Insulin-releasing action of the novel antidiabetic agent BTS 67 582

Neville McClenaghan, Peter Flatt, CJ Bailey

Research output: Contribution to journalArticle

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Abstract

1 BTS 67 582 (1,1-dimethyl-2-(2-morpholinophenyl)guan fumarate) is a novel antidiabetic agent with a short-acting insulin-releasing effect. This study examined its mode of action in the clonal B-cell line BRIN-BD11. 2 BTS 67 582 increased insulin release from BRIN-BD11 cells in a concentration-dependent manner (10(-8) to 10(-4) M) at both non-stimulating (1.1 mM) and stimulating (16.7 mM) concentrations of glucose. 3 BTS 67 582 (10(-4) M) potentiated the insulin-releasing effect of a depolarizing concentration of K+ (30 mM), whereas the K+ channel openers pinacidil (400 mu M) and diazoxide (300 mu M) inhibited BTS 67 582-induced release. 4 Suppression of Ca+ channel activity with verapamil (20 mu M) reduced the insulin-releasing effect of BTS 67 582 (10(-4) M). 5 BTS 67 582 (10(-4) M) potentiated insulin release induced by amino acids (10 mM), and enhanced the combined stimulant effects of glucose plus either the fatty acid palmitate (10 mM). or agents which raise intracellular cyclic AMP concentrations (25 mu M forskolin and 1 mM isobutylmethylxanthine), or the cholinoceptor agonist carbachol (100 mu M). 6 Inhibition of glucose-stimulated insulin release by adrenaline or noradrenaline (10 mu M) was partially reversed by BTS 67 582 (10(-4) M). 7 These data suggest that the insulin-releasing effect of BTS 67 582 involves regulation of ATP-sensitive K+ channel activity and Ca2+ influx, and that the drug augments the stimulant effects of nutrient insulin secretagogues and agents which enhance adenylate cyclase and phospholipase C. BTS 67 582 may also exert insulin-releasing effects independently of ATP-sensitive K+ channel activity.
LanguageEnglish
Pages400-404
JournalBritish Journal of Pharmacology
Volume123
Issue number3
Publication statusPublished - Feb 1998

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Hypoglycemic Agents
Insulin
Glucose
Adenosine Triphosphate
Short-Acting Insulin
Pinacidil
Diazoxide
BTS 67582
Fumarates
Palmitates
Carbachol
Type C Phospholipases
Cholinergic Receptors
Colforsin
Verapamil
Adenylyl Cyclases
Cyclic AMP
Epinephrine
Norepinephrine
B-Lymphocytes

Cite this

McClenaghan, Neville ; Flatt, Peter ; Bailey, CJ. / Insulin-releasing action of the novel antidiabetic agent BTS 67 582. In: British Journal of Pharmacology. 1998 ; Vol. 123, No. 3. pp. 400-404.
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abstract = "1 BTS 67 582 (1,1-dimethyl-2-(2-morpholinophenyl)guan fumarate) is a novel antidiabetic agent with a short-acting insulin-releasing effect. This study examined its mode of action in the clonal B-cell line BRIN-BD11. 2 BTS 67 582 increased insulin release from BRIN-BD11 cells in a concentration-dependent manner (10(-8) to 10(-4) M) at both non-stimulating (1.1 mM) and stimulating (16.7 mM) concentrations of glucose. 3 BTS 67 582 (10(-4) M) potentiated the insulin-releasing effect of a depolarizing concentration of K+ (30 mM), whereas the K+ channel openers pinacidil (400 mu M) and diazoxide (300 mu M) inhibited BTS 67 582-induced release. 4 Suppression of Ca+ channel activity with verapamil (20 mu M) reduced the insulin-releasing effect of BTS 67 582 (10(-4) M). 5 BTS 67 582 (10(-4) M) potentiated insulin release induced by amino acids (10 mM), and enhanced the combined stimulant effects of glucose plus either the fatty acid palmitate (10 mM). or agents which raise intracellular cyclic AMP concentrations (25 mu M forskolin and 1 mM isobutylmethylxanthine), or the cholinoceptor agonist carbachol (100 mu M). 6 Inhibition of glucose-stimulated insulin release by adrenaline or noradrenaline (10 mu M) was partially reversed by BTS 67 582 (10(-4) M). 7 These data suggest that the insulin-releasing effect of BTS 67 582 involves regulation of ATP-sensitive K+ channel activity and Ca2+ influx, and that the drug augments the stimulant effects of nutrient insulin secretagogues and agents which enhance adenylate cyclase and phospholipase C. BTS 67 582 may also exert insulin-releasing effects independently of ATP-sensitive K+ channel activity.",
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Insulin-releasing action of the novel antidiabetic agent BTS 67 582. / McClenaghan, Neville; Flatt, Peter; Bailey, CJ.

In: British Journal of Pharmacology, Vol. 123, No. 3, 02.1998, p. 400-404.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Insulin-releasing action of the novel antidiabetic agent BTS 67 582

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AU - Flatt, Peter

AU - Bailey, CJ

PY - 1998/2

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N2 - 1 BTS 67 582 (1,1-dimethyl-2-(2-morpholinophenyl)guan fumarate) is a novel antidiabetic agent with a short-acting insulin-releasing effect. This study examined its mode of action in the clonal B-cell line BRIN-BD11. 2 BTS 67 582 increased insulin release from BRIN-BD11 cells in a concentration-dependent manner (10(-8) to 10(-4) M) at both non-stimulating (1.1 mM) and stimulating (16.7 mM) concentrations of glucose. 3 BTS 67 582 (10(-4) M) potentiated the insulin-releasing effect of a depolarizing concentration of K+ (30 mM), whereas the K+ channel openers pinacidil (400 mu M) and diazoxide (300 mu M) inhibited BTS 67 582-induced release. 4 Suppression of Ca+ channel activity with verapamil (20 mu M) reduced the insulin-releasing effect of BTS 67 582 (10(-4) M). 5 BTS 67 582 (10(-4) M) potentiated insulin release induced by amino acids (10 mM), and enhanced the combined stimulant effects of glucose plus either the fatty acid palmitate (10 mM). or agents which raise intracellular cyclic AMP concentrations (25 mu M forskolin and 1 mM isobutylmethylxanthine), or the cholinoceptor agonist carbachol (100 mu M). 6 Inhibition of glucose-stimulated insulin release by adrenaline or noradrenaline (10 mu M) was partially reversed by BTS 67 582 (10(-4) M). 7 These data suggest that the insulin-releasing effect of BTS 67 582 involves regulation of ATP-sensitive K+ channel activity and Ca2+ influx, and that the drug augments the stimulant effects of nutrient insulin secretagogues and agents which enhance adenylate cyclase and phospholipase C. BTS 67 582 may also exert insulin-releasing effects independently of ATP-sensitive K+ channel activity.

AB - 1 BTS 67 582 (1,1-dimethyl-2-(2-morpholinophenyl)guan fumarate) is a novel antidiabetic agent with a short-acting insulin-releasing effect. This study examined its mode of action in the clonal B-cell line BRIN-BD11. 2 BTS 67 582 increased insulin release from BRIN-BD11 cells in a concentration-dependent manner (10(-8) to 10(-4) M) at both non-stimulating (1.1 mM) and stimulating (16.7 mM) concentrations of glucose. 3 BTS 67 582 (10(-4) M) potentiated the insulin-releasing effect of a depolarizing concentration of K+ (30 mM), whereas the K+ channel openers pinacidil (400 mu M) and diazoxide (300 mu M) inhibited BTS 67 582-induced release. 4 Suppression of Ca+ channel activity with verapamil (20 mu M) reduced the insulin-releasing effect of BTS 67 582 (10(-4) M). 5 BTS 67 582 (10(-4) M) potentiated insulin release induced by amino acids (10 mM), and enhanced the combined stimulant effects of glucose plus either the fatty acid palmitate (10 mM). or agents which raise intracellular cyclic AMP concentrations (25 mu M forskolin and 1 mM isobutylmethylxanthine), or the cholinoceptor agonist carbachol (100 mu M). 6 Inhibition of glucose-stimulated insulin release by adrenaline or noradrenaline (10 mu M) was partially reversed by BTS 67 582 (10(-4) M). 7 These data suggest that the insulin-releasing effect of BTS 67 582 involves regulation of ATP-sensitive K+ channel activity and Ca2+ influx, and that the drug augments the stimulant effects of nutrient insulin secretagogues and agents which enhance adenylate cyclase and phospholipase C. BTS 67 582 may also exert insulin-releasing effects independently of ATP-sensitive K+ channel activity.

M3 - Article

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JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

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