دورية أكاديمية
أعرض في EDS

Milder loss of insulin-containing islets in individuals with type 1 diabetes and type 2 diabetes-associated TCF7L2 genetic variants.

التفاصيل البيبلوغرافية
العنوان: Milder loss of insulin-containing islets in individuals with type 1 diabetes and type 2 diabetes-associated TCF7L2 genetic variants.
المؤلفون: Redondo MJ; Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA. redondo@bcm.edu., Richardson SJ; Islet Biology Group (IBEx), Exeter Centre of Excellence for Diabetes Research (EXCEED), University of Exeter College of Medicine and Health, Exeter, UK. s.richardson@exeter.ac.uk., Perry D; Departments of Pathology and Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA., Minard CG; Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA., Carr ALJ; Islet Biology Group (IBEx), Exeter Centre of Excellence for Diabetes Research (EXCEED), University of Exeter College of Medicine and Health, Exeter, UK., Brusko T; Departments of Pathology and Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA., Kusmartseva I; Departments of Pathology and Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA., Pugliese A; Diabetes Research Institute, Department of Medicine, Division of Endocrinology, Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA., Atkinson MA; Departments of Pathology and Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA.
المصدر: Diabetologia [Diabetologia] 2023 Jan; Vol. 66 (1), pp. 127-131. Date of Electronic Publication: 2022 Oct 25.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0006777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0428 (Electronic) Linking ISSN: 0012186X NLM ISO Abbreviation: Diabetologia Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Berlin Springer Verlag
مواضيع طبية MeSH: Diabetes Mellitus, Type 1*/genetics , Diabetes Mellitus, Type 2*/genetics, Male ; Humans ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Adult ; Female ; Insulin ; Transcription Factor 7-Like 2 Protein/genetics
مستخلص: Aims/hypothesis: TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme.
Methods: We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African American, 7.3% Hispanic) using data pertaining to residual beta cell number; quantified islets containing insulin-positive beta cells in pancreatic tissue sections; and expressed these values as a percentage of the total number of islets from each donor (mean ± SD ICI% 9.8±21.5, range 0-92.2).
Results: Donors with a high ICI% (≥5) (n=30; 27%) vs a low ICI% (<5) (n=80; 73%) were older at onset (15.3±6.9 vs 11.1±8 years, p=0.013), had a shorter diabetes duration at donor tissue procurement (7.0±7.4 vs 18.5±14.3 years, p<0.001), a higher African ancestry score (0.2±0.3 vs 0.1±0.2, p=0.043) and a lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). After adjustment for age of onset (p=0.105), diabetes duration (p<0.001), BMI z score (p=0.145), sex (p=0.351) and African American race (p=0.053), donors with the TCF7L2 rs7903146 T allele (TC or TT, 45.5%) were 2.93 times (95% CI 1.02, 8.47) more likely to have a high ICI% than those without it (CC) (p=0.047).
Conclusions/interpretation: Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor that predisposes to type 2 diabetes, with donors in this category exhibiting less severe beta cell loss. It is possible that in these individuals the disease pathogenesis may include mechanisms associated with type 2 diabetes and thus this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment in these individuals.
(© 2022. The Author(s).)
References: Diabetes Care. 2018 Feb;41(2):311-317. (PMID: 29025879)
Pediatr Diabetes. 2017 Dec;18(8):794-802. (PMID: 28127835)
Pediatr Diabetes. 2014 Feb;15(1):1-9. (PMID: 24325575)
Diabet Med. 2017 Feb;34(2):286-290. (PMID: 27027642)
Diabetes Care. 2020 Mar;43(3):580-587. (PMID: 31937610)
Diabetes Care. 2017 May;40(5):698-701. (PMID: 28202550)
Nat Genet. 2006 Mar;38(3):320-3. (PMID: 16415884)
Diabetes Care. 2020 Jan;43(1):5-12. (PMID: 31753960)
Nat Genet. 2021 Jul;53(7):962-971. (PMID: 34127860)
Diabetologia. 2018 Sep;61(9):2043-2053. (PMID: 29931415)
Diabetes Metab Res Rev. 2012 Oct;28(7):608-17. (PMID: 22585677)
Clin Exp Immunol. 2016 Jul;185(1):33-41. (PMID: 27029857)
معلومات مُعتمدة: R01 DK121843 United States DK NIDDK NIH HHS; R01 DK124395 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: African American; Genetics; Heterogeneity; Insulin-containing cells; Pancreas; Phenotype; Precision medicine; Race; TCF7L2; Type 1 diabetes
المشرفين على المادة: 0 (Insulin)
0 (TCF7L2 protein, human)
0 (Transcription Factor 7-Like 2 Protein)
تواريخ الأحداث: Date Created: 20221025 Date Completed: 20221215 Latest Revision: 20231118
رمز التحديث: 20231118
مُعرف محوري في PubMed: PMC9729318
DOI: 10.1007/s00125-022-05818-y
PMID: 36282337
قاعدة البيانات: MEDLINE
الوصف
تدمد:1432-0428
DOI:10.1007/s00125-022-05818-y