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PubMed1996

Mechanisms of sulfonylurea's stimulation of insulin secretion in vivo: selective amplification of insulin secretory burst mass.

Although sulfonylureas enhance insulin secretion, it is unknown whether these hypoglycemic chemicals stimulate insulin secretion through the augmentation of the pulsatile or basal modes of insulin release. Enhanced pulsatile insulin could occur in turn through amplification of the burst mass or an increase in burst frequency. To address the mechanism of sulfonylurea action, we employed a recently validated canine model with a portal vein sampling catheter and flow probe to measure pulsatile insulin secretion in vivo directly in response to tolbutamide infusion or ingestion. After a 16-h fast, seven dogs were studied in the postabsorptive basal state and during a tolbutamide (0.2 mg/min) infusion when their plasma glucose concentrations were clamped at euglycemia. Insulin concentrations in the carotid artery (basal vs. tolbutamide, 85 +/- 12 vs. 325 +/- 66 pmol/l; P < 0.01) and portal vein (basal vs. tolbutamide, 345 +/- 55 vs. 1,288 +/- 230 pmol/l; P < 0.01) increased during tolbutamide infusion, but the portal vein plasma flow did not change. Increased plasma insulin concentrations were achieved by a fourfold increase in the total insulin secretion rate (2.3 +/- 0.2 to 9.4 +/- 1.9 pmol x kg(-1) x min(-1); basal vs. tolbutamide, P < 0.01). The augmented total insulin secretion was achieved mechanistically via a marked and selective increase in the insulin secretory burst mass (basal vs. tolbutamide, 266 +/- 64 vs. 817 +/- 144 pmol/pulse; P < 0.01), with no change in portal-vein insulin pulse frequency (basal vs. tolbutamide, 10.1 +/- 0.6 vs. 11.1 +/- 0.8 pulses/h; P = 0.3). Oral (250 mg) tolbutamide also magnified the endogenous insulin secretion rate by the preferential amplification of the secretory pulse mass (basal vs. tolbutamide, 167 +/- 37 vs. 362 +/- 50 pmol/pulse; P < 0.01). Neither the infusion nor the ingestion of tolbutamide changed the calculated clearance rates of endogenously secreted insulin. We conclude that sulfonylurea (tolbutamide) induced insulin secretion in vivo is achieved by the highly selective amplification of insulin secretory burst mass with no change in basal insulin release or the frequency of the beta-cell-network pacemaker.

Animals↗
PubMed2000

Drug-induced desensitization of insulinotropic actions of sulfonylureas.

K(ATP)-channel-dependent and K(ATP)-channel-independent insulin-releasing actions of the sulfonylurea, tolbutamide, were examined in the clonal BRIN-BD11 cell line. Tolbutamide stimulated insulin release at both nonstimulatory (1.1 mM) and stimulatory (16. 7 mM) glucose. Under depolarizing conditions (16.7 mM glucose plus 30 mM KCl) tolbutamide evoked a stepwise K(ATP) channel-independent insulinotropic response. Culture (18 h) with tolbutamide or the guanidine derivative BTS 67 582 (100 microM) markedly reduced (P < 0. 001) subsequent responsiveness to acute challenge with tolbutamide, glibenclamide, and BTS 67 582 but not the imidazoline drug, efaroxan. Conversely, 18 h culture with efaroxan reduced (P < 0.001) subsequent insulinotropic effects of efaroxan but not that of tolbutamide, glibenclamide, or BTS 67 582. Culture (18 h) with tolbutamide reduced the K(ATP) channel-independent actions of both tolbutamide and glibenclamide. Whereas culture with efaroxan exerted no effect on the K(ATP) channel-independent actions of sulfonylureas, BTS 67 582 abolished the response of tolbutamide and inhibited that of glibenclamide. These data demonstrate that prolonged exposure to tolbutamide desensitizes both K(ATP)-channel-dependent and -independent insulin-secretory actions of sulfonylureas, indicating synergistic pathways mediated by common sulfonylurea binding site(s).

Adenosine Triphosphate↗
PubMed1991

Pharmacological studies with the alpha 2-adrenoceptor antagonist midaglizole. Part I: Respiratory and cardiovascular systems.

Respiratory and cardiovascular effects of midaglizole (DG-5128, CAS 66529-17-7) were investigated in comparison with yohimbine, idazoxan and tolbutamide. 1. Respiration: Midaglizole had little or no effect on respiration of anesthetized dogs. Yohimbine and idazoxan augmented respiration at low dose. Tolbutamide depressed respiratory rate and depth at high dose. 2. Blood pressure and heart rate: Midaglizole produced dose-related hypotension and bradycardia in anesthetized dogs which had laparotomy, whereas it had little or no effect on blood pressure and heart rate of dogs which had no laparotomy (unlaparotomized dogs). Tendency of slight hypertension was observed after high dose of tolbutamide in laparotomized dogs, and transient hypotension was induced in unlaparotomized dogs. Yohimbine and idazoxan increased blood pressure at low dose in unlaparotomized dogs. In laparotomized dogs, yohimbine produced hypertension and hypotension at low and high doses, respectively. In isolated guinea pig atria, midaglizole produced bradycardia which was not observed after yohimbine. Tolbutamide decreased the pulse rate at high concentration. 3. Cardiac contractility: Midaglizole produced increase in cardiac contractility of anesthetized dogs. Yohimbine and idazoxan, at low dose, showed similar inotropic activity. Prazosin also produced a positive inotropic effect, whereas tolbutamide lacked the activity. The inotropic effects of midaglizole and yohimbine were antagonized by pretreatment with propranolol or hexamethonium, whereas a similar effect of prazosin was not influenced by both blockers. In isolated guinea pig atria, midaglizole showed slight inotropic activity. Yohimbine was without any effect, whereas tolbutamide reduced the contractile force. 4. Femoral blood flow: Midaglizole produced a transient increase in femoral blood flow and a decrease in femoral arterial resistance of anesthetized dogs. Yohimbine and idazoxan, at low dose, showed similar vasodilator activity. Prazosin also produced a vasodilator effect, whereas tolbutamide lacked the activity. The vasodilator effects of midaglizole and yohimbine were not affected with propranolol, but inhibited after hexamethonium. 5. Mesenteric blood flow: Midaglizole significantly decreased mesenteric blood flow and increased the arterial resistance of anesthetized dogs in a dose dependent manner. Tolbutamide induced a decrease in blood flow and an increase in arterial resistance only at the highest dose used. Yohimbine increased mesenteric blood flow at low dose and decreased it at high dose. 6. Renal blood flow: Midaglizole dose-relatedly decreased renal blood flow of anesthetized dogs. Tolbutamide and yohimbine at high dose produced a long-lasting decrease of the blood flow. Midaglizole produced a slight transient reduction of renal arterial resistance which was followed by a slight increase. Tolbutamide increased the arterial resistance at high dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1988

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

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 insulin-secreting 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 40 microM and 0.2 microM, respectively. 3. Diazoxide (0.6-1.0 mM) 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 (20 mM), 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 17 microM and 27 nM, respectively. The value of Ki for tolbutamide was unchanged when ATP (0.1 mM) was present in the electrode. 6. Diazoxide (0.6 mM) activated the ATP-K+ channels only when they had first been inhibited by intracellular ATP (0.1 mM) or bath applied tolbutamide (3-30 microM). The inhibition produced by glibenclamide could not be reversed by diazoxide. 7. Neither tolbutamide (1.0 mM) nor glibenclamide (10 microM) 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.

Adenosine Triphosphate↗
PubMed1975

Glucagon-induced insulin secretion in normal diabetic subjects.

Eight normal subjects and ten diabetic patients were studied to compare the response of plasma insulin to glucagon with that to glucose and tolbutamide. Oral glucose tolerance test, glucagon test and tolbutamide-glucagon test were performed at intervals of several days. In glucose tolerance test, insulin response was reduced in the patients with severe diabetes. Plasma insulin increased and reached the peak 3 min after glucagon injection (glucagon I) in the normal controls, while plasma insulin response was reduced in diabetic patients, especially in the severe diabetics. In the normal controls plasma insulin rose and reached the peak 6 min after the tolbutamide injection and thereafter fell to the initial level. Glucagon injection following tolbutamide (glucagon II) caused the rise in insulin in the control subjects. In diabetics insulin response to either tolbutamide or glucagon I was reduced. Tolbutamide or glucagon II caused a significant difference in plasma insulin response in all the diabetic groups compared with the normal subjects, while glucose or glucagon I showed a significant increment of plasma insulin between the normal subjects and the severe diabetics. These results suggest that injection of tolbutamide as well as glucagon II provides a definite discrimination of insulin response in diabetics from the normal controls. The usefulness of the tolbutamide-glucagon test in the diagnosis of diabetes mellitus was discussed. -- glucose tolerance test; glucagon test; tolbutamide-glucagon test; plasma insulin.

Administration, Oral↗
PubMed2000

PIP2 and ATP cooperatively prevent cytosolic Ca2+-induced modification of ATP-sensitive K+ channels in rat pancreatic beta-cells.

The factors that influence functional coupling between the sulfonylurea receptor (SUR1) and Kir6.2 subunits of ATP-sensitive K+ (K+(ATP)) channels were studied in rat pancreatic beta-cells using patch clamp and microfluorometric techniques. Tolbutamide at 10 micromol/l inhibited K+(ATP) channels in association with occurrence of action currents, but further exposure of beta-cells to the drug for 30 min or longer resulted in reappearance of K+(ATP) channel events. Half-maximal inhibition concentration (IC50) for tolbutamide was 1.5 microl/mol in 2.8 mmol/l glucose, and it was increased to 13.3 micromol/l when the cellular metabolism was inhibited by 0.5 mmol/l 2,4-dinitrophenol (DNP) for 5 min. Tolbutamide at 10 micromol/l induced an increase in cytosolic Ca2+ concentration ([Ca2+]i), and its amplitude was markedly reduced following exposure to 0.5 mmol/l DNP or long-term (30 min) exposure to 10 micromol/l tolbutamide. This tolbutamide insensitivity, as assessed by the [Ca2+]i response, was not observed when the external Ca2+ was omitted during the long-term exposure to tolbutamide. In cell-attached membrane patches, the tolbutamide insensitivity was also produced by treatment of cells with 150 micromol/l diazoxide and 25 mmol/l KCl in the presence, but not absence, of 2 mmol/l Ca2+ in the external solution. When the cytoplasmic face of inside-out membrane patches was treated with higher Ca2+ concentrations (2 micromol/l), both ADP-evoked activation and tolbutamide-induced inhibition of K+ ATP channels were attenuated with retaining ATP-induced inhibition, indicating the modification of K+(ATP) channels. The Ca2+-induced channel modification was prevented partially by phosphatidylinositol 4,5-bisphosphate (PIP2) and completely by ATP and PIP2 together, but not by ATP alone. Treatment of the channel with cytochalasin D, a disrupter of F-actin, evoked channel modification similar to that induced by Ca2+. The modification was prevented completely by phalloidin, a stabilizer of F-actin. In conclusion, long-term exposure to tolbutamide or metabolic inhibition causes modification of K+ ATP channels via mechanisms involving Ca2+-dependent reaction. The modification, which may reflect functional disconnection between SUR1 and Kir6.2, is prevented by ATP and PIP2, which may act cooperatively to stabilize membrane cytoskeletons (F-actin structures).

2,4-Dinitrophenol↗
PubMed1991

Pharmacological studies with the alpha 2-adrenoceptor antagonist midaglizole. Part III: Smooth muscle, gastrointestinal and miscellaneous systems.

Pharmacological properties of midaglizole (DG-5128, CAS 66529-17-7) on smooth muscle, gastrointestinal and miscellaneous systems were investigated in comparison with those of tolbutamide. 1. Isolated smooth muscle: Midaglizole inhibited the contractile responses of the ileum to nicotine, acetylcholine, serotonin and BaCl2, and especially the response to histamine (guinea pig). Tolbutamide also reduced the contractions. On spontaneous motility of the uterus (estrus, diestrus, pregnant), midaglizole produced an increase in tonus and frequency, and decrease in contractile amplitude (rat). Tolbutamide reduced the motility of the uterus. The contractile response of the vas deferens to norepinephrine was potentiated after midaglizole and tolbutamide (guinea pig). Midaglizole inhibited the contractile response of the trachea to histamine, whereas it had little or no effect on the response to acetylcholine (guinea pig). Tolbutamide reduced the responses to both spasmogens. 2. Gastrointestinal system: Midaglizole induced an increase in gastrointestinal transit (mouse) and potentiated the gastrointestinal motility (dog). Tolbutamide was without any effect on these parameters. Gastric emptying rate, gastric secretion and gastric mucosa were not influenced after midaglizole (rat). Tolbutamide decreased gastric secretion and produced injury of gastric mucosa. 3. Urine volume: Midaglizole and tolbutamide showed a diuretic activity (rat). 4. Anti-inflammatory activity: Midaglizole and tolbutamide inhibited carrageenin-induced paw edema (rat).

Adrenergic alpha-Antagonists↗
PubMed1998

Pharmacological intervention: the antidiabetic approach.

Impaired glucose tolerance (IGT) progresses to non-insulin-dependent diabetes mellitus (NIDDM) in many but not all IGT subjects. It remains unsettled whether long-term antidiabetic (i.e. antihyperglycaemic) pharmacotherapy delays the development of NIDDM, and whether such treatment influences macrovascular morbidity and mortality. This report summarizes the results from long-term (> 4 years) antihyperglycaemic interventions addressing these issues. In an American study, tolbutamide (0.5 g 2-3 times daily) promoted a 4-year improvement of glucose tolerance in young, non-obese, mildly diabetic asymptomatic subjects who apparently comprised a mixture of IGT and NIDDM. In a Swedish 5-year study on 178 survivors of myocardial infarction, of whom 79 had intravenous IGT, tolbutamide treatment was associated with improved glucose tolerance, reduced triglyceride levels, and improved 18-month survival. A British 5-year study on a subgroup of about 200 middle-aged men from the Whitehall cohort indicated that phenformin (50 mg once daily) did not influence the deterioration of glucose levels. In a 10-year British study, 241 middle-aged men and women were 4-square randomized to control, weight reduction, placebo and tolbutamide (0.5 g twice daily). A non-lasting reduction of arterial disease was recorded in those on tolbutamide. No reduction of NIDDM development was seen. In a Swedish 10-year study on middle-aged men with IGT, follow-up comprised 59 controls, 98 on diet advice with or without placebo, and 23 on tolbutamide (0.5 g three times daily) added to diet advice. A total of 29% developed NIDDM among controls and 13% in the diet group. In contrast, no subject maintaining tolbutamide treatment developed NIDDM. Moreover, the tolbutamide-treated subjects had reduced blood pressure, triglyceride and cholesterol levels, as well as fewer macrovascular complications. Recently, a lower mortality rate at 22 years after the start of tolbutamide treatment has been recorded. To summarize, treatment with insulin-releasing drugs might help to reduce the development of NIDDM and macrovascular disease in IGT subjects. However, further studies are needed to verify or refute this notion.

Controlled Clinical Trials as Topic↗
PubMed1992

Human islets chronically exposed in vitro to different stimuli become unresponsive to the same stimuli given acutely: evidence supporting specific desensitization rather than beta-cell exhaustion.

The aim of this study was to evaluate the effects of long term in vitro exposure of human pancreatic islets to different secretagogues on their subsequent secretory activity. Therefore, groups of 100 islets were cultured for 48 h in standard tissue culture medium (CMRL 1066) in the presence of 1 of the following: 5.5 mmol/L glucose, 16.7 mmol/L glucose, 5.5 mmol/L glucose plus 10 mmol/L L-arginine, or 5.5 mmol/L glucose plus 100 mumol/L tolbutamide. Insulin levels in the culture medium declined with time under all culture conditions. Islets were then perifused and acutely stimulated with glucose (16.7 mmol/L), L-arginine (10 mmol/L), and tolbutamide (100 mumol/L). Islets cultured in 16.7 mmol/L glucose showed no response to 16.7 mmol/L glucose [net area under the curve (delta AUC), 11% of control], and a reduced response to acute tolbutamide (delta AUC, 35% of control), but responded to L-arginine (delta AUC, 75% of control). Islets cultured in the presence of 10 mmol/L L-arginine had reduced responses to glucose (delta AUC, 11% of control) and tolbutamide (delta AUC, 27% of control), but responded to L-arginine (delta AUC, 75% of control). Islets cultured in tolbutamide did not respond to tolbutamide (delta AUC, 14% of control) and showed a reduced responses to acute glucose (delta AUC, 36% of control) and L-arginine (delta AUC, 24% of control). In a second set of experiments, islets cultured in 5.5 or 16.7 mmol/L glucose showed an insulin response to a supramaximal glucose stimulation (30 mmol/L glucose plus 0.5 mmol/L isobutylmethylxanthine) that was not statistically different. Similarly, islets that were cultured in the presence of 100 mumol/L tolbutamide still responded to 1 mmol/L tolbutamide. In conclusion, all stimuli evaluated in this study, chronically applied, reduced the insulin response to further acute stimulations. The different patterns of unresponsiveness observed together with the finding of a preserved insulin content in the islets after perifusions and a maintained capability to release insulin in response to supramaximal stimulations suggest that after chronic exposure to different stimuli, human islets become selectively desensitized to the same stimuli given acutely and do not become exhausted.

Arginine↗
PubMed1990

Sulfonylurea mimics the effect of glucose in inducing large amplitude oscillations of cytoplasmic Ca2+ in pancreatic beta-cells.

The effects of the insulin-releasing sulfonylurea tolbutamide on the cytoplasmic Ca2+ concentration [( Ca2+]i) in individual pancreatic beta-cells or suspensions of beta-cells were analyzed using the probe fura-2 and dual-wavelength fluorometry. Subsequent additions of 1, 10, and 100 microM tolbutamide induced a graded response, ranging from a single [Ca2+]i peak to a sustained increase. These effects depended on the presence of extracellular Ca2+ and were reversed by the hyperglycemic sulfonamide diazoxide. The responses were diminished in the presence of albumin and varied considerably between different cells. Sometimes tolbutamide triggered slow large amplitude oscillations in [Ca2+]i similar to those induced by glucose. The increase in [Ca2+]i during each tolbutamide-induced oscillation was often more rapid than for glucose-induced oscillations. Oscillations or steady state increases in [Ca2+]i induced by glucose were little influenced by tolbutamide. However, subthreshold concentrations of glucose could reactivate [Ca2+]i response to tolbutamide that had declined. Although in several ways the abilities of glucose and tolbutamide to raise [Ca2+]i were similar, the sulfonylurea lacked a [Ca2+]i-lowering component. The latter effect of glucose was so pronounced that an increase of its concentration from 3 to 20 mM caused temporary lowering of [Ca2+]i to the basal level, even during tolbutamide stimulation. The results indicate that closure of the ATP-sensitive K(+)-channels is important for the large amplitude oscillations of [Ca2+]i the appearance of which reflects the balance between entry of Ca2+ through the voltage-dependent channels and its removal from the cytoplasm.

Animals↗
PubMed1995

Lack of interaction between fluvastatin and oral hypoglycemic agents in healthy subjects and in patients with non-insulin-dependent diabetes mellitus.

Human drug interaction studies in vivo are conducted when in vitro and/or animal interactions suggest clinical relevance. Studies in vitro have indicated that the new, entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin affects the metabolism of the nonsteroidal anti-inflammatory drug diclofenac and the oral hypoglycemic tolbutamide. Diclofenac and tolbutamide are both model substrates of the CYP2C isozymes, suggesting that this enzyme could be involved in the underlying mechanism of interaction. The concomitant use of lipid-lowering drugs with oral hypoglycemic agents has been recommended in patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, 2 studies were initiated to explore potential pharmacokinetic and pharmacodynamic interactions between fluvastatin, simvastatin, or placebo and the oral hypoglycemic agents tolbutamide (study I) and glyburide (study II), each in 16 healthy subjects. These compounds were selected because of a demonstrated in vitro interaction with tolbutamide and widespread clinical use of glyburide. A further study (study III) was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between fluvastatin and glyburide under therapeutic conditions in 32 patients with NIDDM. Single and multiple coadministration of fluvastatin 40 mg or simvastatin 20 mg increased the mean maximum plasma concentration and area under the concentration-time curve of glyburide by about 20%. The pharmacokinetics of tolbutamide were influenced to only a minor extent. Fluvastatin concentration-time profiles were unaffected by tolbutamide or glyburide coadministration. However, the pharmacokinetic interactions between fluvastatin or simvastatin and tolbutamide and glyburide were not associated with clinically relevant changes in blood glucose and insulin concentrations and, therefore, are not considered to be relevant in therapeutic practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2000

Sulphonylurea drugs reduce hypoxic damage in the isolated perfused rat kidney.

Sulphonylurea drugs have been shown to protect against hypoxic damage in isolated proximal tubules of the kidney. In the present study we investigated whether these drugs can protect against hypoxic damage in a whole kidney preparation. Tolbutamide (200 microM) and glibenclamide (10 microM) were applied to the isolated perfused rat kidney prior to changing the gassing from oxygen to nitrogen for 30 min. Hypoxic perfusions resulted in an increased fractional excretion of glucose (FE % glucose 14.3+/-1.5 for hypoxic perfusions vs 4.9+/-1.6 for normoxic perfusions, mean +/- s.e. mean, P<0.05), which could be completely restored by 200 microM tolbutamide (5.7+/-0.4 for tolbutamide vs 14.3+/-1.5 for untreated hypoxic kidneys, P<0.01). Furthermore, tolbutamide reduced the total amount of LDH excreted in the urine (220+/-100 mU for tolbutamide vs. 1220+/-160 mU for untreated hypoxic kidneys, P<0.01). Comparable results were obtained with glibenclamide (10 microM). In agreement with the effect on functional parameters, ultrastructural analysis of proximal tubules showed increased brush border preservation in tolbutamide treated kidneys compared to untreated hypoxic kidneys. We conclude that glibenclamide and tolbutamide are both able to reduce hypoxic damage to proximal tubules in the isolated perfused rat kidney when applied in the appropriate concentrations.

ATP-Binding Cassette Transporters↗
PubMed1993

Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily.

Evidence from human studies in vivo and in vitro strongly suggests that the methylhydroxylation of tolbutamide and the 4-hydroxylation of phenytoin, the major pathways in the elimination of these two drugs, are catalysed by the same cytochrome P-450 isoenzyme(s). In the present study we used site-directed mutagenesis and cDNA expression in COS cells to characterize in detail the kinetics of tolbutamide and phenytoin hydroxylations by seven CYP2C proteins (2C8, 2C9 and variants, and 2C10) in order to define the effects of small changes in amino acid sequences and the likely proteins responsible in the metabolism of these two drugs in man. Tolbutamide was hydroxylated to varying extents by all expressed cytochrome P-450 isoenzymes, although activity was much lower for the expressed 2C8 protein. While the apparent Km values for the 2C9/10 isoenzymes (71.6-131.7 microM) were comparable with the range of apparent Km values previously observed in human liver microsomes, the apparent Km for 2C8 (650.5 microM) was appreciably higher. The 2C8 enzyme also showed quite different sulphaphenazole inhibition characteristics. The 4-hydroxylation of phenytoin was also more efficiently catalysed by the 2C9/10 enzymes. These enzymes showed similarities in kinetics of phenytoin hydroxylation and sulphaphenazole inhibition compared with human liver phenytoin hydroxylase. Also of interest was the observation that, among the 2C9 variants, small differences in amino acid composition could appreciably affect both tolbutamide and phenytoin hydroxylations. The amino acid substitution Cys-144-->Arg increased both the rates of tolbutamide and phenytoin hydroxylations, while the Leu-359-->Ile change had a greater effect on phenytoin hydroxylation. We conclude that: (1) although 2C8 and 2C9/10 proteins metabolize tolbutamide. only 2C9/10 proteins play a major role in human liver; (2) 2C9/10 proteins also appear to be chiefly responsible for phenytoin hydroxylation; and (3) subtle differences in the amino acid composition of these 2C9/10 proteins can affect the functional specificities towards both tolbutamide and phenytoin.

Amino Acid Sequence↗
PubMed1985

Do hypoglycemic sulfonylureas inhibit Na+,K+-ATPase activity in pancreatic islets?

The view that the insulinotropic response to hypoglycemic sulfonylureas is somehow related to an inhibitory action of these drugs on either the Ca2+-activated K+ permeability or the Na+,K+-ATPase activity in pancreatic islet cells was investigated by measuring the effect of tolbutamide on 86Rb outflow and uptake, 45Ca outflow, and insulin release in rat pancreatic islets. Although tolbutamide inhibited 86Rb efflux from glucose-deprived islets, whether in the absence or presence of extracellular Ca2+ or ouabain, a primary action of the sulfonylurea on the Ca2+-responsive K+ channels appeared unlikely, because tolbutamide failed to suppress the increase in 86Rb outflow evoked by either the ionophore A23187 or ouabain. Glibenclamide also failed to suppress the increase in 86Rb outflow evoked by the ionophore. Moreover, tolbutamide itself stimulated quinine-sensitive 86Rb outflow from glucose-stimulated islets. Likewise, although tolbutamide inhibited an ouabain-resistant modality of 86Rb inflow into the islet cells, an inhibitory action of the sulfonylurea on the Na+,K+-ATPase appeared improbable, because tolbutamide failed to minimize and instead favored the cationic and secretory response to ouabain. It is concluded, therefore, that the capacity of tolbutamide to cause under suitable conditions continuous electrical activity in islet cells cannot be attributed to inhibition of either the Ca2+-sensitive K+ permeability or ouabain-sensitive Na+,K+-ATPase.

Animals↗
PubMed1995

A monitor of secretion from single pancreatic beta-cells.

ATP is known to be coreleased with insulin from pancreatic beta-cells. To monitor insulin secretion from single beta-cells, a single beta-cell was surrounded in culture by Fura 2-loaded calf pulmonary artery endothelium (CPAE) cells, which can detect the ATP. CPAE cells did not respond with an elevation in cytoplasmic calcium concentration ([Ca2+]i) to either tolbutamide (100 mumol/l) or kainate (1 mmol/l) but did respond with an elevation in [Ca2+]i to ATP (0.1-10 mumol/l) without desensitization and in a dose-dependent manner. A brief application of tolbutamide (10 mumol/l) increased [Ca2+]i in both the beta-cell and the adjacent CPAE cells in co-culture. Suramin (100 mumol/l), an ATP-receptor blocker, inhibited the tolbutamide-induced elevation in [Ca2+]i in the CPAE cells but did not inhibit the elevation in [Ca2+]i in the beta-cell, confirming that the insulin secretagogue-induced Ca2+ response in CPAE cells in co-culture is mediated by ATP released from the beta-cell. When co-culture of the beta-cell and CPAE cells was stimulated by kainate (1 mmol/l) and then tolbutamide (10 mumol/l), the CPAE cells showed elevations in [Ca2+]i in response to kainate and tolbutamide during elevation in [Ca2+]i in the beta-cell. This strongly suggests that insulin secretion as well as an increase in [Ca2+]i in response to different agents, i.e., kainate and tolbutamide, occurs in a single beta-cell. A long exposure of tolbutamide (100 mumol/l, 4 min) resulted in a long-lasting elevation in [Ca2+]i in the beta-cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1996

Somatostatin and insulin secretion due to common mechanisms by a new hypoglycemic agent, A-4166, in perfused rat pancreas.

N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) is a nonsulfonylurea hypoglycemic agent that decreases blood glucose levels in nondiabetic and diabetic animals. In the present study, we attempted to determine the effect of A-4166 on hormone secretion from the in vitro-perfused rat pancreas and to examine the underlying secretory mechanisms. In the presence of basal glucose (3 mmol/L), A-4166 markedly stimulated insulin and somatostatin release in a concentration-dependent manner over 0.03 to 3 mmol/L. A sulfonylurea, tolbutamide, also stimulated insulin and somatostatin release. A-4166 and tolbutamide elevated the level of glucagon release; however, the change lacked a clear concentration-dependent property. A-4166 at 0.3 mmol/L and tolbutamide at 3 mmol/L exhibited maximal stimulation of insulin release to a similar extent, indicating that A-4166 is one log-order more potent than and as effective as tolbutamide. By contrast, A-4166 stimulated somatostatin release to a threefold greater extent than tolbutamide. A-4166 evoked an increase in the cytosolic free-Ca2+ concentration ([Ca2+]i) in rat pancreatic beta cells. [Ca2+]i and insulin secretory responses to A-4166 were inhibited by nitrendipine (NTD), a blocker of the L-type Ca2+ channel, and by diazoxide (DAZ), an opener of the adenosine triphosphate (ATP)-sensitive K+ channel. Furthermore, A-4166-stimulated somatostatin release was also inhibited by NTD and by DAZ. The results indicate that A-4166 and tolbutamide stimulate the release of insulin and somatostatin, and that A-4166 is much more effective than tolbutamide in releasing somatostatin, a hormone that attenuates hyperglycemia under certain circumstances. It is concluded that A-4166-induced insulin release is mediated by an increase in [Ca2+]i in beta cells. An inhibition of ATP-sensitive K+ channels and a consequent activation of L-type Ca2+ channels appear to play a key role not only in insulin secretion from beta cells, but also in somatostatin secretion from delta cells in response to A-4166.

Adenosine Triphosphate↗
PubMed1996

Similar physiological and symptomatic responses to sulphonylurea and insulin induced hypoglycaemia in normal subjects.

There is little information concerning the physiological response to hypoglycaemia induced by sulphonylureas. We compared the physiological and symptomatic responses to insulin and tolbutamide induced hypoglycaemia in 8 normal subjects. While infusing either insulin or tolbutamide, we used a glucose clamp to maintain blood glucose at 4.5 mmol l-1 for 30 min and lowered it to 2.9 mmol l-1 for a further 30 min. Mean peripheral insulin levels during the insulin infusion arm in comparison with the tolbutamide infusion were not significantly different during the euglycaemic plateau: 106 +/- 4 vs 77 +/- 15 mU l-1 (mean +/- SEM) (mean difference 29 mU l-1, 95% CI -22 to 80; p = NS) but were greater during the hypoglycaemic plateau: 106 +/- 3.5 vs 21.0 +/- 4.0 mU l-1 (mean difference 85 mU l-1, 95% CI 72 to 98; p < 0.0001). Portal insulin concentrations, calculated from C-peptide data were not significantly different during the euglycaemic plateau with insulin as compared to tolbutamide. However, during hypoglycaemia portal insulin concentrations were significantly higher 15 min from the start of the plateau, during insulin infusion. During hypoglycaemia induced by either insulin or tolbutamide there were similar peak responses of glucagon: 124 +/- 14 vs 128 +/- 7 ng l-1 (mean difference -4, 95% CI -39 to 31; p = NS) and adrenaline: 2.9 +/- 0.4 vs 2.8 +/- 0.3 nmol l-1, (mean difference 0.1, 95% CI -0.9 to 1.0; p = NS). Increases in tremor and sweating and deterioration in reaction time were similar during both periods of hypoglycaemia as were increases in total: 18.5 +/- 1.4 vs 19.6 +/- 2.2 (mean difference -1.0, 95% CI -3.8 to 1.8; p = NS) and autonomic: 8.9 +/- 0.9 vs. 9.9 +/- 1.3 (mean difference -1.1, 95% CI -5.9 to 3.6; p = NS) symptom scores. We conclude that there is no difference in the glucagon, sympathoadrenal, cognitive or symptomatic response during hypoglycaemia induced by either insulin or tolbutamide. This suggests that the different insulin concentrations produced by these contrasting models of hypoglycaemia had no effect on the physiological response and patients taking sulphonylureas can be expected to develop similar warning symptoms to those on insulin.

Adult↗
PubMed1987

Distinct mechanisms for two amplification systems of insulin release.

The mechanisms whereby activation of the cyclic AMP-dependent protein kinase A or the Ca2+-phospholipid-dependent protein kinase C amplifies insulin release were studied with mouse islets. Forskolin and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) were used to stimulate adenylate cyclase and protein kinase C respectively. The sulphonylurea tolbutamide was used to initiate insulin release in the presence of 3 mM-glucose. Tolbutamide alone inhibited 86Rb+ efflux, depolarized beta-cell membrane, triggered electrical activity, accelerated 45Ca2+ influx and efflux and stimulated insulin release. Forskolin alone only slightly inhibited 86Rb+ efflux, but markedly increased the effects of tolbutamide on electrical activity, 45Ca2+ influx and efflux, and insulin release. In the absence of Ca2+, only the inhibition of 86Rb+ efflux persisted. TPA (100 nM) alone slightly accelerated 45Ca2+ efflux and insulin release without affecting 45Ca2+ influx or beta-cell membrane potential. It increased the effects of tolbutamide on 45Ca2+ efflux and insulin release without changing 86Rb+ efflux, 45Ca2+ influx or electrical activity. Omission of extracellular Ca2+ suppressed all effects due to the combination of TPA and tolbutamide, but not those of TPA alone. Though ineffective alone, 10 nM-TPA amplified the releasing action of tolbutamide without affecting its ionic and electrical effects. In conclusion, the two amplification systems of insulin release involve at least partially distinct mechanisms. The cyclic AMP but not the protein kinase C system initiating signal (Ca2+ influx) triggered by the primary secretagogue.

Animals↗

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