Formaldehyde (FA) can be produced in the environment and by cell metabolism and has been classified as a carcinogen in animals and humans. Metformin is the most commonly used drug for the treatment of type 2 diabetes. Metformin also has potential benefit in cancer prevention and treatment. The aim of this study was to determine whether metformin can directly react with FA and attenuate its toxicity in vitro. Metformin was incubated at pH 7.4 and 37 C in the presence of FA, and the reaction mixture was analyzed by UV spectrophotometry, high-performance liquid chromatography (HPLC), and mass spectrometry. Fluorescence spectrophotometry, immunofluorescence, and western blot were used to measure FA-induced bovine serum albumin (BSA) crosslinking and DNA damage in HepG2 cells treated with or without metformin. According to the HPLC and mass spectrometry data, we speculate that the reaction of metformin with FA (1:1) initially results in the formation of a conjugated intermediate followed by the subsequent generation of a stable six-membered ring structure. Correspondingly, metformin attenuated FA-induced fluorescence in BSA as well as the aggregation of γH2AX in HepG2 cells. These results suggest that metformin can protect protein and DNA damage induced by FA at least partly through a direct reaction process.

The widely used lipid-lowering drug niacin was reported to increase blood glucose in diabetes. How does niacin regulate β Cell function in diabetic patients remains unclear. This study aimed to investigate the effect of niacin on β cell lipotoxicity in vitro and in vivo. Niacin treatment sensitized the palmitate-induced cytotoxicity and apoptosis in INS-1 cells. In addition, palmitate significantly increased the niacin receptor GPR109A and PPARγ2 levels, which could be further boosted by niacin co-treatment, creating a vicious cycle. In contrast, knocking down of GPR109A could reverse both PPARγ2 expression and niacin toxicity in the INS-1 cells. Interestingly, we found that GLP-1 receptor agonist exendin-4 showed similar inhibitive effects on the GPR109A/PPARγ2 axis and was able to reverse niacin induced lipotoxicity in INS-1 cells. In diet-induced obesity (DIO) mouse model, niacin treatment resulted in elevated blood glucose, impaired glucose tolerance and insulin secretion, accompanied by the change of islets morphology and the decrease of β cell mass. The combination of niacin and DPP-4 inhibitor sitagliptin can improve glucose tolerance, insulin secretion and islet morphology and β cell mass, even better than sitagliptin alone. Our results show that niacin increased β cell lipotoxicity partially through upregulation of GPR109A and PPARγ2, which can be alleviated by incretin drugs. We provide a new mechanism of niacin toxicity, and suggest that the combination of niacin and incretin may have better blood glucose and lipid control effect in clinical practice.

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