Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells.

Patanè, Giovanni; Piro, Salvatore; Rabuazzo, Agata Maria; Anello, M.; Vigneri, Riccardo; Purrello, Francesco

doi:10.2337/diabetes.49.5.735

Cited by 149 publications

(103 citation statements)

References 42 publications

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“…These effects of metformin on glucose metabolism in islets are similar to effects at the level of peripheral tissues (18). Our results with the therapeutic concentration of metformin are similar to findings in rat islets, in which metformin caused reduction of FFA oxidation (10). Moreover, metformin has been reported to prevent the development of diabetes in the Zucker diabetic fatty rat (19).…”

Section: Discussionsupporting

confidence: 79%

Lipotoxicity in Human Pancreatic Islets and the Protective Effect of Metformin

et al. 2002

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Human pancreatic islets from eight donors were incubated for 48 h in the presence of 2.0 mmol/l free fatty acid (FFA) (oleate to palmitate, 2 to 1). Insulin secretion was then assessed in response to glucose (16.7 mmol/l), arginine (20 mmol/l), and glyburide (200 mol/l) during static incubation or by perifusion. Glucose oxidation and utilization and intra-islet triglyceride content were measured. The effect of metformin (2.4 g/ml) was studied because it protects rat islets from lipotoxicity. Glucose-stimulated but not arginine-or glyburide-stimulated insulin release was significantly lower from FFA-exposed islets. Impairment of insulin secretion after exposure to FFAs was mainly accounted for by defective early-phase release. In control islets, increasing glucose concentration was associated with an increase in glucose utilization and oxidation. FFA incubation reduced both glucose utilization and oxidation at maximal glucose concentration. Islet triglyceride content increased significantly after FFA exposure. Addition of metformin to high-FFA media prevented impairment in glucose-mediated insulin release, decline of first-phase insulin secretion, and reduction of glucose utilization and oxidation without significantly affecting islet triglyceride accumulation. These results show that lipotoxicity in human islets is characterized by selective loss of glucose responsiveness and impaired glucose metabolism, with a clear defect in early-phase insulin release. Metformin prevents these deleterious effects, supporting a direct protective action on human ␤-cells. Diabetes 51 (Suppl. 1):S134 -S137, 2002

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Section: Discussionsupporting

confidence: 79%

Lipotoxicity in Human Pancreatic Islets and the Protective Effect of Metformin

et al. 2002

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“…2a). Metformin at 15 μmol/l has previously been shown to have direct effects on beta cell function [6]. As before, addition of rosiglitazone stimulated a two-fold increase in Ipf1 promoter activity compared with 5 mmol/l glucose alone.…”

Section: Resultssupporting

confidence: 68%

“…Metformin has been shown to restore insulin secretion following chronic exposure of rat islets to non-esterified fatty acids or high glucose [6], an effect mediated through direct effects on beta cell glucose and fatty acid metabolism. The effects of metformin on glucose-induced insulin secretion have been linked to the activation of AMP-dependent protein kinase (AMPK) [7,8].…”

Section: Introductionmentioning

confidence: 99%

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

et al. 2006

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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.

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“…However, in A Diabetes Outcome Progression Trial (ADOPT), metformin exhibited a reduced risk of monotherapy failure compared with the sulfonylurea glibenclamide (known as glyburide in the USA and Canada) and slower rate of loss of beta cell function, although it was inferior to the thiazolidinedione rosiglitazone [20]. Metformin has also been shown to improve insulin secretion from rat islets chronically exposed to high levels of NEFA or glucose [21], suggesting a direct effect on pancreatic beta cells indepen- dent of its glucose-lowering action. What is the mechanism of these effects of metformin on pancreatic beta cells?…”

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 99%

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Cho

Kieffer

2010

Diabetologia

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The two major deficits in type 2 diabetes, insulin resistance and impaired beta cell function, are often treated with metformin and incretin-based drugs, respectively. However, there may be unappreciated benefits of this combination of therapies. In this issue of Diabetologia, Maida et al. (doi:10.1007Maida et al. (doi:10. /s00125-010-1937 report that metformin acutely increases plasma levels of glucagon-like peptide 1 (GLP-1) in mice. Moreover, they show that metformin enhances the expression of the genes encoding the receptors for both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in mouse islets and also increases the effects of GIP and GLP-1 on insulin secretion from beta cells. Interestingly, these incretin-sensitising effects of metformin appear to be mediated by a peroxisome proliferator-activated receptor α-dependent pathway, as opposed to the more commonly ascribed pathway of metformin action involving AMP-activated protein kinase. These provocative findings by Maida et al. extend our understanding of the mechanism of action of metformin and provide further insights into the benefits of combining metformin with incretin-based drugs to combat diabetes.

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Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells.

Cited by 149 publications

References 42 publications

Lipotoxicity in Human Pancreatic Islets and the Protective Effect of Metformin

Lipotoxicity in Human Pancreatic Islets and the Protective Effect of Metformin

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

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