Deficiency of M-LP/Mpv17L leads to development of β-cell hyperplasia and improved glucose tolerance via activation of the Wnt and TGF-β pathways

M-LP/Mpv17L is a protein that was initially identified during screening of age-dependently expressed genes in mice. We have recently demonstrated that M-LP/Mpv17L-knockout (M-LP/Mpv17L-KO) in human hepatoma cells leads to a reduction of cellular cyclic nucleotide phosphodiesterase (PDE) activity, and that in vitro -synthesized M-LP/Mpv17L possesses PDE activity. These findings suggest that M-LP/Mpv17L functions as an atypical PDE, even though it has none of the well-conserved catalytic region or other structural motifs characteristic of the PDE family. In this study, we found that M-LP/Mpv17L-KO mice developed beta-cell hyperplasia and improved glucose tolerance. Deficiency of M-LP/Mpv17L in islets from KO mice at early postnatal stages or siRNA-mediated suppression of M-LP/Mpv17L in rat insulinoma cells led to marked upregulation of lymphoid enhancer binding factor 1 (Lef1) and transcription factor 7 (Tcf7), key nuclear effectors in the Wnt signaling pathway, and some of the factors essential for the development and maintenance of beta-cells. Moreover, at the protein level, increases in the levels of phosphorylated beta-catenin and glycogen synthase kinase-3 beta (GSK-3 beta) were observed, indicating activation of the Wnt and TGF-beta signaling pathways. Taken together, these findings suggest that protein kinase A (PKA)-dependent phosphorylations of beta-catenin and GSK-3 beta, the key mediators of the Wnt and/or TGF-beta signaling pathways, are the most upstream events triggering beta-cell hyperplasia and improved glucose tolerance caused by M-LP/Mpv17L deficiency.

Automated summary

M-LP/Mpv17L is a unique PDE protein that plays a role in beta-cell hyperplasia and improved glucose tolerance. Its deficiency leads to activation of the Wnt and TGF-β signaling pathways, affecting the development and maintenance of beta-cells.