The hepatokine fetuin-A disrupts functional maturation of pancreatic beta cells
Saved in:
| Title: | The hepatokine fetuin-A disrupts functional maturation of pancreatic beta cells |
|---|---|
| Authors: | Gerst F., Kemter E., Lorza-Gil E., Kaiser G., Fritz A. -K., Nano R., Piemonti L., Gauder M., Dahl A., Nadalin S., Konigsrainer A., Fend F., Birkenfeld A. L., Wagner R., Heni M., Stefan N., Wolf E., Haring H. -U., Ullrich S. |
| Source: | Diabetologia Diabetologia 64, 1358–1374 (2021) |
| Publisher Information: | Springer Science and Business Media LLC, 2021. |
| Publication Year: | 2021 |
| Subject Terms: | 0301 basic medicine, Swine, alpha-2-HS-Glycoprotein, Smad Proteins, Pancreatic beta cells, Article, Islets of Langerhans, 03 medical and health sciences, Phosphorylation/drug effects [MeSH], Islets of Langerhans/drug effects [MeSH], Swine [MeSH], Humans [MeSH], Insulin Secretion/drug effects [MeSH], Adaptive proliferation, FOXM1, Functional maturity, Glucose Intolerance/metabolism [MeSH], Animals [MeSH], Fetuin-A, Islets of Langerhans/metabolism [MeSH], TGFBR–SMAD2/3, Signal Transduction/drug effects [MeSH], Smad Proteins/metabolism [MeSH], Gene Expression Profiling [MeSH], Diabetes Mellitus, Type 2/metabolism [MeSH], Cell Proliferation/drug effects [MeSH], alpha-2-HS-Glycoprotein/pharmacology [MeSH], Insulin/metabolism [MeSH], Glucose Intolerance, Insulin Secretion, Animals, Humans, Insulin, Phosphorylation, Cell Proliferation, 0303 health sciences, Gene Expression Profiling, Adaptive Proliferation, Foxm1, Fetuin-a, Functional Maturity, Pancreatic Beta Cells, Tgfbr–smad2/3, Diabetes Mellitus, Type 2, Signal Transduction |
| Description: | Aims/hypothesis Neonatal beta cells carry out a programme of postnatal functional maturation to achieve full glucose responsiveness. 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. Methods 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. Results 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 NEUROD1, UCN3, ABCC8 and CASR (Log2 fold change [Log2FC] > 1.6). An active TGFβ receptor (TGFBR)–SMAD2/3 pathway facilitates NICC maturation, since the TGFBR inhibitor SB431542 counteracted the upregulation of aforementioned genes and de-repressed ALDOB, 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 TGFβ-1- and SMAD2/3-regulated transcription. However, contrary to SB431542 and regardless of cMYC upregulation, fetuin-A inhibited beta cell proliferation (0.27 ± 0.08% vs 1.0 ± 0.1% Ki67-positive cells in control NICCs). This effect was sustained by reduced expression (Log2FC ≤ −2.4) of FOXM1, CENPA, CDK1 or TOP2A. In agreement, the number of insulin-positive cells was lower in fetuin-A-treated NICCs than in control NICCs (14.4 ± 1.2% and 22.3 ± 1.1%, respectively). In adult human islets fetuin-A abolished glucose responsiveness, i.e. 1.7- and 1.1-fold change over 2.8 mmol/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 (p = 0.013) with islet beta cell area. Conclusions/interpretation 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. Data availability The RNAseq datasets and computer code produced in this study are available in the Gene Expression Omnibus (GEO): GSE144950; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144950 Graphical abstract |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1432-0428 0012-186X |
| DOI: | 10.1007/s00125-021-05435-1 |
| Access URL: | https://link.springer.com/content/pdf/10.1007/s00125-021-05435-1.pdf https://pubmed.ncbi.nlm.nih.gov/33765181 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099843 https://pubmed.ncbi.nlm.nih.gov/33765181/ http://pubmed.ncbi.nlm.nih.gov/33765181/ https://link.springer.com/article/10.1007/s00125-021-05435-1 https://link.springer.com/content/pdf/10.1007/s00125-021-05435-1.pdf https://europepmc.org/article/PMC/PMC8099843 https://hdl.handle.net/20.500.11768/115647 https://doi.org/10.1007/s00125-021-05435-1 https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=61684 https://repository.publisso.de/resource/frl:6451918 |
| Rights: | CC BY |
| Accession Number: | edsair.doi.dedup.....007234bbf4f52a95f386bcd40fdcf14b |
| Database: | OpenAIRE |
Full Text Finder 
Nájsť tento článok vo Web of Science | Abstract: | Aims/hypothesis Neonatal beta cells carry out a programme of postnatal functional maturation to achieve full glucose responsiveness. 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. Methods 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. Results 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 NEUROD1, UCN3, ABCC8 and CASR (Log2 fold change [Log2FC] > 1.6). An active TGFβ receptor (TGFBR)–SMAD2/3 pathway facilitates NICC maturation, since the TGFBR inhibitor SB431542 counteracted the upregulation of aforementioned genes and de-repressed ALDOB, 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 TGFβ-1- and SMAD2/3-regulated transcription. However, contrary to SB431542 and regardless of cMYC upregulation, fetuin-A inhibited beta cell proliferation (0.27 ± 0.08% vs 1.0 ± 0.1% Ki67-positive cells in control NICCs). This effect was sustained by reduced expression (Log2FC ≤ −2.4) of FOXM1, CENPA, CDK1 or TOP2A. In agreement, the number of insulin-positive cells was lower in fetuin-A-treated NICCs than in control NICCs (14.4 ± 1.2% and 22.3 ± 1.1%, respectively). In adult human islets fetuin-A abolished glucose responsiveness, i.e. 1.7- and 1.1-fold change over 2.8 mmol/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 (p = 0.013) with islet beta cell area. Conclusions/interpretation 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. Data availability The RNAseq datasets and computer code produced in this study are available in the Gene Expression Omnibus (GEO): GSE144950; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144950 Graphical abstract |
|---|---|
| ISSN: | 14320428 0012186X |
| DOI: | 10.1007/s00125-021-05435-1 |