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

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 12.27.9 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.

Automated summary

This study found that TCF7L2 genetic variants are significantly associated with a higher percentage of residual insulin-containing cells in individuals with type 1 diabetes. This suggests the existence of a subtype of type 1 diabetes that is associated with genetic factors predisposing to type 2 diabetes, and these individuals exhibit less severe beta cell loss.