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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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Sirdah MM, Reading NS. Genetic predisposition in type 2 diabetes: A promising approach toward a personalized management of diabetes. Clin Genet 2020; 98:525-547. [PMID: 32385895 DOI: 10.1111/cge.13772] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 05/04/2020] [Accepted: 05/04/2020] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus, also known simply as diabetes, has been described as a chronic and complex endocrine metabolic disorder that is a leading cause of death across the globe. It is considered a key public health problem worldwide and one of four important non-communicable diseases prioritized for intervention through world health campaigns by various international foundations. Among its four categories, Type 2 diabetes (T2D) is the commonest form of diabetes accounting for over 90% of worldwide cases. Unlike monogenic inherited disorders that are passed on in a simple pattern, T2D is a multifactorial disease with a complex etiology, where a mixture of genetic and environmental factors are strong candidates for the development of the clinical condition and pathology. The genetic factors are believed to be key predisposing determinants in individual susceptibility to T2D. Therefore, identifying the predisposing genetic variants could be a crucial step in T2D management as it may ameliorate the clinical condition and preclude complications. Through an understanding the unique genetic and environmental factors that influence the development of this chronic disease individuals can benefit from personalized approaches to treatment. We searched the literature published in three electronic databases: PubMed, Scopus and ISI Web of Science for the current status of T2D and its associated genetic risk variants and discus promising approaches toward a personalized management of this chronic, non-communicable disorder.
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Affiliation(s)
- Mahmoud M Sirdah
- Division of Hematology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.,Biology Department, Al Azhar University-Gaza, Gaza, Palestine
| | - N Scott Reading
- Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah, USA.,Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
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Tanaka H, Tanaka S, Sekine K, Kita S, Okamura A, Takebe T, Zheng YW, Ueno Y, Tanaka J, Taniguchi H. The generation of pancreatic β-cell spheroids in a simulated microgravity culture system. Biomaterials 2013; 34:5785-5791. [PMID: 23642538 DOI: 10.1016/j.biomaterials.2013.04.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 04/03/2013] [Indexed: 01/27/2023]
Abstract
Islet transplantation can induce a substantial improvement in the treatment of type 1 diabetes mellitus. However, the clinical application of islet transplantation is severely limited by the shortage of donor organs. It is thus essential to improve the engraftment rate to achieve the expected outcome in the treatment of diabetes mellitus using a limited amount of donor islets. In this manuscript, we describe the generation of β-cell spheroids using mouse insulinoma cells (MIN6) as a model of β-cells. We established a 3D culture system that simulates microgravity using a 3D clinostat. Using this method, we were able to produce 100 spheroids per mL of culture media. The optimization of the culture conditions in the clinostat produced spheroids with a size of approximately 250 μm, which is a size that is known to induce good graft survival after islet transplantation. The spheroids produced in the clinostat expressed several β-cell signature genes at higher levels than the levels that were found in MIN6 cells that were cultured in a standard 2D culture dish (MIN6-2D). The transplantation of the spheroids into the portal vein of streptozotocin-induced diabetic mice ameliorates hyperglycemia, whereas the transplantation of the equivalent number of 2D-cultured cells failed to cure diabetes. These results indicate that the clinostat culture provides a new method for the reconstitution of a large number of functional β-cell spheroids for diabetes treatment.
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Affiliation(s)
- Hiroyasu Tanaka
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Yokohama, Kanagawa 236-0004, Japan
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Limbert C, Päth G, Jakob F, Seufert J. Beta-cell replacement and regeneration: Strategies of cell-based therapy for type 1 diabetes mellitus. Diabetes Res Clin Pract 2008; 79:389-99. [PMID: 17854943 DOI: 10.1016/j.diabres.2007.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2007] [Accepted: 06/20/2007] [Indexed: 01/09/2023]
Abstract
Pancreatic islet transplantation has demonstrated that long-term insulin independence may be achieved in patients suffering from diabetes mellitus type 1. However, because of limited availability of islet tissue, new sources of insulin producing cells that are responsive to glucose are required. Development of pancreatic beta-cell lines from rodent or human origin has progressed slowly in recent years. Current experiments for ex vivo expansion of beta cells and in vitro differentiation of embryonic and adult stem cells into insulin producing beta-cell phenotypes led to promising results. Nevertheless, the cells generated to date lack important characteristics of mature beta cells and generally display reduced insulin secretion and loss of proliferative capacity. Therefore, much better understanding of the mechanisms that regulate expansion and differentiation of stem/progenitor cells is necessary. Here, we review recent advances in the identification of potential cellular sources, and the development of strategies to regenerate or fabricate insulin producing and glucose sensing cells that might enable future cell-based therapies of diabetes mellitus type 1.
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Affiliation(s)
- C Limbert
- Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital Freiburg, Freiburg, Germany
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Mfopou JK, Bouwens L. Hedgehog signals in pancreatic differentiation from embryonic stem cells: revisiting the neglected. Differentiation 2007; 76:107-17. [PMID: 17573915 DOI: 10.1111/j.1432-0436.2007.00191.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Recent demonstrations of insulin expression by progenies of mouse and human embryonic stem (ES) cells have attracted interest in setting up these cells as alternative sources of beta-cells needed in diabetes cell therapy. It is widely acknowledged that information gathered in the field of developmental biology as applied to the pancreas is of relevance for designing in vitro differentiation strategies. However, looking back at the protocols used so far, it appears that the natural route toward the pancreas, which goes via the definitive endoderm, was usually bypassed. As a consequence Hedgehog signaling, the earliest inhibitor of pancreas initiation from the endoderm, was generally not considered. A recall of the status of this pathway during ES cell differentiation appears necessary, especially in the light of findings that Activin A treatment of mouse and human ES cells coax them into definitive endoderm, a lineage showing wide Hedgehog ligands expression with the potential to hinder pancreatic programming.
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Affiliation(s)
- J K Mfopou
- Cell Differentiation Unit, Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
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Lin HT, Kao CL, Lee KH, Chang YL, Chiou SH, Tsai FT, Tsai TH, Sheu DC, Ho LLT, Ku HH. Enhancement of insulin-producing cell differentiation from embryonic stem cells using pax4-nucleofection method. World J Gastroenterol 2007; 13:1672-9. [PMID: 17461469 PMCID: PMC4146945 DOI: 10.3748/wjg.v13.i11.1672] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To enhance the differentiation of insulin producing cell (IPC) ability from embryonic stem (ES) cells in vitro.
METHODS: Four-day embryoid body (EB)-formatted ES cells were dissociated as single cells for the followed plasmid DNA delivery. The use of Nucleofector™electroporator (Amaxa biosystems, Germany) in combination with medium-contained G418 provided a high efficiency of gene delivery for advanced selection. Neucleofected cells were plated on the top of fibronectin-coated Petri dishes. Addition of Ly294002 and raised the glucose in medium at 24 h before examination. The differentiation status of these cells was monitored by semi-quantitative PCR (SQ-PCR) detection of the expression of relative genes, such as oct-4, sox-17, foxa2, mixl1, pdx-1, insulin 1, glucagons and somatostatin. The percentage of IPC population on d 18 of the experiment was investigated by immunohistochemistry (IHC), and the content/secretion of insulin was estimated by ELISA assay. The mice with severe combined immunodeficiency disease (SCID) pretreated with streptozotocin (STZ) were used to eliminate plasma glucose restoration after pax4+ ES implantation.
RESULTS: A high efficiency of gene delivery was demonstrated when neucleofection was used in the present study; approximately 70% cells showed DsRed expression 2 d after neucleofection. By selection of medium-contained G418, the percentage of DsRed expressing cells kept high till the end of study. The pancreatic differentiation seemed to be accelerated by pax4 nucleofection. When compared to the group of cells with mock control, foxa2, mixl1, pdx1, higher insulin and somatostatin levels were detected by SQ-PCR 4 d after nucleofection in the group of pax4 expressing plasmid delivery. Approximately 55% of neucleofected cells showed insulin expression 18 d after neucleofection, and only 18% of cells showed insulin expression in mock control. The disturbance was shown by nucleofected pax4 RNAi vector; only 8% of cells expressed insulin 18 d after nucleofection. A higher IPC population was also detected in the insulin content by ELISA assay, and the glucose dependency was demonstrated in insulin secretion level. In the animal model, improvement of average plasma glucose concentration was observed in the group of pax-4 expressed ES of SCID mice pretreated with STZ, but no significant difference was observed in the group of STZ-pretreated SCID mice who were transplanted ES with mock plasmid.
CONCLUSION: Enhancement of IPC differentiation from EB-dissociated ES cells can be revealed by simply using pax4 expressing plasmid delivery. Not only more IPCs but also pancreatic differentiation-related genes can be detected by SQ-PCR. Expression of relative genes, such as foxa 2, mixl 1, pdx-1, insulin 1 and somatostatin after nucleofection, suggests that pax4 accelerates the whole differentiation progress. The higher insulin production with glucose dependent modulation suggests that pax4 expression can drive more mature IPCs. Although further determination of the entire mechanism is required, the potential of pax-4-nucleofected cells in medical treatment is promising.
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Affiliation(s)
- Han-Tso Lin
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, China
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Yatoh S, Akashi T, Chan PP, Kaneto H, Sharma A, Bonner-Weir S, Weir GC. NeuroD and reaggregation induce beta-cell specific gene expression in cultured hepatocytes. Diabetes Metab Res Rev 2007; 23:239-49. [PMID: 16921545 DOI: 10.1002/dmrr.678] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Our goal was to convert adult mouse hepatocytes to pancreatic beta-cells. METHODS AND RESULTS To facilitate conversion, cultured primary hepatocytes were dedifferentiated by the removal of dexamethasone (Dex) from the culture media. Removal of Dex caused detachment of hepatocytes from the culture dish, but the addition of betacellulin prevented this from happening. With the combination of lack of Dex and addition of betacellulin, albumin mRNA levels decreased. Cultured hepatocytes had a faint expression of insulin 2 mRNA, Nkx 6.1 and Pax 6 mRNA. Dedifferentiated hepatocytes were transduced with adenoviruses expressing NeuroD1, Ngn 3, or Pax 4. NeuroD1 transduction increased the insulin 2 mRNA but caused detachment of cells. However, when hepatocytes were allowed to reaggregate for 4 and 6 days in hydrophobic plates after transduction with NeuroD1, further increases of insulin 2 mRNA were found along with induction of PDX-1, IAPP, NeuroD1, Ngn3, Pax 4, Isl-1, PC1, PC2 and islet glucokinase. Additionally, glucagon, pancreatic polypeptide and somatostatin expression were induced, but neither elastase 1 nor insulin 1 mRNA could be detected. Ngn 3 and Pax 4 had effects similar to NeuroD1, but did not increase insulin 2 mRNA as much as NeuroD1. CONCLUSION We conclude that the combination of NeuroD1 and reaggregation promotes cultured dedifferentiated hepatocytes to differentiate towards a pancreatic beta-cell phenotype.
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Affiliation(s)
- Shigeru Yatoh
- Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
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Sanchez Dominguez M, Maillard E, Krafft MP, Sigrist S, Belcourt A. Prevention of Adhesion and Promotion of Pseudoislets Formation from a β-Cell Line by Fluorocarbon Emulsions. Chembiochem 2006; 7:1160-3. [PMID: 16927312 DOI: 10.1002/cbic.200600056] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Margarita Sanchez Dominguez
- Systèmes Organisés Fluorés à Finalités Thérapeutiques (SOFFT). Institut Charles Sadron (CNRS), 6 rue Boussingault, 67083 Strasbourg Cedex, France
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Bunnell BA, Deng W, Robinson CM, Waldron PR, Bivalacqua TJ, Baber SR, Hyman AL, Kadowitz PJ. Potential application for mesenchymal stem cells in the treatment of cardiovascular diseases. Can J Physiol Pharmacol 2006; 83:529-39. [PMID: 16091779 DOI: 10.1139/y05-043] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Stem cells isolated from various sources have been shown to vary in their differentiation capacity or pluripotentiality. Two groups of stem cells, embryonic and adult stem cells, may be capable of differentiating into any desired tissue or cell type, which offers hope for the development of therapeutic applications for a large number of disorders. However, major limitations with the use of embryonic stem cells for human disease have led researchers to focus on adult stem cells as therapeutic agents. Investigators have begun to examine postnatal sources of pluripotent stem cells, such as bone marrow stroma or adipose tissue, as sources of mesenchymal stem cells. The following review focuses on recent research on the use of stem cells for the treatment of cardiovascular and pulmonary diseases and the future application of mesenchymal stem cells for the treatment of a variety of cardiovascular disorders.
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Affiliation(s)
- Bruce A Bunnell
- Department of Pharmacology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
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Taneera J, Rosengren A, Renstrom E, Nygren JM, Serup P, Rorsman P, Jacobsen SEW. Failure of transplanted bone marrow cells to adopt a pancreatic beta-cell fate. Diabetes 2006; 55:290-6. [PMID: 16443759 DOI: 10.2337/diabetes.55.02.06.db05-1212] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Recent studies in normal mice have suggested that transplanted bone marrow cells can transdifferentiate into pancreatic beta-cells at relatively high efficiency. Herein, adopting the same and alternative approaches to deliver and fate map-transplanted bone marrow cells in the pancreas of normal as well as diabetic mice, we further investigated the potential of bone marrow transplantation as an alternative approach for beta-cell replacement. In contrast to previous studies, transplanted bone marrow cells expressing green fluorescence protein (GFP) under the control of the mouse insulin promoter failed to express GFP in the pancreas of normal as well as diabetic mice. Although bone marrow cells expressing GFP under the ubiquitously expressed beta-actin promoter efficiently engrafted the pancreas of normal and hyperglycemic mice, virtually all expressed CD45 and Mac-1/Gr-1, demonstrating that they adopt a hematopoietic rather than beta-cell fate, a finding further substantiated by the complete absence of GFP(+) cells expressing insulin and the beta-cell transcription factors pancreatic duodenal homeobox factor-1 and homeodomain protein. Thus, transplanted bone marrow cells demonstrated little, if any, capacity to adopt a beta-cell fate.
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Affiliation(s)
- Jalal Taneera
- Hematopoietic Stem Cell Laboratory, Lund University, Sweden
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Abstract
New sources of insulin-producing cells are needed to overcome the limited availability of islet tissue for transplantation to diabetic patients. The engineering of murine or human transformed beta-cell lines and of non beta-cells has progressed slowly in recent years, while significant achievements have been claimed in the differentiation of insulin-producing cells from embryonic and adult stem cells. Some of the results have been questioned, however, and the generated cells lack many characteristics of differentiated beta-cells. A much better understanding of the processes that govern the expansion and differentiation of stem cells is needed.
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Affiliation(s)
- Eduard Montanya
- Endocrine Unit, Hospital Universitari Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
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Abstract
Two major initiatives are under way to correct the beta-cell deficit of diabetes: one would generate beta-cells ex vivo that are suitable for transplantation, and the second would stimulate regeneration of beta-cells in the pancreas. Studies of ex vivo expansion suggest that beta-cells have a potential for dedifferentiation, expansion, and redifferentiation. Work with mouse and human embryonic stem (ES) cells has not yet produced cells with the phenotype of true beta-cells, but there has been recent progress in directing ES cells to endoderm. Putative islet stem/progenitor cells have been identified in mouse pancreas, and formation of new beta-cells from duct, acinar and liver cells is an active area of investigation. Peptides, including glucagon-like peptide-1/exendin-4 and the combination of epidermal growth factor and gastrin, can stimulate regeneration of beta-cells in vivo. Recent progress in the search for new sources of beta-cells has opened promising new opportunities and spawned clinical trials.
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Affiliation(s)
- Susan Bonner-Weir
- Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA.
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Halban PA. Cellular sources of new pancreatic beta cells and therapeutic implications for regenerative medicine. Nat Cell Biol 2004; 6:1021-5. [PMID: 15516994 DOI: 10.1038/ncb1104-1021] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Replacing missing insulin-producing beta cells to treat diabetes is a major challenge for regenerative medicine. A better understanding of beta-cell embryogenesis and regeneration in adult life is needed to devise means to derive these specialized cells in sufficiently large numbers from stem or precursor cells. It is also critical to ensure that any surrogate or regenerated beta cells have perfectly regulated insulin production, which is essential for physiological glucose homeostasis.
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Affiliation(s)
- Philippe A Halban
- Department of Genetic Medicine and Development, University Medical Centre, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
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