“Intuitively, one would expect a family history of any form of diabetes to be associated with an increased disease risk and faster progression to clinical T1D,” says Riitta Veijola, Professor at the University of Oulu and Chief Physician at the Oulu University Hospital in Finland.

In fact, as first author of a recent study, she reports quite the opposite.

“Our main finding was that in children with HLA-conferred genetic susceptibility, a family history of T1D or T2D has different effects on the two phases of T1D pathogenesis,” Veijola explains.

These phases are, first, the development of islet autoimmunity and, second, the progression to clinical disease. While a family history of T1D increased the risk of developing islet autoimmunity, as expected from previous studies, a family history of T2D significantly protected against progression from islet autoimmunity to clinical T1D. The results were published in Diabetologia.

TEDDY: Tracking the earliest stages of type 1 diabetes

The analysis was conducted as part of The Environmental Determinants of Diabetes in the Young (TEDDY) study. TEDDY is a large prospective observational cohort study which is designed to investigate environmental factors that influence the development of islet autoimmunity and T1D.

A total of 8,676 children with high-risk HLA genotypes were enrolled as newborns in 2004 at clinical centres in Finland, Germany, Sweden and the USA and followed until 2016. Of these children, 669 developed persistent islet autoantibodies, defined as the presence of at least one of IAA, GADA or IA-2A. By the end of the follow-up period, 233 children had progressed to clinical T1D.

Contrasting effects of T1D and T2D in the family

Unexpectedly, children with a second-degree relative (SDR) with T2D – such as a grandparent, aunt, uncle or half-sibling showed significantly delayed progression from autoantibody positivity to a clinical diagnosis of T1D (hazard ratio [HR]: 0.61; 95 % confidence interval [CI]: 0.44 – 0.86; p = 0.004; see Figure 1). b. By contrast, the preceding disease phase, i.e. the development of islet autoimmunity, was not found to be affected by having an SDR with T2D.

The authors demonstrate this delaying effect by considering the time point at which 80 % of TEDDY children with persistent islet autoimmunity had not yet developed T1D. As it turns out, for children with an SDR with T2D, this time point was reached 14.3 months later. The study further suggests that the effect likely applies to first-degree relatives (FDRs) with T2D as well. However, only 1.7 % of children in the cohort had an FDR with T2D, compared to 32.4 % with an affected SDR. Lastly, the delaying effect was consistent across all four countries (with the greatest difference observed in Finland), further supporting the robustness of the finding.

On the other hand, having an FDR with T1D accelerated the development of the first disease phase, islet autoimmunity, as anticipated (HR: 2.2; 95 % CI: 1.8 – 2.8; p < 0.001). A similar, though more modest, effect was observed for SDRs with T1D when FDRs were excluded from the analysis (HR: 1.4; 95 % CI: 1.1 – 1.8; p = 0.017). Consistent with other studies, the effect was stronger for paternal or sibling T1D than for maternal T1D. 

Could genetic factors explain the delayed progression?

How might these results arise? One explanation the authors were able to rule out are lifestyle or dietary changes related to active diabetes prevention efforts within families. Also, in-depth analyses considering the two main pathways which initiate islet autoimmunity – based on the type of autoantibody that appears first, yielded similar results and were therefore discounted as a cause.

So, the study turned to the genetic level, where the susceptibility genes for T1D and T2D differ substantially in their functions. T2D-associated genes mostly influence beta-cell function and insulin sensitivity. Thus, the authors hypothesise that genetic variants enhancing beta-cell function – similarly to early-stage T2D being characterised by hyperinsulinaemia – could be responsible for the protective effect against T1D progression.

“It is possible that children who are having a family member with T2D might have an enhanced beta-cell functional capacity which is linked to their genetic background. We plan to test this hypothesis within the TEDDY study,” says Veijola.

However, even a large cohort such as TEDDY may lack sufficient power to properly investigate this effect.

“Further studies should include large prospective datasets with information about T2D family history and explore the possible contribution of genetic factors to the delaying effect of T2D family history in islet autoantibody positive individuals.”

Why separating disease phases matters

With these findings, the authors were for the first time able to show that the two phases of the T1D disease process are differentially affected by family history of diabetes. For example, previous research has established, that children with a parent affected by T2D tend to be older at the time of T1D diagnosis. However, little data was available on the preclinical stages of the disease.

Beyond family history of T1D and T2D, additional factors may have an inpact to the critical transition from islet autoimmunity to clinical diagnosis. “Several studies have shown that certain genetic factors increase the risk of islet autoimmunity, e.g., class II HLA, but the genes affecting progression from islet autoimmunity to clinical diabetes are different.” In addition, environmental factors associated with development of T1D unfortunately still remain poorly understood.

“It is extremely important to understand the risk factors of T1D and the disease process before clinical diagnosis. It is possible that there are different subtypes or disease pathways of T1D which require specific interventions or preventive tools,” Veijola says.

Clarifying these pathways, she argues, is a prerequisite for developing and testing effective preventive approaches in individuals most likely to benefit.

Future preventive trials

In conclusion, having a family history of T2D was shown to delay the progression from autoimmunity to clinical T1D, while having a relative with T1D increased the risk of developing islet autoimmunity.

“It is important to keep in mind our observations about the role of family history when assessing the risk of islet autoimmunity or progression speed from autoimmunity to clinical T1D,” Veijola emphasises.

In future preventive trials, she urges to collect and consider information about family history of T1D and T2D when evaluating possible effects of a specific intervention, for example, by adjusting the statistical analyses by family history information. Overall, the unanticipated effect of T2D family history calls for a more differentiated approach to risk assessment and trial design.

Key Points:

• Family history of T1D and T2D affects different disease phases of T1D, with distinct effects on development islet autoimmunity and progression to clinical T1D.
• In TEDDY children with genetic susceptibility, a family history of T2D was associated with slower progression from islet autoimmunity to clinical T1D. Having a relative with T1D increased the risk for development islet autoimmunity.
• Genetic factors linked to beta-cell function and insulin sensitivity may modulate disease progression and influence the preclinical course of T1D.
• The findings underline the importance of accounting for family history of both T1D and T2D in the design and analysis of future prevention trials.

To read this paper visit: Veijola R, Tamura RN, Clasen JL, et al. Family history of type 2 diabetes delays development of type 1 diabetes in TEDDY children with islet autoimmunity. Diabetologia. Published online December 8, 2025. doi:10.1007/s00125-025-06613-1   

Author: Hanna Gabriel, BA MSc. Any opinions expressed in this article are the responsibility of EASD e-Learning.