The multifactorial aetiology of diabetes mellitus in children and adolescents: A systematic review

Objectives: The global incidence of paediatric diabetes mellitus (DM) is rising, characterised by increasing rates of both autoimmune type 1 DM (T1DM) and obesity-driven type 2 DM (T2DM) in children and adolescents. The aetiology is multifactorial, involving complex interplays between genetic susceptibility and modifiable environmental, lifestyle, and socioeconomic factors. A comprehensive synthesis of contemporary evidence is needed to inform prevention and precision management strategies. This systematic review aims to identify, evaluate, and synthesise the genetic, environmental, lifestyle, and socioeconomic determinants contributing to the onset and progression of all major forms of DM in individuals under 18 years of age. Material and Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines. Electronic databases (PubMed, National Centre for Biotechnology Information Bookshelf) were searched for peer-reviewed systematic reviews, meta-analyses, cohort studies, and authoritative narrative reviews published between 2010 and 2025. Of the 90 unique records identified, 35 studies met the inclusion criteria after screening and were included for narrative synthesis. Data on risk factors and outcomes were extracted and thematically analysed. Results: The evidence confirms distinct pathogenic pathways. T1DM risk is predominantly driven by high-risk genetic susceptibility (e.g., human leucocyte antigen-DR3/DR4 haplotypes) interacting with environmental triggers such as enteroviral infections (odds ratio OR 1.5–3), caesarean delivery (OR ~1.2), and early dietary exposures. The incidence continues to rise by 2–5% annually. T2DM in youth is strongly associated with modifiable factors, primarily obesity (body mass index ≥95 th percentile), sedentary behaviour, and poor diet, operating atop a polygenic familial risk (40–60% if a parent is affected). Monogenic forms (e.g., maturity-onset diabetes of the young), accounting for 1–6% of cases, are often misdiagnosed. Profound disparities exist: Ethnic minority status and lower socioeconomic position are associated with higher T2DM risk, increased frequency of diabetic ketoacidosis at T1DM presentation, and poorer glycaemic outcomes. Conclusion: The aetiology of paediatric DM is multifaceted, demanding a differentiated approach. Addressing the epidemic requires dual strategies: Investigating environmental modulators of autoimmunity for T1DM and implementing robust public health policies to combat childhood obesity for T2DM. Enhanced clinician awareness and genetic testing for atypical cases are crucial for accurate diagnosis of monogenic diabetes. Future efforts must integrate precision medicine with equitable interventions targeting the underlying social determinants of health to mitigate this growing global health challenge.