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Abidov M, Sokolova K, Danilova I, Baykenova M, Gette I, Mychlynina E, Aydin Ozgur B, Gurol AO, Yilmaz MT. Hepatic insulin synthesis increases in rat models of diabetes mellitus type 1 and 2 differently. PLoS One 2023; 18:e0294432. [PMID: 38019818 PMCID: PMC10686419 DOI: 10.1371/journal.pone.0294432] [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: 07/14/2023] [Accepted: 11/01/2023] [Indexed: 12/01/2023] Open
Abstract
Insulin-positive (+) cells (IPCs), detected in multiple organs, are of great interest as a probable alternative to ameliorate pancreatic beta-cells dysfunction and insulin deficiency in diabetes. Liver is a potential source of IPCs due to it common embryological origin with pancreas. We previously demonstrated the presence of IPCs in the liver of healthy and diabetic rats, but detailed description and analysis of the factors, which potentially can induced ectopic hepatic expression of insulin in type 1 (T1D) and type 2 diabetes (T2D), were not performed. In present study we evaluate mass of hepatic IPCs in the rat models of T1D and T2D and discuss factors, which may stimulate it generation: glycaemia, organ injury, involving of hepatic stem/progenitor cell compartment, expression of transcription factors and inflammation. Quantity of IPCs in the liver was up by 1.7-fold in rats with T1D and 10-fold in T2D compared to non-diabetic (ND) rats. We concluded that ectopic hepatic expression of insulin gene is activated by combined action of a number of factors, with inflammation playing a decision role.
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Affiliation(s)
- Musa Abidov
- Institute of Immunopathology and Preventive Medicine, Ljubljana, Slovenia
| | - Ksenia Sokolova
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation
| | - Irina Danilova
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation
| | - Madina Baykenova
- Kostanay Oblast Tuberculosis Dispensary, Kostanay, Republic of Kazakhstan
| | - Irina Gette
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation
| | - Elena Mychlynina
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation
| | - Burcin Aydin Ozgur
- Department of Medical Biology and Genetics, Faculty of Medicine, Demiroglu Bilim University, Istanbul, Turkey
- Diabetes Application and Research Center, Demiroglu Bilim University, Istanbul, Turkey
| | - Ali Osman Gurol
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Diabetes Application and Research Center, Istanbul University, Istanbul, Turkey
| | - M. Temel Yilmaz
- International Diabetes Center, Acibadem University, Istanbul, Turkey
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2
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Fujikawa H, Kojima H, Terashima T, Katagi M, Yayama T, Kumagai K, Mori K, Saito H, Imai S. Expression of proinflammatory cytokines and proinsulin by bone marrow-derived cells for fracture healing in long-term diabetic mice. BMC Musculoskelet Disord 2023; 24:585. [PMID: 37464323 DOI: 10.1186/s12891-023-06710-5] [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: 03/06/2023] [Accepted: 07/09/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) causes bone dysfunction due to poor bone quality, leading to severe deterioration in patient of quality of life. The mechanisms of bone metabolism in DM remain unclear, although chemical and/or mechanical factors are known to disrupt the homeostasis of osteoblasts and osteoclasts. The purpose of this study was to identify the changes of osteoblasts and osteoclasts under long-term hyperglycaemic conditions, using a mouse fracture model of long-term hyperglycemia (LT-HG). METHODS C57BL/6J mice and green fluorescent protein (GFP) -positive bone marrow transplanted C57BL/6J mice with LT-HG, maintained under a state of hyperglycaemia for 2 months, were used in this study. After the experimental fracture, we examined the immunohistochemical expression of proinsulin and tumor necrosis factor (TNF) -α at the fracture site. C57BL/6J fracture model mice without hyperglycaemia were used as controls. RESULTS In the LT-HG mice, chondrocyte resorption was delayed, and osteoblasts showed an irregular arrangement at the callus site. The osteoclasts were scattered with a decrement in the number of nuclei. The expression of proinsulin was confirmed in bone marrow derived cells (BMDCs) with neovascularization 2 and 3 weeks after fracture. Immunopositivity for TNF-α was also confirmed in immature chondrocytes and BMDCs with neovascularization at 2 weeks, and the number of positive cells was not decreased at 3 weeks. Examination of GFP-grafted hyperglycaemic mice showed that the majority of cells at the fracture site were GFP-positive. Immunohistochemistry showed that the rate of double positives was 15% for GFP and proinsulin and 47% for GFP and TNF-α. CONCLUSION LT-HG induces an increase in the number of proinsulin and TNF-α positive cells derived from BMDCs. We suggest that proinsulin and TNF-α positive cells are involved in both bone formation and bone resorption after fracture under hyperglycaemic conditions, resulting in the delay of bone healing.
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Affiliation(s)
- Hitomi Fujikawa
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan.
| | - Hideto Kojima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, 520-2192, Shiga, Japan
| | - Tomoya Terashima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, 520-2192, Shiga, Japan
| | - Miwako Katagi
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, 520-2192, Shiga, Japan
| | - Takafumi Yayama
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan
| | - Kosuke Kumagai
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan
| | - Kanji Mori
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan.
| | - Hideki Saito
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan
| | - Shinji Imai
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan
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Jiang H, Jiang FX. Human pluripotent stem cell-derived β cells: Truly immature islet β cells for type 1 diabetes therapy? World J Stem Cells 2023; 15:182-195. [PMID: 37180999 PMCID: PMC10173812 DOI: 10.4252/wjsc.v15.i4.182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/30/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
A century has passed since the Nobel Prize winning discovery of insulin, which still remains the mainstay treatment for type 1 diabetes mellitus (T1DM) to this day. True to the words of its discoverer Sir Frederick Banting, “insulin is not a cure for diabetes, it is a treatment”, millions of people with T1DM are dependent on daily insulin medications for life. Clinical donor islet transplantation has proven that T1DM is curable, however due to profound shortages of donor islets, it is not a mainstream treatment option for T1DM. Human pluripotent stem cell derived insulin-secreting cells, pervasively known as stem cell-derived β cells (SC-β cells), are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy. Here we briefly review how islet β cells develop and mature in vivo and several types of reported SC-β cells produced using different ex vivo protocols in the last decade. Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown, the SC-β cells have not been directly compared to their in vivo counterparts, generally have limited glucose response, and are not yet fully matured. Due to the presence of extra-pancreatic insulin-expressing cells, and ethical and technological issues, further clarification of the true nature of these SC-β cells is required.
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Affiliation(s)
- Helen Jiang
- Sir Charles Gairdner Hospital, University of Western Australia, Perth 6009, Australia
| | - Fang-Xu Jiang
- School of Biomedical Sciences, University of Western Australia, Perth 6009, Australia
- School of Health and Medical Sciences, Edith Cowan University, Perth 6027, Australia
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4
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Malfunctioning CD106-positive, short-term hematopoietic stem cells trigger diabetic neuropathy in mice by cell fusion. Commun Biol 2021; 4:575. [PMID: 33990693 PMCID: PMC8121918 DOI: 10.1038/s42003-021-02082-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 03/25/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetic neuropathy is an incurable disease. We previously identified a mechanism by which aberrant bone marrow-derived cells (BMDCs) pathologically expressing proinsulin/TNF-α fuse with residential neurons to impair neuronal function. Here, we show that CD106-positive cells represent a significant fraction of short-term hematopoietic stem cells (ST-HSCs) that contribute to the development of diabetic neuropathy in mice. The important role for these cells is supported by the fact that transplantation of either whole HSCs or CD106-positive ST-HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion. Furthermore, we show that transient episodic hyperglycemia produced by glucose injections leads to abnormal fusion of pathological ST-HSCs with residential neurons, reproducing neuropathy in nondiabetic mice. In conclusion, we have identified hyperglycemia-induced aberrant CD106-positive ST-HSCs underlie the development of diabetic neuropathy. Aberrant CD106-positive ST-HSCs constitute a novel therapeutic target for the treatment of diabetic neuropathy. Katagi et al. show that abnormal bone marrow-derived cells originated from hematopoietic stem cells (CD106-positive short-term HSCs) aberrantly fuse with neurons to develop diabetic neuropathy. This study suggests that the pathological abnormality is memorized in the bone marrow and that it cannot be erased by conventional therapy.
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5
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de Pablo F, Hernández-Sánchez C, de la Rosa EJ. The Prohormone Proinsulin as a Neuroprotective Factor: Past History and Future Prospects. Front Mol Neurosci 2018; 11:426. [PMID: 30534050 PMCID: PMC6275302 DOI: 10.3389/fnmol.2018.00426] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 11/02/2018] [Indexed: 01/22/2023] Open
Abstract
Proinsulin was first identified as the primary translation product of the insulin gene in Donald Steiner’s laboratory in 1967, and was the first prohormone to be isolated and sequenced. While its role as an insulin precursor has been extensively studied in the field of endocrinology, the bioactivity of the proinsulin molecule itself has received much less attention. Insulin binds to isoforms A and B of the insulin receptor (IR) with high affinity. Proinsulin, in contrast, binds with high affinity only to IR-A, which is present in the nervous system, among other tissues and elicits antiapoptotic and neuroprotective effects in the developing and postnatal nervous system. Proinsulin specifically exerts neuroprotection in the degenerating retina in mouse and rat models of retinitis pigmentosa (RP), delaying photoreceptor and vision loss after local administration in the eye or systemic (intramuscular) administration of an adeno-associated viral (AAV) vector that induces constitutive proinsulin release. AAV-mediated proinsulin expression also decreases the expression of neuroinflammation markers in the hippocampus and sustains cognitive performance in a mouse model of precocious brain senescence. We have therefore proposed that proinsulin should be considered a functionally distinct member of the insulin superfamily. Here, we briefly review the legacy of Steiner’s research, the neural expression of proinsulin, and the tissue expression patterns and functional characteristics of IR-A. We discuss the neuroprotective activity of proinsulin and its potential as a therapeutic tool in neurodegenerative conditions of the central nervous system, particularly in retinal dystrophies.
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Affiliation(s)
- Flora de Pablo
- 3D Lab, Development, Differentiation and Degeneration, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CIB/CSIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Catalina Hernández-Sánchez
- 3D Lab, Development, Differentiation and Degeneration, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CIB/CSIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Enrique J de la Rosa
- 3D Lab, Development, Differentiation and Degeneration, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CIB/CSIC), Madrid, Spain
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Carvalho FR, Fernandes AR, Cancela ML, Gavaia PJ. Improved regeneration and de novo bone formation in a diabetic zebrafish model treated with paricalcitol and cinacalcet. Wound Repair Regen 2017; 25:432-442. [PMID: 28380670 DOI: 10.1111/wrr.12536] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 03/15/2017] [Indexed: 02/06/2023]
Abstract
Bone changes related to diabetes have been well stablished, but few strategies have been developed to prevent this growing health problem. In our work, we propose to investigate the effects of calcitriol as well as of a vitamin D analog (paricalcitol) and a calcimimetic (cinacalcet), in fin regeneration and de novo mineralization in a zebrafish model of diabetes. Following exposure of diabetic transgenic Tg(ins:nfsb-mCherry) zebrafish to calcitriol, paricalcitol and cinacalcet, caudal fins were amputated to assess their effects on tissue regeneration. Caudal fin mineralized and regenerated areas were quantified by in vivo alizarin red staining. Quantitative real-time PCR was performed using RNA from the vertebral column. Diabetic fish treated with cinacalcet and paricalcitol presented increased regenerated and mineralized areas when compared with non-treated diabetic group, while no significant increase was observed in non-diabetic fish treated with both drugs. Gene expression analysis showed an up-regulation for runt-related transcription factor 2b (runx2b), bone gamma-carboxyglutamic acid-containing protein (bglap), insulin a (insa) and insulin b (insb) and a trend of increase for sp7 transcription factor (sp7) in diabetic groups treated with cinacalcet and paricalcitol. Expression of insra and vdra was up-regulated in both diabetic and nondiabetic fish treated with cinacalcet. In nondiabetic fish treated with paricalcitol and cinacalcet a similar increase in gene expression could be observed but not so pronounced. The increased mineralization and regeneration in diabetic zebrafish treated with cinacalcet and paricalcitol can be explained by increased osteoblastic differentiation and increased insulin expression indicating pro-osteogenic potential of both drugs.
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Affiliation(s)
- Filipe R Carvalho
- Center of Marine Sciences (CCMAR), Faro, Portugal.,PhD Program in Biomedical Sciences, University of Algarve, Faro, Portugal
| | - Ana R Fernandes
- Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
| | - M Leonor Cancela
- Center of Marine Sciences (CCMAR), Faro, Portugal.,Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
| | - Paulo J Gavaia
- Center of Marine Sciences (CCMAR), Faro, Portugal.,Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
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7
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Li L, Bai S, Sheline CT. hZnT8 (Slc30a8) Transgenic Mice That Overexpress the R325W Polymorph Have Reduced Islet Zn2+ and Proinsulin Levels, Increased Glucose Tolerance After a High-Fat Diet, and Altered Levels of Pancreatic Zinc Binding Proteins. Diabetes 2017; 66:551-559. [PMID: 27899481 PMCID: PMC5248993 DOI: 10.2337/db16-0323] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 11/17/2016] [Indexed: 01/23/2023]
Abstract
Zinc (Zn2+) is involved in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The wild-type (WT) form of the β-cell-specific Zn2+ transporter, ZNT8, is linked to T2DM susceptibility. ZnT8 null mice have a mild phenotype with a slight decrease in glucose tolerance, whereas patients with the ZnT8 R325W polymorphism (rs13266634) have decreased proinsulin staining and susceptibility to T2DM. We measured Zn2+, insulin, and proinsulin stainings and performed intraperitoneal glucose tolerance testing in transgenic mice overexpressing hZnT8 WT or hZnT8 R325W fed a normal or high-fat diet. The hZnT8 R325W transgenic line had lower pancreatic [Zn2+]i and proinsulin and higher insulin and glucose tolerance compared with control littermates after 10 weeks of a high-fat diet in male mice. The converse was true for the hZnT8 WT transgenic line, and dietary Zn2+ supplementation also induced glucose intolerance. Finally, pancreatic zinc binding proteins were identified by Zn2+-affinity chromatography and proteomics. Increasing pancreatic Zn2+ (hZnT8WT) induced nucleoside diphosphate kinase B, and Zn2+ reduction (hZnT8RW) induced carboxypeptidase A1. These data suggest that pancreatic Zn2+ and proinsulin levels covary but are inversely variant with insulin or glucose tolerance in the HFD model of T2DM suggesting novel therapeutic targets.
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Affiliation(s)
- Li Li
- Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
| | - Shi Bai
- Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
| | - Christian T Sheline
- Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
- Department of Neurology, Stony Brook University Hospital, Stony Brook, NY
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8
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Jiang FX, Morahan G. Insulin-secreting β cells require a post-genomic concept. World J Diabetes 2016; 7:198-208. [PMID: 27226815 PMCID: PMC4873311 DOI: 10.4239/wjd.v7.i10.198] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 03/18/2016] [Indexed: 02/05/2023] Open
Abstract
Pancreatic insulin-secreting β cells are essential in maintaining normal glucose homeostasis accomplished by highly specialized transcription of insulin gene, of which occupies up to 40% their transcriptome. Deficiency of these cells causes diabetes mellitus, a global public health problem. Although tremendous endeavors have been made to generate insulin-secreting cells from human pluripotent stem cells (i.e., primitive cells capable of giving rise to all cell types in the body), a regenerative therapy to diabetes has not yet been established. Furthermore, the nomenclature of β cells has become inconsistent, confusing and controversial due to the lack of standardized positive controls of developmental stage-matched in vivo cells. In order to minimize this negative impact and facilitate critical research in this field, a post-genomic concept of pancreatic β cells might be helpful. In this review article, we will briefly describe how β cells were discovered and islet lineage is developed that may help understand the cause of nomenclatural controversy, suggest a post-genomic definition and finally provide a conclusive remark on future research of this pivotal cell.
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9
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Shi L, Rui YF, Li G, Wang C. Alterations of tendons in diabetes mellitus: what are the current findings? INTERNATIONAL ORTHOPAEDICS 2015; 39:1465-73. [PMID: 25944078 DOI: 10.1007/s00264-015-2775-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 03/23/2015] [Indexed: 12/13/2022]
Abstract
As a connective tissue, tendon connects the muscle and bone, and plays the key role in the locomotor system. Some previous studies have shown the pathological alternations in diabetic tendons, which might result in the structural and functional changes, and even accelerate the process of diabetic foot. In this review, we examined the current findings of the diabetic tendons in the form of various aspects, and summarized the clinical presentation, imaging, biomechanical, histopathological, cellular and molecular abnormalities in the diabetic tendons. The progress of diabetic tendon damage is complicated and the main hypotheses include the excessive accumulation of AGEs, the altered inflammatory response, neovascularization and insensitive neuropathy. However, the cellular and molecular mechanisms of these alterations are still ambiguous. Tendon stem/progenitor cells (TSPCs) have been discovered to play important roles in both tendon physiology and tendon pathology. Recently, we identified TSPCs from patellar tendons in our well-established diabetic rat model and found impaired tenogenic differentiation potential of these cells. We proposed a new hypothesis that the impaired cell functions of diabetic TSPCs might be the underlying cellular and molecular mechanism of the diabetic tendon alternations. These findings should be helpful to establish a better therapeutic strategy for diabetic tendon repair and regeneration.
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Affiliation(s)
- Liu Shi
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, China
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10
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Fujimiya M, Nagaishi K, Yamashita T, Ataka K. Bone Marrow Stem Cell Abnormality and Diabetic Complications. Anat Rec (Hoboken) 2012; 295:917-21. [DOI: 10.1002/ar.22445] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Revised: 12/13/2011] [Accepted: 01/04/2012] [Indexed: 11/09/2022]
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Yamakawa I, Kojima H, Terashima T, Katagi M, Oi J, Urabe H, Sanada M, Kawai H, Chan L, Yasuda H, Maegawa H, Kimura H. Inactivation of TNF-α ameliorates diabetic neuropathy in mice. Am J Physiol Endocrinol Metab 2011; 301:E844-52. [PMID: 21810933 PMCID: PMC3213998 DOI: 10.1152/ajpendo.00029.2011] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumor necrosis factor (TNF)-α is a potent proinflammatory cytokine involved in the pathogenesis of diabetic neuropathy. We inactivated TNF-α to determine if it is a valid therapeutic target for the treatment of diabetic neuropathy. We effected the inactivation in diabetic neuropathy using two approaches: by genetic inactivation of TNF-α (TNF-α(-/-) mice) or by neutralization of TNF-α protein using the monoclonal antibody infliximab. We induced diabetes using streptozotocin in wild-type and TNF-α(-/-) mice. We measured serum TNF-α concentration and the level of TNF-α mRNA in the dorsal root ganglion (DRG) and evaluated nerve function by a combination of motor (MNCV) and sensory (SNCV) nerve conduction velocities and tail flick test, as well as cytological analysis of intraepidermal nerve fiber density (IENFD) and immunostaining of DRG for NF-κB p65 serine-276 phosphorylated and cleaved caspase-3. Compared with nondiabetic mice, TNF-α(+/+) diabetic mice displayed significant impairments of MNCV, SNCV, tail flick test, and IENFD as well as increased expression of NF-κB p65 and cleaved caspase-3 in their DRG. In contrast, although nondiabetic TNF-α(-/-) mice showed mild abnormalities of IENFD under basal conditions, diabetic TNF-α(-/-) mice showed no evidence of abnormal nerve function tests compared with nondiabetic mice. A single injection of infliximab in diabetic TNF-α(+/+) mice led to suppression of the increased serum TNF-α and amelioration of the electrophysiological and biochemical deficits for at least 4 wk. Moreover, the increased TNF-α mRNA expression in diabetic DRG was also attenuated by infliximab, suggesting infliximab's effects may involve the local suppression of TNF-α. Infliximab, an agent currently in clinical use, is effective in targeting TNF-α action and expression and amelioration of diabetic neuropathy in mice.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Anti-Inflammatory Agents/therapeutic use
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/pathology
- Diabetic Neuropathies/drug therapy
- Diabetic Neuropathies/genetics
- Diabetic Neuropathies/metabolism
- Diabetic Neuropathies/pathology
- Drug Evaluation, Preclinical
- Ganglia, Spinal/metabolism
- Ganglia, Spinal/pathology
- Gene Expression Regulation/drug effects
- Gene Silencing/physiology
- Infliximab
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Molecular Targeted Therapy
- Streptozocin
- Transcription Factor RelA/metabolism
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism
- Tumor Necrosis Factor-alpha/physiology
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Affiliation(s)
- Isamu Yamakawa
- Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
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Li Y, Kojima H, Fujino K, Matsumura K, Katagi M, Urabe H, Chan L, Eguchi Y, Zhao L, Kimura H. Homing of the bone marrow-derived interstitial cells of Cajal is decreased in diabetic mouse intestine. J Gastroenterol Hepatol 2011; 26:1072-8. [PMID: 21265880 PMCID: PMC3321643 DOI: 10.1111/j.1440-1746.2011.06670.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Interstitial cells of Cajal (ICCs), which express c-Kit receptor tyrosine kinase (KIT), play an important role in gastrointestinal motility. Loss of ICCs likely contributes to diabetic gastrointestinal motility disorder, however, the mechanism of attrition remains unknown. Here, we test the hypothesis that the bone marrow-derived progenitors are an important source of intestinal ICCs and that decreased homing of these progenitors in diabetes contributes to ICC diminution. METHODS Wild type mice were X-ray irradiated, transplanted with bone marrow (BMT) from green fluorescence protein (GFP)-transgenic (TG)-mice and subsequently made diabetic by streptozotocin (STZ) injection. Intestinal homing of GFP-positive bone marrow-derived cells was examined 2 or 5 months after STZ treatment. RESULTS In the BMT-mice, we found many GFP-positive bone marrow-derived cells (BMDCs) in most parts of the intestinal area, the number of BMDCs was significantly decreased in diabetic mice compared with nondiabetic controls. As a representative area, we further examined the myenteric plexus of the proximal small intestine, and found that the cell numbers of ICCs marked by c-Kit-positive immunoreactivity were decreased by more than 40% in diabetic versus nondiabetic mice. Furthermore, numbers of c-Kit+/GFP+ and c-Kit+/GFP- cells were similar in nondiabetic mice, and decreased by 45.8% and 42.0%, respectively, in diabetic mice. CONCLUSION These results suggest that the decreased homing from the bone marrow is a major cause of ICC loss in the intestine in diabetes mellitus.
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Affiliation(s)
- Yimin Li
- Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
,Department of Anatomy, Harbin Medical University, Harbin, China
| | - Hideto Kojima
- Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Kazunori Fujino
- Department of Emergency and Intensive Care, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Kazuhiro Matsumura
- Department of Emergency and Intensive Care, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Miwako Katagi
- Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Hiroshi Urabe
- Division of Neurology, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Lawrence Chan
- Division of Diabetes, Endocrinology and Metabolism, Departments of Medicine, Molecular and Cellular Biology, and Biochemistry, Baylor College of Medicine, Houston, TX, USA
| | - Yutaka Eguchi
- Department of Emergency and Intensive Care, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Linghui Zhao
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Hiroshi Kimura
- Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
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Ferguson LA, Docherty HM, MacKenzie AE, Docherty K. An engineered zinc finger protein reveals a role for the insulin VNTR in the regulation of the insulin and adjacent IGF2 genes. FEBS Lett 2009; 583:3181-6. [PMID: 19733567 DOI: 10.1016/j.febslet.2009.08.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2009] [Revised: 08/05/2009] [Accepted: 08/29/2009] [Indexed: 01/27/2023]
Abstract
An engineered zinc finger protein (eZFP) was isolated from a library based on its ability to activate expression of the endogenous insulin gene in HEK-293 cells. Using a panel of insulin promoter constructs, the eZFP was shown to act through the variable number of tandem repeat (VNTR) region located 365 base pairs upstream of the transcription start site. The eZFP also activated expression of the IGF2 gene that lies close to INS on chromosome 11p15. These results demonstrate that the INSVNTR controls expression of the insulin and IGF2 genes and provide a mechanistic explanation for previous studies that demonstrated an association between INSVNTR genotypes and placental levels of IGF2.
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Affiliation(s)
- Laura A Ferguson
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
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Vorobeychik M, Bloch K, Zemel R, Bachmetov L, Tur-Kaspa R, Vardi P. Immunohistochemical evaluation of hepatic oval cell activation and differentiation toward pancreatic beta-cell phenotype in streptozotocin-induced diabetic mice. J Mol Histol 2008; 39:463-8. [DOI: 10.1007/s10735-008-9185-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2008] [Accepted: 07/15/2008] [Indexed: 11/28/2022]
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15
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Embryonic stem cell therapy for diabetes mellitus. Semin Cell Dev Biol 2007; 18:827-38. [DOI: 10.1016/j.semcdb.2007.09.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2007] [Accepted: 09/06/2007] [Indexed: 12/20/2022]
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16
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Cunha DA, de Alves MC, Stoppiglia LF, Jorge AG, Módulo CM, Carneiro EM, Boschero AC, Saad MJA, Velloso LA, Rocha EM. Extra-pancreatic insulin production in RAt lachrymal gland after streptozotocin-induced islet β-cells destruction. Biochim Biophys Acta Gen Subj 2007; 1770:1128-35. [PMID: 17561349 DOI: 10.1016/j.bbagen.2007.05.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2006] [Revised: 04/03/2007] [Accepted: 05/09/2007] [Indexed: 10/23/2022]
Abstract
Previous work has revealed that insulin is secreted in the tear film; its mRNA is expressed in the lachrymal gland (LG) and its receptor in tissues of the ocular surface. To test the hypothesis of insulin production in the LG, we compared normal and diabetic rats for: (1) the presence of insulin and C-peptide, (2) glucose- and carbachol-induced insulin secretion ex-vivo, and (3) biochemical and histological characteristics of diabetic LG that would support this possibility. Four weeks after streptozotocin injection, blood and tears were collected from streptozotocin-diabetic male Wistar rats. Insulin levels in the tear film rose after glucose stimulation in diabetic rats, but remained unchanged in the blood. Ex vivo static secretion assays demonstrated that higher glucose and 200 microM carbachol significantly increased mean insulin levels from LG samples of both groups. Insulin and C-peptide were expressed in LG of diabetic rats as determined by RIA. Comparable synaptophysin immune staining and peroxidase activity in the LG of both groups suggest that the structure and function of these tissues were maintained. These findings provide evidence of insulin production by LG. Higher expression of reactive oxygen species scavengers may prevent oxidative damage to LG compared to pancreatic beta-cells.
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Affiliation(s)
- Daniel Andrade Cunha
- Institute of Biology, State University of Campinas (UNICAMP), Campinas, SP, Brazil
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Fujimiya M, Kojima H, Ichinose M, Arai R, Kimura H, Kashiwagi A, Chan L. Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes. Proc Natl Acad Sci U S A 2007; 104:4030-5. [PMID: 17360472 PMCID: PMC1820703 DOI: 10.1073/pnas.0700220104] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2006] [Indexed: 11/18/2022] Open
Abstract
We previously reported that diabetes in mice is associated with the appearance of proinsulin-producing (Proins-P) cells in the liver. It was unclear, however, whether these Proins-P bone marrow-derived cells (BMDC) merely transit through the liver or undergo fusion with hepatocytes, normally an extremely rare event. In this study, we found that, in diabetes, BMDC in the liver produce not only Proins but also TNF-alpha, suggesting that diabetes reprograms gene expression in BMDC, turning on "inappropriate" genes. Bone marrow transplantation using genetically marked donor and recipient mice showed that fusion occurs between Proins-P BMDC and hepatocytes. Cell fusion is further supported by the presence of the Y chromosome in Proins-P cells in female mice that received male bone marrow transplantation cells. Morphologically, Proins-P fusion cells are albumin-producing hepatocytes that constitute approximately 2.5% of the liver section area 5 months after diabetes induction. An extensive search failed to reveal any fusion cells in nondiabetic mice. Thus, diabetes causes fusion between Proins-P BMDC and hepatocytes in vivo, an observation that has implications for the pathophysiology of diabetes as well as the fundamental biology of heterotypic cell fusion.
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Affiliation(s)
- Mineko Fujimiya
- Departments of *Anatomy
- Division of Diabetes, Endocrinology, and Metabolism, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030
| | - Hideto Kojima
- Molecular Genetics in Medicine, and
- Division of Diabetes, Endocrinology, and Metabolism, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030
| | | | | | | | - Atsunori Kashiwagi
- Medicine, Section of Endocrinology and Metabolism, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan; and
| | - Lawrence Chan
- Division of Diabetes, Endocrinology, and Metabolism, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030
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