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PubMed1985

Effect of tolbutamide on myocardial energy metabolism of the ischemic heart.

The oral hypoglycemic agent tolbutamide has been found to protect the ischemic myocardium against irreversible mechanical failure. The possibility that this salutary effect of tolbutamide was related to its ability to alter energy metabolism was examined in ischemic rat hearts perfused with 5 mM glucose, 5mM acetate and 2.5 units/l insulin. In the presence of 0.6 mM tolbutamide, coronary flow and oxygen consumption were unaltered; however, glucose utilization was stimulated by 30%, glycogenolysis was enhanced by 23%, and the drop in ATP content was reduced by 17% after 30 min, of low-flow perfusion. This elevation in glycolytic flux occurred without a parallel rise in the production of inhibitory metabolites; lactate production was unaltered and tissue lactate/pyruvate ratio decreased. Pyruvate dehydrogenase flux measurements reveal that the mechanism by which tolbutamide increases glycolysis without increasing lactate production is by promoting the entry of pyruvate into the mitochondria. The basis for the observed stimulation of anaerobic metabolism and pyruvate oxidation and how this contributes to the increase in ATP content and benefits the ischemic heart is discussed.

Adenosine Triphosphate↗
PubMed1984

Insulin secretion: combined tolbutamide, forskolin and TPA mimic action of glucose.

We have proposed that the two phases of glucose-induced insulin secretion are regulated by two distinct branches of the calcium messenger system: the initial phase by a calmodulin branch, and the sustained phase by a C-kinase branch. To provide further support for this concept, we examined the separate and combined effects of tolbutamide, TPA, and forskolin upon insulin secretion from rat islets perifused in the absence of added fuels. Addition of 200 microM tolbutamide to the perfusate induces only a first phase of insulin secretion, addition of 200 nM TPA only a second phase, and addition of 10 microM forskolin only a small elevation in the basal rate of secretion. The combination of tolbutamide and TPA induces a biphasic secretory response qualitatively and quantitatively similar to that evoked by an increase in glucose concentration from 2.75 to 7 mM. The combination of TPA, tolbutamide, and forskolin evokes a biphasic pattern of insulin secretion qualitatively and quantitatively similar to that evoked by an increase in glucose concentration from 2.75 to 10 mM.

Animals↗
PubMed2001

Desensitization of insulin secretory response to imidazolines, tolbutamide, and quinine. II. Electrophysiological and fluorimetric studies.

Prolonged in vitro exposure (18 h) of pancreatic islets to insulin secretagogues that block ATP-dependent K(+) channels (K(ATP) channels), such as sulfonylureas, imidazolines, and quinine, induced a desensitization of insulin secretion (Rustenbeck et al., pages 1685-1694, this issue). To elucidate the underlying mechanisms, K(ATP) channel activity, plasma membrane potential and the cytosolic Ca(2+) concentration ([Ca(2+)](i)) were measured in mouse single B-cells. In B-cells desensitized by phentolamine or quinine (100 microM each) K(ATP) channel activity was virtually absent and could not be elicited by diazoxide. Desensitization by alinidine (100 microM) induced a marked reduction of K(ATP) channel activity, which could be reversed by diazoxide, whereas exposure to idazoxan (100 microM) or tolbutamide (500 microM) had no lasting effect on K(ATP) channel activity. Correspondingly, phentolamine-, alinidine-, and quinine-desensitized B-cells were markedly depolarized, whereas B-cells that had been exposed to tolbutamide or idazoxan had an unchanged resting membrane potential. The increase in [Ca(2+)](i) normally elicited by phentolamine and alinidine was suppressed after desensitization by these compounds, whereas the [Ca(2+)](i) increase by re-exposure to quinine was markedly reduced and that by tolbutamide only minimally affected as compared with control-cultured B-cells. The increase in [Ca(2+)](i) elicited by a K(+) depolarization was diminished in secretagogue-pretreated B-cells, the extent depending on the secretagogue. This effect was closely correlated with the degree of depolarization after pretreatment with the respective secretagogue. In conclusion, the apparently uniform desensitization of secretion by K(ATP) channel blockers is due to different effects at two stages located distally in the stimulus-secretion coupling: either at the stage of [Ca(2+)](i) regulation, where the increase is depressed as a consequence of a persistent depolarization (e.g. in the case of phentolamine or alinidine) and/or at the stage of exocytosis, which responds only weakly to substantial increases in [Ca(2+)](i) (in the case of tolbutamide).

Animals↗
PubMed1989

Diagnostic interpretation of the intravenous tolbutamide test for insulinoma.

The plasma glucose and insulin responses to intravenous administration of tolbutamide in patients with insulinoma and healthy control subjects were compared to determine the sensitivity and specificity of the intravenous tolbutamide test for the diagnosis of insulinoma. The records of 406 healthy persons without concurrent disease known to affect glucose homeostasis or insulin concentrations and 41 patients with histologically confirmed insulinoma who underwent standard intravenous tolbutamide testing during the period from 1976 to 1986 were reviewed. The 5th percentile of the mean of plasma glucose levels at the 120-, 150-, and 180-minute points (G120-180) after injection of tolbutamide was 55 mg/dl for lean and 62 mg/dl for obese control subjects. With 95% specificity, the sensitivity of these criteria was 95% for lean and 100% for obese patients with insulinoma. Minimal differences were observed between men and women. At 95% specificity, the sensitivities were less for the ratio of the 180-minute plasma glucose to fasting plasma glucose level (64% in lean and 75% in obese patients), for mean of plasma insulin at the 120-, 150-, and 180-minute points (IRI120-180) (53% in lean and 36% in obese patients), for maximal insulin concentration (27% in lean and 31% in obese patients), for increase in insulin concentration above basal (18% in lean and 23% in obese patients), and for the combined criteria of the 5th percentile of G120-180 and the 95th percentile of IRI120-180 (47% in lean and 73% in obese patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Islet Cell↗
PubMedDate not supplied

Tolbutamide and insulin stimulation of fructose-2,6-bisphosphate formation in hepatocytes differ.

The effects of tolbutamide and pancreatic hormones on liver fructose-2,6-bisphosphate (F-2,6-P2) formation were examined using isolated rat hepatocytes. Glucagon decreased the F-2,6-P2 level in a dose-dependent manner. Insulin (greater than 10(-9) M) increased the F-2,6-P2 level reduced by glucagon (less than 10(-9) M), but did not show a stimulatory effect on this activator formation in the absence of glucagon. On the other hand, tolbutamide increased the F-2,6-P2 level in hepatocytes regardless of the presence or absence of glucagon. Tolbutamide (2 mM) stimulation on liver F-2,6-P2 formation was enhanced by the concomitant addition of insulin (10(-8) M) in the presence of glucagon (3 X 10(-11) M). These observations suggest that the regulatory effect of tolbutamide on liver F-2,6-P2 level is independent of that of insulin.

Animals↗
PubMed2000

Influence of surfactants (present in the dissolution media) on the release behaviour of tolbutamide from its inclusion complex with beta-cyclodextrin.

The possible competitive displacement of a drug from its cyclodextrin-based inclusion complex by a third substance was investigated by studying the dissolution behaviour of tolbutamide-beta-cyclodextrin inclusion complex in demineralised water and in aqueous solution of different surfactants. Physical mixtures and kneaded systems were prepared in 1:1 and 1:2 drug-beta-cyclodextrin mol/mol ratios and they were characterised by hot-stage microscopy, differential scanning calorimetry, and X-ray powder diffractometry. The release behaviour of tolbutamide from its inclusion complex was studied by studying the dissolution of the binary systems in water and in aqueous solutions of three surfactants: polysorbate 20, poloxyl 23-lauryl ether, and sodium lauryl sulphate. When demineralised water was used as the dissolution media, the fastest dissolution of tolbutamide was obtained from 1:2 kneaded system followed by 1:1 kneaded system. The presence of poloxyl 23-lauryl ether and sodium lauryl sulphate in the media caused a decrement in the rate and extent of dissolution of the drug from both kneaded systems in comparison with that obtained from the same systems in water. However, the release of tolbutamide from the kneaded systems remains unaffected when polysorbate 20 was present in the dissolution media. Results of this study suggest that the simultaneous presence of beta-cyclodextrin and surfactants of proper molecular structure in a pharmaceutical formulation can give rise to an unexpected dissolution of the drug.

Calorimetry, Differential Scanning↗
PubMed2000

Induced desensitization of the insulinotropic effects of antidiabetic drugs, BTS 67 582 and tolbutamide.

Acute and chronic mechanisms of action of novel insulinotropic antidiabetic drug, BTS 67 582 (1, 1-dimethyl-2-(2-morpholinophenyl)guanidine fumarate), were examined in the stable cultured BRIN-BD11 cell line. BTS 67 582 (100 - 400 microM) stimulated a concentration-dependent increase (P<0.01) in insulin release at both non-stimulatory (1.1 mM) and stimulatory (8. 4 mM) glucose. Long-term exposure (3 - 18 h) to 100 microM BTS 67 582 in culture time-dependently decreased subsequent responsiveness to acute challenge with 200 microM BTS 67 582 or 200 microM tolbutamide at 12 - 18 h (P<0.001). Similarly 3 - 18 h culture with the sulphonylurea, tolbutamide (100 microM), also effectively suppressed subsequent insulinotropic responses to both BTS 67 582 and tolbutamide. Culture with 100 microM BTS 67 582 or 100 microM tolbutamide did not affect basal insulin secretion, cellular insulin content, or cell viability and exerted no influence on the secretory responsiveness to 200 microM of the imidazoline, efaroxan. While 18 h BTS 67 582 culture did not affect the insulin-releasing actions (P<0.001) of 16.7 mM glucose, 10 mM arginine, 30 mM KCl, 25 microM forskolin or 10 nM phorbol-12-myristate 13-acetate (PMA), significant inhibition (P<0.001) of the insulinotropic effects of 10 mM 2-ketoisocaproic acid (KIC) and 10 mM alanine were observed. These data suggest that BTS 67 582 shares a common signalling pathway to sulphonylurea but not imidazoline drugs. Desensitization of drug action may provide an important approach to dissect sites of action of novel and established insulinotropic antidiabetic agents.

Animals↗
PubMed1977

Tolbutamide-induced insulin release in pregnant diabetics.

A study was undertaken to determine whether the abnormal insulin release pattern in insulin-independent pregnant diabetics (IID) was due to a lack of stored insulin and whether their clinical response to treatment with tolbutamide was correlated with enhanced plasma insulin values. Ten pregnant diabetics in the third trimester of pregnancy were subjected to both an oral glucose tolerance test and an intravenous tolbutamide tolerance test. The results indicated that an enhanced early release of insulin could be evoked by intravenous tolbutamide. The biochemical inertia of the beta cell noted in pregnant IID is therefore more likely to be associated with a relative insensitivity of the beta cell to glucose or to a defect in the enteroinsular axis. Although the individual hypoglycaemic effect of intravenous insulin was similar, the plasma insulin response varied greatly. The clinical improvement in tolbutamide-treated diabetics cannot be explained solely on the basis of enhanced insulin release.

Adult↗
PubMed1983

A stimulatory effect of tolbutamide on the insulin-mediated glucose uptake in subjects with impaired glucose tolerance (IGT).

Several studies have indicated that the long-term effectiveness of sulfonylurea therapy in the treatment of type-II diabetics is due to a potentiation of insulin action. The present investigation was undertaken in order to elucidate whether or not there is also an acute effect of sulfonylureas on insulin-mediated glucose uptake. Nine non-obese subjects classified as having impaired glucose tolerance formed the study group. In vivo insulin sensitivity was assessed by using the glucose controlled insulin infusion system (Biostator) without or with a contemporary 3-hour tolbutamide infusion. Studies were performed on subsequent days, and each subject served as its own control. Glucose was given at a fixed rate of 0.011 mmol/kg b.w./min. The computer program was set to maintain plasma glucose concentration at 3.89 mmol/l. The amount of exogenous insulin necessary to keep glycemia at this steady-state level has been accepted as an estimate of insulin sensitivity. Mean plasma glucose and insulin concentrations were constant and comparable in control and sulfonylurea treated groups. Under our experimental conditions tolbutamide did not provoke any increase of C-peptide secretion. There was no significant alteration of insulin counterregulatory hormones (glucagon and growth hormone) either. On the other hand, for the disposal of identical quantities of glucose the necessary amount of insulin has been found to be reduced by one third due to tolbutamide treatment indicating a higher insulin sensitivity. The mechanism by which tolbutamide intensifies the insulin effect is unknown. It seems to be that a successful short-term sulfonylurea therapy on glucose utilization is associated with some alterations on the receptor and/or post-receptor level.

Blood Glucose↗
PubMed1988

Tolbutamide inhibits gastrin release in man.

Tolbutamide significantly decreased fasting plasma gastrin after 5 min of intravenous infusion in patients with atrophic gastritis, duodenal ulcer, or insulin-dependent diabetes mellitus (IDDM) as well as in healthy volunteers. Increased plasma insulin and decreased blood glucose were observed in patients with atrophic gastritis, duodenal ulcer and healthy volunteers, but not in patients with IDDM. Suppression of plasma gastrin in healthy volunteers was also observed following oral administration of tolbutamide. Despite the observed decrease in plasma gastrin, neither basal nor tetragastrin-stimulated acid output was changed for 30 min following tolbutamide infusion in healthy volunteers. Thus, our data suggest that tolbutamide inhibits gastrin release in man via mechanisms independent of changes in plasma insulin, blood glucose or acid secretion.

Adult↗
PubMed1998

Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration.

High concentrations of glucose are considered to be toxic for the pancreatic beta-cell. However, the mechanisms underlying beta-cell dysfunction and resulting cell death are not fully characterized. In the present study we have demonstrated that incubation of pancreatic islets and beta-cells from ob/ob mice and Wistar rats with glucose induced a process of apoptotic beta-cell death, as shown by DNA laddering, TdT-mediated dUTP-biotin nick end-labeling (TUNEL) technique, and by using DNA-staining dye HOECHST 33342. The obtained results show that the percentage of apoptotic cells was dependent on glucose concentration, being minimal at 11 mM glucose. At a concentration of 100 microM, aurintricarboxylic acid, an inhibitor of endonuclease activity, almost completely inhibited apoptosis triggered by 17 mM glucose. We have also shown that long term incubation with 100 microM sulfonylurea, tolbutamide, triggered apoptosis in pancreatic beta-cells. The process of beta-cell death induced by high glucose concentration and tolbutamide were Ca2+-dependent, because introduction to the culture medium of 50 microM D-600 or 200 microM diazoxide, which blocked glucose- and tolbutamide-induced [Ca2+]i increase, inhibited apoptosis. Thus, this study shows for the first time that high glucose concentrations and tolbutamide induce apoptosis in pancreatic beta-cells, and that this process is Ca2+-dependent.

Animals↗
PubMed1996

The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism.

Tolbutamide undergoes hydroxylation in humans via a cytochrome P450-mediated pathway. The primary P450 isozyme responsible for this metabolism is thought to be CYP2C9. Population studies have indicated the existence of slow metabolizers of tolbutamide (approximately 1 in 500) suggesting a rare polymorphism associated with 2C9. Several allelic variants of 2C9 have been identified; however, the effect of these allelic variations on metabolism in vivo is not established. In the present study, the coding regions, intron-exon junctions, and upstream region of CYP2C9 were amplified by PCR and sequenced in two slow metabolizers. One individual was homozygous for Leu359/Leu359 and the other individual was heterozygous for Arg144/Cys144 and for Ile359/Leu359. No other genetic variations in 2C9 were detected in these individuals. PCR-RFLP tests showed that Arg144 Tyr358 Ile359 Gly417 is the principle CYP2C9 allele. Frequencies of the rarer Leu359 and Cys144 alleles were 0.06 and 0.08, respectively, in a Caucasian-American population and 0.005 and 0.01 respectively in African-Americans. The frequency of the Leu359 allele was 0.026 in Chinese-Taiwanese, but the Cys144 allele was not detected in this population. Studies in a recombinant yeast expression system showed that the Leu359 variant had the highest Km and the lowest Vmac for hydroxylation of tolbutamide of all the CYP2C9 allelic variants. This allelic variant also had the highest Km for the 7-hydroxylation of S-warfarin. The present data suggest that the incidence of the Leu359 allelic variant of CYP2C9 may account for the occurrence of poor metabolizers of tolbutamide.

Alleles↗
PubMed1981

Effect of naproxen on glucose metabolism and tolbutamide kinetics and dynamics in maturity onset diabetics.

1 The influence of the nonsteroidal anti-inflammatory drug naproxen on glucose metabolism and on tolbutamide pharmacokinetics and pharmacodynamics has been studied in ten maturity-onset diabetics. 2 Comparison of both plasma glucose decay curves and insulin responses during an intravenous glucose tolerance test before and after eight 12 hourly doses of naproxen revealed that naproxen had no significant influence on fasting glucose levels or on rates of glucose elimination. 3 When the subjects were given a combination of naproxen and tolbutamide for 3 days naproxen had no influence on tolbutamide absorption, protein binding, disposition or pharmacological effect. 4 Treatment with tolbutamide in maturity-onset diabetics need not be modified if concurrent administration of naproxen is contemplated.

Adult↗
PubMed1988

In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines.

1. A number of compounds have been examined for their ability to inhibit tolbutamide hydroxylase activity in human liver microsomes (control value at a substrate concentration of 150 microM being 0.27 +/- 0.12 nmol min-1 mg-1 protein; mean +/- s.d.; n = 7). 2. IC50 (concentration of inhibitor producing 50% inhibition) values were determined for a range of sulphonamides, imidazoles and aminoquinoline compounds. The most potent inhibition was evident with the 1-substituted imidazole antimycotic drugs ketoconazole, clotrimazole and miconazole and the sulphonamide sulphaphenazole (IC50 values of 16.5, 2.5, 0.85 and 0.5 microM respectively). A number of compounds showed little or no inhibition of tolbutamide hydroxylase as judged by an IC50 of greater than or equal to 500 microM. 3. The Km value for tolbutamide hydroxylase was 125 microM and Vmax, 0.44 nmol min-1 mg-1 protein. All the substituted imidazoles examined in kinetic studies 1v vs 1s, Line-weaver-Burk plots) produced either non-competitive or mixed inhibition. The sulphonamides exhibited competitive inhibition, the Ki for sulphaphenazole being 0.22 microM. Primaquine showed mixed inhibition. Dixon plots confirmed the type of inhibition produced. 4. Although the competitive inhibition between some sulphonamides and tolbutamide is consistent with metabolism by the same isozyme of cytochrome P-450 it does not prove it and further studies with purified enzymes will be necessary to confirm this.

Adolescent↗
PubMed1985

Normal metabolism of debrisoquine and theophylline in a slow tolbutamide metaboliser.

The metabolism of debrisoquine and theophylline has been studied in a healthy male who was identified as a slow hydroxylator of tolbutamide. Tolbutamide clearance in this subject was three-fold lower than the lowest tolbutamide clearance observed in other healthy males and the drug's half-life was approximately three-fold longer. Despite this, his ability to 4-hydroxylate debrisoquine and both N-demethylate and 8-hydroxylate theophylline was normal. Along with previously published information the data from this subject suggest that tolbutamide hydroxylation, debrisoquine hydroxylation, theophylline N-demethylation, and theophylline 8-hydroxylation involve four distinct isozymes of cytochrome P-450. Furthermore, this report illustrates the difficulties of using the metabolic clearance of a model drug to predict the ability of an individual to clear a range of metabolised drugs.

Adult↗
PubMed1989

Basal and tolbutamide-induced plasma somatostatin in healthy subjects and in patients with diabetes and impaired glucose tolerance.

Peripheral levels of basal and tolbutamide-induced somatostatin have been measured in patients with diabetes or impaired glucose tolerance (IGT) and compared with those in normal individuals. Basal somatostatin was significantly higher in patients with Type 1 diabetes than in age-matched control subjects. This increase was most pronounced at diagnosis, and appeared to be related to metabolic control in insulin-treated patients. No increase was noted in patients with Type 2 diabetes or with IGT. Intravenous bolus injection of tolbutamide enhanced peripheral somatostatin levels in healthy volunteers in a biphasic manner. Patients with IGT also exhibited a biphasic response but the amplitude of the first phase was higher. No secretory response was detected in 27/29 Type 1 diabetic patients at diagnosis; a somatostatin response to tolbutamide became detectable again in Type 1 patients with normalization of their basal somatostatin levels but was then paradoxically related to poor blood glucose control. In Type 2 diabetes, basal somatostatin levels were similar to age-matched control subjects, but decreased upon intravenous tolbutamide administration.

Adult↗
PubMed1990

Tolbutamide excites rat glucoreceptive ventromedial hypothalamic neurones by indirect inhibition of ATP-K+ channels.

1. The sulphonylureas, tolbutamide (0.1-10 mM) and glibenclamide (0.1-100 microM) shown not to inhibit ATP-K+ channel currents when applied to inside-out membrane patches excised from rat cultured cerebral cortex or freshly-dispersed ventromedial hypothalamic nucleus (VMHN) neurones. 2. Saturable binding sites for [3H]-glibenclamide, with similar affinity constants are present in rat cerebral cortex and hypothalamic membranes. The density of binding sites was lower in the hypothalamus than cortex. 3. Intracellular recordings from glucoreceptive VMHN neurones in hypothalamic slices were obtained. In the absence of glucose, tolbutamide (0.1 mM) depolarized these cells, increased membrane resistance and elicited action potentials. 4. Tolbutamide (0.1 mM) inhibited ATP-K+ channel currents and induced action current activity in cell-attached recordings from glucoreceptive VMHN neurones. 5. Glibenclamide (10-500 nM) had no effect per se on glucoreceptive VMHN neurones but did antagonize the actions of tolbutamide. 6. It is concluded that the hypothalamic (and perhaps cortical) sulphonylurea receptors are not directly coupled to ATP-K+ channels.

Action Potentials↗
PubMed1978

Paradoxical enhancement of tolbutamide-induced insulin release by diazoxide in a patient with islet cell hyperplasia.

A case of islet cell hyperplasia in a ten year old black male with symptomatic fasting hypoglycemia was documented histopathologically. Provocative studies with glucose, tolbutamide, glucagon, and diazoxide were performed to test the insulin response of hyperplastic islets. The islets responded to glucose, glucagon, and tolbutamide. Diazoxide potentiated the tolbutamide-induced insulin response, and this effect of diazoxide was not blocked by propranolol. In the diagnostic work up of islet cell hyperplasia, dizoxide may paradoxically potentiate tolbutamide-induced insulin release, a finding which may falsely suggest progression of the disease.

Blood Glucose↗