Abstract
In the present study, we examine the effects of the treatment with 1,25-dihydroxyvitamin D3 [150 IU/Kg (3.75 μg/Kg) once a day, for 15 days] to non-diabetic and streptozotocin-induced diabetic rats. The results indicate that treatment with 1,25-dihydroxyvitamin D3 had minor effects in non-diabetic rats. The same treatment in streptozotocin-induced diabetic rats, although it did not correct the hyperglycemia and hypoinsulinemia induced by the diabetes, caused other actions that could mean beneficial effects on the amelioration of diabetes e.g., it avoided body weight loss, increased calcium and phosphorus plasma levels, and corrected the over-expression of the insulin receptor mRNA species of 9.5 and 7.5 Kb present in the hind limb muscle and heart of these animals. These genomic 1,25-dihydroxyvitamin D3 effects could involve transcriptional mechanisms of repression mediated by vitamin D response elements in the rat insulin receptor gene promoter. Using computer analysis of this promoter, we propose the -249/-235 bp VDRE (5’GGGTGACCCGGGGTT3’) with a pyrimidine (T) in the (+7) position of the3’half-site as the best candidate for negative control by 1,25-dihydroxy-vitamin D3. In addition, posttranscriptional mechanisms of regulation could also be implicated. Thus, computer inspection of the5’untranslated region of the rat insulin receptor pre-mRNA indicated the presence of a virtual internal ribosome entry segment whereas the computer inspection of the3’untranslated region localized various destabilizing sequences, including various AU-rich elements. We propose that through these virtual cis-regulatory sequences, 1,25-dihydroxyvitamin D3 could control the translation and stability of insulin receptor mRNA species in the hind limb muscle and heart of diabetic rats.
Highlights
1,25-dihydroxyvitamin D3 (1,25D3), acting through the vitamin D receptor (VDR), can produce multiple biological effects in different physiological systems [1]
We examine the effects of the treatment with 1,25-dihydroxyvitamin D3 [150 IU/Kg (3.75 μg/Kg) once a day, for 15 days] to non-diabetic and streptozotocin-induced diabetic rats
The same treatment in streptozotocin-induced diabetic rats, it did not correct the hyperglycemia and hypoinsulinemia induced by the diabetes, caused other actions that could mean beneficial effects on the amelioration of diabetes e.g., it avoided body weight loss, increased calcium and phosphorus plasma levels, and corrected the over-expression of the insulin receptor mRNA species of 9.5 and 7.5 Kb present in the hind limb muscle and heart of these animals. These genomic 1,25-dihydroxyvitamin D3 effects could involve transcriptional mechanisms of repression mediated by vitamin D response elements in the rat insulin receptor gene promoter
Summary
1,25-dihydroxyvitamin D3 (1,25D3), acting through the vitamin D receptor (VDR), can produce multiple biological effects in different physiological systems [1]. We reported that 1,25D3 treatment reversed the over-expression of the rat INSR gene in the liver and adipose tissue of STZ-induced diabetic rats without altering the normal expression of this gene in the kidney [12] These effects were accompanied by a normalization of the number of INSRs and an improvement of the insulin response to glucose transport in adipocytes of these animals. In support of a transcriptional participation of 1,25D3 in these processes, we localized by computer search two candidate DNA sequences in the rat INSR promoter containing virtual VDREs [12] With these antecedents, in the present work we examine the possible existence of in vivo 1,25D3 effects in other two important insulin target tissues: the hind limb muscle and heart of non-diabetic and STZ-induced diabetic rats. We postulated the possible alteration by 1,25D3 of INSR mRNA levels and the possible participation of transcriptional and/or posttranscriptional mechanisms in this regulation
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