Genes predisposing to type 1 diabetes mellitus and pathophysiology: a narrative review

Keywords: autoimmunity, hyperglycemia, insulin, pancreas, type 1 diabetes mellitus

Abstract

The possibility of targeting the causal genes along with the mechanisms of pathogenically complex diseases has led to numerous studies on the genetic etiology of some diseases. In particular, studies have added more genes to the list of type 1 diabetes mellitus (T1DM) suspect genes, necessitating an update for the interest of all stakeholders. Therefore this review articulates T1DM suspect genes and their pathophysiology. Notable electronic databases, including Medline, Scopus, PubMed, and Google-Scholar were searched for relevant information. The search identified over 73 genes suspected in the pathogenesis of T1DM, with human leukocyte antigen, insulin gene, and cytotoxic T lymphocyte-associated antigen 4 accounting for most of the cases. Mutations in these genes, along with environmental factors, may produce a defective immune response in the pancreas, resulting in β-cell autoimmunity, insulin deficiency, and hyperglycemia. The mechanisms leading to these cellular reactions are gene-specific and, if targeted in diabetic individuals, may lead to improved treatment. Medical practitioners are advised to formulate treatment procedures that target these genes in patients with T1DM.

References

National Institute of Diabetes and Digestive and Kidney Diseases. Type 1 diabetes: what is type 1 diabetes? [Internet]. 2017 [cited 2018 Jul 18]. Available from: https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/type-1-diabetes.

Type 1 diabetes. [Internet]. 2018 [cited 2018 Oct 28]. Available from: https://www.webmd.com/diabetes/type-1-diabetes#1.

Norman J. What is type 1 diabetes [Internet]. EndocrineWeb; 2018 [cited 2018 Oct 3]. Available from: https://www.endocrineweb.com/conditions/type-1-diabetes/type-1-diabetes.

Bennington-Castro J. What Is type 1 diabetes? [Internet]. Everyday Health. 2015. [cited 2018 Sep 3]. Available from https://www.everydayhealth.com/type-1-diabetes/guide/.

Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA. 2014;311(17):1778-86. https://doi.org/10.1001/jama.2014.3201

Pociot F, McDermott MF. Genetics of type 1 diabetes mellitus. Genes Immun. 2002;3(5):235-49. https://doi.org/10.1038/sj.gene.6363875

Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003;33(2):177-82. https://doi.org/10.1038/ng1071

Bacchetta R, Maccari ME. Type 1 diabetes mellitus in monogenic autoimmune diseases. In: Barbetti F, Ghizzoni L, Guaraldi F, editors. Diabetes associated with single gene defects and chromosomal abnormalities. vol 25th. Basel: Karger; 2017. p. 78-90. https://doi.org/10.1159/000454703

Baxter AG, Jordan MA. From markers to molecular mechanisms: type 1 diabetes in the post-GWAS era. Rev Diabet Stud. 2012;9(4):201-23. https://doi.org/10.1900/RDS.2012.9.201

Giliani S, Mori L, de Saint Basile G, Le Deist F, Rodriguez-Perez C, Forino C, et al. Interleukin-7 receptor alpha (IL-7Ralpha) deficiency: cellular and molecular bases. analysis of clinical, immunological, and molecular features in 16 novel patients. Immunol Rev. 2005;203:110-26. https://doi.org/10.1111/j.0105-2896.2005.00234.x

Hulme MA, Wasserfall CH, Atkinson MA, Brusko TM. Central role for interleukin-2 in type 1 diabetes. Diabetes. 2012;61(1):14-22. https://doi.org/10.2337/db11-1213

del-Rio ML, Bernhardt G, Rodriguez-Barbosa JI, Förster R. Development and functional specialization of CD103+ dendritic cells. Immunol Rev. 2010;234(1):268-81. https://doi.org/10.1111/j.0105-2896.2009.00874.x

Hotta-Iwamura C, Tarbell KV. Type 1 diabetes genetic susceptibility and dendritic cell function: potential targets for treatment. J Leukoc Biol. 2016;100(1):65-80. https://doi.org/10.1189/jlb.3MR1115-500R

Daley SR, Coakley KM, Hu DY, Randall KL, Jenne CN, Limnander A, et al. Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies. Elife. 2013;2:e01020. https://doi.org/10.7554/eLife.01020

Boehm BO, Bluestone JA. Differential roles of costimulatory signaling pathways in type 1 diabetes mellitus. Rev Diabet Stud. 2004;1(4):156-64. https://doi.org/10.1900/RDS.2004.1.156

Tiittanen M, Huupponen JT, Knip M, Vaarala O. Insulin treatment in patients with type 1 diabetes induces upregulation of regulatory T-cell markers in peripheral blood mononuclear cells stimulated with insulin in vitro. Diabetes. 2006;55(12):3446-54. https://doi.org/10.2337/db06-0132

Jiang Z, Handler ES, Rossini AA, Woda BA. Immunopathology of diabetes in the RT6-depleted diabetes-resistant BB/Wor rat. Am J Pathol. 1990;137(4):767-77.

Ge Y, Paisie TK, Newman JRB, McIntyre LM, Concannon P. UBASH3A mediates risk for type 1 diabetes through inhibition of T-cell receptor-induced NF-κB signaling. Diabetes. 2017;66(7):2033-43. https://doi.org/10.2337/db16-1023

Fung EY, Smyth DJ, Howson JM, Cooper JD, Walker NM, Stevens H, et al. Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun. 2009;10(2):188-91. https://doi.org/10.1038/gene.2008.99

Noble JA, Erlich HA. Genetics of type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2:a007732. https://doi.org/10.1101/cshperspect.a007732

Visperas A, Vignali DA. Are Tregs defective in type 1 diabetes and can we fix them? J Immunol. 2016;197(10):3762-70. https://doi.org/10.4049/jimmunol.1601118

Sánchez-Zamora YI, Rodriguez-Sosa M. The role of MIF in type 1 and type 2 diabetes mellitus. J Diabetes Res. 2014;2014:804519. https://doi.org/10.1155/2014/804519

Mattana TC, Santos AS, Fukui RT, Mainardi-Novo DT, Costa VS, Santos RF, et al. CD226 rs763361 is associated with the susceptibility to type 1 diabetes and greater frequency of GAD65 autoantibody in a Brazilian cohort. Mediators Inflamm. 2014;694948. https://doi.org/10.1155/2014/694948

Gardner A. IL6 (Interleukin 6) [Internet]. 2018 [cited 2018 Nov 3]. Available from: https://www.mygenefood.com/genes/il6/.

Guo B. IL-10 modulates Th17 pathogenicity during autoimmune diseases. J Clin Cell Immunol. 2016;7(2):400. https://doi.org/10.4172/2155-9899.1000400

Bergholdt R, Ghandil P, Johannesen J, Kristiansen OP, Kockum I, Luthman H, et al. Genetic and functional evaluation of an interleukin-12 polymorphism (IDDM18) in families with type 1 diabetes. J Med Genet. 2004;41(4):e39. https://doi.org/10.1136/jmg.2003.010454

Stene LC, Barriga K, Hoffman MK, Kean J, Klingensmith G, Norris JM, et al. Normal but increasing hemoglobin A1c levels predict progression from islet autoimmunity to overt type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). Pediatr Diabetes. 2006;7(5):247-53. https://doi.org/10.1111/j.1399-5448.2006.00198.x

Iyer A, Lanham-Newusan S, Khoja S, Al-Ghamdi M, Al Doghaither H. Relationship between vitamin D receptor gene polymorphisms and type 1 diabetes mellitus in Saudi patients. Int J Pharmacol. 2017;13(8):1092-7. https://doi.org/10.3923/ijp.2017.1092.1097

Meller S, Di Domizio J, Voo KS, Friedrich HC, Chamilos G, Ganguly D, et al. T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nature Immunol. 2015;16(9):970-9. https://doi.org/10.1038/ni.3211

Liao W, Spolski R, Li P, Du N, West EE, Ren M, et al. Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc Natl Acad Sci U S A. 2014;111(9):3508-13. https://doi.org/10.1073/pnas.1301138111

Izumi, K, Mine K, Inoue Y, Teshima M, Ogawa S, Kai Y, et al. Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes. Nat Commun. 2015;6:6748. https://doi.org/10.1038/ncomms7748

Kibirige D, Lumu W, Jones AG, Smeeth L, Hattersley AT, Nyirenda MJ. Understanding the manifestation of diabetes in sub Saharan Africa to inform therapeutic approaches and preventive strategies: a narrative review. Clin Diabetes Endocrinol. 2019;5:2. https://doi.org/10.1186/s40842-019-0077-8

National Center for Biotechnology Information, U.S. National Library of Medicine. OAS1 2'-5'-oligoadenylate synthetase 1 [Homo sapiens (human)] [Internet]. Bethesda: National Center for Biotechnology Information, U.S. National Library of Medicine; 2018 [cited 2018 Jun 3]. Available from: https://www.ncbi.nlm.nih.gov/gene/4938.

Mehers KL, Gillespie KM. The genetic basis for type 1 diabetes. British Med Bull. 2008; 88 (1):115-29. https://doi.org/10.1093/bmb/ldn045

Yang P, Li HL, Wang CY. FUT2 nonfunctional variant: a "missing link" between genes and environment in type 1 diabetes? Diabetes. 2011;60(11):2685-7. https://doi.org/10.2337/db11-1104

Brix L. Gene defect causes type 1 diabetes [Internet]. 2013 [cited 2018 Mar 15]. Available from: http://sciencenordic.com/gene-defect-causes-type-1-diabetes.

Lemos NE, Dieter C, Dorfman LE, Assmann TS, Duarte GC, Canani LH, et al. The rs2292239 polymorphism in ERBB3 gene is associated with risk for type 1 diabetes mellitus in a Brazilian population. Gene. 2018;644:122-8. https://doi.org/10.1016/j.gene.2017.11.009

Fukushima A, Loh K, Galic S, Fam B, Shields B, Wiede F, et al. T-cell protein tyrosine phosphatase attenuates STAT3 and insulin signaling in the liver to regulate gluconeogenesis. Diabetes. 2010;59(8):1906-14. https://doi.org/10.2337/db09-1365

Marroquí L, Santin I, Dos Santos RS, Marselli L, Marchetti P, Eizirik DL. BACH2, a candidate risk gene for type 1 diabetes, regulates apoptosis in pancreatic β-cells via JNK1 modulation and crosstalk with the candidate gene PTPN2. Diabetes. 2014;63(7):2516-27. https://doi.org/10.2337/db13-1443

Spolski R, Kashyap M, Robinson C, Yu Z, Leonard WJ. IL-21 signaling is critical for the development of type I diabetes in the NOD mouse. Proc Natl Acad Sci U S A. 2008;105(37):14028-33. https://doi.org/10.1073/pnas.0804358105

Brorsson CA, Pociot F. Shared genetic basis for type 1 diabetes, islet autoantibodies, and autoantibodies associated with other immune-mediated diseases in families with type 1 diabetes. Diabetes Care. 2015;38 Suppl 2(Suppl 2):S8-13. https://doi.org/10.2337/dcs15-2003

Wallace C, Rotival M, Cooper JD, Rice CM, Yang JH, McNeill M, et al. Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes. Hum Mol Genet. 2012;21(12):2815-24. https://doi.org/10.1093/hmg/dds098

Fukaya M, Brorsson CA, Meyerovich K, Catrysse L, Delaroche D, Vanzela EC, et al. A20 inhibits β-cell apoptosis by multiple mechanisms and predicts residual β-cell function in type 1 diabetes. Mol Endocrinol. 2016;30(1):48-61. https://doi.org/10.1210/me.2015-1176

Wallace C, Smyth DJ, Maisuria-Armer M, Walker NM, Todd JA, Clayton DG. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet. 2010;42(1):68-71. https://doi.org/10.1038/ng.493

Dos Santos RS, Marroqui L, Velayos T, Olazagoitia-Garmendia A, Jauregi-Miguel A, Castellanos-Rubio A, et al. DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway. Diabetologia. 2019;62(3):459-72. https://doi.org/10.1007/s00125-018-4782-0

Zamani F, Almasi S, Kazemi T, Esfahlan RJ, Aliparasti MR. New approaches to the immunotherapy of type 1 diabetes mellitus using interleukin-27. Adv Pharm Bull. 2015;5(Suppl 1):599-603. https://doi.org/10.15171/apb.2015.081

Costes S, Vandewalle B, Tourrel-Cuzin C, Broca C, Linck N, Bertrand G, et al. Degradation of cAMP-responsive element-binding protein by the ubiquitin-proteasome pathway contributes to glucotoxicity in beta-cells and human pancreatic islets. Diabetes. 2009;58(5):1105-15. https://doi.org/10.2337/db08-0926

McKenzie MD, Jamieson E, Jansen ES, Scott CL, Huang DC, Bouillet P, et al. Glucose induces pancreatic islet cell apoptosis that requires the BH3-only proteins Bim and Puma and multi-BH domain protein Bax. Diabetes. 2010;59(3):644-52. https://doi.org/10.2337/db09-1151

Juntti-Berggren L, Refai E, Appelskog I, Andersson M, Imreh G, Dekki N, et al. Apolipoprotein CIII promotes Ca2+-dependent beta cell death in type 1 diabetes. Proc Natl Acad Sci U S A. 2004;101(27):10090-4. https://doi.org/10.1073/pnas.0403551101

National Center for Biotechnology Information, U.S. National Library of Medicine. BAD BCL2 associated agonist of cell death [Homo sapiens (human)] [Internet]. Bethesda: National Center for Biotechnology Information, U.S. National Library of Medicine; 2018 [cited 2019 Mar 13]. Available from: https://www.ncbi.nlm.nih.gov/gene/572.

Boyd CS, Cadenas E. Nitric oxide and cell signaling pathways in mitochondrial-dependent apoptosis. Biol Chem. 2002;383(3- 4):411-23. https://doi.org/10.1515/BC.2002.045

Ishihara H, Sasaoka T, Kagawa S, Murakami S, Fukui K, Kawagishi Y, et al. Association of the polymorphisms in the 5'-untranslated region of PTEN gene with type 2 diabetes in a Japanese population. FEBS Lett. 2003:554(3):450-4. https://doi.org/10.1016/S0014-5793(03)01225-0

Babu, SR, Bao F, Roberts CM, Martin AK, Gowan K, Eisenbarth GS, et al. Caspase 7 is a positional candidate gene for IDDM 17 in a Bedouin Arab family. Ann N Y Acad Sci. 2003;1005:340-3. https://doi.org/10.1196/annals.1288.054

Berchtold LA, Størling ZM, Ortis, F, Lage K, Bang-Berthelsen C, Bergholdt R, et al. Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis. Proc Natl Acad Sci U S A. 2011;108(37):E681-8. https://doi.org/10.1073/pnas.1104384108

Weaver JR, Nadler JL, Taylor-Fishwick DA. Interleukin-12 (IL-12)/ STAT4 axis is an important element for β-Cell dysfunction induced by inflammatory cytokines. PLoS One. 2015;10(11):e0142735. https://doi.org/10.1371/journal.pone.0142735

Cameron MJ, Arreaza GA, Grattan M, Meagher C, Sharif S, Burdick MD, et al. Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type i diabetes. J Immunol, 2000;165(2):1102-10. https://doi.org/10.4049/jimmunol.165.2.1102

Rorsman P, Ashcroft FM. Pancreatic β-cell electrical activity and insulin secretion: of mice and men. Physiol Rev. 98: 117-214. https://doi.org/10.1152/physrev.00008.2017

Shoelson S, Haneda M, Blix P, Nanjo A, Sanke T, Inouye K, et al. Three mutant insulins in man. Nature. 1983;302(5908): 540-3. https://doi.org/10.1038/302540a0

Genetics Home Reference. HNF1A gene [Internet]. Bethesda: National Center for Biotechnology Information, U.S. National Library of Medicine; 2018 [cited 2018 Jun 26]. Available from: https://ghr.nlm.nih.gov/gene/HNF1A#conditions.

Santer R, Groth S, Kinner M, Dombrowski A, Berry GT, Brodehl J, et al. The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome. Hum Genet. 2002;110(1):21-9. https://doi.org/10.1007/s00439-001-0638-6

Götz J, Lim YA, Eckert A. Lessons from two prevalent amyloidoses-what amylin and Aβ have in common. Front Aging Neurosci. 2013;5:38. https://doi.org/10.3389/fnagi.2013.00038

Gutiérrez GD, Bender AS, Cirulli V, Mastracci TL, Kelly SM, Tsirigos A, et al. Pancreatic β cell identity requires continual repression of non–β cell programs. Clin Invest. 2017;127(1):244-59. https://doi.org/10.1172/JCI88017

Wen X, Yang Y. Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes. J Mol Endocrinol. 2017;58(2):R73-85. https://doi.org/10.1530/JME-16-0232

Romer AI, Singer RA, Sui L, Egli D, Sussel L. Murine perinatal β-cell proliferation and the differentiation of human stem cell-derived insulin-expressing cells require NEUROD1. Diabetes. 2019;68(12):2259-71. https://doi.org/10.2337/db19-0117

Fløyel T, Brorsson C, Nielsen LB, Miani M, Bang-Berthelsen CH, Friedrichsen M, et al. CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. Proc Natl Acad Sci U S A. 2014;111(28):10305-10. https://doi.org/10.1073/pnas.1402571111

Santos MA, Sarmento LM, Rebelo M, Doce AA, Maillard I, Dumortier A, et al. Notch1 engagement by delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells. Proc Natl Acad Sci U S A. 2007;104(39):15454-9. https://doi.org/10.1073/pnas.0702891104

Holm LJ, Krogvold L, Hasselby JP, Kaur S, Claessens LA, Russell MA, et al. Abnormal islet sphingolipid metabolism in type 1 diabetes. Diabetologia. 2018;61:1650-61. https://doi.org/10.1007/s00125-018-4614-2

Rachdi L, Balcazar N, Elghazi L, Barker DJ, Krits I, Kiyokawa H, et al. Differential effects of p27 in regulation of β-cell mass during development, neonatal period, and adult life. Diabetes. 2006;55(12):3520-8. https://doi.org/10.2337/db06-0861

Kulkarni RN. New insights into the roles of insulin/IGF-I in the development and maintenance of beta-cell mass. Rev Endocr Metab Disord. 2005;6(3):199-210. https://doi.org/10.1007/s11154-005-3051-y

Dendrou CA, Wicker LS. The IL-2/CD25 pathway determines susceptibility to T1D in humans and NOD mice. J Clin Immunol. 2008;28(60):685-96. https://doi.org/10.1007/s10875-008-9237-9

Genetics Home Reference. Histocompatibility complex [Intenet]. Bethesda: National Center for Biotechnology Information, U.S. National Library of Medicine; 2018 [cited 2018 Jun 26]. Available from: https://ghr.nlm.nih.gov/primer/genefamily/hla.

Notkins AL. Immunologic and genetic factors in type 1 diabetes. J Biol Chem. 2002:277(46):43545-8. https://doi.org/10.1074/jbc.R200012200

National Center for Biotechnology Information, U.S. National Library of Medicine. INS insulin [Homo sapiens (human)] [Internet]. Bethesda: National Center for Biotechnology Information, U.S. National Library of Medicine; 2018 [cited 2018 Jun 27]. Available from: https://www.ncbi.nlm.nih.gov/gene/3630#gene-expression.

Concannon P, Erlich HA, Julier C, Morahan G, Nerup J, Pociot F, et al. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes. 2005;54(10):2995-3001. https://doi.org/10.2337/diabetes.54.10.2995

Kantárová D, Buc M. Genetic susceptibility to type 1 diabetes mellitus in humans. Physiol Res. 2007;56(3):255-66.

Sharp RC, Abdulrahim M, Naser ES, Naser SA. Genetic variations of PTPN2 and PTPN22: role in the pathogenesis of type 1 diabetes and Crohn's disease. Front Cell Infect Microbiol. 2015;5:95. https://doi.org/10.3389/fcimb.2015.00095

Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem. 2011;57(2):176-85. https://doi.org/10.1373/clinchem.2010.148221

Bingley PJ, Bonifacio E, Ziegler AG, Schatz DA, Atkinson MA, Eisenbarth GS, et al. Proposed guidelines on screening for risk of type 1 diabetes. Diabetes Care. 2001;24(2):398. https://doi.org/10.2337/diacare.24.2.398

Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163-89. https://doi.org/10.1189/jlb.0603252

Published
2020-03-26
How to Cite
1.
Yahaya T, Salisu T. Genes predisposing to type 1 diabetes mellitus and pathophysiology: a narrative review. Med J Indones [Internet]. 2020Mar.26 [cited 2024Feb.23];29(1):100-9. Available from: https://mji.ui.ac.id/journal/index.php/mji/article/view/3732
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Review Article