No abstract

Background and Purpose. Metformin, a widely used antidiabetic drug, has been shown to have anti-inflammatory properties; nevertheless, its influence on β-cell meta-inflammation remains unclear. The following study investigated the effects of metformin on meta-inflammatory in β-cells and whether the underlying mechanisms were associated with the G protein-coupled receptor 40-phospholipase C-inositol 1, 4, 5-trisphosphate (GPR40-PLC-IP3) pathway. Materials and Methods. Lipotoxicity-induced β-cells and the high-fat diet-induced obese rat model were used in the study. Results. Metformin-reduced lipotoxicity-induced β-cell meta-inflammatory injury was associated with the expression of GPR40. GPR40 was involved in metformin reversing metabolic inflammation key marker TLR4 activation-mediated β-cell injury. Furthermore, downstream signaling protein PLC-IP3 of GPR40 was involved in the protective effect of metformin on meta-inflammation, and the above process of metformin was partially regulated by AMPK activity. In addition, the anti-inflammatory effects of metformin were observed in obese rats. Conclusion. Metformin can reduce lipotoxicity-induced meta-inflammation in β-cells through the regulation of the GPR40-PLC-IP3 pathway and partially via the regulation of AMPK activity.

Metabolic inflammatory damage, characterized by Toll-like receptor 4 (TLR4) signaling activation, is a major mechanism underlying lipotoxicity-induced β-cell damage. The present study is aimed at determining whether G protein-coupled receptor 4 (GPR40) agonist can improve β-cell lipotoxicity-induced damage by inhibiting the TLR4-NF-κB pathway. Lipotoxicity, inflammation-damaged β-cells, obese SD, and TLR4KO rat models were used in the study. In vitro, TAK-875 inhibited the lipotoxicity- and LPS-induced β-cell apoptosis in a concentration-dependent manner, improved the insulin secretion, and inhibited the expression of TLR4 and NF-κB subunit P65. Besides, silencing of TLR4 expression enhanced the protective effects of TAK-875, while TLR4 overexpression attenuated this protective effect. Activation of TLR4 or NF-κB attenuated the antagonism of TAK-875 on PA-induced damage. Moreover, the above process of TAK-875 was partially independent of GPR40 expression. TAK-875 reduced the body weight and inflammatory factors, rebalanced the number and distribution of α or β-cells, inhibited the apoptosis of islet cells, and inhibited the expression of TLR4 and NF-κB subunit P65 in obese rats. Further knockout of the rat TLR4 gene delayed the damage induced by the high-fat diet and synergy with the action of TAK-875. These data suggest that GPR40 agonists antagonized the lipotoxicity β-cell damage by inhibiting the TLR4-NF-κB pathway.