Inhibitory effect of TCF7L2 on pancreatic β-cell dedifferentiation via ERK/MAPK signaling pathway in diabetes

Abstract

Abstract Background Transcription factor 7-like 2 (TCF7L2) variants seem to affect diabetes susceptibility through β-cell dysfunction, underlying basis of which has been considered to be β-cell dedifferentiation rather than apoptotic β-cell death. However，little is known about how TCF7L2 variation contributes to β-cell dedifferentiation and how pancreatic β-cell dedifferentiation changes during diabetes progression. Methods To clarify the effects of TCF7L2 on β-cell dedifferentiation and insulin secretion, MIN6 cells were transfected with TCF7L2 shRNA or lenti-TCF7L2 virus for 48h and then the degree of β-cells dedifferentiation and insulin concentrations in supernatant were measured respectively. To further determine whether the effects are mediated by ERK/MAPK signal pathway, MIN6 cells were administrated with ERK phosphorylation inhibitor U0126 prior to TCF7L2 shRNA virus transfection. Subsequently, changes of TCF7L2 expression and pancreatic β-cell dedifferentiation were measured respectively in db/db mice after 2, 6 and 10 weeks of ND or HFD feeding. Results Our present study demonstrated that stable shRNA-mediated knockdown of TCF7L2 significantly increased β-cell dedifferentiation and drastically decreased insulin secretion of MIN6 cells. The opposite results were observed following lenti-TCF7L2 virus transfection. Interestingly, TCF7L2 exerted an inhibitory effect on the activation of ERK/MAPK signal and the effects of TCF7L2 on β-cells dedifferentiation and insulin secretion were totally attenuated when the phosphorylation of ERK was blocked using its chemical inhibitor U0126. Additionally, the declined TCF7L2 expression in paralleled with sustained activation of ERK/MAPK signal and increased pancreatic β-cell dedifferentiation were observed simultaneously in db/db mice. All animals showed impaired glucose tolerance during intraperitoneal glucose tolerance tests. Conclusion The pancreatic β-cell dedifferentiation which mediated by ERK/MAPK signaling pathway might be the essential component of TCF7L2 variants to develop diabetes.