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A partial loss of the mature phenotype of adult beta cells may contribute to a reduction of functional beta cell mass and accelerate the onset of type 2 diabetes. We previously found that fetuin-A, a hepatokine increasingly secreted by the fatty liver and a determinant of type 2 diabetes, inhibits glucose-stimulated insulin secretion (GSIS) of human islets. Since fetuin-A is a ubiquitous fetal glycoprotein that declines peripartum, we examined here whether fetuin-A interferes with the functional maturity of beta cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The effects of fetuin-A were assessed during in vitro maturation of porcine neonatal islet cell clusters (NICCs) and in adult human islets. Expression alterations were examined via microarray, RNA sequencing and reverse transcription quantitative real-time PCR (qRT-PCR), proteins were analysed by western blotting and immunostaining, and insulin secretion was quantified in static incubations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NICC maturation was accompanied by the gain of glucose-responsive insulin secretion (twofold stimulation), backed up by mRNA upregulation of genes governing beta cell identity and function, such as\n                      <jats:italic>NEUROD1<\/jats:italic>\n                      ,\n                      <jats:italic>UCN3<\/jats:italic>\n                      ,\n                      <jats:italic>ABCC8<\/jats:italic>\n                      and\n                      <jats:italic>CASR<\/jats:italic>\n                      (Log\n                      <jats:sub>2<\/jats:sub>\n                      fold change [Log\n                      <jats:sub>2<\/jats:sub>\n                      FC]\u2009&gt;\u20091.6). An active TGF\u03b2 receptor (TGFBR)\u2013SMAD2\/3 pathway facilitates NICC maturation, since the TGFBR inhibitor SB431542 counteracted the upregulation of aforementioned genes and de-repressed\n                      <jats:italic>ALDOB<\/jats:italic>\n                      , a gene disallowed in mature beta cells. In fetuin-A-treated NICCs, upregulation of beta cell markers and the onset of glucose responsiveness were suppressed. Concomitantly, SMAD2\/3 phosphorylation was inhibited. Transcriptome analysis confirmed inhibitory effects of fetuin-A and SB431542 on TGF\u03b2-1- and SMAD2\/3-regulated transcription. However, contrary to SB431542 and regardless of c\n                      <jats:italic>MYC<\/jats:italic>\n                      upregulation, fetuin-A inhibited beta cell proliferation (0.27\u2009\u00b1\u20090.08% vs 1.0 \u2009\u00b1\u20090.1% Ki67-positive\u2009cells in control NICCs). This effect was sustained by reduced expression (Log\n                      <jats:sub>2<\/jats:sub>\n                      FC\u2009\u2264\u2009\u22122.4) of\n                      <jats:italic>FOXM1<\/jats:italic>\n                      ,\n                      <jats:italic>CENPA<\/jats:italic>\n                      ,\n                      <jats:italic>CDK1<\/jats:italic>\n                      or\n                      <jats:italic>TOP2A<\/jats:italic>\n                      . In agreement, the number of insulin-positive cells was lower in fetuin-A-treated NICCs than in control NICCs (14.4\u2009\u00b1\u20091.2% and 22.3\u2009\u00b1\u20091.1%, respectively). In adult human islets fetuin-A abolished glucose responsiveness, i.e. 1.7- and 1.1-fold change over 2.8\u00a0mmol\/l glucose in control- and fetuin-A-cultured islets, respectively. In addition, fetuin-A reduced SMAD2\/3 phosphorylation and suppressed expression of proliferative genes. Of note, in non-diabetic humans, plasma fetuin-A was negatively correlated (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.013) with islet beta cell area.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Our results suggest that the perinatal decline of fetuin-A relieves TGFBR signalling in islets, a process that facilitates functional maturation of neonatal beta cells. Functional maturity remains revocable in later life, and the occurrence of a metabolically unhealthy milieu, such as liver steatosis and elevated plasma fetuin-A, can impair both function and adaptive proliferation of beta cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data availability<\/jats:title>\n                    <jats:p>\n                      The RNAseq datasets and computer code produced in this study are available in the Gene Expression Omnibus (GEO): GSE144950;\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE144950\">https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE144950<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-021-05435-1","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T03:03:01Z","timestamp":1616641381000},"page":"1358-1374","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The hepatokine fetuin-A disrupts functional maturation of pancreatic beta cells"],"prefix":"10.1007","volume":"64","author":[{"given":"Felicia","family":"Gerst","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Kemter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estela","family":"Lorza-Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Kathrin","family":"Fritz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Nano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Piemonti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Gauder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Dahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio","family":"Nadalin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"K\u00f6nigsrainer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Falko","family":"Fend","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas L.","family":"Birkenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Heni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Stefan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eckhard","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Ulrich","family":"H\u00e4ring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Ullrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"issue":"2","key":"5435_CR1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1111\/jdi.12701","volume":"9","author":"JC Henquin","year":"2018","unstructured":"Henquin JC, Nenquin M (2018) Immaturity of insulin secretion by pancreatic islets isolated from one human neonate. 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