Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

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 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.

Pre-transplant signal induction for vascularisation in human islets

“…The improved insulin secretory profile after RC might be explained by the 'β-cell recruitment' phenomenon in which the detection of increased extracellular glucose by a few individual β-cells initiates the insulin secretory cascade and recruitment of adjacent β-cells to participate in insulin secretion. 54 Additionally, TZDs have been shown to support β-cell function and viability, [34][35][36] and our data corroborate these findings under both SC and RC conditions. While β-cells did not show an additive increase in insulin secretion in response to the combined effects of RC and exposure to a TZD, there was an additional increase in measured soluble VEGF-A release from the combined RC + TZD treatment group.…”

“…43 The molecular mechanism pertaining to increased insulin secretion following exposure of islets to rosiglitazone has been studied by a number of groups. Richardson et al 35 have shown that rosiglitazone induced the nuclear accumulation of insulin promoter factor 1 (IPF1) and forkhead homeobox A2 (FOXA2), independent of glucose concentration, and also resulted in a twofold increase in the activity of the IPF1 gene promoter. Yang et al exposed islets to high levels of free fatty acids that caused a significant reduction in insulin receptor substrate-2 (IRS-2) protein and the association of IRS-2 with the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase), resulting in increased basal insulin secretion and reduced glucose-stimulated insulin secretion.…”

“…Additional potential advantages to this approach are that TZDs have been reported to increase islet β-cell granulation, support β-cell insulin secretion 33 and exert genomic effects such as downregulation of caspase-3 and P-JNK and upregulation of insulin that improve β-cell survival 34,35 and preserve β-cell function in patients with adult-onset latent autoimmune diabetes. 36 The purpose of this study was to test the hypothesis that in vitro islet pre-treatment by stimulation of PPARγ can improve endocrine islet function and upregulate islet VEGF-A with a view to support post-transplant insulin secretory capacity and enhance revascularisation.…”

Beta Cell Replacement Therapy

“…GLP-1 has also been shown to increase PDX1 gene expression in ductal cells during the regeneration of pancreas (Sharma et al, 1999). A similar line of action has been proposed for thiazolidinediones in the enhancement of neogenic beta cell function through activation of nuclear receptor peroxisome proliferator activator gamma (PPAR) (Richardson et al, 2006) …”

The Dual Peroxisome Proliferator-Activated Receptor α/γ Activator Muraglitazar Prevents the Natural Progression of Diabetes in db/db Mice

“…Finally, pancreatic islets have been shown to express both PPAR␣ and PPAR␥ (Yoshikawa et al, 2001;Rosen et al, 2003;Lin et al, 2005;Park et al, 2006;Richardson et al, 2006). It is possible that muraglitazar may protect ␤-cells directly by favorably altering the expression of PPAR␣-or PPAR␥-target genes, which are implicated in important functions, such as glucose sensing, fatty acid transport, control of cell differentiation, apoptosis, and insulin secretion in ␤-cells (Yoshikawa et al, 2001;Rosen et al, 2003;Lin et al, 2005;Park et al, 2006;Richardson et al, 2006).…”