Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas

Nigel Irwin, J. M. McKinney, C. J. Bailey, Peter Flatt, Neville McClenaghan

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Abstract

Methods: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin-secreting BRIN-BD11 cells. Results: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2-1.7-fold; p < 0.001) the insulin-releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide-induced insulin release at all concentrations (50-400 mu M) examined, but tolbutamide-stimulated insulin secretion was only augmented at higher concentrations (300-400 mu M). Exposure for 18 h to 100 mu M tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 mu M) prevented or partially reversed many of the adverse effects on K-ATP channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP-1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co-culture with metformin, but cellular insulin content was depressed. Conclusions: The results suggest that metformin can prevent the aspects of sulphonylurea-induced beta-cell desensitization.
LanguageEnglish
Pages1066-1071
JournalDIABETES OBESITY &amp; METABOLISM
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2010

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Metformin
Glyburide
Insulin
Tolbutamide
Glucose
Glucagon-Like Peptide 1
Coculture Techniques
Alanine
Cell Count
Adenosine Triphosphate

Cite this

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title = "Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas",
abstract = "Methods: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin-secreting BRIN-BD11 cells. Results: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2-1.7-fold; p < 0.001) the insulin-releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide-induced insulin release at all concentrations (50-400 mu M) examined, but tolbutamide-stimulated insulin secretion was only augmented at higher concentrations (300-400 mu M). Exposure for 18 h to 100 mu M tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 mu M) prevented or partially reversed many of the adverse effects on K-ATP channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP-1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co-culture with metformin, but cellular insulin content was depressed. Conclusions: The results suggest that metformin can prevent the aspects of sulphonylurea-induced beta-cell desensitization.",
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Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas. / Irwin, Nigel; McKinney, J. M.; Bailey, C. J.; Flatt, Peter; McClenaghan, Neville.

In: DIABETES OBESITY &amp; METABOLISM, Vol. 12, No. 12, 12.2010, p. 1066-1071.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas

AU - Irwin, Nigel

AU - McKinney, J. M.

AU - Bailey, C. J.

AU - Flatt, Peter

AU - McClenaghan, Neville

PY - 2010/12

Y1 - 2010/12

N2 - Methods: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin-secreting BRIN-BD11 cells. Results: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2-1.7-fold; p < 0.001) the insulin-releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide-induced insulin release at all concentrations (50-400 mu M) examined, but tolbutamide-stimulated insulin secretion was only augmented at higher concentrations (300-400 mu M). Exposure for 18 h to 100 mu M tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 mu M) prevented or partially reversed many of the adverse effects on K-ATP channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP-1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co-culture with metformin, but cellular insulin content was depressed. Conclusions: The results suggest that metformin can prevent the aspects of sulphonylurea-induced beta-cell desensitization.

AB - Methods: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin-secreting BRIN-BD11 cells. Results: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2-1.7-fold; p < 0.001) the insulin-releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide-induced insulin release at all concentrations (50-400 mu M) examined, but tolbutamide-stimulated insulin secretion was only augmented at higher concentrations (300-400 mu M). Exposure for 18 h to 100 mu M tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 mu M) prevented or partially reversed many of the adverse effects on K-ATP channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP-1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co-culture with metformin, but cellular insulin content was depressed. Conclusions: The results suggest that metformin can prevent the aspects of sulphonylurea-induced beta-cell desensitization.

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DO - 10.1111/j.1463-1326.2010.01294.x

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ER -