Abstract
Decidualization refers to the functional differentiation of endometrial stromal cells and plays a significant role in embryo implantation and pregnancy. C-peptide is excreted in equimolar concentrations as that of insulin during the metabolism of proinsulin in pancreatic beta-cells. High levels of C-peptide are correlated with hyperinsulinemia and polycystic ovarian syndrome, which show a defect in decidualization. However, the role of C-peptide in decidualization has not yet been studied. Here, we identified C-peptide as an endogenous antideciduogenic factor. This inhibitory function was confirmed by the reduced expression of decidual markers, including prolactin, insulin-like growth factor-binding protein-1, and Forkhead box protein O1 as well as by the fibroblastic morphological change in the presence of C-peptide. C-peptide also enhanced cellular senescence and decreased the proportion of apoptotic cells during decidualization. In addition, C-peptide potentiated the inhibitory effects of both insulin and palmitic acid in an AKT- and autophagy-independent manner, respectively. Furthermore, C-peptide augmented protein phosphatase 1 (PP1) activity, leading to a reduction in the inhibitory phosphorylation of glycogen synthase kinase (GSK)3β, which resulted in enhanced cellular senescence and decreased apoptosis during decidualization. Taken together, our findings suggest that C-peptide is an antideciduogenic factor acting via the regulation between PP1 and GSK3β in patients with hyperinsulinemia.
Highlights
The human proinsulin connecting peptide (C-peptide) is composed of 31 amino acids, which are cleaved from proinsulin during proteolytic processing (Bhatt et al, 2014; Leno-Duran et al, 2014)
The cells were differentiated in the presence of 8-Br-cAMP as shown by increased mRNA expression of decidualization markers, including PRL, insulin-like growth factor-binding protein-1 (IGFBP1), and Forkhead box protein O1 (FOXO1) (Figure 1A)
This reversal in the presence of C-peptide was comparable to the observations made in the absence of C-peptide (Figure 1D; second bar vs. third bar), indicating that C-peptide did not facilitate the restoration of the growth status of human eSCs
Summary
The human proinsulin connecting peptide (C-peptide) is composed of 31 amino acids, which are cleaved from proinsulin during proteolytic processing (Bhatt et al, 2014; Leno-Duran et al, 2014). It has been shown to stimulate mitogen-activated protein kinase (MAPK), leading to the activation of Na+-K+ATPase and numerous transcription factors, including cAMP response element-binding protein (CREB), nuclear factor kappa beta (NF-κB), and activating transcription factor 1 (ATF1) These functions may play some protective roles in diabetic vascular dysfunction, micro- and/or macro-vascular damage, and diabetic neuropathy (Wahren et al, 2000). C-peptide induces cyclin D1 expression, promoting the critical transition of cell proliferation from G1- to S-phase via the activation of retinoblastoma protein phosphorylation in smooth muscles of both rats and humans (Walcher et al, 2006) These results suggest that C-peptide plays several functional roles in diverse tissues and biological contexts, in addition to its role in diabetes. The potential effects of C-peptide signaling on endometrium differentiation during embryo implantation and pregnancy maintenance have not yet been investigated
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