EXPRESSION OF THE GROWTH-HORMONE GENE AND THE PITUITARY-SPECIFIC TRANSCRIPTION FACTOR GHF-1 IN DIABETIC RATS

Diabetes in the rat is associated with poor growth and decreased GH in the pituitary. In this study we have examined whether this reduction reflects an impairment of GH gene expression. Diabetes was induced by the administration of streptozotocin (7 mg/100 g BW), and 18 days later, GH content, GH mRNA, and GH transcription rate were determined. GH mRNA levels were reduced by more than 80% in the pituitaries of diabetic rats, which had a similarly reduced GH content. The differences observed in transcription fully account for the changes in mRNA concentration, since the transcription rate of the gene was also reduced by a factor of 10 in the diabetic pituitaries. Insulin therapy (3 U/15 days) partially restored these parameters. The expression of the specific transcription factor GHF-1/Pit-1 in diabetic rats was also analyzed. Both GHF-1 mRNA levels and the binding of nuclear proteins to an oligodeoxynucleotide conforming to the GHF-1 proximal binding site in the promoter of the GH gene were normal in the diabetic pituitaries, thus excluding the possibility that decreased availability of this factor could be responsible for the decreased GH transcription. Since diabetes produced an approximately 3-fold reduction of circulating T3, the potential role of thyroid hormones on GH gene expression was also evaluated in thyroidectomized and thyroidectomized diabetic rats. Thyroidectomy decreased GH and GH mRNA to less than 5% of the values found in intact animals, and a single saturating injection of T3 (250-mu-g/100 g BW) resulted in a 8- to 10-fold induction of GH mRNA after 6 h. This response was markedly depressed in thyroidectomized diabetic rats, in which T3 produced only a minor increase in GH mRNA. Administration of insulin alone to these animals did not alter GH mRNA, but partially restored the response to T3, and GH mRNA levels increased 3- to 4-fold in this group. The changes in GH mRNA were not accompanied by concomitant changes in the abundance of GHF-1. These results show that transcription of the rat GH gene is altered in diabetes, and that insulin is required for a normal regulation of the GH gene by thyroid hormone.