Inhibitory Effect of TCF7L2 on Pancreatic β-Cell Dedifferentiation via ERK/MAPK Signaling Pathway in Diabetes.

Abstract

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. The Extracellular regulated protein kinases/Mitogen-activated protein kinase signaling pathway (ERK/MAPK signaling pathway) has been confirmed to be significantly associated with multiple cellular process, including cellular dedifferentiation. However, the effects of TCF7L2 on β-cell function and ERK/MAPK signaling pathway are poorly understood. This study aimed to elucidate the regulation of TCF7L2 in β-cell function and ERK/MAPK signaling pathway, which further participate in glucose metabolism and diabetes progression. After transfection of TCF7L2 siRNA and lenti-TCF7L2 plasmids, the activation of ERK/MAPK signaling and β-cell dedifferentiation were evaluated respectively. Six week-old male db/db mice were randomly grouped and fed a normal or high-fat diet, and then pancreatic level of TCF7L2 protein were measured respectively when the mice were fed to 8, 12, and 16 weeks of age. Furthermore, the contributions of TCF7L2 to ERK/MAPK signaling and glucose metabolism were investigated in a β-cell-specific TCF7L2 deletion mice model (TCF7L2β-/-). The results demonstrated that impaired TCF7L2 induces β-cell dedifferentiation and decreases insulin secretion of MIN6 cells via ERK/MAPK signaling pathway. Consistently, decreased pancreatic TCF7L2 protein in parallel with reduced functional β-cells were observed in db/db mice after weeks of normal or high-fat diet. However, the differences between were only significant when the mice were fed to 12 weeks of age. After weeks of high-fat diet feeding, impaired glucose tolerance and increased activation of ERK/MAPK signaling were simultaneously observed in TCF7L2β-/- mice. The study indicate that the induction of β-cell dedifferentiation mediated by ERK/MAPK signaling pathway might be an essential component of TCF7L2 variants in the development of diabetes.