Fetuin-A reverses functional maturation of beta-cells

Introduction and aim:

Type 2 diabetic islets lose their glucose responsiveness, this process being a major cause of chronic hyperglycaemia. We previously reported that the foetal protein fetuin-A, which is secreted by the fatty liver, inhibits glucose-stimulated insulin secretion (GSIS) in isolated human islets. The hepatokine fetuin-A is a TGFbeta antagonist, pathway essential for the functional maturation of the neonatal beta-cells. The aim of this study is to assess whether fetuin-A impacts on neonatal islet maturation by interfering with TGFBR/BMPR signalling and to decipher the underlying signalling pathways.

Methods:

The effects of fetuin-A on beta-cells maturation were examined in pig neonatal islet cell clusters (NICCs). Freshly isolated, glucose-unresponsive NICCs were maturated in serum-free medium supplemented with 0.6 mg/ml human serum albumin (control). TGFbetaR/BMPR signalling was inhibited by either fetuin-A (0.6 mg/ml) or pharmacologically by SB431542 or LDN193189. Gene expression was analysed by RNA sequencing and RT-qPCR, protein expression by western blotting.

Results:

RNAs sequencing analysis revealed upregulation of islet cell specific genes during in vitro maturation including INS, GCG, SST, PPY; hormone convertases PCSK1/2; transcription factors NEUROD1, PAX4, MAFB; proteins important for GSIS: GCK, ABCC8 (SUR1), SLC2A2 (GLUT2), SYT4/7/13, PPP1R1A; membrane receptors: FFAR3/4, SSTR2/3, GIPR and the marker of the functionally mature beta-cells UCN3. TGFbetaR inhibitor SB431542 lowered the expression of beta-cell genes, which suggests that NICCs maturation depends on active TGFBR pathway. Fetuin-A inhibited phosphorylation of SMAD2/3 and reduced the expression of islet cell specific genes.

Conclusion:

These observations suggest that fetuin-A impairs beta-cell maturation via inhibition of TGFBR.