict of interest..