Genetic and Metabolic Basis of Increased Diabetes Mellitus Risk in Down Syndrome: A Narrative Review.

Down syndrome (DS), caused by trisomy 21, is associated with a range of comorbidities, including a significantly increased risk of diabetes mellitus (DM). Type 1 DM (T1DM) and type 2 DM (T2DM) are more prevalent in individuals with DS compared with the general population, presenting significant clinical challenges. This review explores the genetic and metabolic factors underlying this elevated risk, focusing on the interplay of gene dosage effects, immune dysregulation, insulin resistance, and endocrine dysfunction. A systematic and critical assessment of the current literature reveals that the triplication of chromosome 21 leads to gene dosage effects that disrupt immune regulation, thereby promoting autoimmunity and increasing susceptibility to T1DM. Simultaneously, insulin resistance associated with obesity and altered adipokine secretion contributes to the development of T2DM. Endocrine abnormalities, particularly hypothyroidism, further impair beta-cell function and exacerbate peripheral insulin resistance. These combined mechanisms create a complex metabolic environment that predisposes individuals with DS to both forms of diabetes. Understanding these interconnected pathways is essential for early diagnosis and the development of tailored management strategies. Continued research is necessary to identify specific biomarkers and refine therapeutic approaches to improve clinical outcomes in this vulnerable population.