In:
Diabetologia, Springer Science and Business Media LLC, Vol. 66, No. 1 ( 2023-01), p. 127-131
Abstract:
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. Graphical abstract
Type of Medium:
Online Resource
ISSN:
0012-186X
,
1432-0428
DOI:
10.1007/s00125-022-05818-y
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2023
detail.hit.zdb_id:
1458993-X
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