Amalia Ioana Arhire Dorian Sorin Ioacara Teodora Papuc Gratiela Gradisteanu Parcalibioru Simona Fica


Type 1 diabetes mellitus (T1DM) is a chronic condition characterized by pancreatic autoimmunity and destruction of the insulin producing beta-cells. The risk of familial type 1 diabetes (FT1DM) is greater in families with paternal T1DM. The children with paternal FT1DM   have a more severe form of the disease with diabetic ketoacidosis. Three families with FT1DM, out of which two with paternal diabetes and daughters diagnosed with this disease, and one family with sibling FT1DM were evaluated between 2019-2021 in the Pediatric Diabetes and the Diabetes, Nutrition and Metabolic Departments of a tertiary hospital. Clinical, biological, and genetic evaluations were performed, together with an assessment of the gastrointestinal microbiota. The Romanian children with FT1DM had a more severe onset, a median of age at onset of 9 years old and a genetic predisposition with positive HLA DR3/R4, DQB1*02:01. The protecting allele, DPB1*04:01, was found only in the siblings with FT1DM. A gastrointestinal dysbiosis, characterized by pro-inflammatory bacteria, with high levels of Enterobacteriaceae and Candida, was observed in the gut microbiota. This is the first case series of FT1DM in Romanian patients that shows the presence of genetic determinants but also a pathological microbiota which may determine a more severe and an early-age onset of disease.



familial type 1 diabetes, pediatric diabetes, case series, microbiota

1. Undlien DE, Thorsby E. HLA associations in type 1 diabetes: merging genetics and immunology. Trends Immunol. 2001 Sep;22(9):467-9. doi: 10.1016/s1471-4906(01)01997-4. PMID: 11525926.
2. Alyafei F, Soliman A, Alkhalaf F, et al. Clinical and biochemical characteristics of familial type 1 diabetes mellitus (FT1DM) compared to non-familial type 1 DM (NFT1DM). Acta Biomed. 2018 May 23;89(S5):27-31. doi: 10.23750/abm.v89iS4.7358. PMID: 30049929; PMCID: PMC6179093.
3. Turtinen M, Härkönen T, Parkkola A, Ilonen J, Knip M; Finnish Pediatric Diabetes Register. Characteristics of familial type 1 diabetes: effects of the relationship to the affected family member on phenotype and genotype at diagnosis. Diabetologia. 2019 Nov;62(11):2025-2039. doi: 10.1007/s00125-019-4952-8. PMID: 31346657; PMCID: PMC6805821.
4. Veijola R, Reijonen H, Vähäsalo P, et al. HLA-DQB1-defined genetic susceptibility, beta cell autoimmunity, and metabolic characteristics in familial and nonfamilial insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group. J Clin Invest. 1996 Dec 1;98(11):2489-95. doi: 10.1172/JCI119067. PMID: 8958211; PMCID: PMC507706.
5. Julier C, Hyer RN, Davies J, et al. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature. 1991 Nov 14;354(6349):155-9. doi: 10.1038/354155a0. PMID: 1944595.
6. Parkkola A, Härkönen T, Ryhänen SJ, Ilonen J, Knip M; Finnish Pediatric Diabetes Register. Extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children. Diabetes Care. 2013 Feb;36(2):348-54. doi: 10.2337/dc12-0445. PMID: 23033245; PMCID: PMC3554291.
7. Familial risk of type I diabetes in European children. The Eurodiab Ace Study Group and The Eurodiab Ace Substudy 2 Study Group. Diabetologia. 1998 Oct;41(10):1151-6. doi: 10.1007/s001250051044. Erratum in: Diabetologia 1999 Feb;42(2):262. PMID: 9794100.
8. Caramalho I, Matoso P, Ligeiro D, et al. The rare DRB1*04:08-DQ8 haplotype is the main HLA class II genetic driver and discriminative factor of Early-onset Type 1 diabetes in the Portuguese population. Front Immunol. 2024 Jan 3;14:1299609. doi: 10.3389/fimmu.2023.1299609. PMID: 38318503; PMCID: PMC10839680.
9. Del Chierico F, Rapini N, Deodati A, et al. Pathophysiology of Type 1 Diabetes and Gut Microbiota Role. Int J Mol Sci. 2022 Nov 24;23(23):14650. doi: 10.3390/ijms232314650. PMID: 36498975; PMCID: PMC9737253.
10. Gradisteanu Pircalabioru G, Corcionivoschi N, Gundogdu O, et al. Dysbiosis in the Development of Type I Diabetes and Associated Complications: From Mechanisms to Targeted Gut Microbes Manipulation Therapies. Int J Mol Sci. 2021 Mar 9;22(5):2763. doi: 10.3390/ijms22052763. PMID: 33803255; PMCID: PMC7967220.
11. Giongo A, Gano KA, Crabb DB, et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 2011 Jan;5(1):82-91. doi: 10.1038/ismej.2010.92. PMID: 20613793; PMCID: PMC3105672.
12. de Goffau MC, Luopajärvi K, Knip M, et al. Fecal microbiota composition differs between children with β-cell autoimmunity and those without. Diabetes. 2013 Apr;62(4):1238-44. doi: 10.2337/db12-0526. PMID: 23274889; PMCID: PMC3609581.
13. Vatanen T, Franzosa EA, Schwager R, et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature. 2018 Oct;562(7728):589-594. doi: 10.1038/s41586-018-0620-2. PMID: 30356183; PMCID: PMC6296767.
14. van Heck JIP, Gacesa R, Stienstra R, et al. The Gut Microbiome Composition Is Altered in Long-standing Type 1 Diabetes and Associates With Glycemic Control and Disease-Related Complications. Diabetes Care. 2022 Sep 1;45(9):2084-2094. doi: 10.2337/dc21-2225. PMID: 35766965.
15. Zhang L, Jonscher KR, Zhang Z, et al. Islet autoantibody seroconversion in type-1 diabetes is associated with metagenome-assembled genomes in infant gut microbiomes. Nat Commun. 2022 Jun 21;13(1):3551. doi: 10.1038/s41467-022-31227-1. PMID: 35729161; PMCID: PMC9213500.
16. Hemminki K, Li X, Sundquist J, Sundquist K. Familial association between type 1 diabetes and other autoimmune and related diseases. Diabetologia. 2009 Sep;52(9):1820-8. doi: 10.1007/s00125-009-1427-3. PMID: 19543881.
17. Orzan A, Novac C, Mihu M, Tirgoviste CI, Balgradean M. Type 1 Diabetes and Thyroid Autoimmunity in Children. Maedica (Bucur). 2016 Dec;11(4):308-312. PMID: 28828047; PMCID: PMC5543522.
18. Undlien DE, Kockum I, Rønningen KS, et al. HLA associations in type 1 diabetes among patients not carrying high-risk DR3-DQ2 or DR4-DQ8 haplotypes. Tissue Antigens. 1999 Dec;54(6):543-51. doi: 10.1034/j.1399-0039.1999.540602.x. PMID: 10674967.
19. Giwa AM, Ahmed R, Omidian Z, et al. Current understandings of the pathogenesis of type 1 diabetes: Genetics to environment. World J Diabetes. 2020 Jan 15;11(1):13-25. doi: 10.4239/wjd.v11.i1.13. PMID: 31938470; PMCID: PMC6927819.
20. Soyucen E, Gulcan A, Aktuglu-Zeybek AC, et al. Differences in the gut microbiota of healthy children and those with type 1 diabetes. Pediatr Int. 2014 Jun;56(3):336-43. doi: 10.1111/ped.12243. PMID: 24475780.
How to Cite
Arhire, A. I., Ioacara, D. S., Papuc, T., Gradisteanu Parcalibioru, G., & Fica, S. (2024). Exploring the severity and early onset of familial type 1 diabetes in Romania: genetic and microbiota insights. Archive of Clinical Cases, 11(1), 29-33.
Case Reports

How to Cite

Arhire, A. I., Ioacara, D. S., Papuc, T., Gradisteanu Parcalibioru, G., & Fica, S. (2024). Exploring the severity and early onset of familial type 1 diabetes in Romania: genetic and microbiota insights. Archive of Clinical Cases, 11(1), 29-33.