4-phenylbutyric acid attenuates diabetes mellitus secondary to thiamine-responsive megaloblastic anaemia syndrome by modulating endoplasmic reticulum stress.

INTRODUCTION

Thiamine-responsive megaloblastic anaemia syndrome (TRMA) is a rare genetic disease caused by mutations in the SLC19A2 gene that encodes thiamine transporter 1 (THTR-1). The common manifestations are diabetes, anaemia, and deafness. The pathogenic mechanism has not yet been clarified.

MATERIAL AND

METHODS

Rat pancreatic islet tumour cells INS.1 were used to construct cell lines stably overexpressing wild-type SLC19A2 and SLC19A2 (c.1409insT) mutants. The mRNA and protein expressions of THTR-1 and endoplasmic reticulum stress (ERS)-associated factors were detected by real-time fluorescence quantitative polymerase chain reaction (PCR) and western blot methods, respectively. Flow cytometry and cell counting kit-8 were used to analyse the effects of SLC19A2 (c.1409insT) mutation on cell apoptosis and proliferation, respectively. 4-Phenylbutyric acid (4-PBA), an ERS inhibitor, was administered to SLC19A2 (c.1409insT)-mutated INS.1 cells, and then the mRNA and protein expressions of ERS-related factors in cells were detected.

RESULTS

Mutations in the SLC19A2 (c.1409insT) promote apoptosis and inhibit cell proliferation, thereby upregulating the mRNA and protein levels of ERS-associated factors glucose-regulated protein 78, protein kinase R-like endoplasmic reticulum kinase, C/EBP homologous protein, and activating transcription factor 4. 4-PBA could inhibit ERS caused by SLC19A2 (c.1409insT) mutations, downregulate mRNA and protein expression levels of GRP78, CHOP, and phosphorylated eukaryotic initiation factor 2α, and protect pancreatic islet β-cells.

CONCLUSION

THTR-1 deficiency triggers diabetes in TRMA patients through ERS, and 4-PBA protects pancreatic islet β-cells by inhibiting ERS, which provides new ideas and intervention targets for the prevention and treatment of TRMA and diabetes.