IL-33 promotes pancreatic β-cell survival and insulin secretion under diabetogenic conditions through PPARγ

Pancreatic β-cell dysfunction plays a vital role in the development of diabetes. IL-33 exerts anti-diabetic effects via its anti-inflammatory properties and has been demonstrated to increase insulin secretion in animal models. However, IL-33, as a pleiotropic cytokine, may also exert a deleterious effect on β-cells, which has not been rigorously studied. In the present study, we found that IL-33 promoted cell survival and insulin secretion in MIN6 (a mouse pancreatic β-cell line) cells under diabetogenic conditions. IL-33 increased the expression of its receptor ST2 and the transcription factor PPARγ, whereas PPARγ inhibition impaired IL-33-mediated β-cell survival and insulin release. IL-33 did not repress the expression of pro-inflammatory mediators, including Tf , Icam1 , Cxcl10 , and Il1b , whereas it significantly reduced the expression of Ccl2 . IL-33 decreased TNF-α secretion and increased IL-10 secretion; these effects were completely reversed by PPARγ inhibition. IL-33 increased glucose uptake and expression of Glut2 . It upregulated the expression of glycolytic enzyme genes, namely, Pkm2, Hk2 , Gpi1 , and Tpi , and downregulated the expression of Gck , Ldha, and Mct4 . However, it did not alter hexokinase activity. Moreover, IL-33 increased the number and activity of mitochondria, accompanied by increased ATP production and reduced accumulation of ROS . IL-33 upregulated the expression of PGC-1α and cytochrome c , and mitochondrial fission- and fusion-associated genes, including Mfn1 , Mfn2 , and Dnm1l . IL-33-mediated mitochondrial homeostasis was partially reversed by PPARγ inhibition. Altogether, IL-33 protects β-cell survival and insulin secretion that could be partially driven via PPARγ, which regulates glucose uptake and promotes mitochondrial function and anti-inflammatory responses.

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