SRA

Neonatal beta-cells undergo a maturation process to acquire glucose responsiveness. We hypothesize that in later life, a partial reversal of this maturation might promote beta-cell dysfunction. We previously ascertained that fetuin-A, a fetal glycoprotein downregulated at birth but increasingly secreted when fatty liver develops, inhibits insulin secretion. Here, we evaluate fetuin-A's impact on beta-cell maturation. In vitro maturation of neonatal porcine islet cell clusters (NICCs) promoted expression of beta-cell markers and TGFBR/SMAD signaling. Fetuin-A reduced both functional and proliferative gene expression and SMAD phosphorylation. Consequently, fetuin-A impaired glucose- and forskolin-dependent secretion, and reduced adaptive beta-cell proliferation. In adult human islets, fetuin-A abolished glucose responsiveness, diminished SMAD phosphorylation and downregulated functional and proliferative genes. Our findings suggest that perinatal decline of fetuin-A relieves TGFBR signaling in neonatal beta-cells, thereby facilitating the onset of postnatal maturation. However, this program remains revocable during adulthood, since fatty liver-derived fetuin-A reverses beta-cells' maturity, conferring them a neonatal-like phenotype and contributing to their failure. Overall design: 24 samples derived from porcine neonatal pancreatic islets. The neonatal islets were subjected to in vitro maturation for 10 days. Maturation was conducted in standard culture medium or in the presence of five different treatment conditions. The experiment was replicated in four idependent islet preparations.The immature islets (islets at culture day 6; HSA/day 6) represent the control for the maturated islets in standard culture medium (islets at culture day 10; HSA/day 10). The maturated islet in standard medium (HSA/day 10) represents the control for the different treatment conditions (fetuin-A, HSA + SB, HSA + LDN and HSA + SB + LDN) during the maturation process.