Predominantly genetic, intrauterine, and lifestyle aetiologies of type 2 diabetes are associated with distinct clinical presentations and risk of complications: a Danish cross-sectional and follow-up study

Background We investigated whether individuals who likely developed type 2 diabetes (T2D) through predominantly genetic, adverse intrauterine, or lifestyle aetiologies have different clinical presentations and complications. Methods In this Danish nationwide combined cross-sectional and registry-based follow-up study, we included 7867 individuals with newly diagnosed T2D from the DD2 cohort, enrolled during 2010–2023 through general practices and hospital outpatient clinics across Denmark. Participants were required to have available genotyping and birthweight data; those with GAD antibody levels >30 were excluded. Individuals were grouped by presumed predominant aetiologies: genetic (highest-quartile T2D genetic risk score (GRS), birthweight above lowest quartile; n=1435); intrauterine (lowest-quartile birthweight, GRS below highest quartile; n=1195); and lifestyle (birthweight above lowest quartile, GRS below highest quartile; n=4380). Baseline characteristics at diagnosis were examined using linear and log-binomial or robust Poisson regression. The main follow-up outcomes were standardised 10-year risks of major adverse cardiovascular events and microvascular complications after DD2 enrolment, estimated using the Aalen–Johansen method. Findings Compared with the genetic group (18%), intrauterine (15%) and lifestyle (56%) aetiologies both showed −6.9% lower Homeostatic Model Assessment-2 (HOMA2) insulin sensitivity, higher triglycerides (+6.6% and +5.3%), higher HOMA2 beta-cell function (+8.9% and +9.6%), and higher high-sensitivity C-reactive protein (+14.8% and +24.1%). Age at T2D diagnosis was 1.2 years lower (intrauterine) and 2.3 year higher (lifestyle). The 10-year risk of major adverse cardiovascular events was 14.8% (intrauterine), 13.2% (lifestyle), and 11.5% (genetic), corresponding to absolute risk differences (RDs) of +3.3% (95% confidence interval [CI] 0.6, 6.0) for intrauterine, and +1.7% (95% CI −0.3, 3.6) for lifestyle, vs . genetic aetiology. The 10-year risk of microvascular complications was 25.9% (intrauterine), 25.4% (lifestyle), and 21.8% (genetic), yielding RDs of +4.1% (95% CI 0.7, 7.5) for intrauterine and +3.5% (95% CI 1.0, 6.1) for lifestyle aetiology. Interpretation Individuals who developed T2D with predominant intrauterine or lifestyle rather than genetic aetiology exhibited distinct characteristics including higher long-term complication risks. Future studies should validate this framework in more diverse populations and assess whether these proxy-based aetiological domains can improve risk stratification and guide treatment. Funding This work was funded by Danish Agency for Science, the Danish Health and Medicines Authority, the Danish Diabetes Association, the Region of Southern Denmark, the Swedish Research Council, the Novo Nordisk Foundation, the Swedish ALF for Region Skåne, the Crafoord Foundation, and the Swedish Diabetes Association.