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Cobo‐Vuilleumier N, Rodríguez‐Fernandez S, López‐Noriega L, Lorenzo PI, Franco JM, Lachaud CC, Vazquez EM, Legido RA, Dorronsoro A, López‐Férnandez‐Sobrino R, Fernández‐Santos B, Serrano CE, Salas‐Lloret D, van Overbeek N, Ramos‐Rodriguez M, Mateo‐Rodríguez C, Hidalgo L, Marin‐Canas S, Nano R, Arroba AI, Caro AC, Vertegaal ACO, Martín‐Montalvo A, Martín F, Aguilar‐Diosdado M, Piemonti L, Pasquali L, Prieto RG, Sánchez MIG, Eizirik DL, Martínez‐Brocca MA, Vives‐Pi M, Gauthier BR. LRH-1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype. Clin Transl Med 2024; 14:e70134. [PMID: 39702941 PMCID: PMC11659195 DOI: 10.1002/ctm2.70134] [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: 07/12/2024] [Revised: 11/01/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross-talk between the immune system and insulin-producing beta cells, has hindered the development of effective disease-modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH-1/NR5A2 activation and improve islet survival. METHODS Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH-1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T-cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001-target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co-cultures of PBMCs and iPSCs-derived islet organoids were performed to assess the impact of BL001 on beta cell viability. RESULTS LRH-1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro-inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro-inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro-inflammatory to an anti-inflammatory/tolerogenic state, resulting in the inhibition of CD4+ and CD8+ T-cell proliferation. BL001 treatment also increased CD4+/CD25+/FoxP3+ regulatory T-cells and Th2 cells within PBMCs while decreasing CD8+ T-cell proliferation. Additionally, BL001 alleviated PBMC-induced apoptosis and maintained insulin expression in human iPSC-derived islet organoids. CONCLUSION These findings demonstrate the potential of LRH-1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach. KEY POINTS LRH-1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro-inflammatory cell surface markers and cytokine release. LRH-1/NR5A2 promotes a mitohormesis-induced immuno-resistant phenotype to pro-inflammatory macrophages. Mature dendritic cells acquire a tolerogenic phenotype via LRH-1/NR5A2-stimulated mitochondria turnover. LRH-1/NR5A2 agonistic activation expands a CD4+/CD25+/FoxP3+ T-cell subpopulation. Pharmacological activation of LRH-1/NR5A2 improves the survival iPSC-islets-like organoids co-cultured with PBMCs from individuals with T1D.
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Rohban R, Martins CP, Esni F. Advanced therapy to cure diabetes: mission impossible is now possible? Front Cell Dev Biol 2024; 12:1484859. [PMID: 39629270 PMCID: PMC11611888 DOI: 10.3389/fcell.2024.1484859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Cell and Gene therapy are referred to as advanced therapies that represent overlapping fields of regenerative medicine. They have similar therapeutic goals such as to modify cellular identity, improve cell function, or fight a disease. These two therapeutic avenues, however, possess major differences. While cell therapy involves introduction of new cells, gene therapy entails introduction or modification of genes. Furthermore, the aim of cell therapy is often to replace, or repair damaged tissue, whereas gene therapy is used typically as a preventive approach. Diabetes mellitus severely affects the quality of life of afflicted individuals and has various side effects including cardiovascular, ophthalmic disorders, and neuropathy while putting enormous economic pressure on both the healthcare system and the patient. In recent years, great effort has been made to develop cutting-edge therapeutic interventions for diabetes treatment, among which cell and gene therapies stand out. This review aims to highlight various cell- and gene-based therapeutic approaches leading to the generation of new insulin-producing cells as a topmost "panacea" for treating diabetes, while deliberately avoiding a detailed molecular description of these approaches. By doing so, we aim to target readers who are new to the field and wish to get a broad helicopter overview of the historical and current trends of cell- and gene-based approaches in β-cell regeneration.
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Affiliation(s)
- Rokhsareh Rohban
- Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria
| | - Christina P. Martins
- Department of Surgery, Division of Pediatric General and Thoracic Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Farzad Esni
- Department of Surgery, Division of Pediatric General and Thoracic Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, United States
- UPMC Hillman Cancer Center, Pittsburgh, PA, United States
- McGowan Institute for regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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Lachaud CC, Cobo-Vuilleumier N, Fuente-Martin E, Diaz I, Andreu E, Cahuana GM, Tejedo JR, Hmadcha A, Gauthier BR, Soria B. Umbilical cord mesenchymal stromal cells transplantation delays the onset of hyperglycemia in the RIP-B7.1 mouse model of experimental autoimmune diabetes through multiple immunosuppressive and anti-inflammatory responses. Front Cell Dev Biol 2023; 11:1089817. [PMID: 36875761 PMCID: PMC9976335 DOI: 10.3389/fcell.2023.1089817] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 02/03/2023] [Indexed: 02/17/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disorder specifically targeting pancreatic islet beta cells. Despite many efforts focused on identifying new therapies able to counteract this autoimmune attack and/or stimulate beta cells regeneration, TD1M remains without effective clinical treatments providing no clear advantages over the conventional treatment with insulin. We previously postulated that both the inflammatory and immune responses and beta cell survival/regeneration must be simultaneously targeted to blunt the progression of disease. Umbilical cord-derived mesenchymal stromal cells (UC-MSC) exhibit anti-inflammatory, trophic, immunomodulatory and regenerative properties and have shown some beneficial yet controversial effects in clinical trials for T1DM. In order to clarify conflicting results, we herein dissected the cellular and molecular events derived from UC-MSC intraperitoneal administration (i.p.) in the RIP-B7.1 mouse model of experimental autoimmune diabetes. Intraperitoneal (i.p.) transplantation of heterologous mouse UC-MSC delayed the onset of diabetes in RIP-B7.1 mice. Importantly, UC-MSC i. p. transplantation led to a strong peritoneal recruitment of myeloid-derived suppressor cells (MDSC) followed by multiple T-, B- and myeloid cells immunosuppressive responses in peritoneal fluid cells, spleen, pancreatic lymph nodes and the pancreas, which displayed significantly reduced insulitis and pancreatic infiltration of T and B Cells and pro-inflammatory macrophages. Altogether, these results suggest that UC-MSC i. p. transplantation can block or delay the development of hyperglycemia through suppression of inflammation and the immune attack.
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Affiliation(s)
- C C Lachaud
- Department of Cell Therapy and Regeneration, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - N Cobo-Vuilleumier
- Department of Cell Therapy and Regeneration, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - E Fuente-Martin
- Department of Cell Therapy and Regeneration, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - I Diaz
- Department of Cell Therapy and Regeneration, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - E Andreu
- Institute of Bioengineering and Health Research Institute (ISABIAL), Dr. Balmis University Hospital (HGUA), Miguel Hernández University School of Medicine, Alicante, Spain.,Department of Applied Physics, University Miguel Hernández, Alicante, Spain
| | - G M Cahuana
- Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain.,Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain
| | - J R Tejedo
- Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain.,Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain
| | - A Hmadcha
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.,Instituto de Investigación Biosanitaria, Universidad Internacional de Valencia (VIU), Valencia, Spain
| | - B R Gauthier
- Department of Cell Therapy and Regeneration, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain.,Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain
| | - B Soria
- Institute of Bioengineering and Health Research Institute (ISABIAL), Dr. Balmis University Hospital (HGUA), Miguel Hernández University School of Medicine, Alicante, Spain.,Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain.,Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain
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Glucagon-receptor-antagonism-mediated β-cell regeneration as an effective anti-diabetic therapy. Cell Rep 2022; 39:110872. [PMID: 35649369 DOI: 10.1016/j.celrep.2022.110872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 02/12/2022] [Accepted: 05/04/2022] [Indexed: 01/10/2023] Open
Abstract
Type 1 diabetes mellitus (T1D) is a chronic disease with potentially severe complications, and β-cell deficiency underlies this disease. Despite active research, no therapy to date has been able to induce β-cell regeneration in humans. Here, we discover the β-cell regenerative effects of glucagon receptor antibody (anti-GcgR). Treatment with anti-GcgR in mouse models of β-cell deficiency leads to reversal of hyperglycemia, increase in plasma insulin levels, and restoration of β-cell mass. We demonstrate that both β-cell proliferation and α- to β-cell transdifferentiation contribute to anti-GcgR-induced β-cell regeneration. Interestingly, anti-GcgR-induced α-cell hyperplasia can be uncoupled from β-cell regeneration after antibody clearance from the body. Importantly, we are able to show that anti-GcgR-induced β-cell regeneration is also observed in non-human primates. Furthermore, anti-GcgR and anti-CD3 combination therapy reverses diabetes and increases β-cell mass in a mouse model of autoimmune diabetes.
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Martin Vázquez E, Cobo-Vuilleumier N, Araujo Legido R, Marín-Cañas S, Nola E, Dorronsoro A, López Bermudo L, Crespo A, Romero-Zerbo SY, García-Fernández M, Martin Montalvo A, Rojas A, Comaills V, Bérmudez-Silva FJ, Gannon M, Martin F, Eizirik D, Lorenzo PI, Gauthier BR. NR5A2/LRH-1 regulates the PTGS2-PGE 2-PTGER1 pathway contributing to pancreatic islet survival and function. iScience 2022; 25:104345. [PMID: 35602948 PMCID: PMC9117883 DOI: 10.1016/j.isci.2022.104345] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/30/2022] [Accepted: 04/28/2022] [Indexed: 11/29/2022] Open
Abstract
LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglycemia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE2 levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist-ONO-8130-negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE2/PTGER1 signaling axis as a key pathway mediating BL001 survival properties.
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Affiliation(s)
- Eugenia Martin Vázquez
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Nadia Cobo-Vuilleumier
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Raquel Araujo Legido
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Sandra Marín-Cañas
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Emanuele Nola
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Akaitz Dorronsoro
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Lucia López Bermudo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Alejandra Crespo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Silvana Y. Romero-Zerbo
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
- Facultad de Medicina, Departamento de Fisiología Humana, Anatomía Patológica y Educación Físico Deportiva, Universidad de Málaga, Málaga, Spain
| | - Maria García-Fernández
- Facultad de Medicina, Departamento de Fisiología Humana, Anatomía Patológica y Educación Físico Deportiva, Universidad de Málaga, Málaga, Spain
| | - Alejandro Martin Montalvo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Anabel Rojas
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Valentine Comaills
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Francisco J. Bérmudez-Silva
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Maureen Gannon
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville USA
| | - Franz Martin
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Decio Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Petra I. Lorenzo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Benoit R. Gauthier
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
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Falcetta P, Aragona M, Bertolotto A, Bianchi C, Campi F, Garofolo M, Del Prato S. Insulin discovery: A pivotal point in medical history. Metabolism 2022; 127:154941. [PMID: 34838778 DOI: 10.1016/j.metabol.2021.154941] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 11/10/2021] [Accepted: 11/20/2021] [Indexed: 01/12/2023]
Abstract
The discovery of insulin in 1921 - due to the efforts of the Canadian research team based in Toronto - has been a landmark achievement in the history of medicine. Lives of people with diabetes were changed forever, considering that in the pre-insulin era this was a deadly condition. Insulin, right after its discovery, became the first hormone to be purified for human use, the first to be unraveled in its amino acid sequence and to be synthetized by DNA-recombinant technique, the first to be modified in its amino acid sequence to modify its duration of action. As such the discovery of insulin represents a pivotal point in medical history. Since the early days of its production, insulin has been improved in its pharmacokinetic and pharmacodynamic properties in the attempt to faithfully reproduce diurnal physiologic plasma insulin fluctuations. The evolution of insulin molecule has been paralleled by evolution in the way the hormone is administered. Once-weekly insulins will be available soon, and glucose-responsive "smart" insulins start showing their potential in early clinical studies. The first century of insulin as therapy was marked by relentless search for better formulations, a search that has not stopped yet. New technologies may have, indeed, the potential to provide further improvement of safety and efficacy of insulin therapy and, therefore, contribute to improvement of the quality of life of people with diabetes.
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Affiliation(s)
- Pierpaolo Falcetta
- Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Via Trivella, 56124 Pisa, Italy.
| | - Michele Aragona
- Section of Metabolic Diseases and Diabetes, Azienda Ospedaliero-Universitaria Pisana, Via Trivella, 56124 Pisa, Italy.
| | - Alessandra Bertolotto
- Section of Metabolic Diseases and Diabetes, Azienda Ospedaliero-Universitaria Pisana, Via Trivella, 56124 Pisa, Italy.
| | - Cristina Bianchi
- Section of Metabolic Diseases and Diabetes, Azienda Ospedaliero-Universitaria Pisana, Via Trivella, 56124 Pisa, Italy.
| | - Fabrizio Campi
- Section of Metabolic Diseases and Diabetes, Azienda Ospedaliero-Universitaria Pisana, Via Trivella, 56124 Pisa, Italy.
| | - Monia Garofolo
- Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Via Trivella, 56124 Pisa, Italy.
| | - Stefano Del Prato
- Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Via Trivella, 56124 Pisa, Italy.
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Gauthier BR, Cobo-Vuilleumier N, López-Noriega L. Roles of extracellular vesicles associated non-coding RNAs in Diabetes Mellitus. Front Endocrinol (Lausanne) 2022; 13:1057407. [PMID: 36619588 PMCID: PMC9814720 DOI: 10.3389/fendo.2022.1057407] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022] Open
Abstract
Extracellular vesicles (EVs), especially exosomes (50 to 150 nm), have been shown to play important roles in a wide range of physiological and pathological processes, including metabolic diseases such as Diabetes Mellitus (DM). In the last decade, several studies have demonstrated how EVs are involved in cell-to-cell communication. EVs are enriched in proteins, mRNAs and non-coding RNAs (miRNAs, long non-coding RNAs and circRNAS, among others) which are transferred to recipient cells and may have a profound impact in either their survival or functionality. Several studies have pointed out the contribution of exosomal miRNAs, such as miR-l42-3p and miR-26, in the development of Type 1 and Type 2 DM (T1DM and T2DM), respectively. In addition, some miRNA families such as miR-let7 and miR-29 found in exosomes have been associated with both types of diabetes, suggesting that they share common etiological features. The knowledge about the role of exosomal long non-coding RNAs in this group of diseases is more immature, but the exosomal lncRNA MALAT1 has been found to be elevated in the plasma of individuals with T2DM, while more than 169 lncRNAs were reported to be differentially expressed between healthy donors and people with T1DM. Here, we review the current knowledge about exosomal non-coding RNAs in DM and discuss their potential as novel biomarkers and possible therapeutic targets.
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Affiliation(s)
- Benoit R. Gauthier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain
- Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Madrid, Spain
- *Correspondence: Benoit R. Gauthier, ; Livia López-Noriega,
| | - Nadia Cobo-Vuilleumier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain
| | - Livia López-Noriega
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain
- *Correspondence: Benoit R. Gauthier, ; Livia López-Noriega,
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González-Mariscal I, Pozo-Morales M, Romero-Zerbo SY, Espinosa-Jimenez V, Escamilla-Sánchez A, Sánchez-Salido L, Cobo-Vuilleumier N, Gauthier BR, Bermúdez-Silva FJ. Abnormal cannabidiol ameliorates inflammation preserving pancreatic beta cells in mouse models of experimental type 1 diabetes and beta cell damage. Biomed Pharmacother 2021; 145:112361. [PMID: 34872800 DOI: 10.1016/j.biopha.2021.112361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 11/02/2022] Open
Abstract
The atypical cannabinoid Abn-CBD improves the inflammatory status in preclinical models of several pathologies, including autoimmune diseases. However, its potential for modulating inflammation in autoimmune type 1 diabetes (T1D) is unknown. Herein we investigate whether Abn-CBD can modulate the inflammatory response during T1D onset using a mouse model of T1D (non-obese diabetic- (NOD)-mice) and of beta cell damage (streptozotocin (STZ)-injected mice). Six-week-old female NOD mice were treated with Abn-CBD (0.1-1 mg/kg) or vehicle during 12 weeks and then euthanized. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1 mg/kg of body weight) or vehicle for 1 week, following STZ challenge, and euthanized 1 week later. Blood, pancreas, pancreatic lymph nodes (PLNs) and T cells were collected and processed for analysis. Glycemia was also monitored. In NOD mice, treatment with Abn-CBD significantly reduced the severity of insulitis and reduced the pro-inflammatory profile of CD4+ T cells compared to vehicle. Concomitantly, Abn-CBD significantly reduced islet cell apoptosis and improved glucose tolerance. In STZ-injected mice, Abn-CBD decreased circulating proinflammatory cytokines and ameliorated islet inflammation reducing intra-islet phospho-NF-κB and TXNIP. Abn-CBD significantly reduced 2 folds intra-islet CD8+ T cells and reduced Th1/non-Th1 ratio in PLNs of STZ-injected mice. Islet cell apoptosis and intra-islet fibrosis were also significantly reduced in Abn-CBD pre-treated mice compared to vehicle. Altogether, Abn-CBD reduces circulating and intra-islet inflammation, preserving islets, thus delaying the progression of insulitis. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat the early stages of T1D.
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Affiliation(s)
- Isabel González-Mariscal
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, 29009 Málaga, Spain.
| | - Macarena Pozo-Morales
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, 29009 Málaga, Spain
| | - Silvana Y Romero-Zerbo
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, 29009 Málaga, Spain; Facultad de Medicina, Departamento de Fisiología Humana, Anatomía Patológica y Educación Físico Deportiva, Universidad de Málaga, 29071 Málaga, Spain
| | - Vanesa Espinosa-Jimenez
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, 29009 Málaga, Spain
| | - Alejandro Escamilla-Sánchez
- Facultad de Medicina, Departamento de Fisiología Humana, Anatomía Patológica y Educación Físico Deportiva, Universidad de Málaga, 29071 Málaga, Spain
| | | | - Nadia Cobo-Vuilleumier
- Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain
| | - Benoit R Gauthier
- Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain
| | - Francisco J Bermúdez-Silva
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, 29009 Málaga, Spain; Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain.
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9
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Insuela DBR, Ferrero MR, Gonçalves-de-Albuquerque CF, Chaves ADS, da Silva AYO, Castro-Faria-Neto HC, Simões RL, Barja-Fidalgo TC, Silva PMRE, Martins MA, Silva AR, Carvalho VF. Glucagon Reduces Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice. Front Immunol 2021; 12:633540. [PMID: 34295325 PMCID: PMC8290340 DOI: 10.3389/fimmu.2021.633540] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 06/21/2021] [Indexed: 11/28/2022] Open
Abstract
Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. 21 days after diabetes induction by intravenous injection of alloxan, we induced moderate sepsis in Swiss-Webster mice through cecum ligation and puncture (CLP). The glucagon receptor (GcgR) antagonist des-his1-[Glu9]-glucagon amide was injected intraperitoneally 24h and 1h before CLP. We also tested the effect of glucagon on CXCL1/KC-induced neutrophil migration to the peritoneal cavity in mice. Neutrophil chemotaxis in vitro was tested using transwell plates, and the expression of total PKA and phospho-PKA was evaluated by western blot. GcgR antagonist restored neutrophil migration, reduced CFU numbers in the peritoneal cavity and improved survival rate of diabetic mice after CLP procedure, however, the treatment did no alter hyperglycemia, CXCL1/KC plasma levels and blood neutrophilia. In addition, glucagon inhibited CXCL1/KC-induced neutrophil migration to the peritoneal cavity of non-diabetic mice. Glucagon also decreased the chemotaxis of neutrophils triggered by CXCL1/KC, PAF, or fMLP in vitro. The inhibitory action of glucagon occurred in parallel with the reduction of CXCL1/KC-induced actin polymerization in neutrophils in vitro, but not CD11a and CD11b translocation to cell surface. The suppressor effect of glucagon on CXCL1/KC-induced neutrophil chemotaxis in vitro was reversed by pre-treatment with GcgR antagonist and adenylyl cyclase or PKA inhibitors. Glucagon also increased PKA phosphorylation directly in neutrophils in vitro. Furthermore, glucagon impaired zymosan-A-induced ROS production by neutrophils in vitro. Human neutrophil chemotaxis and adherence to endothelial cells in vitro were inhibited by glucagon treatment. According to our results, this inhibition was independent of CD11a and CD11b translocation to neutrophil surface or neutrophil release of CXCL8/IL-8. Altogether, our results suggest that glucagon may be involved in the reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. This work collaborates with better understanding of the increased susceptibility and worsening of sepsis in diabetics, which can contribute to the development of new effective therapeutic strategies for diabetic septic patients.
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Affiliation(s)
| | - Maximiliano Ruben Ferrero
- Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Cassiano Felippe Gonçalves-de-Albuquerque
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.,Laboratory of Immunopharmacology, Biomedical Institute, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Amanda da Silva Chaves
- Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | | | - Hugo Caire Castro-Faria-Neto
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.,Laboratory of Inflammation, National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
| | - Rafael Loureiro Simões
- Laboratory of Cellular and Molecular Pharmacology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Thereza Christina Barja-Fidalgo
- Laboratory of Cellular and Molecular Pharmacology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Marco Aurélio Martins
- Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Adriana Ribeiro Silva
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.,Laboratory of Inflammation, National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
| | - Vinicius Frias Carvalho
- Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.,Laboratory of Inflammation, National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
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10
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Lorenzo PI, Martin Vazquez E, López-Noriega L, Fuente-Martín E, Mellado-Gil JM, Franco JM, Cobo-Vuilleumier N, Guerrero Martínez JA, Romero-Zerbo SY, Perez-Cabello JA, Rivero Canalejo S, Campos-Caro A, Lachaud CC, Crespo Barreda A, Aguilar-Diosdado M, García Fuentes E, Martin-Montalvo A, Álvarez Dolado M, Martin F, Rojo-Martinez G, Pozo D, Bérmudez-Silva FJ, Comaills V, Reyes JC, Gauthier BR. The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity. Theranostics 2021; 11:6983-7004. [PMID: 34093866 PMCID: PMC8171100 DOI: 10.7150/thno.57237] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/30/2021] [Indexed: 12/12/2022] Open
Abstract
Rationale: We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce reactive astrogliosis in an attempt to preserve the neuronal network and re-establish glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote reactive astrogliosis and increase susceptibility of neurons to stress-induced apoptosis. Such effects could be reversed by ORY1001 treatment both in vitro and in vivo, paving the way for a new therapeutic approach for Type 2 Diabetes Mellitus.
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Affiliation(s)
- Petra I. Lorenzo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Eugenia Martin Vazquez
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Livia López-Noriega
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Esther Fuente-Martín
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - José M. Mellado-Gil
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Jaime M. Franco
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Nadia Cobo-Vuilleumier
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - José A. Guerrero Martínez
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Silvana Y. Romero-Zerbo
- Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain
| | - Jesús A. Perez-Cabello
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Sabrina Rivero Canalejo
- Department of Normal and Pathological Histology and Cytology, University of Seville School of Medicine, Seville, Spain
| | - Antonio Campos-Caro
- University Hospital “Puerta del Mar”, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain
| | - Christian Claude Lachaud
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Alejandra Crespo Barreda
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Manuel Aguilar-Diosdado
- University Hospital “Puerta del Mar”, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain
- Endocrinology and Metabolism Department, University Hospital “Puerta del Mar”, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain
| | - Eduardo García Fuentes
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Spain
| | - Alejandro Martin-Montalvo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Manuel Álvarez Dolado
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Franz Martin
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Gemma Rojo-Martinez
- Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - David Pozo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Francisco J. Bérmudez-Silva
- Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Valentine Comaills
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - José C. Reyes
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Benoit R. Gauthier
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
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11
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Lorenzo PI, Cobo-Vuilleumier N, Martín-Vázquez E, López-Noriega L, Gauthier BR. Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes? Int J Mol Sci 2021; 22:4239. [PMID: 33921851 PMCID: PMC8073058 DOI: 10.3390/ijms22084239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetes is a chronic metabolic disease caused by an absolute or relative deficiency in functional pancreatic β-cells that leads to defective control of blood glucose. Current treatments for diabetes, despite their great beneficial effects on clinical symptoms, are not curative treatments, leading to a chronic dependence on insulin throughout life that does not prevent the secondary complications associated with diabetes. The overwhelming increase in DM incidence has led to a search for novel antidiabetic therapies aiming at the regeneration of the lost functional β-cells to allow the re-establishment of the endogenous glucose homeostasis. Here we review several aspects that must be considered for the development of novel and successful regenerative therapies for diabetes: first, the need to maintain the heterogeneity of islet β-cells with several subpopulations of β-cells characterized by different transcriptomic profiles correlating with differences in functionality and in resistance/behavior under stress conditions; second, the existence of an intrinsic islet plasticity that allows stimulus-mediated transcriptome alterations that trigger the transdifferentiation of islet non-β-cells into β-cells; and finally, the possibility of using agents that promote a fully functional/mature β-cell phenotype to reduce and reverse the process of dedifferentiation of β-cells during diabetes.
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Affiliation(s)
- Petra I. Lorenzo
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
| | - Nadia Cobo-Vuilleumier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
| | - Eugenia Martín-Vázquez
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
| | - Livia López-Noriega
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
| | - Benoit R. Gauthier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 028029 Madrid, Spain
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12
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Wang KL, Tao M, Wei TJ, Wei R. Pancreatic β cell regeneration induced by clinical and preclinical agents. World J Stem Cells 2021; 13:64-77. [PMID: 33584980 PMCID: PMC7859987 DOI: 10.4252/wjsc.v13.i1.64] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/16/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes, one of the most common chronic diseases in the modern world, has pancreatic β cell deficiency as a major part of its pathophysiological mechanism. Pancreatic regeneration is a potential therapeutic strategy for the recovery of β cell loss. However, endocrine islets have limited regenerative capacity, especially in adult humans. Almost all hypoglycemic drugs can protect β cells by inhibiting β cell apoptosis and dedifferentiation via correction of hyperglycemia and amelioration of the consequent inflammation and oxidative stress. Several agents, including glucagon-like peptide-1 and γ-aminobutyric acid, have been shown to promote β cell proliferation, which is considered the main source of the regenerated β cells in adult rodents, but with less clarity in humans. Pancreatic progenitor cells might exist and be activated under particular circumstances. Artemisinins and γ-aminobutyric acid can induce α-to-β cell conversion, although some disputes exist. Intestinal endocrine progenitors can transdeterminate into insulin-producing cells in the gut after FoxO1 deletion, and pharmacological research into FoxO1 inhibition is ongoing. Other cells, including pancreatic acinar cells, can transdifferentiate into β cells, and clinical and preclinical strategies are currently underway. In this review, we summarize the clinical and preclinical agents used in different approaches for β cell regeneration and make some suggestions regarding future perspectives for clinical application.
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Affiliation(s)
- Kang-Li Wang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Ming Tao
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Tian-Jiao Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
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13
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Qiu D, Nikita D, Zhang L, Deng J, Xia Z, Zhan J, Huang J, Liu L, Liu F, Duan J, Li J. ICAM-1 deletion delays the repair process in aging diabetic mice. Metabolism 2021; 114:154412. [PMID: 33164859 DOI: 10.1016/j.metabol.2020.154412] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 10/11/2020] [Accepted: 10/20/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND The delayed repair process in the aging diabetic population is becoming an alarming public health concern. ICAM-1 plays an important role in orchestrating the repair process by mediating neutrophil recruitment and phagocytosis. However, little is known about the role of ICAM-1 in aging diabetic repair. METHODS By causing injury in aging diabetic mice with ICAM-1 deletion (AD-ICAM-1-/-), we found that AD-ICAM-1-/- mice exhibited a delayed repair process with incomplete re-epithelialization and reduced angiogenesis. Additionally, high-throughput Illumina sequencing was performed to evaluate the microbiota of such mice. RESULTS The results indicate that the microbiota of the AD-ICAM-1-/- injury site differed taxonomically at both the phylum and genus levels. Neutrophil recruitment and phagocytic function were also reduced in the AD-ICAM-1-/- group. Notably, major inflammatory biomarker expression was also detected in AD-ICAM-1-/- injured tissue. CONCLUSIONS Overall, this study demonstrated that AD-ICAM-1-/- mice exhibit delayed repair. In addition, neutrophil recruitment and phagocytic activity were impaired in the AD-ICAM-1-/- group, which may have allowed microbes to colonize the injury site.
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Affiliation(s)
- Dongxu Qiu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - David Nikita
- School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Lei Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Jun Deng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Zhiwei Xia
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Junkun Zhan
- Department of Geriatrics, The Second Hospital of Xiangya, Hunan 410011, PR China
| | - Jiabing Huang
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Lanzhi Liu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Fan Liu
- Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Jingfeng Duan
- Department of Geriatrics, The Third Clinical Hospital of Xiangya Medical School, Hunan 410011, PR China
| | - Jing Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, PR China.
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14
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Artificial Pancreas Control Strategies Used for Type 1 Diabetes Control and Treatment: A Comprehensive Analysis. APPLIED SYSTEM INNOVATION 2020. [DOI: 10.3390/asi3030031] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
This paper presents a comprehensive survey about the fundamental components of the artificial pancreas (AP) system including insulin administration and delivery, glucose measurement (GM), and control strategies/algorithms used for type 1 diabetes mellitus (T1DM) treatment and control. Our main focus is on the T1DM that emerges due to pancreas’s failure to produce sufficient insulin due to the loss of beta cells (β-cells). We discuss various insulin administration and delivery methods including physiological methods, open-loop, and closed-loop schemes. Furthermore, we report several factors such as hyperglycemia, hypoglycemia, and many other physical factors that need to be considered while infusing insulin in human body via AP systems. We discuss three prominent control algorithms including proportional-integral- derivative (PID), fuzzy logic, and model predictive, which have been clinically evaluated and have all shown promising results. In addition, linear and non-linear insulin infusion control schemes have been formally discussed. To the best of our knowledge, this is the first work which systematically covers recent developments in the AP components with a solid foundation for future studies in the T1DM field.
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Buzzetti R, Zampetti S, Pozzilli P. Impact of obesity on the increasing incidence of type 1 diabetes. Diabetes Obes Metab 2020; 22:1009-1013. [PMID: 32157790 DOI: 10.1111/dom.14022] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/04/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023]
Abstract
Published estimates of the incidence of type 1 diabetes (T1D) in children in the last decade varies between 2% and 4% per annum. If this trend continued, the disease incidence would double in the next 20 years. The risk of developing T1D is determined by a complex interaction between multiple genes (mainly human leukocyte antigens) and environmental factors. Notwithstanding that genetic susceptibility represents a relevant element in T1D risk, genetics alone cannot explain the increase in incidence. Various environmental factors have been suggested as potential triggers for T1D, including several viruses and the hygiene hypothesis; however, none of these seems to explain the large increase in T1D incidence observed over the last decades. Several studies have demonstrated that the prevalence of childhood/adolescence overweight and obesity has risen during the past 30 years in T1D. Currently, at diagnosis, the majority of patients with T1D have normal or elevated body weight and ~50% of patients with longstanding T1D are either overweight or obese. The growing prevalence of obesity in childhood and adolescence offers a plausible explanation for the increase in T1D incidence observed in recent decades. Possible mechanisms of the enhancement of β-cell autoimmunity by obesity include: a) insulin resistance-induced β-cell secretory demand triggering autoimmunity through cytokine release, neo-epitope antigen formation and increase in β-cell apoptosis, and b) obesity-induced low-grade inflammation with pro-inflammatory cytokines secreted by locally infiltrating macrophages, which contribute to the presentation by islet cells of autoantigens generally not accessible to T cells. Further studies are needed to clarify whether the control of body weight can prevent or delay the current and continuing rise in T1D incidence.
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Affiliation(s)
| | - Simona Zampetti
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Paolo Pozzilli
- Department of Medicine, Unit of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Rome, Italy
- Centre of Immunobiology, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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