Transcriptional repressors are increased in pancreatic islets of type 2 diabetic rats

To further clarify the mechanism of impaired insulin gene transcription in the diabetic state, we investigated the expression and function of the transcriptional repressor CREM (CRE modulator) in rat pancreatic islets. The CREM gene generates both transcriptional activators and repressors by alternative splicing and an intronic promoter. We isolated a novel alternatively spliced CREM isoform, CREM-17X, which efficiently represses insulin gene transcription, in addition to the three previously reported repressors. We also compared mRNA levels of insulin and the CREM repressors in pancreatic islets of Wistar and GK (Goto-Kakizaki) rats, the well-characterized spontaneous animal model of type 2 diabetes. The CREM repressor levels are increased, and the expression of insulin mRNA is decreased in GK rats, suggesting that increased CREM repressor expression in pancreatic islets could contribute to the decreased insulin gene transcription that results in impaired insulin secretion in type 2 diabetes.