Tub and beta-catenin play a key role in insulin and leptin resistance-induced pancreatic beta-cell differentiation


Ercin M. , Sancar-Bas S. , Bolkent S. , Gezginci-Oktayoglu S.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, cilt.1865, sa.12, ss.1934-1944, 2018 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1865 Konu: 12
  • Basım Tarihi: 2018
  • Doi Numarası: 10.1016/j.bbamcr.2018.09.010
  • Dergi Adı: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
  • Sayfa Sayıları: ss.1934-1944

Özet

The aim of this study was to investigate the molecular mechanism of pancreatic islet-derived mesenchymal stem cell (PID-MSC) differentiation into beta-cells in the presence of insulin and leptin resistance stimulators. We determined that beta-cell differentiation was stimulated by glucose, insulin, and leptin. Co-administration of insulin and leptin resulted in greater, at a further stage of differentiation but non-functional beta-cell formation. The levels of p-AKT(Ser473) did not change; SOCS3, PTP1B, p-IRS1(Ser307), PTEN levels increased and p-IRS1(Try) levels decreased due to insulin and leptin co-administration. These findings suggest that co-administration of insulin and leptin to PID-MSCs results in the development of both insulin and leptin resistance together. We showed that this differentiation signaling is mainly mediated by AKT/GSK-3 beta/beta-catenin and Tub. Moreover, beta-catenin and Tub were linked to each other in the nucleus under this condition. Furthermore, we found that Tub and beta-catenin contributes to insulin production by increasing the expression of transcription factors by binding to the promoter regions of ins1, ins2, and pdx1 genes. In addition, Tub is also bound to the promoter region of the MafA gene. These findings demonstrate that when insulin and leptin resistance develop together in rat PID-MSCs beta-cell differentiation increases markedly via beta-catenin and Tub. New therapeutic agents that inhibit AKT/GSK-3 beta/beta-catenin and in particular Tub may help prevent the development or retard the progression of type 2 diabetes.