Effect of a new hypoglycaemic agent (HB 699) on the in vivo secretion of pancreatic hormones in the dog

Ribes, G; Trimble, Elisabeth R.; Blayac, Jean-Pierre; Wollheim, Claes B.; Puech, R; Loubatières-Mariani, Marie-Madeleine

doi:10.1007/bf00253415

Cited by 23 publications

(12 citation statements)

References 12 publications

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“…The effects of these drugs were shown to be concentration-dependent (Figure 2), half-maximal release being elicited by approximately 40M tolbu- (Geisen et al, 1985) and cause insulin release in vivo (Ribes et al, 1981) and in vitro (Glatt & Schatz, 1981).…”

Section: Insulin Release Studiesmentioning

confidence: 99%

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

Sturgess

Kozlowski

Carrington

et al. 1988

British J Pharmacology

166

113

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1 The effects of various sulphonylureas and diazoxide on insulin secretion and the activity of various channels have been studied using tissue culture and patch-clamp methods in an insulinsecreting cell line derived from a rat islet cell tumour. 2 Tolbutamide, glibenclamide and HB699 increased the rate of insulin release by 2-5 fold. The concentrations of tolbutamide and glibenclamide giving half-maximum effects on insulin secretion were approximately 40pM and 0.2pm, respectively. 3 Diazoxide (0.6-1.0mM) per se, had either no effect or produced a small increase in insulin secretion, whereas when secretion was maximally stimulated by the combination of glucose (3 mM) and leucine (20mM), it produced inhibition. Tolbutamide-induced release was also inhibited by diazoxide. 4 Tolbutamide, glibenclamide, HB699 and HB985 reduced the open-state probability of the ATP-K+ channel in a dose-dependent manner. Tolbutamide and glibenclamide were shown to be effective regardless of which side of the membrane they were applied. 5 In whole cell recording, in which the total ATP-sensitive K+ conductance of the cell could be measured, dose-inhibition curves for tolbutamide and glibenclamide were constructed, resulting in Ki values of 17pM and 27nm, respectively. The value of Ki for tolbutamide was unchanged when ATP (0.1 mM) was present in the electrode. 6 Diazoxide (0.6mM) activated the ATP-K+ channels only when they had first been inhibited by intracellular ATP (0.1 mM) or bath applied tolbutamide (3-30 pM). The inhibition produced by glibenclamide could not be reversed by diazoxide. 7 Neither tolbutamide (1.0mM) nor glibenclamide (10 M) altered the open-state probability of the Ca2 + -activated K+ channel or the Ca2 + -activated non-selective cation channel which are present in this cell line. 8 It is concluded that the sulphonylureas and related hypoglycaemic drugs and diazoxide regulate insulin secretion by direct effects on the ATP-K+ channel or a protein closely associated with this channel.

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Section: Insulin Release Studiesmentioning

confidence: 99%

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

Sturgess

Kozlowski

Carrington

et al. 1988

British J Pharmacology

166

113

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“…The sensitivity, defined as above, was 15pg/ml. Plasma immunoreactive somatostatin was measured by a method using the 80 C antiserum of Unger et al [14]. The antiserum was a gift from Dr. R. Unger (Dallas) and the tracer a gift from Clin Midy Laboratories (Montpellier).…”

Section: Methods O F /Toavs Blood Glucose Was Measured With a Techniconmentioning

confidence: 99%

“…The sen sitivity, defined as above, was 10pg/ml. Pancreatic polypeptide in plasma was assayed according to the technique previously described [14] using Chance's antibody. The sensitivity was 2 pg/ml.…”

Section: Methods O F /Toavs Blood Glucose Was Measured With a Techniconmentioning

confidence: 99%

Effects of Fenugreek Seeds on Endocrine Pancreatic Secretions in Dogs

Ribes¹,

Sauvaire²,

Baccou³

et al. 1984

Ann Nutr Metab

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The components of fenugreek seeds were separated and analyzed to determine which fraction of the seed had hypoglycemic activity. These fractions were administered orally to normal or diabetic dogs for 8 days. The effect on blood glucose and pancreatic hormones was studied in normal dogs. The lipid extract had no effect; the defatted fraction (50.2% fibers: gum 17.7%, hemicellulose 22%, cellulose 8.3%, lignin 2.2%) lowered basal blood glucose level, plasma glucagon and somatostatin levels and reduced the orally induced hyperglycemia. The addition of this fraction to the insulin treatment resulted in a decrease of hyperglycemia and glycosuria in diabetic dogs. The results indicate that the defatted part is responsible for the antidiabetic action. However, the present study does not permit one to know whether the effects are caused by an unknown pharmacological compound or by the gastrointestinal action of fibers.

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“…Plasma somatostatin was evaluated by a method using 80 C antiserum (a gift from Dr. R. Unger, Dallas, Texas), and tracer (a gift from Clin-Midy Laboratories, Montpellier, France). The procedure has been described previously [6]. Hormonal output rate in experiments in vivo and in vitro was determined by multiplying the concentration of hormone (ng/ml or pg/ml) by the liquid flow (ml/min); in experiments in vivo the venous blood flow was corrected using haematocrit values.…”

Section: Methodsmentioning

confidence: 99%

A new benzothiadiazine derivative, LN 5330: effects on pancreatic hormones

Hillaire‐Buys¹,

Ribes²,

Blayac³

et al. 1984

Diabetologia

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Summary. LN 5330 is a new benzothiadiazine which is a structural analogue of diazoxide. Its effects in vivo were studied on blood glucose levels and insulin, glucagon and somatostatin secretion in normal dogs, and in vitro on glucagon and insulin secretion from the isolated perfused rat pancreas. The results were compared with those obtained with diazoxide at equimolar dose or concentration. In the normal anaesthetized dog having a T-shaped catheter inserted in the pancreaticoduodenal vein, the infusion of LN 5330 (87.8 lxmol/kg for 20 rain) induced (1) a progressive increase in blood glucose levels, (2) a rapid decrease in insulin and somatostatin output rate, (3) an immediate increase in pancreatic glucagon secretion, and (4) a delayed decrease of arterial blood pressure. The equimolar dose of diazoxide provoked the same effects on blood glucose levels, insulin and somatostatin output, but a marked decrease in glucagon output and in arterial blood pressure. In the isolated rat pancreas perfused with 8.3 retool/1 glucose, the infusion of LN 5330 (440 p.mol/1 for 30 rain) induced a drastic fall in insulin and a rapid and persistent increase in glucagon output. This stimulatory effect on glucagon secretion was not found with diazoxide at equimolar concentration. These findings show that LN 5330 is a substance which is distinct from diazoxide and interesting because of its double action: inhibition of insulin secretion and stimulation of glucagon secretion.Key words: Benzothiadiazine analogue, LN 5330, diazoxide, glucagon, insulin, somatostatin secretion, dog, isolated perfused rat pancreas.Chloro-7 trifluoromethyl-6 benzothiadiazine-a,2,4 dioxide-l,1 (LN5330) is a new benzothiadiazine (Fig.l) which is a structural analogue of diazoxide, a known inhibitor of insulin secretion. We have shown previously that LN 5330, like diazoxide, strongly inhibits insulin secretion from the isolated perfused pancreas of the rat. However, after ceasing the LN 5330 infusion, we observed a marked increase in insulin output, which was not found with diazoxide [1].The aim of the present study was to investigate the effects of LN 5330 on pancreatic hormones in the dog in vivo and to compare them with those obtained with diazoxide. Since these revealed that LN 5330 and diazoxide had different effects on glucagon secretion, we investigated whether this difference could be found also in the isolated perfused rat pancreas.Cl %7 ~ Materials and methods AnimalsStudies were carried out either in vivo in normal dogs or in vitro on isolated perfused rat pancreas. Experiments in vivoNormal mongrel dogs were used, weighing 15-20kg. Before experiments, the animals had free access to water and a standard balanced diet (UAR121, Villemoisson-sur-Orge, France). They were fasted for 18 h before the experiment. The animals were anaesthetized intravenously with pentobarbital (30mg/kg body weight). After a median laparotomy, a T-shaped catheter was inserted into the pancreaticoduodenal vein. The animals were given heparin intravenously (5 mg/kg). Venous ...

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Effect of a new hypoglycaemic agent (HB 699) on the in vivo secretion of pancreatic hormones in the dog

Cited by 23 publications

References 12 publications

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

Effects of Fenugreek Seeds on Endocrine Pancreatic Secretions in Dogs

A new benzothiadiazine derivative, LN 5330: effects on pancreatic hormones

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