Effects of rosiglitazone and metformin on pancreatic beta cell gene expression.
OBJECTIVE
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 gamma 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
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.
Institute for Cell and Molecular Biosciences, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.
H
H
Richardson
S C
SC
Campbell
S A
SA
Smith
W M
WM
Macfarlane
D021581:Active Transport, Cell Nucleus; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D011384:Proinsulin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; C496503:Foxa2 protein, mouse; D018398:Homeodomain Proteins; D045162:Thiazolidinediones; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D000077154:Rosiglitazone; D051542:Hepatocyte Nuclear Factor 3-beta; D004247:DNA; D011384:Proinsulin; D008687:Metformin; D005947:Glucose