Bevezetés
A cukorbetegség, latinul diabetes mellitus (DM), magyarosan diabétesz, a glükóz feldolgozási zavara. Kiváltó okai alapján megkülönböztetünk 1-es típusú, inzulindependens (T1D) és 2-es típusú, inzulinindependens (T2D) diabetes mellitust. Míg az előbbit az inzulintermelődés zavara váltja ki, addig az utóbbit a szervezet inzulinnal szembeni érzéketlensége, rezisztenciája okozza.
Jelenleg nagyjából 463 millió diabéteszes páciens él a világon, a betegség pedig egyre növekvő tendenciát mutat. A becslések szerint 2030-ra már 578,4 millió, 2045-re pedig már 700,2 millió cukorbeteg emberrel számolhatunk. (Que et al., 2021)
Az állatok szénhidrátforgalmának, így a vércukorszint szabályozásában is fontos szerepet vállalnak hormonok. Míg a vércukorszintet számos hormon (adrenalin, glükagon, glükokortikoidok, ACTH, GH) emeli, addig csupán egyetlen hormon csökkenti, az inzulin (1. ábra). Utóbbit a hasnyálmirigy Langerhans-szigeteinek β-sejtjei termelik (2. ábra), így könnyen belátható, ha ezek károsodást szenvednek, elkerülhetetlenül inzulinhiány alakul ki.
A cukorbetegség tünetei sokfélék lehetnek. A fáradtságot az emelkedett vércukorszint (hyperglikémia) miatt kialakuló gyakori vizelés (polyuria) és szomjúságérzet, megnövekedett vízfogyasztás (polydipsia) társul. A folyadék és elektrolitháztartás zavarai járhatnak izomgörcsökkel, látászavarral. Kialakulhat viszketés és vöröses arcszínezet (rubeosis diabetica). A T2D kezdeti fázisában a magas vérinzulinszint okozhat extrém éhségérzetet.
Amennyiben nem kezelik, a cukorbetegséget kísérhetik súlyos szövődmények. Az érrendszeri szövődményeknek több formája van, érdemes megemlíteni az érelmeszesedést, nephropathiát, retinopathiát, neuropathiat és a diabéteszes láb szindrómát. (Pociot and Bergholdt, 2006)
Cukorbetegség típusai
1-es típusú cukorbetegség
Az 1-es típusú, inzulindependens diabetes mellitus egy autoimmun betegség. Mint ilyen, az állat immunrendszere idegenként azonosítja a saját hasnyálmirigyének inzulintermelő β-sejtjeit, így azok végül autoimmun gyulladás következtében károsodnak, illetve elpusztulnak, totális inzulinhiányt eredményezve. Bármely életkorban előfordulhat, de általában gyermekkorban jelentkezik és tipikusan egyébként egészséges embereket érint. A betegség gyógyíthatatlan, kezelési lehetőségei az életmódváltás, diéta, illetve exogén úton pótolt inzulin. Mint minden autoimmun betegségnél, így itt is fontosak a hajlamosító tényezők. Szóba jöhet genetikai hajlam, táplálkozási szokások, köztük a tehéntej-tejfehérjéje, a gliadin (a glutén egyik összetevője) és vírusfertőzések is. (Syed, 2022)
2-es típusú cukorbetegség
Hivatkozások
1. Alidjinou EK, Hober D (2015) Enteroviruses and Type 1 Diabetes: Candidate Genes Linked With Innate Immune Response. EBioMedicine 2:636–637.
2. Andréoletti L, Lévêque N, Boulagnon C, Brasselet C, Fornes P (2009) Viral causes of human myocarditis. Archives of Cardiovascular Diseases 102:559–568.
3. Bae Y-S, Eun H-M, Yoon J-W (1989) Molecular Identification of Diabetogenic Viral Gene. Diabetes 38:316–320.
4. Bae Y-S, Yoon J-W (1993) Determination of Diabetogenicity Attributable to a Single Amino Acid, Ala776, on the Polyprotein of Encephalomyocarditis Virus. Diabetes 42:435–443.
5. Belkaid Y, Hand TW (2014) Role of the Microbiota in Immunity and Inflammation. Cell 157:121–141.
6. Bendinelli M, Matteucci D, Toniolo A, Patanè AM, Pistillo MP (1982) Impairment of Immunocompetent Mouse Spleen Cell Functions by Infection with Coxsackievirus B3. The Journal of Infectious Diseases 146:797–805.
7. Boucher DW, Notkins AL (1973) VIRUS-INDUCED DIABETES MELLITUS. Journal of Experimental Medicine 137:1226–1239.
8. Brodin P, Jojic V, Gao T, Bhattacharya S, Angel CJL, Furman D, Shen-Orr S, Dekker CL, Swan GE, Butte AJ, Maecker HT, Davis MM (2015) Variation in the Human Immune System Is Largely Driven by Non-Heritable Influences. Cell 160:37–47.
9. Cavalcante P, Barberis M, Cannone M, Baggi F, Antozzi C, Maggi L, Cornelio F, Barbi M, Dido P, Berrih-Aknin S, Mantegazza R, Bernasconi P (2010) Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis. Neurology 74:1118–1126.
10. Coppieters KT, Boettler T, von Herrath M (2012) Virus Infections in Type 1 Diabetes. Cold Spring Harbor Perspectives in Medicine 2:a007682–a007682.
11. de Goffau MC, Fuentes S, van den Bogert B, Honkanen H, de Vos WM, Welling GW, Hyöty H, Harmsen HJM (2014) Aberrant gut microbiota composition at the onset of type 1 diabetes in young children. Diabetologia 57:1569–1577.
12. de Groot P et al. (2021) Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial. Gut 70:92–105.
13. De Riva A, Wållberg M, Ronchi F, Coulson R, Sage A, Thorne L, Goodfellow I, McCoy KD, Azuma M, Cooke A, Busch R (2017) Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment Fiorina P, ed. PLoS ONE 12:e0181964.
14. Derrien M, Alvarez A-S, de Vos WM (2019) The Gut Microbiota in the First Decade of Life. Trends in Microbiology 27:997–1010.
15. Diaz-Horta O, Baj A, Maccari G, Salvatoni A, Toniolo A (2012) Enteroviruses and causality of type 1 diabetes: how close are we? Pediatric Diabetes 13:92–99.
16. Drescher KM, von Herrath M, Tracy S (2015) Enteroviruses, hygiene and type 1 diabetes: toward a preventive vaccine: Enterovirus vaccine for diabetes. Rev Med Virol 25:19–32.
17. Endesfelder D, Engel M, Davis-Richardson AG, Ardissone AN, Achenbach P, Hummel S, Winkler C, Atkinson M, Schatz D, Triplett E, Ziegler A-G, zu Castell W (2016) Towards a functional hypothesis relating anti-islet cell autoimmunity to the dietary impact on microbial communities and butyrate production. Microbiome 4:17.
18. Esposito S, Toni G, Tascini G, Santi E, Berioli MG, Principi N (2019) Environmental Factors Associated With Type 1 Diabetes. Front Endocrinol 10:592.
19. Fairweather D, Rose NR (2002) Type 1 diabetes: virus infection or autoimmune disease? Nat Immunol 3:338–340.
20. Frisk G, Friman G, Tuvemo T, Fohlman J, Diderholm H (1992) Coxsackie B virus IgM in children at onset of Type 1 (insulin-dependent) diabetes mellitus: evidence for IgM induction by a recent or current infection. Diabetologia 35:249–253.
21. Hammerstad SS, Tauriainen S, Hyöty H, Paulsen T, Norheim I, Dahl-Jørgensen K (2013) Detection of enterovirus in the thyroid tissue of patients with graves’ disease. J Med Virol 85:512–518.
22. Harris HF (1899) A Case of Diabetes Mellitus Quickly Following Mumps: On the Pathological Alterations of the Salivary Glands, Closely Resembling Those Found in the Pancreas, in a Case of Diabetes Mellitus. The Boston Medical and Surgical Journal 140:465–469.
23. Hay DR (1953) Maternal rubella and congenital deafness in New Zealand. N Z Med J 52:16–19.
24. Horwitz MS, Bradley LM, Harbertson J, Krahl T, Lee J, Sarvennick N (1998) Diabetes induced by Coxsackie virus: Initiation by bystander damage and not molecular mimicry. Nat Med 4:781–785.
25. Hu Y, Peng J, Li F, Wong FS, Wen L (2018) Evaluation of different mucosal microbiota leads to gut microbiota-based prediction of type 1 diabetes in NOD mice. Sci Rep 8:15451.
26. Imagawa A, Hanafusa T (2011) Fulminant type 1 diabetes-an important subtype in East Asia. Diabetes Metab Res Rev 27:959–964.
27. Inoue T, Nakayama J, Moriya K, Kawaratani H, Momoda R, Ito K, Iio E, Nojiri S, Fujiwara K, Yoneda M, Yoshiji H, Tanaka Y (2018) Gut Dysbiosis Associated With Hepatitis C Virus Infection. Clinical Infectious Diseases 67:869–877.
28. Izumi K et al. (2015) Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes. Nat Commun 6:6748.
29. Jack M. G (2021) Encephalomyocarditis Virus Infection in Animals - Generalized Conditions. MSD Veterinary Manual Available at: https://www.msdvetmanual.com/generalized-conditions/encephalomyocarditis-virus-infection/encephalomyocarditis-virus-infection-in-animals [Accessed May 3, 2022].
30. Jonietz E (2012) Pathology: Cause and effect. Nature 485:S10–S11.
31. Jun HS, Kang Y, Notkins AL, Yoon JW (1997) Gain or loss of diabetogenicity resulting from a single point mutation in recombinant encephalomyocarditis virus. J Virol 71:9782–9785.
32. Jun HS, Yoon JW (2001) The role of viruses in Type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals. Diabetologia 44:271–285.
33. Kang Y, Yoon J-W (1993) A genetically determined host factor controlling susceptibility to encephalomyocarditis virus-induced diabetes in mice. Journal of General Virology 74:1207–1213.
34. Knip M, Siljander H (2016) The role of the intestinal microbiota in type 1 diabetes mellitus. Nat Rev Endocrinol 12:154–167.
35. Kostic AD et al. (2015) The Dynamics of the Human Infant Gut Microbiome in Development and in Progression toward Type 1 Diabetes. Cell Host & Microbe 17:260–273.
36. Kounoue E, Izumi K, Ogawa S, Kondo S, Katsuta H, Akashi T, Niho Y, Harada M, Tamiya S, Kurisaki H, Nagafuchi S (2008) The significance of T cells, B cells, antibodies and macrophages against encephalomyocarditis (EMC)-D virus-induced diabetes in mice. Arch Virol 153:1223–1231.
37. Krischer JP, Lynch KF, Lernmark Å, Hagopian WA, Rewers MJ, She J-X, Toppari J, Ziegler A-G, Akolkar B, the TEDDY Study Group (2017) Genetic and Environmental Interactions Modify the Risk of Diabetes-Related Autoimmunity by 6 Years of Age: The TEDDY Study. Diabetes Care 40:1194–1202.
38. Krogvold L, Skog O, Sundström G, Edwin B, Buanes T, Hanssen KF, Ludvigsson J, Grabherr M, Korsgren O, Dahl-Jørgensen K (2015) Function of Isolated Pancreatic Islets From Patients at Onset of Type 1 Diabetes: Insulin Secretion Can Be Restored After Some Days in a Nondiabetogenic Environment In Vitro. Diabetes 64:2506–2512.
39. Kuehl U, Lassner D, Gast M, Stroux A, Rohde M, Siegismund C, Wang X, Escher F, Gross M, Skurk C, Tschoepe C, Loebel M, Scheibenbogen C, Schultheiss H-P, Poller W (2015) Differential Cardiac MicroRNA Expression Predicts the Clinical Course in Human Enterovirus Cardiomyopathy. Circ: Heart Failure 8:605–618.
40. Laitinen OH, Honkanen H, Pakkanen O, Oikarinen S, Hankaniemi MM, Huhtala H, Ruokoranta T, Lecouturier V, André P, Harju R, Virtanen SM, Lehtonen J, Almond JW, Simell T, Simell O, Ilonen J, Veijola R, Knip M, Hyöty H (2014) Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes. Diabetes 63:446–455.
41. Larsson PG, Lakshmikanth T, Svedin E, King C, Flodström-Tullberg M (2013) Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice. Diabetologia 56:867–874.
42. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E (2017) Dysbiosis and the immune system. Nat Rev Immunol 17:219–232.
43. Markle JGM, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS (2013) Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity. Science 339:1084–1088.
44. Matteucci D, Toniolo A, Conaldi PG, Basolo F, Gori Z, Bendinelli M (1985) Systemic Lymphoid Atrophy in Coxsackievirus B3-Infected Mice: Effects of Virus and Immunopotentiating Agents. Journal of Infectious Diseases 151:1100–1108.
45. McCall KD, Thuma JR, Courreges MC, Benencia F, James CBL, Malgor R, Kantake N, Mudd W, Denlinger N, Nolan B, Wen L, Schwartz FL (2015) Toll-Like Receptor 3 Is Critical for Coxsackievirus B4-Induced Type 1 Diabetes in Female NOD Mice. Endocrinology 156:453–461.
46. McDermott MT (2020) Endocrine secrets. Available at: https://www.clinicalkey.com.au/dura/browse/bookChapter/3-s2.0-C20170006493 [Accessed May 4, 2022].
47. Mein CharlesA, Esposito L, Dunn MG, Johnson GCL, Timms AE, Goy JV, Smith AN, Sebag-Montefiore L, Merriman ME, Wilson AJ, Pritchard LE, Cucca F, Barnett AH, Bain SC, Todd JA (1998) A search for type 1 diabetes susceptibility genes in families from the United Kingdom. Nat Genet 19:297–300.
48. Mejía-León ME, Petrosino JF, Ajami NJ, Domínguez-Bello MG, de la Barca AMC (2015) Fecal microbiota imbalance in Mexican children with type 1 diabetes. Sci Rep 4:3814.
49. Mercalli A, Lampasona V, Klingel K, Albarello L, Lombardoni C, Ekström J, Sordi V, Bolla A, Mariani A, Bzhalava D, Dillner J, Roivainen M, Bosi E, Piemonti L (2012) No evidence of enteroviruses in the intestine of patients with type 1 diabetes. Diabetologia 55:2479–2488.
50. Michaux H, Martens H, Jaïdane H, Halouani A, Hober D, Geenen V (2015) How Does Thymus Infection by Coxsackievirus Contribute to the Pathogenesis of Type 1 Diabetes? Front Immunol 6:338.
51. Morgan NG, Richardson SJ (2014) Enteroviruses as causative agents in type 1 diabetes: loose ends or lost cause? Trends in Endocrinology & Metabolism 25:611–619.
52. Morse ZJ, Horwitz MS (2021) Virus Infection Is an Instigator of Intestinal Dysbiosis Leading to Type 1 Diabetes. Front Immunol 12:751337.
53. Nagafuchi S et al. (2015) TYK2 Promoter Variant and Diabetes Mellitus in the Japanese. EBioMedicine 2:744–749.
54. Nagafuchi S, Toniolo A (2015) VIRAL DIABETES: VIRUS DIABETOGENICITY AND HOST SUSCEPTIBILITY. Immunoendocrinology Available at: http://www.smartscitech.com/index.php/ie/article/view/1026 [Accessed May 3, 2022].
55. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA (2009) Rare Variants of IFIH1 , a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes. Science 324:387–389.
56. Notkins AL, Yoon J-W (1982) Virus-Induced Diabetes in Mice Prevented by a Live Attenuated Vaccine. N Engl J Med 306:486–486.
57. Oikarinen M, Tauriainen S, Oikarinen S, Honkanen T, Collin P, Rantala I, Mäki M, Kaukinen K, Hyöty H (2012) Type 1 Diabetes Is Associated With Enterovirus Infection in Gut Mucosa. Diabetes 61:687–691.
58. Oikarinen S et al. (2014) Virus Antibody Survey in Different European Populations Indicates Risk Association Between Coxsackievirus B1 and Type 1 Diabetes. Diabetes 63:655–662.
59. Onodera T, Yoon J-W, Brown KS, Notkins AL (1978) Evidence for a single locus controlling susceptibility to virus-induced diabetes mellitus. Nature 274:693–696.
60. Parikka V, Näntö-Salonen K, Saarinen M, Simell T, Ilonen J, Hyöty H, Veijola R, Knip M, Simell O (2012) Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia 55:1926–1936.
61. Pociot F, Bergholdt R (2006) Type 1 and 2 Diabetes. In: Cytokine Gene Polymorphisms in Multifactorial Conditions (Vandenbroeck K, ed), pp 305–319. CRC Press. Available at: http://www.crcnetbase.com/doi/10.1201/9781420005325.ch21 [Accessed May 4, 2022].
62. Pugliese A, Yang M, Kusmarteva I, Heiple T, Vendrame F, Wasserfall C, Rowe P, Moraski JM, Ball S, Jebson L, Schatz DA, Gianani R, Burke GW, Nierras C, Staeva T, Kaddis JS, Campbell‐Thompson M, Atkinson MA (2014) The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes ( nPOD ) Program: goals, operational model and emerging findings. Pediatr Diabetes 15:1–9.
63. Que Y, Cao M, He J, Zhang Q, Chen Q, Yan C, Lin A, Yang L, Wu Z, Zhu D, Chen F, Chen Z, Xiao C, Hou K, Zhang B (2021) Gut Bacterial Characteristics of Patients With Type 2 Diabetes Mellitus and the Application Potential. Front Immunol 12:722206.
64. Rewers M, Ludvigsson J (2016) Environmental risk factors for type 1 diabetes. The Lancet 387:2340–2348.
65. Richardson SJ, Morgan NG, Foulis AK (2014) Pancreatic Pathology in Type 1 Diabetes Mellitus. Endocr Pathol 25:80–92.
66. Richardson SJ, Willcox A, Bone AJ, Morgan NG, Foulis AK (2011) Immunopathology of the human pancreas in type-I diabetes. Semin Immunopathol 33:9–21.
67. Robertson RC, Manges AR, Finlay BB, Prendergast AJ (2019) The Human Microbiome and Child Growth – First 1000 Days and Beyond. Trends in Microbiology 27:131–147.
68. Ross ME, Onodera T, Brown KS, Notkins AL (1976) Virus-induced Diabetes Mellitus: IV. Genetic and Environmental Factors Influencing the Development of Diabetes After Infection with the M Variant of Encephalomyocarditis Virus. Diabetes 25:190–197.
69. Schulte BM, Gielen PR, Kers-Rebel ED, Schreibelt G, van Kuppeveld FJM, Adema GJ (2015) Enterovirus-Infected β-Cells Induce Distinct Response Patterns in BDCA1+ and BDCA3+ Human Dendritic Cells Appel S, ed. PLoS ONE 10:e0121670.
70. Sommer F, Bäckhed F (2013) The gut microbiota — masters of host development and physiology. Nat Rev Microbiol 11:227–238.
71. Syed FZ (2022) Type 1 Diabetes Mellitus. Ann Intern Med 175:ITC33–ITC48.
72. Tabrah FL (2011) Koch’s postulates, carnivorous cows, and tuberculosis today. Hawaii Med J 70:144–148.
73. Taylor KW, Hyöty H, Toniolo A, Zuckerman AJ eds. (2013) Diabetes and viruses. New York: Springer.
74. Thomas NJ, Jones SE, Weedon MN, Shields BM, Oram RA, Hattersley AT (2018) Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank. The Lancet Diabetes & Endocrinology 6:122–129.
75. Toniolo A, Onodera T, Jordan G, Yoon JW, Notkins AL (1982) Virus-induced diabetes mellitus. Glucose abnormalities produced in mice by the six members of the Coxsackie B virus group. Diabetes 31:496–499.
76. Tracy S, Drescher KM, Chapman NM (2011) Enteroviruses and type 1 diabetes. Diabetes Metab Res Rev 27:820–823.
77. Tracy S, Drescher KM, Chapman NM, Kim K-S, Carson SD, Pirruccello S, Lane PH, Romero JR, Leser JS (2002) Toward Testing the Hypothesis that Group B Coxsackieviruses (CVB) Trigger Insulin-Dependent Diabetes: Inoculating Nonobese Diabetic Mice with CVB Markedly Lowers Diabetes Incidence. J Virol 76:12097–12111.
78. Tracy S, Smithee S, Alhazmi A, Chapman N (2015) Coxsackievirus can persist in murine pancreas by deletion of 5′ terminal genomic sequences: Coxsackievirus Persistence in the Pancreas. J Med Virol 87:240–247.
79. Vatanen T et al. (2018) The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature 562:589–594.
80. Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ, Hernandez RD, Lederman MM, Huang Y, Somsouk M, Deeks SG, Hunt PW, Lynch SV, McCune JM (2013) Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism. Sci Transl Med 5 Available at: https://www.science.org/doi/10.1126/scitranslmed.3006438 [Accessed May 4, 2022].
81. Yildiz S, Mazel-Sanchez B, Kandasamy M, Manicassamy B, Schmolke M (2018) Influenza A virus infection impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis. Microbiome 6:9.
82. Yoon J-W, Austin M, Onodera T, Notkins AL (1979) Virus-Induced Diabetes Mellitus: Isolation of a Virus from the Pancreas of a Child with Diabetic Ketoacidosis. N Engl J Med 300:1173–1179.
83. Zhang X, Zheng Z, Shu B, Liu X, Zhang Z, Liu Y, Bai B, Hu Q, Mao P, Wang H (2013) Human Astrocytic Cells Support Persistent Coxsackievirus B3 Infection. J Virol 87:12407–12421.