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.
A single extra copy of Down syndrome critical region 1–4 results in impaired hepatic glucose homeostasis
Objectives: During fasting, hepatic gluconeogenesis is induced to maintain energy homeostasis. Moreover, abnormal dysregulation of hepatic glucose production is commonly observed in type 2 diabetes. However, the signaling components controlling hepatic glucose production to maintain normal glucose levels are not fully understood. Here, we examined the physiological role of Down syndrome critical region 1–4 (DSCR1-4), an endogenous calcineurin signaling inhibitor in the liver that mediates metabolic adaptation to fasting.
Methods: We assessed the effect of cyclosporine A, an inhibitor of calcineurin signaling on gluconeogenic gene expression in primary hepatocytes. DSCR1-4 expression was examined in diet- and genetically-induced mouse models of obesity. We also investigated the metabolic phenotype of a single extra copy of DSCR1-4 in transgenic mice and how DSCR1-4 regulates glucose homeostasis in the liver.
Results: Treatment with cyclosporin A increased hepatic glucose production and gluconeogenic gene expression. The expression of DSCR1-4 was induced by refeeding and overexpressed in obese mouse livers. Moreover, transgenic mice with a single extra copy of DSCR1-4 exhibited pyruvate intolerance and impaired glucose homeostasis. Mechanistically, DSCR1-4 overexpression increased phosphorylation of the cAMP response element-binding protein, which led to elevated expression levels of gluconeogenic genes and, thus, enhanced hepatic glucose production during fasting.
Conclusions: A single extra copy of DSCR1-4 results in dysregulated hepatic glucose homeostasis and pyruvate intolerance. Our findings suggest that nutrient-sensitive DSCR1-4 is a novel target for controlling hepatic gluconeogenesis in diabetes.