The prevalence of diabetes in children with Down syndrome is threefold higher than in unaffected children. Additionally, metabolic syndrome and type 2 diabetes occur at relatively early ages in those with Down syndrome. However, the molecular basis of dysregulated glucose homeostasis in patients with Down syndrome is not well understood. Seo et al. investigated the role of Down syndrome critical region 1-4 (DSCR1-4) in the liver by introducing a single extra copy of DSCR1-4 into mice. Their analysis reveals that a single extra copy of DSCR1-4 increases hepatic glucose production and expression of gluconeogenic genes, resulting in pathological states such as insulin resistance and pyruvate intolerance.