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Lookup NU author(s): Dr Hannah Richardson, Dr Susan Campbell, Sarah Smith
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Aims/hypothesis: Rosiglitazone and metformin are two oral antihyperglycaemic drugs used to treat type 2 diabetes. While both drugs have been shown to improve insulin-sensitive glucose uptake, the direct effects of these drugs on pancreatic beta cells is only now beginning to be clarified. The aim of the present study was to determine the direct effects of these agents on beta cell gene expression. Methods: We used reporter gene analysis to examine the effects of rosiglitazone and metformin on the activity of the proinsulin and insulin promoter factor 1 (IPF1) gene promoters in the glucose-responsive mouse beta cell line Min6. Western blot and gel retardation analyses were used to examine the effects of both drugs on the regulation of IPF1 protein production, nuclear accumulation and DNA binding activity in both Min6 cells and isolated rat islets of Langerhans. Results: Over 24 h, rosiglitazone promoted the nuclear accumulation of IPF1 and forkhead homeobox A2 (FOXA2), independently of glucose concentration, and stimulated a two-fold increase in the activity of the Ipf1 gene promoter (p<0.01). Stimulation of the Ipf1 promoter by rosiglitazone was unaffected by the presence of the peroxisome proliferator activated receptor γ antagonist GW9662. No effect of either rosiglitazone or metformin was observed on proinsulin promoter activity. Metformin stimulated IPF1 nuclear accumulation and DNA binding activity in a time-dependent manner, with maximal effects observed after 2 h. Conclusions/interpretation: Metformin and rosiglitazone have direct effects on beta cell gene expression, suggesting that these agents may play a previously unrecognised role in the direct regulation of pancreatic beta cell function. © Springer-Verlag 2006.
Author(s): Richardson H, Campbell SC, Smith SA, Macfarlane WM
Publication type: Article
Publication status: Published
Journal: Diabetologia
Year: 2006
Volume: 49
Issue: 4
Pages: 685-696
ISSN (print): 0012-186X
ISSN (electronic): 1432-0428
Publisher: Springer
URL: http://dx.doi.org/10.1007/s00125-006-0155-1
DOI: 10.1007/s00125-006-0155-1
PubMed id: 16489446
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