Repression of Glucagon Gene Transcription by Peroxisome Proliferator-activated Receptor through Inhibition of Pax6

The nuclear receptor peroxisome proliferator-acti-vated receptor (PPAR) is involved in glucose homeo-stasis and synthetic PPAR ligands, the thiazolidinedio-nes, a new class of antidiabetic agents that reduce insulin resistance and, as a secondary effect, reduce hepatic glucose output. PPAR is highly expressed in normal human pancreatic islet -cells that produce glu-cagon. This peptide hormone is a functional antagonist of insulin stimulating hepatic glucose output. There-fore, the effect of PPAR and thiazolidinediones on glu-cagon gene transcription was investigated. After tran-sient transfection of a glucagon-reporter fusion gene into a glucagon-producing pancreatic islet cell line, thiazolidinediones inhibited glucagon gene transcrip-tion when PPAR was coexpressed. They also reduce