#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

The potential of induced pluripotent stem cells in the study and treatment of monogenic diabetes


Authors: Terézia Valkovičová 1;  Martina Škopková 1;  Ying Cai 3;  Juraj Staník 1,2;  Miriam Cnop 3;  Daniela Gašperíková 1
Authors‘ workplace: DIABGENE & Ústav experimentálnej endokrinológie, Biomedicínske centrum SAV, Bratislava 1;  Detská klinika LF UK a NÚDCH, Bratislava 2;  ULB Center for Diabetes Research, Université Libre de Bruxelles, Belgicko 3
Published in: Diab Obez 2021; 21(41): 7-15
Category: Reviews

Overview

MEHMO and Wolfram syndrome are monogenic diseases, whose one of the clinical manifestations is nonautoimmune diabetes mellitus. Both are classified as a rare disease. Acquisition of the patients´ B-cells, that would be suitable for the study of the mechanisms leading to diabetes, is complicated or even impossible. However, new opportunities for diabetes studies are brought by the reprogramming of somatic patient cells into the stem cells and their subsequent differentiation into pancreatic B-cells. Such cells could be used also for cell therapy of the patients with both monogenic and polygenic types of diabetes.

Keywords:

human-induced pluripotent stem cell (hiPSC) – MEHMO – monogenic diabetes – Wolfram syndrome


Sources
  1. [American Diabetes Association]. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care 2019; 42(Suppl 1): S13-S28. Dostupné z DOI: <http://dx.doi.org/10.2337/dc19-S002].
  2. Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 2008; 4(4): 200–213. Dostupné z DOI: <http://dx.doi.org/10.1038/ncpendmet0778>.
  3. Mayer-Davis EJ, Kahkoska AR, Jefferies C et al. ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes 2018; 19(Suppl 27): S7-S19. Dostupné z DOI: <http://dx.doi.org/10.1111/pedi.12773>.
  4. Hattersley A, Bruining J, Shield J et al. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2009; 10(Suppl 12): S33-S42. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1399–5448.2009.00571.x>.
  5. Thanabalasingham G, Pal A, Selwood MP et al. Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young. Diabetes Care 2012; 35(6): 1206–1212. Dostupné z DOI: <http://dx.doi.org/10.2337/dc11–1243>.
  6. Murphy R, Turnbull DM, Walker M et al. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med 2008; 25(4):383–399. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1464–5491.2008.02359.x>.
  7. Steinmuller R, Steinberger D, Muller U. MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to xp21.1-p22.13. Eur J Hum Genet 1998; 6(3): 201–206. Dostupné z DOI: <http://dx.doi.org/10.1038/sj.ejhg.5200180>.
  8. Skopkova M, Hennig F, Shin BS et al. EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO. Hum Mutat 2017; 38(4): 409–425. Dostupné z DOI: <http://dx.doi.org/10.1002/humu.23170>.
  9. Matsunaga K, Tanabe K, Inoue H et al. Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features. PLoS One 2014; 9(9): e106906. Dostupné z DOI: <http://dx.doi.org/10.1371/journal.pone.0106906>.
  10. de Heredia ML, Cleries R, Nunes V. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. Genet Med 2013; 15(7): 497–506. Dostupné z DOI: <http://dx.doi.org/10.1038/gim.2012.180>.
  11. Hatanaka M, Tanabe K, Yanai A et al. Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic beta-cells. Hum Mol Genet 2011; 20(7):1274–1284. Dostupné z DOI: <http://dx.doi.org/10.1093/hmg/ddq568>.
  12. Barrett TG, Poulton K, Bundey S. DIDMOAD syndrome; further studies and muscle biochemistry. J Inherit Metab Dis 1995; 18(2): 218–220. Dostupné z DOI: <http://dx.doi.org/10.1007/BF00711771>.
  13. Bespalova IN, Van Camp G, Bom SJ, et al. Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet 2001; 10(22): 2501–2508. Dostupné z DOI: <http://dx.doi.org/10.1093/hmg/10.22.2501>.
  14. Bonnycastle LL, Chines PS, Hara T et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes 2013; 62(11): 3943–3950. Dostupné z DOI: <http://dx.doi.org/10.2337/db13–0571>.
  15. Hogewind BF, Pennings RJ, Hol FA et al. Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1. Mol Vis 2010; 16: 26–35.
  16. De Franco E, Flanagan SE, Yagi T et al. Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. Diabetes 2017; 66(7): 2044–2053. Dostupné z DOI: <http://dx.doi.org/10.2337/db16–1296>.
  17. Geraghty RJ, Capes-Davis A, Davis JM et al. Guidelines for the use of cell lines in biomedical research. Br J Cancer 2014; 111(6): 1021–1046. Dostupné z DOI: <http://dx.doi.org/10.1038/bjc.2014.166>.
  18. Taneera J, Fadista J, Ahlqvist E et al. Identification of novel genes for glucose metabolism based upon expression pattern in human islets and effect on insulin secretion and glycemia. Hum Mol Genet 2015; 24(7): 1945–1955. Dostupné z DOI: <http://dx.doi.org/10.1093/hmg/ddu610>.
  19. Fadista J, Vikman P, Laakso EO et al. Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci U S A 2014; 111(38): 13924–13929. Dostupné z DOI: <http://dx.doi.org/10.1073/pnas.1402665111>.
  20. Pasquali L, Gaulton KJ, Rodriguez-Segui SA et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat Genet 2014; 46(2): 136–143. Dostupné z DOI: <http://dx.doi.org/10.1038/ng.2870>.
  21. van de Bunt M, Manning Fox JE, Dai X et al. Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. PLoS Genet 2015; 11(12): e1005694. Dostupné z DOI: <http://dx.doi.org/10.1371/journal.pgen.1005694>.
  22. Moran I, Akerman I, van de Bunt M et al. Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab 2012; 16(4): 435–448. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cmet.2012.08.010>.
  23. Gazdar AF, Carney DN, Russell EK et al. Establishment of continuous, clonable cultures of small-cell carcinoma of lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res 1980; 40(10): 3502–3507.
  24. Santerre RF, Cook RA, Crisel RM et al. Insulin synthesis in a clonal cell line of simian virus 40-transformed hamster pancreatic beta cells. Proc Natl Acad Sci U S A 1981; 78(7): 4339–4343. Dostupné z DOI: <http://dx.doi.org/10.1073/pnas.78.7.4339>.
  25. Efrat S, Leiser M, Surana M et al. Murine insulinoma cell line with normal glucose-regulated insulin secretion. Diabetes 1993; 42(6): 901–907. Dostupné z DOI: <http://dx.doi.org/10.2337/diab.42.6.901>.
  26. Miyazaki J, Araki K, Yamato E et al. Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology 1990; 127(1): 126–132. Dostupné z DOI: <http://dx.doi.org/10.1210/endo-127–1-126>.
  27. Ravassard P, Hazhouz Y, Pechberty S et al. A genetically engineered human pancreatic beta cell line exhibiting glucose-inducible insulin secretion. J Clin Invest 2011; 121(9): 3589–3597. Dostupné z DOI: <http://dx.doi.org/10.1172/JCI58447>.
  28. Carlessi R, Chen Y, Rowlands J et al. GLP-1 receptor signaling promotes beta-cell glucose metabolism via mTOR-dependent HIF-1alpha activation. Sci Rep 2017; 7(1): 2661. Dostupné z DOI: <http://dx.doi.org/10.1038/s41598–017–02838–2>.
  29. Ulrich AB, Schmied BM, Standop J et al. Pancreatic cell lines: a review. Pancreas 2002; 24(2): 111–120. Dostupné z DOI: <http://dx.doi.org/10.1097/00006676–200203000–00001>.
  30. Skelin M, Rupnik M, Cencic A. Pancreatic beta cell lines and their applications in diabetes mellitus research. ALTEX 2010; 27(2): 105–113. Dostupné z DOI: <http://dx.doi.org/10.14573/altex.2010.2.105>.
  31. Fusaki N, Ban H, Nishiyama A et al. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 2009; 85(8): 348–362. Dostupné z DOI: <http://dx.doi.org/10.2183/pjab.85.348>
  32. Young-Baird SK, Shin BS, Dever TE. MEHMO syndrome mutation EIF2S3-I259M impairs initiator Met-tRNAiMet binding to eukaryotic translation initiation factor eIF2. Nucleic Acids Res 2019; 47(2): 855–867. Dostupné z DOI: <http://dx.doi.org/10.1093/nar/gky1213>.
  33. Urano F. Wolfram syndrome iPS cells: the first human cell model of endoplasmic reticulum disease. Diabetes 2014; 63(3): 844–846. Dostupné z DOI: <http://dx.doi.org/10.2337/db13–1809>.
  34. Lu S, Kanekura K, Hara T et al. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proc Natl Acad Sci U S A 2014; 111(49): E5292-E5301. Dostupné z DOI: <http://dx.doi.org/10.1073/pnas.1421055111>.
  35. Shang L, Hua H, Foo K et al. beta-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. Diabetes 2014; 63(3): 923–933. Dostupné z DOI: <http://dx.doi.org/10.2337/db13–0717>.
  36. Grzela DP, Marciniak B, Pulaski L. Characterization of an induced pluripotent stem cell line (IMBPASi001-A) derived from fibroblasts of a patient affected by Wolfram Syndrome. Stem Cell Res 2020; 46: 101858. Dostupné z DOI: <http://dx.doi.org/10.1016/j.scr.2020.101858>.
  37. Cierpka-Kmiec K, Wronska A, Kmiec Z. In vitro generation of pancreatic beta-cells for diabetes treatment. I. beta-like cells derived from human pluripotent stem cells. Folia Histochem Cytobiol 2019; 57(1): 1–14. Dostupné z DOI: <http://dx.doi.org/10.5603/FHC.a2019.0001>.
  38. Zhou Q, Melton DA. Pancreas regeneration. Nature 2018; 557(7705): 351–358. Dostupné z DOI: <http://dx.doi.org/10.1038/s41586–018–0088–0>.
  39. Laurent LC, Ulitsky I, Slavin I et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 2011; 8(1): 106–118. Dostupné z DOI: <http://dx.doi.org/10.1016/j.stem.2010.12.003>.
  40. Imreh MP, Gertow K, Cedervall J et al. In vitro culture conditions favoring selection of chromosomal abnormalities in human ES cells. J Cell Biochem 2006; 99(2): 508–516. Dostupné z DOI: <http://dx.doi.org/10.1002/jcb.20897>.
  41. Baker DE, Harrison NJ, Maltby E et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol 2007; 25(2): 207–215. Dostupné z DOI: <http://dx.doi.org/10.1038/nbt1285>.
  42. Maitra A, Arking DE, Shivapurkar N et al. Genomic alterations in cultured human embryonic stem cells. Nat Genet 2005; 37(10): 1099–1103. Dostupné z DOI: <http://dx.doi.org/10.1038/ng1631>.
  43. Mitalipova MM, Rao RR, Hoyer DM et al. Preserving the genetic integrity of human embryonic stem cells. Nat Biotechnol 2005; 23(1): 19–20. <http://dx.doi.org/10.1038/nbt0105–19>.
  44. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007; 448(7151): 313–317. <http://dx.doi.org/10.1038/nature05934>.
  45. Ramos-Mejia V, Munoz-Lopez M, Garcia-Perez JL et al. iPSC lines that do not silence the expression of the ectopic reprogramming factors may display enhanced propensity to genomic instability. Cell Res 2010; 20(10): 1092–1095. Dostupné z DOI: <http://dx.doi.org/10.1038/cr.2010.125>.
  46. Miura K, Okada Y, Aoi T et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 2009; 27(8): 743–745. Dostupné z DOI: <http://dx.doi.org/10.1038/nbt.1554>.
  47. Mayshar Y, Ben-David U, Lavon N et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 2010; 7(4): 521–531. Dostupné z DOI: <http://dx.doi.org/10.1016/j.stem.2010.07.017>.
  48. Yamanaka S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 2012; 10(6): 678–684. Dostupné z DOI: <http://dx.doi.org/10.1016/j.stem.2012.05.005>.
  49. Choi KD, Yu J, Smuga-Otto K et al. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells 2009; 27(3): 559–567. <http://dx.doi.org/10.1634/stemcells.2008–0922>.
  50. Demine S, Schiavo AA, Marin-Canas S et al. Pro-inflammatory cytokines induce cell death, inflammatory responses, and endoplasmic reticulum stress in human iPSC-derived beta cells. Stem Cell Res Ther 2020; 11(1): 7. Dostupné z DOI: <http://dx.doi.org/10.1186/s13287–019–1523–3>.
  51. Hu BY, Weick JP, Yu J et al. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci U S A 2010; 107(9): 4335–4340. Dostupné z DOI: <http://dx.doi.org/10.1073/pnas.0910012107>.
  52. KarbalaeiMahdi A, Shahrousvand M, Javadi HR et al. Neural differentiation of human induced pluripotent stem cells on polycaprolactone/gelatin bi-electrospun nanofibers. Mater Sci Eng C Mater Biol Appl 2017; 78: 1195–1202. <http://dx.doi.org/10.1016/j.msec.2017.04.083>.
  53. Chichagova V, Hilgen G, Ghareeb A et al. Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent. Stem Cells 2020; 38(2): 195–201. <http://dx.doi.org/10.1002/stem.3116>.
  54. Kroon E, Martinson LA, Kadoya K et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008; 26(4): 443–452. Dostupné z DOI: <http://dx.doi.org/10.1038/nbt1393>.
  55. D’Amour KA, Bang AG, Eliazer S et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 2006; 24(11): 1392–1401. Dostupné z DOI: <http://dx.doi.org/10.1038/nbt1259>.
  56. Lyttle BM, Li J, Krishnamurthy M et al. Transcription factor expression in the developing human fetal endocrine pancreas. Diabetologia 2008; 51(7): 1169–1180. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–008–1006-z>.
  57. Rezania A, Bruin JE, Xu J et al. Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo. Stem Cells 2013; 31(11): 2432–2442. Dostupné z DOI: <http://dx.doi.org/10.1002/stem.1489>.
  58. Rezania A, Bruin JE, Riedel MJ et al. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 2012; 61(8): 2016–2029. Dostupné z DOI: <http://dx.doi.org/10.2337/db11–1711>.
  59. Onaca N, Naziruddin B, Matsumoto S et al. Pancreatic islet cell transplantation: update and new developments. Nutr Clin Pract 2007; 22(5): 485–493. Dostupné z DOI: <http://dx.doi.org/10.1177/0115426507022005485>.
  60. Robertson RP. Islet transplantation for type 1 diabetes, 2015: what have we learned from alloislet and autoislet successes? Diabetes Care 2015; 38(6): 1030–1035. Dostupné z DOI: <http://dx.doi.org/10.2337/dc15–0079>.
  61. Bruin JE, Saber N, Braun N et al. Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs. Stem Cell Reports 2015; 4(4): 605–620. Dostupné z DOI: <http://dx.doi.org/10.1016/j.stemcr.2015.02.011>.
  62. Rezania A, Bruin JE, Arora P et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 2014; 32(11): 1121–1133. Dostupné z DOI: <http://dx.doi.org/10.1038/nbt.3033>.
  63. Jeon K, Lim H, Kim JH et al. Differentiation and transplantation of functional pancreatic beta cells generated from induced pluripotent stem cells derived from a type 1 diabetes mouse model. Stem Cells Dev 2012; 21(14): 2642–2655. Dostupné z DOI: <http://dx.doi.org/10.1089/scd.2011.0665>.
  64. Xie R, Everett LJ, Lim HW et al. Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell 2013; 12(2): 224–237. <http://dx.doi.org/10.1016/j.stem.2012.11.023>.
  65. Kelly OG, Chan MY, Martinson LA et al. Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol 2011; 29(8): 750–756. Dostupné z DOI: <http://dx.doi.org/10.1038/nbt.1931>.
  66. van der Torren CR, Zaldumbide A, Duinkerken G et al. Immunogenicity of human embryonic stem cell-derived beta cells. Diabetologia 2017; 60(1): 126–133. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–016–4125-y>.
  67. Dinnyes A, Schnur A, Muenthaisong S et al. Integration of nano- and biotechnology for beta-cell and islet transplantation in type-1 diabetes treatment. Cell Prolif 2020; 53(5): e12785. Dostupné z DOI: <http://dx.doi.org/10.1111/cpr.12785>.
  68. Kondo Y, Toyoda T, Inagaki N et al. iPSC technology-based regenerative therapy for diabetes. J Diabetes Investig 2018; 9(2): 234–243. Dostupné z DOI: <http://dx.doi.org/10.1111/jdi.12702>.
  69. Lysy PA. [Cellular therapy of diabetes: focus on the latest developments]. Med Sci (Paris) 2016; 32(4): 401–407. Dostupné z DOI: <http://dx.doi.org/10.1051/medsci/20163204019>.
  70. Barkai U, Rotem A, de Vos P. Survival of encapsulated islets: More than a membrane story. World J Transplant 2016; 6(1): 69–90. Dostupné z DOI: <http://dx.doi.org/10.5500/wjt.v6.i1.69>.
  71. Kunisada Y, Tsubooka-Yamazoe N, Shoji M et al. Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells. Stem Cell Res 2012; 8(2): 274–284. Dostupné z DOI: <http://dx.doi.org/10.1016/j.scr.2011.10.002>.
  72. Pagliuca FW, Millman JR, Gurtler M et al. Generation of functional human pancreatic beta cells in vitro. Cell 2014; 159(2): 428–439. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cell.2014.09.040>.
  73. Suchy F, Yamaguchi T, Nakauchi H. iPSC-Derived Organs In Vivo: Challenges and Promise. Cell Stem Cell 2018; 22(1): 21–24. Dostupné z DOI: <http://dx.doi.org/10.1016/j.stem.2017.12.003>.
  74. Zhu Z, Li QV, Lee K et al. Genome Editing of Lineage Determinants in Human Pluripotent Stem Cells Reveals Mechanisms of Pancreatic Development and Diabetes. Cell Stem Cell 2016; 18(6): 755–768. <http://dx.doi.org/10.1016/j.stem.2016.03.015>.
  75. McGrath PS, Watson CL, Ingram C et al. The Basic Helix-Loop-Helix Transcription Factor NEUROG3 Is Required for Development of the Human Endocrine Pancreas. Diabetes 2015; 64(7): 2497–2505. Dostupné z DOI: <http://dx.doi.org/10.2337/db14–1412>.
  76. Tiyaboonchai A, Cardenas-Diaz FL, Ying L et al. GATA6 Plays an Important Role in the Induction of Human Definitive Endoderm, Development of the Pancreas, and Functionality of Pancreatic beta Cells. Stem Cell Reports 2017; 8(3): 589–604. Dostupné z DOI: <http://dx.doi.org/10.1016/j.stemcr.2016.12.026>.
  77. Saarimaki-Vire J, Balboa D, Russell MA et al. An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation. Cell Rep 2017; 19(2): 281–294. Dostupné z DOI: <http://dx.doi.org/10.1016/j.celrep.2017.03.055>.
  78. Balboa D, Saarimaki-Vire J, Borshagovski D et al. Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes. Elife 2018; 7: e38519. Dostupné z DOI: <http://dx.doi.org/10.7554/eLife.38519>.
  79. Green AD, Vasu S, Flatt PR. Cellular models for beta-cell function and diabetes gene therapy. Acta Physiol (Oxf) 2018; 222(3). <http://dx.doi.org/10.1111/apha.13012>.
  80. Informácie dostupné z WWW: <https://smart.servier.com>.
Labels
Diabetology Obesitology

Article was published in

Diabetes and obesity

Issue 41

2021 Issue 41

Most read in this issue
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#