Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

Richardson, H.; Campbell, S. C.; Smith, S. A.; Macfarlane, W. M.

doi:10.1007/s00125-006-0155-1

Cited by 34Pancreatic function and diabetesDiabetes Treatment and ManagementPeroxisome Proliferator-Activated Receptors

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

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Richardson, H., Campbell, S. C., Smith, S. A., Macfarlane, W. M.·2006·Diabetologia

DOI 10.1007/s00125-006-0155-1

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Abstract

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 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/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.

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Metformin increases insulin gene expression, possibly by nuclear accumulation of pdx1 and improved DNA-binding activity.
“With respect to its effects on β-cell function, metformin was shown to increase insulin gene expression,346 possibly by nuclear accumulation of pdx1 and its subsequently improved DNA-binding activity.347”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [347]
Citation 346 is attached to the claim that metformin increases insulin gene expression; the proposed PDX1 mechanism has a separate citation. In the Results section, the cited paper instead reports no effect of metformin on proinsulin gene promoter activity in Min6 beta cells over 24 hours. The paper does report short-term IPF1 nuclear accumulation and increased DNA-binding activity, but that does not establish the expression claim attributed to citation 346 (page unavailable). (LLM, conf=0.88)
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Authors: Richardson, H., Campbell, S. C., Smith, S. A., & Macfarlane, W. M.
Affiliations: Newcastle University (GB)
GlaxoSmithKline (United Kingdom) (GB)
Corresponding author: Macfarlane, W. M.
ORCID: Macfarlane, W. M.
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2006-02-18
Volume: 49
Issue: 4
Pages: 685-696
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-006-0155-1
OpenAlex: W2020461632
Cited by: 34
References: 42
Citations by year: 2026: 1 · 2025: 1 · 2023: 2 · 2018: 1 · 2016: 3 · 2015: 1 · 2013: 3 · 2012: 1
FWCI: 5.05
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Diabetologia (publishedVersion)
PubMed (publishedVersion)
University of Brighton Repository (University of Brighton) (submittedVersion)
Newcastle University ePrints (Newcastle Univesity)
Funders: GlaxoSmithKline
Diabetes UK
Directorate for Biological Sciences
Topics: Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: rosiglitazone, metformin, pancreatic beta cells, beta-cell gene expression, insulin promoter factor 1, FOXA2, type 2 diabetes, antidiabetic drugs, PPARγ, MIN6 cells, pancreatic islets, insulin secretion
MeSH terms: Rosiglitazone, Anilides, Animals, Cell Line, Cell Nucleus, DNA, Glucose, Metformin, Proinsulin, Promoter Regions, Genetic, Protein Binding, Time Factors, Trans-Activators, Gene Expression, Homeodomain Proteins, Active Transport, Cell Nucleus, Thiazolidinediones, Insulin-Secreting Cells, Mice, Rats, Hepatocyte Nuclear Factor 3-beta

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Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

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