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Auddino S, Aiello E, Grieco GE, Fignani D, Licata G, Bruttini M, Mori A, Berteramo AF, Pedace E, Nigi L, Formichi C, Guay C, Quero G, Tondolo V, Di Giuseppe G, Soldovieri L, Ciccarelli G, Mari A, Giaccari A, Mezza T, Po A, Regazzi R, Dotta F, Sebastiani G. Comprehensive sequencing profile and functional analysis of IsomiRs in human pancreatic islets and beta cells. Diabetologia 2025; 68:1261-1278. [PMID: 40102237 PMCID: PMC12069488 DOI: 10.1007/s00125-025-06397-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 01/28/2025] [Indexed: 03/20/2025]
Abstract
AIMS/HYPOTHESIS MiRNAs regulate gene expression, influencing beta cell function and pathways. Isoforms of miRNA (isomiRs), sequence variants of miRNAs with post-transcriptional modifications, exhibit cell-type-specific expression and functions. Despite their biological significance, a comprehensive isomiR profile in human pancreatic islets and beta cells remains unexplored. This study aims to profile isomiR expression in four beta cell sources: (1) laser capture microdissected human islets (LCM-HI); (2) collagenase-isolated human islets (CI-HI); (3) sorted beta cells; and (4) the EndoC-βH1 beta cell line, and to investigate their potential role in beta cell function. METHODS Small RNA-seq and/or small RNA dataset analysis was conducted on human pancreatic islets and beta cells. Data were processed using the sRNAbench bioinformatics pipeline to classify isomiRs based on sequence variations. A beta cell-specific isomiR signature was identified via cross-validation across datasets. Correlations between LCM-HI isomiR expression and in vivo clinical parameters were analysed using regression models. Functional validation of isomiR-411-5p-Ext5p(+1) was performed via overexpression in EndoC-βH1 cells and CI-HI, followed by glucose-stimulated insulin secretion (GSIS) assays and/or transcriptomic analysis. RESULTS IsomiRs constituted 59.2 ± 1.9% (LCM-HI), 59.6 ± 2.4% (CI-HI), 42.3 ± 7.2% (sorted beta cells) and 43.8 ± 1.2% (EndoC-βH1) of total miRNA reads (data represented as mean ± SD), with 3' end trimming (Trim3p) being the predominant modification. A beta cell-specific isomiR signature of 30 sequences was identified, with isomiR-411-5p-Ext5p(+1) showing a significant inverse correlation with basal insulin secretion (p=0.0009, partial R2=0.68) and total insulin secretion (p=0.005, partial R2=0.54). Overexpression of isomiR-411-5p-Ext5p(+1), but not of its canonical counterpart, importantly reduced GSIS by 51% ( ± 15.2%; mean ± SD) (p=0.01) in EndoC-βH1 cells. Transcriptomic analysis performed in EndoC-βH1 cells and CI-HI identified 47 genes significantly downregulated by isomiR-411-5p-Ext5p(+1) (false discovery rate [FDR]<0.05) but not by the canonical miRNA, with enriched pathways related to Golgi vesicle biogenesis (FDR=0.017) and trans-Golgi vesicle budding (FDR=0.018). TargetScan analysis confirmed seed sequence-dependent target specificity for 81 genes uniquely regulated by the isomiR (p=1.1 × 10⁻⁹). CONCLUSIONS/INTERPRETATION This study provides the first comprehensive isomiR profiling in human islets and beta cells, revealing their substantial contribution to miRNA regulation. IsomiR-411-5p-Ext5p(+1) emerges as a distinct key modulator of insulin secretion and granule dynamics in beta cells. These findings highlight isomiRs as potential biomarkers and therapeutic targets for diabetes, warranting further exploration of their roles in beta cell biology.
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Affiliation(s)
- Stefano Auddino
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Elena Aiello
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Giuseppina E Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Marco Bruttini
- Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
| | - Alessia Mori
- Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
| | - Andrea F Berteramo
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Erika Pedace
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Claudiane Guay
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Giuseppe Quero
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Chirurgia Digestiva, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Vincenzo Tondolo
- General Surgery Unit, Fatebenefratelli Isola Tiberina-Gemelli Isola, Rome, Italy
| | - Gianfranco Di Giuseppe
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Laura Soldovieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gea Ciccarelli
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Andrea Giaccari
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Teresa Mezza
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Agnese Po
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy.
- Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy.
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
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Wang J, Li X, Geng J, Wang R, Ma G, Liu P. Identification of biomarkers and mechanism exploration of ferroptosis related genes regulated by m6A in type 2 diabetes mellitus. Hereditas 2025; 162:24. [PMID: 39966875 PMCID: PMC11834627 DOI: 10.1186/s41065-025-00385-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/04/2025] [Indexed: 02/20/2025] Open
Abstract
PURPOSE This study is aims to explore the role of ferroptosis genes regulated by N6-methyladenosine (m6A) in Type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS Firstly, differentially expressed m6A-FRGs (DEm6A-FRGs) were obtained by intersecting the differentially expressed genes (DEGs) and the m6A-related ferroptosis genes (m6A-FRGs). After enrichment analysis of DEm6A-FRGs, artificial neural network (ANN) and nomogram models were constructed using 4 biomarkers. Moreover, the gene set enrichment analysis of biomarkers was performed. Furthermore, the transcription factors (TF)-mRNA and competing endogenous RNAs (ceRNA) regulatory networks were constructed to reveal the potential regulation of biomarkers at molecular level. In addition, the targeted drugs of biomarkers were predicted, and the molecular docking was used to study the inter-molecular interactions between biomarkers and targeted drugs by "AutoDockvina". RESULTS Totals of 10 DEm6A-FRGs were obtained by intersecting the 402 DEGs and 299 m6A-FRGs. Moreover, the ANN model and nomogram model were constructed with 4 biomarkers including CDKN1A, MIOX, MYCN and CD82, among them, CDKN1A was the most important biomarker for forecasting T2DM. Notably, the function of extracellular matrix structural constituent was low expression in CD82 and MIOX, the function of mitochondrial protein-containing complex was high expression in CD82 and CDKN1A. Furthermore, TP63 could regulate CD82, CDKN1A and MIOX, GATA3 could regulate CD82, CDKN1A and MYCN at the same time. The ceRNA network was constructed with 4 mRNAs, 51 miRNAs and 37 lncRNAs, among them, XIST was a key lncRNA that associated with 12 miRNAs, which could influence CDKN1A. In addition, bisphenol A was associated with CD82 and MYCN, CGP 25608 was associated with CDKN1A and MIOX. CONCLUSION This study revealed the potential molecular mechanisms of m6A-related ferroptosis genes in T2DM, which could provide novel insights for the clinical diagnosis and treatment of T2DM.
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Affiliation(s)
- Jing Wang
- Department of Anaesthesiology, Northwest Women's and Children's Hospital, Yanxiang Road, Yanta District, Xi'an, 710000, Shanxi Province, China
| | - Xuying Li
- Department of Anesthesiology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Juan Geng
- Department of Anaesthesiology, Northwest Women's and Children's Hospital, Yanxiang Road, Yanta District, Xi'an, 710000, Shanxi Province, China
| | - Ruiduo Wang
- State Key Laboratory of Transient Optics and Photonics, Xi'an Institute of Optics and Precision Mechanics, Chinese Academy of Science, Xi'an, 710119, China
| | - Gang Ma
- Department of Anesthesiology, General Hospital of Ningxia Medical University, Yinchuan, China 704 Shengli Street, Yinchuan, 750004, Ningxia, China.
| | - Pan Liu
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Maojian District, No. 39, Chaoyang Middle Road, Shiyan, Hubei, 442000, People's Republic of China.
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Haberman N, Cheung R, Pizza G, Cvetesic N, Nagy D, Maude H, Blazquez L, Lenhard B, Cebola I, Rutter GA, Martinez-Sanchez A. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. FASEB J 2024; 38:e23885. [PMID: 39139039 PMCID: PMC11378476 DOI: 10.1096/fj.202401078r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024]
Abstract
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell-selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors (TFs) important for β-cell identity, such as FOXA, MAFA or RFX6, and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
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Affiliation(s)
- Nejc Haberman
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Rebecca Cheung
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Grazia Pizza
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Nevena Cvetesic
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Dorka Nagy
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Hannah Maude
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Lorea Blazquez
- Department of Neurosciences, Biogipuzkoa Health Research Institute, San Sebastián, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- CIBERNED, ISCIII (CIBER, Carlos III Institute, Spanish Ministry of Sciences and Innovation), Madrid, Spain
| | - Boris Lenhard
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Inês Cebola
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
- Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Faculté de Médecine, Université de Montréal, Montréal, Quebec, Canada
- Lee Kong Chian Medical School, Nanyang Technological University, Singapore, Singapore
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
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Zhu J, Zhu X, Xu Y, Chen X, Ge X, Huang Y, Wang Z. The role of noncoding RNAs in beta cell biology and tissue engineering. Life Sci 2024; 348:122717. [PMID: 38744419 DOI: 10.1016/j.lfs.2024.122717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/29/2024] [Accepted: 05/11/2024] [Indexed: 05/16/2024]
Abstract
The loss or dysfunction of pancreatic β-cells, which are responsible for insulin secretion, constitutes the foundation of all forms of diabetes, a widely prevalent disease worldwide. The replacement of damaged β-cells with regenerated or transplanted cells derived from stem cells is a promising therapeutic strategy. However, inducing the differentiation of stem cells into fully functional glucose-responsive β-cells in vitro has proven to be challenging. Noncoding RNAs (ncRNAs) have emerged as critical regulatory factors governing the differentiation, identity, and function of β-cells. Furthermore, engineered hydrogel systems, biomaterials, and organ-like structures possess engineering characteristics that can provide a three-dimensional (3D) microenvironment that supports stem cell differentiation. This review summarizes the roles and contributions of ncRNAs in maintaining the differentiation, identity, and function of β-cells. And it focuses on regulating the levels of ncRNAs in stem cells to activate β-cell genetic programs for generating alternative β-cells and discusses how to manipulate ncRNA expression by combining hydrogel systems and other tissue engineering materials. Elucidating the patterns of ncRNA-mediated regulation in β-cell biology and utilizing this knowledge to control stem cell differentiation may offer promising therapeutic strategies for generating functional insulin-producing cells in diabetes cell replacement therapy and tissue engineering.
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Affiliation(s)
- Jiaqi Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Xiaoren Zhu
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Yang Xu
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, Shanghai 200092, China
| | - Xingyou Chen
- Medical School of Nantong University, Nantong 226001, China
| | - Xinqi Ge
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yan Huang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
| | - Zhiwei Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
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Jacovetti C, Donnelly C, Menoud V, Suleiman M, Cosentino C, Sobel J, Wu K, Bouzakri K, Marchetti P, Guay C, Kayser B, Regazzi R. The mitochondrial tRNA-derived fragment, mt-tRF-Leu TAA, couples mitochondrial metabolism to insulin secretion. Mol Metab 2024; 84:101955. [PMID: 38704026 PMCID: PMC11112368 DOI: 10.1016/j.molmet.2024.101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/29/2024] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
OBJECTIVE The contribution of the mitochondrial electron transfer system to insulin secretion involves more than just energy provision. We identified a small RNA fragment (mt-tRF-LeuTAA) derived from the cleavage of a mitochondrially-encoded tRNA that is conserved between mice and humans. The role of mitochondrially-encoded tRNA-derived fragments remains unknown. This study aimed to characterize the impact of mt-tRF-LeuTAA, on mitochondrial metabolism and pancreatic islet functions. METHODS We used antisense oligonucleotides to reduce mt-tRF-LeuTAA levels in primary rat and human islet cells, as well as in insulin-secreting cell lines. We performed a joint transcriptome and proteome analysis upon mt-tRF-LeuTAA inhibition. Additionally, we employed pull-down assays followed by mass spectrometry to identify direct interactors of the fragment. Finally, we characterized the impact of mt-tRF-LeuTAA silencing on the coupling between mitochondrial metabolism and insulin secretion using high-resolution respirometry and insulin secretion assays. RESULTS Our study unveils a modulation of mt-tRF-LeuTAA levels in pancreatic islets in different Type 2 diabetes models and in response to changes in nutritional status. The level of the fragment is finely tuned by the mechanistic target of rapamycin complex 1. Located within mitochondria, mt-tRF-LeuTAA interacts with core subunits and assembly factors of respiratory complexes of the electron transfer system. Silencing of mt-tRF-LeuTAA in islet cells limits the inner mitochondrial membrane potential and impairs mitochondrial oxidative phosphorylation, predominantly by affecting the Succinate (via Complex II)-linked electron transfer pathway. Lowering mt-tRF-LeuTAA impairs insulin secretion of rat and human pancreatic β-cells. CONCLUSIONS Our findings indicate that mt-tRF-LeuTAA interacts with electron transfer system complexes and is a pivotal regulator of mitochondrial oxidative phosphorylation and its coupling to insulin secretion.
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Affiliation(s)
- Cecile Jacovetti
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
| | - Chris Donnelly
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
| | - Véronique Menoud
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Mara Suleiman
- Department of Clinical and Experimental Medicine, Diabetes Unit, University of Pisa, Pisa, Italy
| | - Cristina Cosentino
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Jonathan Sobel
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Kejing Wu
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Karim Bouzakri
- UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, Diabetes Unit, University of Pisa, Pisa, Italy
| | - Claudiane Guay
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Bengt Kayser
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
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Haberman N, Cheung R, Pizza G, Cvetesic N, Nagy D, Maude H, Blazquez L, Lenhard B, Cebola I, Rutter GA, Martinez-Sanchez A. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593867. [PMID: 38798508 PMCID: PMC11118353 DOI: 10.1101/2024.05.13.593867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell- selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors important for β-cell identity, such as FOXA, MAFA or RFX6 and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
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Mitra T, Gulati R, Ramachandran K, Rajiv R, Enninga EAL, Pierret CK, Kumari R S, Janardhanan R. Endocrine disrupting chemicals: gestational diabetes and beyond. Diabetol Metab Syndr 2024; 16:95. [PMID: 38664841 PMCID: PMC11046910 DOI: 10.1186/s13098-024-01317-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 03/21/2024] [Indexed: 04/28/2024] Open
Abstract
Gestational Diabetes Mellitus (GDM) has been on the rise for the last two decades along with the growing incidence of obesity. The ubiquitous use of Endocrine-Disrupting Chemicals (EDCs) worldwide has been associated with this increase in GDM incidence. Epigenetic modifications such as DNA methylation, histone acetylation, and methylation have been associated with prenatal exposure to EDCs. EDC exposure can also drive a sustained disruption of the hypothalamus-pituitary-thyroid axis and various other signaling pathways such as thyroid signaling, PPARγ signaling, PI3K-AKT signaling. This disruption leads to impaired glucose metabolism, insulin resistance as well as β-cell dysfunction, which culminate into GDM. Persistent EDC exposure in pregnant women also increases adipogenesis, which results in gestational weight gain. Importantly, pregnant mothers transfer these EDCs to the fetus via the placenta, thus leading to other pregnancy-associated complications such as intrauterine growth restriction (IUGR), and large for gestational age neonates. Furthermore, this early EDC exposure of the fetus increases the susceptibility of the infant to metabolic diseases in early life. The transgenerational impact of EDCs is also associated with higher vascular tone, cognitive aberrations, and enhanced susceptibility to lifestyle disorders including reproductive health anomalies. The review focuses on the impact of environmental toxins in inducing epigenetic alterations and increasing the susceptibility to metabolic diseases during pregnancy needs to be extensively studied such that interventions can be developed to break this vicious cycle. Furthermore, the use of EDC-associated ExomiRs from the serum of patients can help in the early diagnosis of GDM, thereby leading to triaging of patients based on increasing risk factor of the clinicopathological condition.
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Affiliation(s)
- Tridip Mitra
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India
| | - Richa Gulati
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India
| | - Krithika Ramachandran
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India
| | - Rohan Rajiv
- Dietrich School of Arts and Sciences, University of Pittsburgh, 15260, Pittsburgh, PA, USA
| | | | - Chris K Pierret
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Sajeetha Kumari R
- Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India
| | - Rajiv Janardhanan
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India.
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Gupta D, Burstein AW, Schwalbe DC, Shankar K, Varshney S, Singh O, Paul S, Ogden SB, Osborne-Lawrence S, Metzger NP, Richard CP, Campbell JN, Zigman JM. Ghrelin deletion and conditional ghrelin cell ablation increase pancreatic islet size in mice. J Clin Invest 2023; 133:e169349. [PMID: 38099492 PMCID: PMC10721155 DOI: 10.1172/jci169349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 10/05/2023] [Indexed: 12/18/2023] Open
Abstract
Ghrelin exerts key effects on islet hormone secretion to regulate blood glucose levels. Here, we sought to determine whether ghrelin's effects on islets extend to the alteration of islet size and β cell mass. We demonstrate that reducing ghrelin - by ghrelin gene knockout (GKO), conditional ghrelin cell ablation, or high-fat diet (HFD) feeding - was associated with increased mean islet size (up to 62%), percentage of large islets (up to 854%), and β cell cross-sectional area (up to 51%). In GKO mice, these effects were more apparent in 10- to 12-week-old mice than in 4-week-old mice. Higher β cell numbers from decreased β cell apoptosis drove the increase in β cell cross-sectional area. Conditional ghrelin cell ablation in adult mice increased the β cell number per islet by 40% within 4 weeks. A negative correlation between islet size and plasma ghrelin in HFD-fed plus chow-fed WT mice, together with even larger islet sizes in HFD-fed GKO mice than in HFD-fed WT mice, suggests that reduced ghrelin was not solely responsible for diet-induced obesity-associated islet enlargement. Single-cell transcriptomics revealed changes in gene expression in several GKO islet cell types, including upregulation of Manf, Dnajc3, and Gnas expression in β cells, which supports decreased β cell apoptosis and/or increased β cell proliferation. These effects of ghrelin reduction on islet morphology might prove useful when designing new therapies for diabetes.
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Affiliation(s)
- Deepali Gupta
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Avi W. Burstein
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Dana C. Schwalbe
- Department of Biology, University of Virginia, Charlottesville, Virginia, USA
| | - Kripa Shankar
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Salil Varshney
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Omprakash Singh
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Subhojit Paul
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Sean B. Ogden
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Nathan P. Metzger
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Corine P. Richard
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - John N. Campbell
- Department of Biology, University of Virginia, Charlottesville, Virginia, USA
| | - Jeffrey M. Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine and
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA
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9
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Lin P, Zhang X, Zhu B, Gao J, Yin D, Zeng J, Kang Z. Naringenin protects pancreatic β cells in diabetic rat through activation of estrogen receptor β. Eur J Pharmacol 2023; 960:176115. [PMID: 37866740 DOI: 10.1016/j.ejphar.2023.176115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/27/2023] [Accepted: 10/12/2023] [Indexed: 10/24/2023]
Abstract
Naringenin is a citrus flavonoid that potently improves metabolic parameters in animal models of metabolic disorders, such as type 2 diabetes. Estrogen receptor (ER) activation promotes β cell function and survival, thereby improving systemic glucose metabolism. In this study, we used a luciferase reporter assay, isolated rat islets and a diabetic rat model to investigate the effects of naringenin on ER signaling and the underlying mechanism of naringenin-mediated improvement of islet function in diabetes. Naringenin specifically activated ERβ without affecting the activity of ERα, G protein-coupled estrogen receptor (GPER) or estrogen-related receptor (ERR) α/β/γ. Additionally, treatment with naringenin enhanced glucose-stimulated insulin secretion in isolated rat islets. This effect was abrogated by PHTPP, an ERβ antagonist. Transcriptomic analysis revealed that naringenin upregulated the expression of genes, such as Pdx1 and Mafa, which are closely linked to improved β-cell function. In consistence, single administration of naringenin to normal rats elevated plasma insulin levels and improved glucose responses. These beneficial effects were blocked by PHTPP. In streptozocin-nicotinamide induced diabetic rats, treatment for 2 weeks with naringenin alone, but not in combination with PHTPP, significantly restored pancreatic β cell mass and improved glucose metabolism. Collectively, these data support that naringenin specifically activate ERβ to improve insulin secretion in the primary rat islets. Furthermore, naringenin administration also protected β cell function and reversed glucose dysregulation in diabetic rats. These beneficial effects are at least partially dependent on the ERβ pathway.
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Affiliation(s)
- Peibin Lin
- Department of Basic Medical Research, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Xiaojing Zhang
- Department of Pharmacy, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Baoyi Zhu
- Department of Urology, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China; Guangdong Engineering Research Center of Urinary Continence and Reproductive Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Jun Gao
- Department of Basic Medical Research, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Dazhong Yin
- Department of Basic Medical Research, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Jianwen Zeng
- Department of Urology, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China; Guangdong Engineering Research Center of Urinary Continence and Reproductive Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China.
| | - Zhanfang Kang
- Department of Basic Medical Research, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China; Guangdong Engineering Research Center of Urinary Continence and Reproductive Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China.
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10
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Sohn P, McLaughlin MR, Krishnan P, Wu W, Slak Rupnik M, Takasu A, Senda T, Lee CC, Kono T, Evans-Molina C. Stromal Interaction Molecule 1 Maintains β-Cell Identity and Function in Female Mice Through Preservation of G-Protein-Coupled Estrogen Receptor 1 Signaling. Diabetes 2023; 72:1433-1445. [PMID: 37478155 PMCID: PMC10545557 DOI: 10.2337/db22-0988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 07/07/2023] [Indexed: 07/23/2023]
Abstract
Altered endoplasmic reticulum (ER) Ca2+ signaling has been linked with β-cell dysfunction and diabetes development. Store-operated Ca2+ entry replenishes ER Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). For characterization of the in vivo impact of STIM1 loss, mice with β-cell-specific STIM1 deletion (STIM1Δβ mice) were generated and challenged with high-fat diet. Interestingly, β-cell dysfunction was observed in female, but not male, mice. Female STIM1Δβ mice displayed reductions in β-cell mass, a concomitant increase in α-cell mass, and reduced expression of markers of β-cell maturity, including MafA and UCN3. Consistent with these findings, STIM1 expression was inversely correlated with HbA1c levels in islets from female, but not male, human organ donors. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1Δβ mice was due, in part, to loss of signaling through the noncanonical 17-β estradiol receptor (GPER1), as GPER1 knockdown and inhibition led to a similar loss of expression of β-cell maturity genes in INS-1 cells. Together, these data suggest that STIM1 orchestrates pancreatic β-cell function and identity through GPER1-mediated estradiol signaling. ARTICLE HIGHLIGHTS Store-operated Ca2+ entry replenishes endoplasmic reticulum (ER) Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). β-Cell-specific deletion of STIM1 results in a sexually dimorphic phenotype, with β-cell dysfunction and loss of identity in female but not male mice. Expression of the noncanonical 17-β estradiol receptor (GPER1) is decreased in islets of female STIM1Δβ mice, and modulation of GPER1 levels leads to alterations in expression of β-cell maturity genes in INS-1 cells.
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Affiliation(s)
- Paul Sohn
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Madeline R. McLaughlin
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN
| | - Preethi Krishnan
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
- Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, Canada
| | - Wenting Wu
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
| | - Marjan Slak Rupnik
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Akira Takasu
- Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization, Ibaraki, Japan
| | - Toshiya Senda
- Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization, Ibaraki, Japan
| | - Chih-Chun Lee
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Tatsuyoshi Kono
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
- Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, IN
| | - Carmella Evans-Molina
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
- Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, IN
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
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11
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Macvanin MT, Gluvic Z, Bajic V, Isenovic ER. Novel insights regarding the role of noncoding RNAs in diabetes. World J Diabetes 2023; 14:958-976. [PMID: 37547582 PMCID: PMC10401459 DOI: 10.4239/wjd.v14.i7.958] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/01/2023] [Accepted: 05/22/2023] [Indexed: 07/12/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders defined by hyperglycemia induced by insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. In 2021, the global prevalence of diabetes is anticipated to be 10.7% (537 million people). Noncoding RNAs (ncRNAs) appear to have an important role in the initiation and progression of DM, according to a growing body of research. The two major groups of ncRNAs implicated in diabetic disorders are miRNAs and long noncoding RNAs. miRNAs are single-stranded, short (17-25 nucleotides), ncRNAs that influence gene expression at the post-transcriptional level. Because DM has reached epidemic proportions worldwide, it appears that novel diagnostic and therapeutic strategies are required to identify and treat complications associated with these diseases efficiently. miRNAs are gaining attention as biomarkers for DM diagnosis and potential treatment due to their function in maintaining physiological homeostasis via gene expression regulation. In this review, we address the issue of the gradually expanding global prevalence of DM by presenting a complete and up-to-date synopsis of various regulatory miRNAs involved in these disorders. We hope this review will spark discussion about ncRNAs as prognostic biomarkers and therapeutic tools for DM. We examine and synthesize recent research that used novel, high-throughput technologies to uncover ncRNAs involved in DM, necessitating a systematic approach to examining and summarizing their roles and possible diagnostic and therapeutic uses.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Clinic for Internal Medicine, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladan Bajic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
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12
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Estrogen as a key regulator of energy homeostasis and metabolic health. Biomed Pharmacother 2022; 156:113808. [DOI: 10.1016/j.biopha.2022.113808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/02/2022] [Accepted: 10/03/2022] [Indexed: 11/23/2022] Open
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13
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MiR-34a-5p promotes hepatic gluconeogenesis by suppressing SIRT1 expression. Exp Cell Res 2022; 420:113336. [PMID: 36058294 DOI: 10.1016/j.yexcr.2022.113336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 08/27/2022] [Accepted: 08/27/2022] [Indexed: 11/24/2022]
Abstract
Elevated hepatic gluconeogenesis is a major contributor of fasting hyperglycemia in diabetes. MicroRNAs (miRNAs) are tightly linked to glucose metabolism, but their role in hepatic gluconeogenesis remains largely unkown. In this current study, miR-34a-5p expression was significantly increased in liver tissues of db/db mice. Overexpression of miR-34a-5p promoted hepatic glucose production in mouse primary hepatocytes with increased expressions of gluconeogenic genes while miR-34a-5p inhibition displayed a contrary action. MiR-34a-5p overexpression in mouse primary hepatocytes repressed SIRT1 expression. SIRT1 inhibition by EX527 blocked phosphoenolpyruvate carboxykinase (PEPCK) protein degradation and enhanced hepatic gluconeogenesis. Treatment of A485 (a CBP/p300 inhibitor) decreased miR-34a-5p and PEPCK expressions in the livers of db/db mice, but elevated SIRT1 protein expression. In mouse primary hepatocytes, A485 exhibited a similar result. Overexpression of miR-34a-5p attenuated A485-inhibited gluconeogenic gene expressions and A485-induced SIRT1 protein expression. Finally, after miR-34a-5p was inhibited in the livers of db/db mice, hepatic glucose production and gluconeogenic gene expressions were markedly lowered. Our findings highlight a critical role of miR-34a-5p in the regulation of hepatic gluconeogenesis and miR-34a-5p may be a potential target in the treatment of type 2 diabetes.
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14
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Mauvais-Jarvis F, Lange CA, Levin ER. Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease. Endocr Rev 2022; 43:720-742. [PMID: 34791092 PMCID: PMC9277649 DOI: 10.1210/endrev/bnab041] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Indexed: 12/15/2022]
Abstract
Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized steroid receptor (SR) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, New Orleans, LA, 70112, USA.,Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA, 70112, USA.,Southeast Louisiana Veterans Affairs Medical Center, New Orleans, LA, 70119, USA
| | - Carol A Lange
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.,Department of Medicine (Division of Hematology, Oncology, and Transplantation), University of Minnesota, Minneapolis, MN 55455, USA.,Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ellis R Levin
- Division of Endocrinology, Department of Medicine, University of California, Irvine, Irvine, CA, 92697, USA.,Department of Veterans Affairs Medical Center, Long Beach, Long Beach, CA, 90822, USA
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15
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Berillo O, Huo KG, Richer C, Fraulob-Aquino JC, Briet M, Lipman ML, Sinnett D, Paradis P, Schiffrin EL. Distinct transcriptomic profile of small arteries of hypertensive patients with chronic kidney disease identified miR-338-3p targeting GPX3 and PTPRS. J Hypertens 2022; 40:1394-1405. [PMID: 35703228 DOI: 10.1097/hjh.0000000000003160] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Hypertension is associated with vascular injury, which contributes to end-organ damage. MicroRNAs regulating mRNAs have been shown to play a role in vascular injury in hypertensive mice. We aimed to identify differentially expressed microRNAs and their mRNA targets in small arteries of hypertensive patients with/without chronic kidney disease (CKD) to shed light on the pathophysiological molecular mechanisms of vascular remodeling. METHODS AND RESULTS Normotensive individuals and hypertensive patients with/without CKD were recruited ( n = 15-16 per group). Differentially expressed microRNAs and mRNAs were identified uniquely associated with hypertension (microRNAs: 10, mRNAs: 68) or CKD (microRNAs: 68, mRNAs: 395), and in both groups (microRNAs: 2, mRNAs: 32) with a P less than 0.05 and a fold change less than or greater than 1.3 in subcutaneous small arteries ( n = 14-15). One of the top three differentially expressed microRNAs, miR-338-3p that was down-regulated in CKD, presented the best correlation between RNA sequencing and reverse transcription-quantitative PCR (RT-qPCR, R2 = 0.328, P < 0.001). Profiling of human aortic vascular cells showed that miR-338-3p was mostly expressed in endothelial cells. Two of the selected top nine up-regulated miR-338-3p predicted targets, glutathione peroxidase 3 ( GPX3 ) and protein tyrosine phosphatase receptor type S ( PTPRS ), were validated with mimics by RT-qPCR in human aortic endothelial cells ( P < 0.05) and by a luciferase assay in HEK293T cells ( P < 0.05). CONCLUSION A distinct transcriptomic profile was observed in gluteal subcutaneous small arteries of hypertensive patients with CKD. Down-regulated miR-338-3p could contribute to GPX3 and PTPRS up-regulation via the canonical microRNA targeting machinery in hypertensive patients with CKD. http://links.lww.com/HJH/C27.
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Affiliation(s)
- Olga Berillo
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research
| | - Ku-Geng Huo
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research
| | - Chantal Richer
- Division of Hematology-Oncology, Research Center, CHU Ste-Justine
| | | | - Marie Briet
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research
- INSERM U1083, CNRS UMR 6214, Centre Hospitalo-Universitaire d'Angers, Université d'Angers, Angers, France
| | - Mark L Lipman
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research
- Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University
| | - Daniel Sinnett
- Division of Hematology-Oncology, Research Center, CHU Ste-Justine
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Pierre Paradis
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research
| | - Ernesto L Schiffrin
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research
- Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University
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16
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Brown MR, Matveyenko AV. It's What and When You Eat: An Overview of Transcriptional and Epigenetic Responses to Dietary Perturbations in Pancreatic Islets. Front Endocrinol (Lausanne) 2022; 13:842603. [PMID: 35355560 PMCID: PMC8960041 DOI: 10.3389/fendo.2022.842603] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/07/2022] [Indexed: 01/07/2023] Open
Abstract
Our ever-changing modern environment is a significant contributor to the increased prevalence of many chronic diseases, and particularly, type 2 diabetes mellitus (T2DM). Although the modern era has ushered in numerous changes to our daily living conditions, changes in "what" and "when" we eat appear to disproportionately fuel the rise of T2DM. The pancreatic islet is a key biological controller of an organism's glucose homeostasis and thus plays an outsized role to coordinate the response to environmental factors to preserve euglycemia through a delicate balance of endocrine outputs. Both successful and failed adaptation to dynamic environmental stimuli has been postulated to occur due to changes in the transcriptional and epigenetic regulation of pathways associated with islet secretory function and survival. Therefore, in this review we examined and evaluated the current evidence elucidating the key epigenetic mechanisms and transcriptional programs underlying the islet's coordinated response to the interaction between the timing and the composition of dietary nutrients common to modern lifestyles. With the explosion of next generation sequencing, along with the development of novel informatic and -omic approaches, future work will continue to unravel the environmental-epigenetic relationship in islet biology with the goal of identifying transcriptional and epigenetic targets associated with islet perturbations in T2DM.
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Affiliation(s)
- Matthew R. Brown
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
| | - Aleksey V. Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
- Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
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17
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Hu Q, Mu J, Liu Y, Yang Y, Liu Y, Pan Y, Zhang Y, Li L, Liu D, Chen J, Zhang F, Jin L. Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic β-Cell Proliferation Through the CPEB1/CDKN1B Pathway. Diabetes 2022; 71:394-411. [PMID: 35029277 DOI: 10.2337/db21-0134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022]
Abstract
Pancreatic β-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in β-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated β-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory β-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly(A) tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting β-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of β-cells to meet metabolic demand during obesity.
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Affiliation(s)
- Qianxing Hu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Jinming Mu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yuhong Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yue Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yue Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yi Pan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yanfeng Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
- Pancreatic Research Institute, Southeast University, Nanjing, Jiangsu Province, China
| | - Dechen Liu
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Jianqiu Chen
- College of Engineering, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Fangfang Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Liang Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu Province, China
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18
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Ji H, Fan L, Shan A, Wang W, Ning G, Cao Y, Jiang X. Let7b-5p inhibits insulin secretion and decreases pancreatic β-cell mass in mice. Mol Cell Endocrinol 2022; 540:111506. [PMID: 34801668 DOI: 10.1016/j.mce.2021.111506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/01/2021] [Accepted: 11/08/2021] [Indexed: 10/19/2022]
Abstract
MicroRNAs are crucial regulators for the development, mass and function of pancreatic β-cells. MiRNA dysregulation is associated with β-cell dysfunction and development of diabetes. The members of let7 family are important players in regulating cellular growth and metabolism. In this study we investigated the functional role of let7b-5p in the mouse pancreatic β-cells. We generated pancreatic β-cell-specific let7b-5p transgenic mouse model and analyzed the glucose metabolic phenotype, β-cells mass and insulin secretion in vivo. Luciferase reporter assay, immunofluorescence staining and western blot were carried out to study the target genes of let7b-5p in β-cells. Let7b-5p overexpression impaired the insulin production and secretion of β-cells and resulted impaired glucose tolerance in mice. The overexpressed let7b-5p inhibited pancreatic β-cell proliferation and decreased the expression of cyclin D1 and cyclin D2. Our findings demonstrated that let7b-5p was critical in regulating the proliferation and insulin secretion of pancreatic β-cells.
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Affiliation(s)
- He Ji
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liwen Fan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Aijing Shan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanan Cao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Research Center for Translational Medicine, National Key Scientific Infrastructure for Translational Medicine (Shanghai), Shanghai Jiao Tong University, Shanghai, China
| | - Xiuli Jiang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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19
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Pretorius M, Huang C. Beta-Cell Adaptation to Pregnancy - Role of Calcium Dynamics. Front Endocrinol (Lausanne) 2022; 13:853876. [PMID: 35399944 PMCID: PMC8990731 DOI: 10.3389/fendo.2022.853876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/21/2022] [Indexed: 11/17/2022] Open
Abstract
During pregnancy, the mother develops insulin resistance to shunt nutrients to the growing fetus. As a result, the maternal islets of Langerhans undergo several changes to increase insulin secretion in order to maintain glucose homeostasis and prevent the development of gestational diabetes. These changes include an increase in β-cell proliferation and β-cell mass, upregulation of insulin synthesis and insulin content, enhanced cell-to-cell communication, and a lowering of the glucose threshold for insulin secretion, all of which resulting in an increase in glucose-stimulated insulin secretion. Emerging data suggests that a change in intracellular calcium dynamics occurs in the β-cell during pregnancy as part of the adaptive process. Influx of calcium into β-cells is crucial in the regulation of glucose-stimulated insulin secretion. Calcium fluxes into and out of the cytosol, endoplasmic reticulum, and mitochondria are also important in controlling β-cell function and survival. Here, we review calcium dynamics in islets in response to pregnancy-induced changes in hormones and signaling molecules, and how these changes may enhance insulin secretion to stave off gestational diabetes.
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Dana P, Hayati Roodbari N, Yaghmaei P, Hajebrahimi Z. Effects of empagliflozin on the expression of kisspeptin gene and reproductive system function in streptozotocin-induced diabetic male rats. Front Endocrinol (Lausanne) 2022; 13:1059942. [PMID: 36479221 PMCID: PMC9719967 DOI: 10.3389/fendo.2022.1059942] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 10/25/2022] [Indexed: 11/22/2022] Open
Abstract
One of the main health concerns of diabetes is testicular dysfunction and impairment of reproductive function and sperm quality which can cause male infertility. kisspeptin is a hypothalamic neuropeptide hormone that is involved in the regulation of energy metabolism, gonadotrophin-releasing hormone (GnRH), and reproductive function. In the present study, the therapeutic effects of empagliflozin (sodium-glucose co-transporter 2 inhibitors) on kisspeptin expression along with reproductive function were investigated in diabetic male Wistar rats. Diabetes was induced by a single dose injection of 60 mg/kg streptozotocin. Empagliflozin in doses of 10 and 25 mg/kg body weight was used for 8 weeks. Serum samples, testis, epididymis, and pancreas tissues were collected at the end of the experiments. Lipid profiles, oxidative stress markers, blood hormones, expression of kisspeptin along with pathological alterations of the testis were assayed using real-time PCR, biochemical, and histological technics. Data have shown that empagliflozin improved hyperglycemia, reproductive impairment, oxidative stress condition, and histopathological alterations of pancreatic and testis tissues in diabetic animals. It improved the serum levels of sex hormones, insulin, leptin, and the expression of kisspeptin in the testes tissues. Spermatogenesis is also improved in treated animals. Data indicated that the administration of empagliflozin can ameliorate symptoms of diabetes. It probably has promising antidiabetic potential and may improve the male infertility of diabetic subjects. To our knowledge, this is the first experimental evidence for the potential impact of empagliflozin on kisspeptin expression in diabetic male rats.
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Affiliation(s)
- Parisa Dana
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Nasim Hayati Roodbari
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
- *Correspondence: Nasim Hayati Roodbari,
| | - Parichehreh Yaghmaei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Zahra Hajebrahimi
- A&S Research Institute, Ministry of Science Research and Technology, Tehran, Iran
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21
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Ming J, Sana SRGL, Deng X. Identification of copper-related biomarkers and potential molecule mechanism in diabetic nephropathy. Front Endocrinol (Lausanne) 2022; 13:978601. [PMID: 36329882 PMCID: PMC9623046 DOI: 10.3389/fendo.2022.978601] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 10/05/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a chronic microvascular complication in patients with diabetes mellitus, which is the leading cause of end-stage renal disease. However, the role of copper-related genes (CRGs) in DN development remains unclear. MATERIALS AND METHODS CRGs were acquired from the GeneCards and NCBI databases. Based on the GSE96804 and GSE111154 datasets from the GEO repository, we identified hub CRGs for DN progression by taking the intersection of differentially expressed CRGs (DECRGs) and genes in the key module from Weighted Gene Co-expression Network Analysis. The Maximal Clique Centrality algorithm was used to identify the key CRGs from hub CRGs. Transcriptional factors (TFs) and microRNAs (miRNAs) targeting hub CRGs were acquired from publicly available databases. The CIBERSORT algorithm was used to perform comparative immune cell infiltration analysis between normal and DN samples. RESULTS Eighty-two DECRGs were identified between normal and DN samples, as were 10 hub CRGs, namely PTGS2, DUSP1, JUN, FOS, S100A8, S100A12, NAIP, CLEC4E, CXCR1, and CXCR2. Thirty-nine TFs and 165 miRNAs potentially targeted these 10 hub CRGs. PTGS2 was identified as the key CRG and FOS as the most significant gene among all of DECRGs. RELA was identified as the hub TF interacting with PTGS2 by taking the intersection of potential TFs from the ChEA and JASPAR public databases. let-7b-5p was identified as the hub miRNA targeting PTGS2 by taking the intersection of miRNAs from the miRwalk, RNA22, RNAInter, TargetMiner, miRTarBase, and ENCORI databases. Similarly, CREB1, E2F1, and RELA were revealed as hub TFs for FOS, and miR-338-3p as the hub miRNA. Finally, compared with those in healthy samples, there are more infiltrating memory B cells, M1 macrophages, M2 macrophages, and resting mast cells and fewer infiltrating activated mast cells and neutrophils in DN samples (all p< 0.05). CONCLUSION The 10 identified hub copper-related genes provide insight into the mechanisms of DN development. It is beneficial to examine and understand the interaction between hub CRGs and potential regulatory molecules in DN. This knowledge may provide a novel theoretical foundation for the development of diagnostic biomarkers and copper-related therapy targets in DN.
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Affiliation(s)
- Jie Ming
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Si Ri Gu Leng Sana
- Department of Anaesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Si Ri Gu Leng Sana,
| | - Xijin Deng
- Department of Anaesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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22
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Sałówka A, Martinez-Sanchez A. Molecular Mechanisms of Nutrient-Mediated Regulation of MicroRNAs in Pancreatic β-cells. Front Endocrinol (Lausanne) 2021; 12:704824. [PMID: 34803905 PMCID: PMC8600252 DOI: 10.3389/fendo.2021.704824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic β-cells within the islets of Langerhans respond to rising blood glucose levels by secreting insulin that stimulates glucose uptake by peripheral tissues to maintain whole body energy homeostasis. To different extents, failure of β-cell function and/or β-cell loss contribute to the development of Type 1 and Type 2 diabetes. Chronically elevated glycaemia and high circulating free fatty acids, as often seen in obese diabetics, accelerate β-cell failure and the development of the disease. MiRNAs are essential for endocrine development and for mature pancreatic β-cell function and are dysregulated in diabetes. In this review, we summarize the different molecular mechanisms that control miRNA expression and function, including transcription, stability, posttranscriptional modifications, and interaction with RNA binding proteins and other non-coding RNAs. We also discuss which of these mechanisms are responsible for the nutrient-mediated regulation of the activity of β-cell miRNAs and identify some of the more important knowledge gaps in the field.
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Affiliation(s)
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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23
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Abstract
This review focuses on the human pancreatic islet-including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms. We outline current and future interventions being developed to protect, restore, or replace human islets. The review also highlights unresolved questions about human islets and proposes areas where additional research on human islets is needed.
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Affiliation(s)
- John T Walker
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Diane C Saunders
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Marcela Brissova
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alvin C Powers
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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24
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Salazar-Petres ER, Sferruzzi-Perri AN. Pregnancy-induced changes in β-cell function: what are the key players? J Physiol 2021; 600:1089-1117. [PMID: 33704799 DOI: 10.1113/jp281082] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 02/17/2021] [Indexed: 12/11/2022] Open
Abstract
Maternal metabolic adaptations during pregnancy ensure appropriate nutrient supply to the developing fetus. This is facilitated by reductions in maternal peripheral insulin sensitivity, which enables glucose to be available in the maternal circulation for transfer to the fetus for growth. To balance this process and avoid excessive hyperglycaemia and glucose intolerance in the mother during pregnancy, maternal pancreatic β-cells undergo remarkable changes in their function including increasing their proliferation and glucose-stimulated insulin secretion. In this review we examine how placental and maternal hormones work cooperatively to activate several signalling pathways, transcription factors and epigenetic regulators to drive adaptations in β-cell function during pregnancy. We also explore how adverse maternal environmental conditions, including malnutrition, obesity, circadian rhythm disruption and environmental pollutants, may impact the endocrine and molecular mechanisms controlling β-cell adaptations during pregnancy. The available data from human and experimental animal studies highlight the need to better understand how maternal β-cells integrate the various environmental, metabolic and endocrine cues and thereby determine appropriate β-cell adaptation during gestation. In doing so, these studies may identify targetable pathways that could be used to prevent not only the development of pregnancy complications like gestational diabetes that impact maternal and fetal wellbeing, but also more generally the pathogenesis of other metabolic conditions like type 2 diabetes.
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Affiliation(s)
- Esteban Roberto Salazar-Petres
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
| | - Amanda Nancy Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
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25
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Sharma G, Prossnitz ER. Targeting the G protein-coupled estrogen receptor (GPER) in obesity and diabetes. ENDOCRINE AND METABOLIC SCIENCE 2021; 2. [PMID: 35321004 PMCID: PMC8936744 DOI: 10.1016/j.endmts.2021.100080] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Obesity has become a global epidemic in the modern world with the numbers of obese individuals having risen at alarming rates in the last decades. Obesity represents a serious medical condition that can lead to multiple complications, such as diabetes, dyslipidemia, cardiovascular disease including hypertension and atherosclerosis, stroke and increases in the risk of many types of cancer. Very few effective options exist to treat obesity, with many removed from the market due to associated complications. Obesity and metabolic syndrome display a sexual dichotomy, with (premenopausal) females displaying protection from weight gain and metabolic dysfunction compared to men. These beneficial effects are generally attributed to a class of female ovarian hormone, estrogens, which exert pleiotropic effects in multiple metabolic tissues, such as adipose, skeletal muscle, liver and pancreas. Multiple receptors mediate the actions of estrogens, including the classical nuclear estrogen receptors (ER α and ER β) and the G protein-coupled estrogen receptor (GPER). While the roles of nuclear ERs are more established, evidence of GPER function in metabolic homeostasis is still emerging. In this review, we will discuss the latest advances concerning the contributions of GPER towards obesity and metabolism utilizing GPER-selective pharmacological (agonists or antagonists) or genetic (GPER knock out mice or cells) tools. We present evidence that GPER regulates body weight, fat distribution, inflammation and glucose and lipid homeostasis via effects on metabolic tissues. Selective agonism of GPER by its agonist G-1 can alleviate symptoms of obesity and metabolic dysfunction in multiple murine models, thereby limiting weight gain, reducing insulin resistance and inflammation and improving glucose and lipid homeostasis in vivo. Thus, GPER represents a novel therapeutic target, with G-1 a first-in-class therapeutic agent, to treat obesity and its associated comorbidities, including diabetes.
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26
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Soltani A, Jafarian A, Allameh A. The Predominant microRNAs in β-cell Clusters for Insulin Regulation and Diabetic Control. Curr Drug Targets 2021; 21:722-734. [PMID: 31886749 DOI: 10.2174/1389450121666191230145848] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/04/2019] [Accepted: 12/04/2019] [Indexed: 12/20/2022]
Abstract
micro (mi)-RNAs are vital regulators of multiple processes including insulin signaling pathways and glucose metabolism. Pancreatic β-cells function is dependent on some miRNAs and their target mRNA, which together form a complex regulative network. Several miRNAs are known to be directly involved in β-cells functions such as insulin expression and secretion. These small RNAs may also play significant roles in the fate of β-cells such as proliferation, differentiation, survival and apoptosis. Among the miRNAs, miR-7, miR-9, miR-375, miR-130 and miR-124 are of particular interest due to being highly expressed in these cells. Under diabetic conditions, although no specific miRNA profile has been noticed, the expression of some miRNAs and their target mRNAs are altered by posttranscriptional mechanisms, exerting diverse signs in the pathobiology of various diabetic complications. The aim of this review article is to discuss miRNAs involved in the process of stem cells differentiation into β-cells, resulting in enhanced β-cell functions with respect to diabetic disorders. This paper will also look into the impact of miRNA expression patterns on in vitro proliferation and differentiation of β-cells. The efficacy of the computational genomics and biochemical analysis to link the changes in miRNA expression profiles of stem cell-derived β-cells to therapeutically relevant outputs will be discussed as well.
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Affiliation(s)
- Adele Soltani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arefeh Jafarian
- Immunology, Asthma, and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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27
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Tenenbaum M, Plaisance V, Boutry R, Pawlowski V, Jacovetti C, Sanchez-Parra C, Ezanno H, Bourry J, Beeler N, Pasquetti G, Gmyr V, Dalle S, Kerr-Conte J, Pattou F, Hirai SI, Regazzi R, Bonnefond A, Froguel P, Abderrahmani A. The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta-cell proliferation during postnatal development. Cell Mol Life Sci 2021; 78:287-298. [PMID: 32189007 PMCID: PMC11072213 DOI: 10.1007/s00018-020-03499-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 03/04/2020] [Indexed: 12/13/2022]
Abstract
Unveiling the key pathways underlying postnatal beta-cell proliferation can be instrumental to decipher the mechanisms of beta-cell mass plasticity to increased physiological demand of insulin during weight gain and pregnancy. Using transcriptome and global Serine Threonine Kinase activity (STK) analyses of islets from newborn (10 days old) and adult rats, we found that highly proliferative neonatal rat islet cells display a substantially elevated activity of the mitogen activated protein 3 kinase 12, also called dual leucine zipper-bearing kinase (Dlk). As a key upstream component of the c-Jun amino terminal kinase (Jnk) pathway, Dlk overexpression was associated with increased Jnk3 activity and was mainly localized in the beta-cell cytoplasm. We provide the evidence that Dlk associates with and activates Jnk3, and that this cascade stimulates the expression of Ccnd1 and Ccnd2, two essential cyclins controlling postnatal beta-cell replication. Silencing of Dlk or of Jnk3 in neonatal islet cells dramatically hampered primary beta-cell replication and the expression of the two cyclins. Moreover, the expression of Dlk, Jnk3, Ccnd1 and Ccnd2 was induced in high replicative islet beta cells from ob/ob mice during weight gain, and from pregnant female rats. In human islets from non-diabetic obese individuals, DLK expression was also cytoplasmic and the rise of the mRNA level was associated with an increase of JNK3, CCND1 and CCND2 mRNA levels, when compared to islets from lean and obese patients with diabetes. In conclusion, we find that activation of Jnk3 signalling by Dlk could be a key mechanism for adapting islet beta-cell mass during postnatal development and weight gain.
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Affiliation(s)
- Mathie Tenenbaum
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France.
| | - Valérie Plaisance
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
- Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France
| | - Raphael Boutry
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
| | - Valérie Pawlowski
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
- Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France
| | - Cécile Jacovetti
- Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland
| | - Clara Sanchez-Parra
- Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland
| | - Hélène Ezanno
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
| | - Julien Bourry
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
| | - Nicole Beeler
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
| | - Gianni Pasquetti
- Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France
| | - Valery Gmyr
- Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France
| | - Stéphane Dalle
- Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U1191, Montpellier University, Montpellier, France
| | - Julie Kerr-Conte
- Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France
| | - François Pattou
- Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France
| | - Syu-Ichi Hirai
- Départment of Biology, Wakayama University, Wakayama, Japan
| | - Romano Regazzi
- Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland
| | - Amélie Bonnefond
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
- Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK
| | - Philippe Froguel
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
- Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK
| | - Amar Abderrahmani
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France.
- Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France.
- Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK.
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Yahaya TO, Salisu T, Abdulrahman YB, Umar AK. Update on the genetic and epigenetic etiology of gestational diabetes mellitus: a review. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020; 21:13. [DOI: 10.1186/s43042-020-00054-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 02/11/2020] [Indexed: 02/08/2023] Open
Abstract
Abstract
Background
Many studies have been conducted on the genetic and epigenetic etiology of gestational diabetes mellitus (GDM) in the last two decades because of the disease’s increasing prevalence and role in global diabetes mellitus (DM) explosion. An update on the genetic and epigenetic etiology of GDM then becomes imperative to better understand and stem the rising incidence of the disease. This review, therefore, articulated GDM candidate genes and their pathophysiology for the awareness of stakeholders.
Main body (genetic and epigenetic etiology, GDM)
The search discovered 83 GDM candidate genes, of which TCF7L2, MTNR1B, CDKAL1, IRS1, and KCNQ1 are the most prevalent. Certain polymorphisms of these genes can modulate beta-cell dysfunction, adiposity, obesity, and insulin resistance through several mechanisms. Environmental triggers such as diets, pollutants, and microbes may also cause epigenetic changes in these genes, resulting in a loss of insulin-boosting and glucose metabolism functions. Early detection and adequate management may resolve the condition after delivery; otherwise, it will progress to maternal type 2 diabetes mellitus (T2DM) and fetal configuration to future obesity and DM. This shows that GDM is a strong risk factor for T2DM and, in rare cases, type 1 diabetes mellitus (T1DM) and maturity-onset diabetes of the young (MODY). This further shows that GDM significantly contributes to the rising incidence and burden of DM worldwide and its prevention may reverse the trend.
Conclusion
Mutations and epigenetic changes in certain genes are strong risk factors for GDM. For affected individuals with such etiologies, medical practitioners should formulate drugs and treatment procedures that target these genes and their pathophysiology.
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Therapeutic Potentials of MicroRNAs for Curing Diabetes Through Pancreatic β-Cell Regeneration or Replacement. Pancreas 2020; 49:1131-1140. [PMID: 32852323 DOI: 10.1097/mpa.0000000000001655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
MicroRNAs are a type of noncoding RNAs that regulates the expression of target genes at posttranscriptional level. MicroRNAs play essential roles in regulating the expression of different genes involved in pancreatic development, β-cell mass maintenance, and β-cell function. Alteration in the level of miRNAs involved in β-cell function leads to the diabetes. Being an epidemic, diabetes threatens the life of millions of patients posing a pressing demand for its urgent resolve. However, the currently available therapies are not substantial to cure the diabetic epidemic. Thus, researchers are trying to find new ways to replenish the β-cell mass in patients with diabetes. One promising approach is the in vivo regeneration of β-cell mass or increasing the efficiency of β-cell function. Another clinical strategy is the transplantation of in vitro developed β-like cells. Owing to their role in pancreatic β-cell development, maintenance, functioning and their involvement in diabetes, overexpression or attenuation of different miRNAs can cause β-cell regeneration in vivo or can direct the differentiation of various kinds of stem/progenitor cells to β-like cells in vitro. Here, we will summarize different strategies used by researchers to investigate the therapeutic potentials of miRNAs, with focus on miR-375, for curing diabetes through β-cell regeneration or replacement.
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Kaur P, Kotru S, Singh S, Behera BS, Munshi A. Role of miRNAs in the pathogenesis of T2DM, insulin secretion, insulin resistance, and β cell dysfunction: the story so far. J Physiol Biochem 2020; 76:485-502. [PMID: 32749641 DOI: 10.1007/s13105-020-00760-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 07/29/2020] [Indexed: 01/24/2023]
Abstract
Diabetes, the most common endocrine disorder, also known as a silent killer disease, is characterized by uncontrolled hyperglycemia. According to the International Diabetes Federation, there were 451 million people with diabetes mellitus worldwide in 2017. It is a multifactorial syndrome caused by genetic as well as environmental factors. Noncoding RNAs, especially the miRNAs, play a significant role in the development as well as the progression of the disease. This is on account of insulin resistance or defects in β cell function. Various miRNAs including miR-7, miR-9, miR-16, miR-27, miR-24, miR-29, miR-124a, miR-135, miR-130a, miR-144, miR-181a, and miR-375 and many more have been associated with insulin resistance and other pathogenic conditions leading to the development of the disease. These miRNAs play significant roles in various pathways underlying insulin resistance such as PI3K, AKT/GSK, and mTOR. The main target genes of these miRNAs are FOXO1, FOXA2, STAT3, and PTEN. The miRNAs carry out important functions in insulin target tissues like the adipose tissue, liver, and muscle. MiRNAs miR-9, miR-375, and miR-124a, are also associated with the secretion of insulin from pancreatic cells. There is an interplay between the miRNAs and pancreatic cell growth, especially the miRNAs affecting development and proliferation of these cells. Most of the miRNAs target more than one gene which not only justifies their use as biomarkers but also their therapeutic potential. The current review has been compiled with an aim to discuss the role of various miRNAs involved in various pathogenic mechanisms including insulin resistance, insulin secretion, and the β cell dysfunction.
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Affiliation(s)
- Prabhsimran Kaur
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India
| | - Sushil Kotru
- Max Endocrinology, Diabetes and Obesity Care Centre, Max Superspeciality Hospital, Bathinda, 151001, India
| | - Sandeep Singh
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India
| | - Bidwan Sekhar Behera
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India.
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31
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Guay C, Jacovetti C, Bayazit MB, Brozzi F, Rodriguez-Trejo A, Wu K, Regazzi R. Roles of Noncoding RNAs in Islet Biology. Compr Physiol 2020; 10:893-932. [PMID: 32941685 DOI: 10.1002/cphy.c190032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The discovery that most mammalian genome sequences are transcribed to ribonucleic acids (RNA) has revolutionized our understanding of the mechanisms governing key cellular processes and of the causes of human diseases, including diabetes mellitus. Pancreatic islet cells were found to contain thousands of noncoding RNAs (ncRNAs), including micro-RNAs (miRNAs), PIWI-associated RNAs, small nucleolar RNAs, tRNA-derived fragments, long non-coding RNAs, and circular RNAs. While the involvement of miRNAs in islet function and in the etiology of diabetes is now well documented, there is emerging evidence indicating that other classes of ncRNAs are also participating in different aspects of islet physiology. The aim of this article will be to provide a comprehensive and updated view of the studies carried out in human samples and rodent models over the past 15 years on the role of ncRNAs in the control of α- and β-cell development and function and to highlight the recent discoveries in the field. We not only describe the role of ncRNAs in the control of insulin and glucagon secretion but also address the contribution of these regulatory molecules in the proliferation and survival of islet cells under physiological and pathological conditions. It is now well established that most cells release part of their ncRNAs inside small extracellular vesicles, allowing the delivery of genetic material to neighboring or distantly located target cells. The role of these secreted RNAs in cell-to-cell communication between β-cells and other metabolic tissues as well as their potential use as diabetes biomarkers will be discussed. © 2020 American Physiological Society. Compr Physiol 10:893-932, 2020.
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Affiliation(s)
- Claudiane Guay
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Cécile Jacovetti
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Mustafa Bilal Bayazit
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Flora Brozzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Adriana Rodriguez-Trejo
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Kejing Wu
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
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32
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Eliasson L, Esguerra JLS. MicroRNA Networks in Pancreatic Islet Cells: Normal Function and Type 2 Diabetes. Diabetes 2020; 69:804-812. [PMID: 32312896 PMCID: PMC7171954 DOI: 10.2337/dbi19-0016] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022]
Abstract
Impaired insulin secretion from the pancreatic β-cells is central in the pathogenesis of type 2 diabetes (T2D), and microRNAs (miRNAs) are fundamental regulatory factors in this process. Differential expression of miRNAs contributes to β-cell adaptation to compensate for increased insulin resistance, but deregulation of miRNA expression can also directly cause β-cell impairment during the development of T2D. miRNAs are small noncoding RNAs that posttranscriptionally reduce gene expression through translational inhibition or mRNA destabilization. The nature of miRNA targeting implies the presence of complex and large miRNA-mRNA regulatory networks in every cell, including the insulin-secreting β-cell. Here we exemplify one such network using our own data on differential miRNA expression in the islets of T2D Goto-Kakizaki rat model. Several biological processes are influenced by multiple miRNAs in the β-cell, but so far most studies have focused on dissecting the mechanism of action of individual miRNAs. In this Perspective we present key islet miRNA families involved in T2D pathogenesis including miR-200, miR-7, miR-184, miR-212/miR-132, and miR-130a/b/miR-152. Finally, we highlight four challenges and opportunities within islet miRNA research, ending with a discussion on how miRNAs can be utilized as therapeutic targets contributing to personalized T2D treatment strategies.
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Affiliation(s)
- Lena Eliasson
- Islet Cell Exocytosis, Lund University Diabetes Centre; Department of Clinical Sciences Malmö, Lund University; and Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
| | - Jonathan L S Esguerra
- Islet Cell Exocytosis, Lund University Diabetes Centre; Department of Clinical Sciences Malmö, Lund University; and Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
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33
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Micro(RNA) Management and Mismanagement of the Islet. J Mol Biol 2020; 432:1419-1428. [DOI: 10.1016/j.jmb.2019.09.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/10/2019] [Accepted: 09/15/2019] [Indexed: 02/08/2023]
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Radbakhsh S, Sathyapalan T, Banach M, Sahebkar A. Incretins and microRNAs: Interactions and physiological relevance. Pharmacol Res 2020; 153:104662. [PMID: 31982487 DOI: 10.1016/j.phrs.2020.104662] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/22/2020] [Accepted: 01/22/2020] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNA) are one class of the small regulatory RNAs that can impact the expression of numerous genes including incretin hormones and their G protein-coupled receptors. Incretin peptides, including GLP-1, GLP-2, and GIP, are released from the gastrointestinal tract and have an crucial role in the glucose hemostasis and pancreatic beta-cell function. These hormones and their analogs with a longer half-life, glucagon like peptide-1 receptor agonists (GLP1RA), modify the expression of miRNAs. Dipeptidyl peptidase IV (DPP-4) is an enzyme that degrades the incretin hormones and is inactivated by DPP-4 inhibitors, which are a class of compounds used in the management of type 2 diabetes. DPP-4 inhibitors may also increase or reduce the expression of miRNAs. In this review, we describe the possible interactions between miRNAs and incretin hormones and the relevance of such interactions to physiological processes and diseases.
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Affiliation(s)
- Shabnam Radbakhsh
- Department of Medical Biotechnology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull HU3 2JZ, UK
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Pfeiffer S, Sánchez-Lechuga B, Donovan P, Halang L, Prehn JHM, Campos-Caro A, Byrne MM, López-Tinoco C. Circulating miR-330-3p in Late Pregnancy is Associated with Pregnancy Outcomes Among Lean Women with GDM. Sci Rep 2020; 10:908. [PMID: 31969632 PMCID: PMC6976655 DOI: 10.1038/s41598-020-57838-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 12/30/2019] [Indexed: 02/07/2023] Open
Abstract
Gestational Diabetes Mellitus (GDM) is characterised by insulin resistance accompanied by reduced beta-cell compensation to increased insulin demand, typically observed in the second and third trimester and associated with adverse pregnancy outcomes. There is a need for a biomarker that can accurately monitor status and predict outcome in GDM, reducing foetal-maternal morbidity and mortality risks. To this end, circulating microRNAs (miRNAs) present themselves as promising candidates, stably expressed in serum and known to play crucial roles in regulation of glucose metabolism. We analysed circulating miRNA profiles in a cohort of GDM patients (n = 31) and nondiabetic controls (n = 29) during the third trimester for miRNA associated with insulin-secretory defects and glucose homeostasis. We identified miR-330-3p as being significantly upregulated in lean women with GDM compared to nondiabetic controls. Furthermore, increased levels of miR-330-3p were associated with better response to treatment (diet vs. insulin), with lower levels associated with exogenous insulin requirement. We observed miR-330-3p to be significantly related to the percentage of caesarean deliveries, with miR-330-3p expression significantly higher in spontaneously delivered GDM patients. We report this strong novel association of circulating miR-330-3p with risk of primary caesarean delivery as a pregnancy outcome linked with poor maternal glycaemic control, strengthening the growing body of evidence for roles of diabetes-associated miRNAs in glucose homeostasis and adaptation to the complex changes related to pregnancy.
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Affiliation(s)
- Shona Pfeiffer
- Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin, 2, Ireland
| | - Begoña Sánchez-Lechuga
- Servicio de Endocrinología y Nutrición, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | - Paul Donovan
- Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin, 2, Ireland
| | - Luise Halang
- Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin, 2, Ireland
| | - Jochen H M Prehn
- Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin, 2, Ireland
| | - Antonio Campos-Caro
- Servicio de Endocrinología y Nutrición, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | - Maria M Byrne
- Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin, 2, Ireland.,Department of Endocrinology, Mater Misericordiae University Hospital, Eccles Street, Dublin, 7, Ireland
| | - Cristina López-Tinoco
- Servicio de Endocrinología y Nutrición, Hospital Universitario Puerta del Mar, Cádiz, Spain.
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Wan S, Zhang J, Chen X, Lang J, Li L, Chen F, Tian L, Meng Y, Yu X. MicroRNA-17-92 Regulates Beta-Cell Restoration After Streptozotocin Treatment. Front Endocrinol (Lausanne) 2020; 11:9. [PMID: 32038500 PMCID: PMC6989481 DOI: 10.3389/fendo.2020.00009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/07/2020] [Indexed: 02/05/2023] Open
Abstract
Objective: To clarify the role and mechanism of miR-17-92 cluster in islet beta-cell repair after streptozotocin intervention. Methods: Genetically engineered mice (miR-17-92βKO) and control RIP-Cre mice were intraperitoneally injected with multiple low dose streptozotocin. Body weight, random blood glucose (RBG), fasting blood glucose, and intraperitoneal glucose tolerance test (IPGTT) were monitored regularly. Mice were sacrificed for histological analysis 8 weeks later. Morphological changes of pancreas islets, quantity, quality, apoptosis, and proliferation of beta-cells were measured. Islets from four groups were isolated. MiRNA and mRNA were extracted and quantified. Results:MiR-17-92βKO mice showed dramatically elevated fasting blood glucose and impaired glucose tolerance after streptozotocin treatment in contrast to control mice, the reason of which is reduced beta-cell number and total mass resulting from reduced proliferation, enhanced apoptosis of beta-cells. Genes related to cell proliferation and insulin transcription repression were significantly elevated in miR-17-92βKO mice treated with streptozotocin. Furthermore, genes involved in DNA biosynthesis and damage repair were dramatically increased in miR-17-92βKO mice with streptozotocin treatment. Conclusion: Collectively, our results demonstrate that homozygous deletion of miR-17-92 cluster in mouse pancreatic beta-cells promotes the development of experimental diabetes, indicating that miR-17-92 cluster may be positively related to beta-cells restoration and adaptation after streptozotocin-induced damage.
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Affiliation(s)
- Shan Wan
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Zhang
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Chen
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jiangli Lang
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Fei Chen
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Li Tian
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Meng
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xijie Yu ;
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Quesada-Candela C, Tudurí E, Marroquí L, Alonso-Magdalena P, Quesada I, Nadal Á. Morphological and functional adaptations of pancreatic alpha-cells during late pregnancy in the mouse. Metabolism 2020; 102:153963. [PMID: 31593706 DOI: 10.1016/j.metabol.2019.153963] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 08/01/2019] [Accepted: 08/26/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-cell to maintain normoglycemia. However, although pancreatic alpha-cells play a key role in glucose homeostasis and seem to be involved in gestational diabetes, there is no information about their potential adaptations or changes during pregnancy. MATERIAL AND METHODS Non-pregnant (controls) and pregnant C57BL/6 mice at gestational day 18.5 (G18.5) and their isolated pancreatic islets were used for in vivo and ex vivo studies, respectively. The effect of pregnancy hormones was tested in glucagon-secreting α-TC1.9 cells. Immunohistochemical analysis was performed in pancreatic slices. Glucagon gene expression was monitored by RT-qPCR. Glucagon secretion and plasma hormones were measured by ELISA. RESULTS Pregnant mice on G18.5 exhibited alpha-cell hypertrophy as well as augmented alpha-cell area and mass. This alpha-cell mass expansion was mainly due to increased proliferation. No changes in alpha-cell apoptosis, ductal neogenesis, or alpha-to-beta transdifferentiation were found compared with controls. Pregnant mice on G18.5 exhibited hypoglucagonemia. Additionally, in vitro glucagon secretion at low glucose levels was decreased in isolated islets from pregnant animals. Glucagon content was also reduced. Experiments in α-TC1.9 cells indicated that, unlike estradiol and progesterone, placental lactogens and prolactin stimulated alpha-cell proliferation. Placental lactogens, prolactin and estradiol also inhibited glucagon release from α-TC1.9 cells at low glucose levels. CONCLUSIONS The pancreatic alpha-cell in mice undergoes several morphofunctional changes during late pregnancy, which may contribute to proper glucose homeostasis. Gestational hormones are likely involved in these processes.
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Affiliation(s)
- Cristina Quesada-Candela
- Instituto de Biología Molecular y Celular (IBMC), Universitas Miguel Hernández, 03202 Elche, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, 03202 Elche, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain
| | - Eva Tudurí
- Instituto de Biología Molecular y Celular (IBMC), Universitas Miguel Hernández, 03202 Elche, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, 03202 Elche, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain
| | - Laura Marroquí
- Instituto de Biología Molecular y Celular (IBMC), Universitas Miguel Hernández, 03202 Elche, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, 03202 Elche, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain
| | - Paloma Alonso-Magdalena
- Instituto de Biología Molecular y Celular (IBMC), Universitas Miguel Hernández, 03202 Elche, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, 03202 Elche, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain
| | - Ivan Quesada
- Instituto de Biología Molecular y Celular (IBMC), Universitas Miguel Hernández, 03202 Elche, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, 03202 Elche, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain.
| | - Ángel Nadal
- Instituto de Biología Molecular y Celular (IBMC), Universitas Miguel Hernández, 03202 Elche, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, 03202 Elche, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain.
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Mziaut H, Henniger G, Ganss K, Hempel S, Wolk S, McChord J, Chowdhury K, Ravassard P, Knoch KP, Krautz C, Weitz J, Grützmann R, Pilarsky C, Solimena M, Kersting S. MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling. Mol Metab 2019; 31:150-162. [PMID: 31918917 PMCID: PMC6928290 DOI: 10.1016/j.molmet.2019.11.012] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 11/09/2019] [Accepted: 11/15/2019] [Indexed: 12/16/2022] Open
Abstract
Objective MicroRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. Deciphering their targets and precise role, however, remains challenging. In this study, we aimed to identify miRNAs and their downstream targets involved in the regeneration of islet beta cells following partial pancreatectomy in mice. Methods RNA from laser capture microdissected (LCM) islets of partially pancreatectomized and sham-operated mice were profiled with microarrays to identify putative miRNAs implicated in beta cell regeneration. Altered expression of the selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA, protein expression levels, and signaling upon miR-132 knockdown and/or overexpression in mouse MIN6 and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pancreatectomized miR-132−/− and control mice. Results Partial pancreatectomy significantly increased the number of BrdU+/insulin+ islet cells. Microarray profiling revealed that 14 miRNAs, including miR-132 and -141, were significantly upregulated in the LCM islets of the partially pancreatectomized mice compared to the LCM islets of the control mice. In the same comparison, miR-760 was the only downregulated miRNA. The changed expression of these miRNAs in the islets of the partially pancreatectomized mice was confirmed by RT-PCR only in the case of miR-132 and -141. Based on previous knowledge of its function, we focused our attention on miR-132. Downregulation of miR-132 reduced the proliferation of MIN6 cells while enhancing the levels of pro-apoptotic cleaved caspase-9. The opposite was observed in miR-132 overexpressing MIN6 cells. Microarray profiling, RT-PCR, and immunoblotting of the latter cells demonstrated their downregulated expression of Pten with concomitant increased levels of pro-proliferative factors phospho-Akt and phospho-Creb and inactivation of pro-apoptotic Foxo3a via its phosphorylation. Downregulation of Pten was further confirmed in the LCM islets of pancreatectomized mice compared to the sham-operated mice. Moreover, overexpression of miR-132 correlated with increased proliferation of EndoC-βH1 cells. The regeneration of beta cells following partial pancreatectomy was lower in the miR-132/212−/− mice than the control littermates. Conclusions This study provides compelling evidence about the critical role of miR-132 for the regeneration of mouse islet beta cells through the downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell mass.
miR-132 is induced in mouse islets upon partial pancreatectomy. miR-132 promotes regeneration of β-cells in vivo following partial pancreatectomy. miR-132 fosters in vitro proliferation/survival through Pten/Akt/Foxo3 signaling. Downstream targets of miR-132 were identified in pancreatic β-cells. miR-132−/− mice have impaired β-cell proliferation.
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Affiliation(s)
- Hassan Mziaut
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Georg Henniger
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Katharina Ganss
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Sebastian Hempel
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Steffen Wolk
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Johanna McChord
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Kamal Chowdhury
- Max Planck Institute of Biophysical Chemistry, Göttingen, Germany
| | - Philippe Ravassard
- Sorbonne Universités, UPMC Univ Paris 06, INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Épinière, ICM, F-75013, Paris, France
| | - Klaus-Peter Knoch
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Christian Krautz
- Department of Surgery, University of Erlangen, Erlangen, Germany
| | - Jürgen Weitz
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Robert Grützmann
- Department of Surgery, University of Erlangen, Erlangen, Germany
| | | | - Michele Solimena
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
| | - Stephan Kersting
- Department of Surgery, University of Erlangen, Erlangen, Germany.
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125I suppressed the Warburg effect viaregulating miR-338/PFKL axis in hepatocellular carcinoma. Biomed Pharmacother 2019; 119:109402. [PMID: 31514072 DOI: 10.1016/j.biopha.2019.109402] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 08/20/2019] [Accepted: 08/28/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Iodine-125 (125I) irradiation has been widely applied in the treatment of advanced multiple malignant tumors. However, the underlying mechanism of 125I exerted an anti-tumor effect on hepatocellular carcinoma (HCC) was largely unknown. METHODS In both HCCLM3 and SMMC-7721 cells, the effect of 125I irradiation on the glycolysis was detected. The mRNA in HCC tissues and cell lines were detected by RT-qPCR. Cell proliferation, invasion and migration, and apoptosis were examined by CCK-8, Transwell, wound healing assay and flow cytometry assay, respectively. The interaction between miR-338 and PFKL (6-phosphofructokinase) were verified by dual-luciferase reporter gene assay. Western blotting was used to detect the expression of glycolysis-related proteins. We also evaluated the effect of 125I seed implantation on the tumor growth and Warburg effect in vivo. RESULTS 125I irradiation significantly decreased the Warburg effect, cell proliferation, invasion and migration, and induced apoptosis of HCCLM3 and SMMC-7721 cells. miR-338 was upregulated in HCC cells treated with 125I irradiation, which was a negative correlation with tumor size, tumor metastasis, and tumor development. Moreover, miR-338 directly interacted with PFKL and suppressed its expression. Mechanistically, 125I irradiation significantly decreased the Warburg effect and exhibited anti-tumorigenesis function through upregulating the inhibitory effect of miR-338 on PFKL expression. CONCLUSION 125I irradiation upregulated the suppression of miR-338 on PFKL to downregulate the Warburg effect and anti-tumorigenesis in HCC and provided a new potential strategy for HCC clinical treatment.
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Abstract
Hyperglycemia is common during pregnancy, involving multisystem adaptations. Pregnancy-induced metabolic changes increase insulin resistance. Pregnancy-induced insulin resistance adds to preexisting insulin resistance. Preexisting pancreatic β-cell defect compromises the ability to enhance insulin secretion, leading to hyperglycemia. Women with type 2 DM have similar rates of major congenital malformations, stillbirth, and neonatal mortality, but an even higher risk of perinatal mortality. In utero type 2 DM exposure confers greater risk and reduces time to development of type 2 DM in offspring. Preconception care to improve metabolic control in women with type 2 diabetes is critical.
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Affiliation(s)
- Anil Kapur
- World Diabetes Foundation, 30 A, Krogshoejvej, Bagsverd 2880, Denmark; FIGO Pregnancy and NCD Committee, Jabotinski Street, Petah Tiqwa 49100, Israel.
| | - Harold David McIntyre
- FIGO Pregnancy and NCD Committee, Jabotinski Street, Petah Tiqwa 49100, Israel; UQ Mater Clinical Unit, Faculty of Medicine, Mater Health Services, University of Queensland, Raymond Terrace, South Brisbane, Brisbane, Qld 4101, Australia
| | - Moshe Hod
- FIGO Pregnancy and NCD Committee, Jabotinski Street, Petah Tiqwa 49100, Israel; Department of Obstetrics and Gynecology, Clalit Health Services, Mor Women's Health Center, Rabin Medical Center, Tel Aviv University, 18 Aba Ahimeir St., Tel Aviv 6949204, Israel
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Handgraaf S, Philippe J. The Role of Sexual Hormones on the Enteroinsular Axis. Endocr Rev 2019; 40:1152-1162. [PMID: 31074764 DOI: 10.1210/er.2019-00004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 05/03/2019] [Indexed: 12/17/2022]
Abstract
Sex steroid estrogens, androgens, and progesterone, produced by the gonads, which have long been considered as endocrine glands, are implicated in sexual differentiation, puberty, and reproduction. However, the impact of sex hormones goes beyond these effects through their role on energy metabolism. Indeed, sex hormones are important physiological regulators of glucose homeostasis and, in particular, of the enteroinsular axis. In this review, we describe the roles of estrogens, androgens, and progesterone on glucose homeostasis through their effects on pancreatic α- and β-cells, as well as on enteroendocrine L-cells, and their implications in hormonal biosynthesis and secretion. The analysis of their mechanisms of action with the dissection of the receptors implicated in the several protective effects could provide some new aspects of the fine-tuning of hormonal secretion under the influence of the sex. This knowledge paves the way to the understanding of transgender physiology and new potential therapeutics in the field of type 2 diabetes.
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Affiliation(s)
- Sandra Handgraaf
- Laboratory of Molecular Diabetes, Division of Endocrinology, Diabetes, Hypertension, and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School, Geneva, Switzerland
| | - Jacques Philippe
- Laboratory of Molecular Diabetes, Division of Endocrinology, Diabetes, Hypertension, and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School, Geneva, Switzerland
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Kim M, Zhang X. The Profiling and Role of miRNAs in Diabetes Mellitus. JOURNAL OF DIABETES AND CLINICAL RESEARCH 2019; 1:5-23. [PMID: 32432227 PMCID: PMC7236805 DOI: 10.33696/diabetes.1.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus (DM), a complex metabolic disease, has become a global threat to human health worldwide. Over the past decades, an enormous amount of effort has been devoted to understand how microRNAs (miRNAs), a class of small non-coding RNA regulators of gene expression at the post-transcriptional level, are implicated in DM pathology. Growing evidence suggests that the expression signature of a specific set of miRNAs has been altered in the progression of DM. In the present review, we summarize the recent investigations on the miRNA profiles as novel DM biomarkers in clinical studies and in animal models, and highlight recent discoveries on the complex regulatory effect and functional role of miRNAs in DM.
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Affiliation(s)
- Michael Kim
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY, USA
| | - Xiaokan Zhang
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY, USA
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Yin J, Chen X, Wang CC, Zhao Y, Sun YZ. Prediction of Small Molecule–MicroRNA Associations by Sparse Learning and Heterogeneous Graph Inference. Mol Pharm 2019; 16:3157-3166. [DOI: 10.1021/acs.molpharmaceut.9b00384] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Jun Yin
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Xing Chen
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Chun-Chun Wang
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Yan Zhao
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Ya-Zhou Sun
- College of Computer Science and Software Engineering, Shenzhen University, Shenzhen 518060, China
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Banerjee RR. Piecing together the puzzle of pancreatic islet adaptation in pregnancy. Ann N Y Acad Sci 2019; 1411:120-139. [PMID: 29377199 DOI: 10.1111/nyas.13552] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 10/18/2017] [Accepted: 10/24/2017] [Indexed: 12/20/2022]
Abstract
Pregnancy places acute demands on maternal physiology, including profound changes in glucose homeostasis. Gestation is characterized by an increase in insulin resistance, counterbalanced by an adaptive increase in pancreatic β cell production of insulin. Failure of normal adaptive responses of the islet to increased maternal and fetal demands manifests as gestational diabetes mellitus (GDM). The gestational changes and rapid reversal of islet adaptations following parturition are at least partly driven by an anticipatory program rather than post-factum compensatory adaptations. Here, I provide a comprehensive review of the cellular and molecular mechanisms underlying normal islet adaptation during pregnancy and how dysregulation may lead to GDM. Emerging areas of interest and understudied areas worthy of closer examination in the future are highlighted.
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Affiliation(s)
- Ronadip R Banerjee
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, and the Comprehensive Diabetes Center, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
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Wang CC, Chen X, Qu J, Sun YZ, Li JQ. RFSMMA: A New Computational Model to Identify and Prioritize Potential Small Molecule-MiRNA Associations. J Chem Inf Model 2019; 59:1668-1679. [PMID: 30840454 DOI: 10.1021/acs.jcim.9b00129] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
More and more studies found that many complex human diseases occur accompanied by aberrant expression of microRNAs (miRNAs). Small molecule (SM) drugs have been utilized to treat complex human diseases by affecting the expression of miRNAs. Several computational methods were proposed to infer underlying associations between SMs and miRNAs. In our study, we proposed a new calculation model of random forest based small molecule-miRNA association prediction (RFSMMA) which was based on the known SM-miRNA associations in the SM2miR database. RFSMMA utilized the similarity of SMs and miRNAs as features to represent SM-miRNA pairs and further implemented the machine learning algorithm of random forest to train training samples and obtain a prediction model. In RFSMMA, integrating multiple kinds of similarity can avoid the bias of single similarity and choosing more reliable features from original features can represent SM-miRNA pairs more accurately. We carried out cross validations to assess predictive accuracy of RFSMMA. As a result, RFSMMA acquired AUCs of 0.9854, 0.9839, 0.7052, and 0.9917 ± 0.0008 under global leave-one-out cross validation (LOOCV), miRNA-fixed local LOOCV, SM-fixed local LOOCV, and 5-fold cross validation, respectively, under data set 1. Based on data set 2, RFSMMA obtained AUCs of 0.8456, 0.8463, 0.6653, and 0.8389 ± 0.0033 under four cross validations according to the order mentioned above. In addition, we implemented a case study on three common SMs, namely, 5-fluorouracil, 17β-estradiol, and 5-aza-2'-deoxycytidine. Among the top 50 associated miRNAs of these three SMs predicted by RFSMMA, 31, 32, and 28 miRNAs were verified, respectively. Therefore, RFSMMA is shown to be an effective and reliable tool for identifying underlying SM-miRNA associations.
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Affiliation(s)
- Chun-Chun Wang
- School of Information and Control Engineering , China University of Mining and Technology , Xuzhou 221116 , China
| | - Xing Chen
- School of Information and Control Engineering , China University of Mining and Technology , Xuzhou 221116 , China
| | - Jia Qu
- School of Information and Control Engineering , China University of Mining and Technology , Xuzhou 221116 , China
| | - Ya-Zhou Sun
- College of Computer Science and Software Engineering , Shenzhen University , Shenzhen 518060 , China
| | - Jian-Qiang Li
- College of Computer Science and Software Engineering , Shenzhen University , Shenzhen 518060 , China
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Baeyens L, Lemper M, Staels W, De Groef S, De Leu N, Heremans Y, German MS, Heimberg H. (Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives. Physiol Rev 2018; 98:1143-1167. [PMID: 29717931 DOI: 10.1152/physrev.00034.2016] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus results from disturbed glucose homeostasis due to an absolute (type 1) or relative (type 2) deficiency of insulin, a peptide hormone almost exclusively produced by the beta cells of the endocrine pancreas in a tightly regulated manner. Current therapy only delays disease progression through insulin injection and/or oral medications that increase insulin secretion or sensitivity, decrease hepatic glucose production, or promote glucosuria. These drugs have turned diabetes into a chronic disease as they do not solve the underlying beta cell defects or entirely prevent the long-term complications of hyperglycemia. Beta cell replacement through islet transplantation is a more physiological therapeutic alternative but is severely hampered by donor shortage and immune rejection. A curative strategy should combine newer approaches to immunomodulation with beta cell replacement. Success of this approach depends on the development of practical methods for generating beta cells, either in vitro or in situ through beta cell replication or beta cell differentiation. This review provides an overview of human beta cell generation.
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Affiliation(s)
- Luc Baeyens
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Marie Lemper
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Willem Staels
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Sofie De Groef
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Nico De Leu
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Yves Heremans
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Michael S German
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Harry Heimberg
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
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Diabetes in Pregnancy and MicroRNAs: Promises and Limitations in Their Clinical Application. Noncoding RNA 2018; 4:ncrna4040032. [PMID: 30424584 PMCID: PMC6316501 DOI: 10.3390/ncrna4040032] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 10/29/2018] [Accepted: 11/05/2018] [Indexed: 12/12/2022] Open
Abstract
Maternal diabetes is associated with an increased risk of complications for the mother and her offspring. The latter have an increased risk of foetal macrosomia, hypoglycaemia, respiratory distress syndrome, preterm delivery, malformations and mortality but also of life-long development of obesity and diabetes. Epigenetics have been proposed as an explanation for this long-term risk, and microRNAs (miRNAs) may play a role, both in short- and long-term outcomes. Gestation is associated with increasing maternal insulin resistance, as well as β-cell expansion, to account for the increased insulin needs and studies performed in pregnant rats support a role of miRNAs in this expansion. Furthermore, several miRNAs are involved in pancreatic embryonic development. On the other hand, maternal diabetes is associated with changes in miRNA both in maternal and in foetal tissues. This review aims to summarise the existing knowledge on miRNAs in gestational and pre-gestational diabetes, both as diagnostic biomarkers and as mechanistic players, in the development of gestational diabetes itself and also of short- and long-term complications for the mother and her offspring.
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miR-338-3p Is Regulated by Estrogens through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts (CAFs). Cells 2018; 7:cells7110203. [PMID: 30423928 PMCID: PMC6262471 DOI: 10.3390/cells7110203] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 11/02/2018] [Accepted: 11/07/2018] [Indexed: 12/12/2022] Open
Abstract
Estrogens acting through the classic estrogen receptors (ERs) and the G protein estrogen receptor (GPER) regulate the expression of diverse miRNAs, small sequences of non-coding RNA involved in several pathophysiological conditions, including breast cancer. In order to provide novel insights on miRNAs regulation by estrogens in breast tumor, we evaluated the expression of 754 miRNAs by TaqMan Array in ER-negative and GPER-positive SkBr3 breast cancer cells and cancer-associated fibroblasts (CAFs) upon 17β-estradiol (E2) treatment. Various miRNAs were regulated by E2 in a peculiar manner in SkBr3 cancer cells and CAFs, while miR-338-3p displayed a similar regulation in both cell types. By METABRIC database analysis we ascertained that miR-338-3p positively correlates with overall survival in breast cancer patients, according to previous studies showing that miR-338-3p may suppress the growth and invasion of different cancer cells. Well-fitting with these data, a miR-338-3p mimic sequence decreased and a miR-338-3p inhibitor sequence rescued the expression of genes and the proliferative effects induced by E2 through GPER in SkBr3 cancer cells and CAFs. Altogether, our results provide novel evidence on the molecular mechanisms by which E2 may regulate miR-338-3p toward breast cancer progression.
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Moyce BL, Dolinsky VW. Maternal β-Cell Adaptations in Pregnancy and Placental Signalling: Implications for Gestational Diabetes. Int J Mol Sci 2018; 19:ijms19113467. [PMID: 30400566 PMCID: PMC6274918 DOI: 10.3390/ijms19113467] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/24/2018] [Accepted: 10/31/2018] [Indexed: 12/14/2022] Open
Abstract
Rates of gestational diabetes mellitus (GDM) are on the rise worldwide, and the number of pregnancies impacted by GDM and resulting complications are also increasing. Pregnancy is a period of unique metabolic plasticity, during which mild insulin resistance is a physiological adaptation to prioritize fetal growth. To compensate for this, the pancreatic β-cell utilizes a variety of adaptive mechanisms, including increasing mass, number and insulin-secretory capacity to maintain glucose homeostasis. When insufficient insulin production does not overcome insulin resistance, hyperglycemia can occur. Changes in the maternal system that occur in GDM such as lipotoxicity, inflammation and oxidative stress, as well as impairments in adipokine and placental signalling, are associated with impaired β-cell adaptation. Understanding these pathways, as well as mechanisms of β-cell dysfunction in pregnancy, can identify novel therapeutic targets beyond diet and lifestyle interventions, insulin and antihyperglycemic agents currently used for treating GDM.
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Affiliation(s)
- Brittany L Moyce
- Department of Pharmacology & Therapeutics and the Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children's Hospital Research Institute of Manitoba and the Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
| | - Vernon W Dolinsky
- Department of Pharmacology & Therapeutics and the Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children's Hospital Research Institute of Manitoba and the Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
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50
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Wang X, Zhang X, Li F, Ji Q. MiR‐128‐3p accelerates cardiovascular calcification and insulin resistance through ISL1‐dependent Wnt pathway in type 2 diabetes mellitus rats. J Cell Physiol 2018; 234:4997-5010. [PMID: 30341898 DOI: 10.1002/jcp.27300] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 08/01/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Xin‐Yong Wang
- Department of Internal Medicine Linyi Jiaotong Hospital Linyi China
| | - Xian‐Zhao Zhang
- Department of Cardiology Linyi People's Hospital Linyi China
| | - Feng Li
- Clinical Laboratory The Third People's Hospital of Linyi Linyi China
| | - Qing‐Rong Ji
- Department of Cardiology Linyi People's Hospital Linyi China
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