Longevity & AgingNew Molecular Axis Drives Excess Blood Sugar in Type 2 Diabetes
Researchers have uncovered a three-protein molecular axis — HNF4α, TET2, and FBP1 — that controls how much glucose the liver produces during fasting and in type 2 diabetes (T2D). TET2, a DNA demethylation enzyme, is recruited to the FBP1 gene promoter by the transcription factor HNF4α, switching on this key gluconeogenic enzyme. Both fasting and a high-fat diet elevate TET2 levels in mouse liver. Knocking out TET2 in mice improved glucose tolerance and insulin sensitivity without affecting body weight. Crucially, the diabetes drug metformin works partly by triggering a phosphorylation event on HNF4α that blocks its interaction with TET2, thereby reducing FBP1 expression and dampening excess glucose output. This axis represents a promising new therapeutic target for T2D.
