Effects of drugs on glucose and tolbutamide-stimulated insulin release from isolated rat islets of Langerhans

The effects of acetylsalicylic acid, sulphadimidine, phenylbutazone and chlorpromazine on glucose- and tolbutamide-stimulated insulin release by isolated rat islets of Langerhans have been investigated. Acetylsalicylic acid did not influence glucose-stimulated insulin secretion; although at 2.5 mM it potentiated the effect of tolbutamide. Sulphadimidine potentiated the effects of glucose and tolbutamide on insulin secretion, whereas phenylbutazone was found to augment glucose-stimulated insulin release and to antagonize the tolbutamide effect. The effects of glucose and tolbutamide on insulin secretion were inhibited by low concentrations of chlorpromazine (0.005 mM–0.01 mM) and were stimulated by high concentrations (0.5 mM–1 mM). These results are discussed in relation to the possibilities that certain drugs may affect tolbutamide-stimulated insulin release either by altering the binding of tolbutamide to the B-cell or to other proteins, or by affecting the cyclic AMP system of the B-cell.     

Comparative effects of linogliride fumarate and tolbutamide sodium on insulin secretion and glucose utilization in rat pancreatic islets

The effects of linogliride fumarate (0.1 mmol/liter) and tolbutamide sodium (0.5 mmol/liter) on insulin secretion and glucose utilzation were directly compared in isolated perifused rat islets. Both compounds potentiated glucose-primed (5.5 mmol/liter) insulin release. The insulin secretory response at the concentration chosen was qualitatively different for the two agents. In the presence of glucose, the insulin secretory effect of tolbutamide was biphasic, whereas linoglirde predominantly increased second-phase insulin secretion. In the absence of exogenous glucos, tolbutamide stimulated first-phase insulin release wherease linogliride was ineffective without glucose in the perifusion medium. Neither linogliride (0.1 mmol/liter) nor tolbutamide (0.5 mmol/liter) stimulated islet cell glucose usage as measured by conversion of [5?³H]-glucose to ³H₂O. The insulin secretagogue effect of linogliride was completely abolished when islet cell glucose usage was partially blocked (22% reduction) by mannoheptulose (MH) (10 mmol/liter). When glucose usage was significantly inhibited (55%) by 2-deoxyglucose (2DG) (10 mmol/liter), linogliride-stimulated insulin secretion was not significantly reduced. In contrast, tolbutamide-stimulated first-phase insulin release was not inhibited when glucose usage was reduced by either MH or 2-DG, wherease secondphase insulin release was significantly inhibited. In summary, linogliride potentiates insulin secretion in isolated islets by a glucose-dependent process, but with a kinetic profile and response to metabolic inhibitors different from that of tolbutamide.     

Effect of tolbutamide on aminophylline-, 3,5-AMP-dibutyrate-or glucagon-induced insulin release from pancreatic islets after impairment of pyridine nucleotide metabolism caused by 6-aminonicotinamide (6-AN)

Summary The effect of tolbutamide on pyridine nucleotides and insulin secretion stimulated by aminophylline, 3,5-AMP-dibutyrate or glucagon was studied in pancreatic islets of rats previously treated with 6-aminonicotinamide (6-AN), an inhibitor of pyridine nucleotide synthesis.After being incubated for 60 min in a Krebs-Ringer-Bicarbonate-Buffer in the absence of glucose, pancreatic islets of rats i.p. injected with 35 mg/kg of 6-AN 6 hrs before pancreas removal contained about 30% less NADP and NADPH than did islets of control rats. No changes of NAD or NADH were observed in islets of 6-AN-treated animals. Addition of 16.5 mM glucose led to an increase of NADH, NADPH and a decrease of NADP in islets of both groups of animals; NAD levels remained unchanged. In vitro addition of tolbutamide to islets of control rats did not affect the levels of NADPH or NADP in the presence of 5.5 mM glucose. When 16.5 mM glucose were present, a decrease of NADPH and an increase of NADP was obvious. No effect of tolbutamide on insular NADPH or NADP was observed in islets of rats previously treated with 6-AN be it in the presence of 5.5 or 16.5 mM glucose.In islets of 6-AN-treated rats insulin release in response to aminophylline or 3,5-AMP-dibutyrate in the presence of 5.5 mM glucose was significantly depressed, when compared to islets of untreated controls. Addition of tolbutamide increased insulin release due to aminophylline, 3,5-AMP-dibutyrate or glucagon from islets of controls. Tolbutamide alone was without effect. In islets of 6-AN-treated rats aminophylline, 3,5-AMP-dibutyrate or glucagon stimulated insulin release only when tolbutamide was present.Our data suggest that there is no direct interference of tolbutamide with pyridine nucleotides of pancreatic islets, and that tolbutamide increases the secretory response of the -cell to aminophylline, 3,5-AMP-dibutyrate or glucagon when insulin release due to these agents is inhibited during decrease of insular NADP and NADPH, caused by 6-AN.Supported by the Deutsche Forschungsgemeinschaft.     

Effect of yohimbine on urethane-induced hyperglycemia in rats

Urethane is a widely used anesthetic and yohimbine is a well-known alpha 2-adrenergic antagonist. In fasted Wistar rats urethane at an anesthetic dose (1.25 g/kg, i.p.) caused an increase in plasma glucose, while pentobarbital at an anesthetic dose (40 mg/kg, i.p.) did not. Urethane caused no change in plasma glucose in adrenalectomized rats. The hyperglycemic effect of urethane was not inhibited by pretreatment with propranolol (1 mg/kg, p.o.) or prazosin (10 mg/kg, p.o.), but was reduced by pretreatment with phentolamine (10 mg/kg, p.o.) or yohimbine (10 mg/kg, p.o.). Urethane caused an elevation of plasma adrenaline, and yohimbine reduced the elevation. In addition, the pretreatment of yohimbine potentiated the urethane-induced increase in plasma insulin. These results indicate that yohimbine may inhibit the urethane-induced hyperglycemia that is mediated by the central and peripheral alpha 2-adrenergic systems.     

Interactions between diphenylhydantoin and tolbutamide in mice

Diphenylhydantoin (DPH) has been reported to induce alterations in carbohydrate metabolism in some humans and in most species of laboratory animals. These effects are often associated with high or even toxic doses of the drug. The present study was conducted to determine whether the effects of DPH on carbohydrate metabolism could be detected in the mouse when the dosage level of the drug was the anticonvulsant ED50 value. The ip ED50 value of DPH in the supramaximal electroshock test was found to be 5.5 mg/kg. In all subsequent experiments the ip dose of DPH was 5.0 mg/kg. The administration of DPH to normally fed mice did not alter resting blood glucose levels, but it significantly reduced glucose tolerance. Similarly, DPH did not alter the hypoglycemic effect of exogenously administered insulin, but it reversed the hypoglycemic effect of tolbutamide. The reversal of tolbutamide-induced hypoglycemia appears to be mediated through the adrenal glands since DPH reduced but did not reverse the hypoglycemic effect of tolbutamide in adrenalectomized mice. Also, DPH potentiates the hyperglycemic effect of epinephrine. The results of these studies suggest that there may be a clinically significant interaction between DPH and tolbutamide.     

JTT-608 restores impaired early insulin secretion in diabetic Goto-Kakizaki rats.

1. We investigated the pharmacological effects of a new antidiabetic agent, JTT-608, in comparison with the sulphonylurea tolbutamide, in Goto-Kakizaki (GK) rats, a genetic model of non-obese insulin-dependent diabetes mellitus (NIDDM). 2. In isolated perfused pancreas from GK rats, JTT-608 (200 microM) enhanced 11.1 mM glucose-stimulated insulin secretion in the first and second phases, but had little effect on insulin secretion at 2.8 mM glucose. In contrast, tolbutamide (100 microM) markedly stimulated insulin secretion at 2.8 mM glucose and enhanced the second phase of insulin secretion but not the first phase at 11.1 mM glucose. 3. In vivo JTT-608 also enhanced early insulin secretion only with glucose-loading. In contrast, tolbutamide enhanced insulin secretion both with and without glucose-loading. 4. JTT-608 (10-100 mg kg(-1)) improved oral glucose tolerance with enhanced insulin secretion in a meal tolerance test (MTT). In comparison with tolbutamide, JTT-608 improved glucose tolerance more efficiently in GK rats than in Wistar rats. 5. We conclude that in diabetic GK rats JTT-608 suppressed postprandial glucose excursions with enhanced glucose-stimulated insulin secretion, especially the first phase of insulin secretion.     

Increase of insulin sensitivity in diabetic rats received Die—Huang—Wan,a herbal mixture used in Chinese traditional medicine

AIM：Effects on insulin sensitivity of Die-Huang-Wan,the herbal mixture widely used to treat diabetic disorder in Chinese traditional medicine,were investigated in vivo.METHODS:The obese Zucker rats were employed as insulin-resistant animal model.Also,insulin-resistance was induced by the repeatedintraperitoneal injections of long-acting human insulin at 0.5U/kg three times daily into adult male Wistar rats.Insulin resistance was identified using the loss of tolbutamide(10mg/kg) or electroacupuncture(EA)-induced plasma glucose lowering action.The plasma glucose concentration was examined by glucose oxidase assay.RESULTS:The plasma glucose-lowering action induced by tolbutamide was significantly enhanced in obese Zucker rats receiving the repeated administration of Die-Huang-Wan at dosage of 26mg/kg for 3d.Furthermore,administration of Die-Huang-Wan delayed the formation of insulin resistance in rats that were induced by the daily repeated injection of human long-acting insulin at 0.5U/kg three times daily and identified by the loss of tolbutamide-or EA-induced hypoglycemia.In streptozotocininduced diabetic rats,oral administration of metformain at 320mg/kg once daily made an increase of the response to exogenous short-acting human insulin 15d later.This is consistent with the view that metformin can increase insulin sensitivity.Similar treatment sith Die-Huang-Wan at an effective dose(26.0mg/kg) also increased the plasma glucose lowering action of exogenous insulin at 10d later.The effect of Die-Huang-Wang on insulin sensitivity seems to produce more rapidly than that of metformin.CONCLUSION;The present study found that oral administration of Die-Huang-Wan increased insulin sensitivity and delayed the development of insulin resistance in rats.     

Glycemic response to stress stimulation by ether exposure in adrenalectomized rats

Stress was induced by short-term ether exposure (2 min) and tail vein puncture in normal (SO), adrenodemedullated (ADM), and adrenalectomized (ADR) rats. In ADM and SO rats stress provoked a significant hyperglycemic response with no change in plasma insulin levels. In ADR rats, on the other hand, the hyperglycemic response was not present. Actually, a significant rapid decrease in blood glucose, plasma insulin and hepatic glycogen content was observed. When the hypoglycemic effect of stress was prevented by glucose injection into ADR rats the decrease in plasma insulin and hepatic glycogen was not observed. The data suggest that the fall in plasma insulin and hepatic glycogen content observed in ADR animals result from an activation of the sympathetic nervous system induced by the decrease in blood glucose.     

Hypoglycemic activity of 1-alpha-(3,4-dimethoxyphenethylaminomethyl) -2-hydroxybenzylalcohol 1/2 fumarate (TA-078) in the mouse, rat and dog

1-alpha-(3,4-Dimethoxyphenethylaminomethyl)-2-hydroxybenzylalcohol 1/2 fumarate (TA-078) is a new hypoglycemic agent structurally different from any existing hypoglycemic drug. It depresses the rise of blood glucose when it is orally administered to glucose-loaded mice, rats and beagle dogs at minimal doses of 1, 10 and 2.5 mg/kg, respectively. In contrast with tolbutamide, TA-078 hardly affected fasting blood glucose levels in rats and dogs and only weakly reduced fasting blood glucose levels in mice. Oral administration of TA-078 to KK mice also improved glucose tolerance, while no improvement was observed in streptozotocin-diabetic rats. TA-078 elevated plasma immunoreactive insulin (IRI) levels in mice and rats soon after its oral administration. In fasted rats, TA-078 caused only a transient increase in plasma IRI but did not affect plasma immunoreactive glucagon (IRG) levels in the early phase after its administration. On the other hand, tolbutamide induced a sustained increase in plasma IRI and a transient but marked decrease in plasma IRG. In perfused rat pancreas, TA-078 stimulated insulin secretion. The stimulation by 10 micrograms/ml TA-078 in the perfusion liquid required the presence of a normal concn (5.6 mM) of glucose, whereas the same concn of tolbutamide stimulated insulin release even at a low glucose concn (2.8 mM).     

Effects of tolbutamide on insulin binding to isolated fat cells of the rat

In isolated fat cells of the rat the in vitro and in vivo effects of tolbutamide on insulin binding and insulin response were studied. 450 mg tolbutamide/kg/day given for 7 days significantly increased the binding of insulin to isolated adipocytes. The binding curves reflected an increase in the number of receptor sites rather than in the affinity. The effect was associated with an enhanced response to insulin of the adipose tissue, since the fat cells obtained from animals treated with tolbutamide converted significantly more glucose to lipids in the presence of insulin than those obtained from the control group. However, the augmentation of insulin binding sites was observed only at a large tolbutamide dosage, which reduced the pancreatic insulin content, the secretory response of the isolated pancreas, and the serum insulin levels. Smaller doses, sufficient to produce metabolic effects via a stimulation of insulin secretion, did not provide additional insulin binding sites. When added in vitro to the binding assay or to adipose tissue incubated for 16 h, tolbutamide failed to increase insulin binding of the fat cells. It is suggested, therefore, that the effects produced by tolbutamide after in vivo treatment reflect an indirect rather than a direct action of the sulphonylurea.     

Mechanism of the hypoglycemic effect of stevioside, a glycoside of Stevia rebaudiana

We have studied the effects of stevioside on the glucose and insulin metabolism in 2 models of diabetes in rats, STZ-induced diabetic rats and NIDDM diabetic rats induced by feeding with fructose. Stevioside (0.5 mg/kg), lowered the blood glucose levels in STZ-induced diabetic rats, peaking at 90 min. Stevioside administered twice daily also demonstrated dose-dependent effects in lowering the glucose levels in both diabetic rat models. Stevioside reduced the rise in glucose during glucose tolerance testing in normal rats. Stevioside dose-dependently decreased protein levels of phosphoenol pyruvate carboxykinase (PEPCK) and PEPCK mRNA after 15 days of treatment. Stevioside also reduced insulin resistance in the diabetic animals as shown by the glucose lowering effects of tolbutamide. In conclusion, stevioside was able to regulate blood glucose levels by enhancing not only insulin secretion, but also insulin utilization in insulin-deficient rats; the latter was due to decreased PEPCK gene expression in rat liver by stevioside's action of slowing down gluconeogenesis. Further studies of this agent for the treatment of diabetes appear warranted.     

JTT-608 controls blood glucose by enhancement of glucose-stimulated insulin secretion in normal and diabetes mellitus rats

We investigated the pharmacological effects of a new anti-hyperglycemic agent, JTT-608 [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid], in normal and neonatally streptozotocin-treated rats. In normal rats, JTT-608 improved glucose tolerance at 3-30 mg/kg, doses that did not cause a decrease in fasting blood glucose levels. In contrast, tolbutamide (10-100 mg/kg) and glibenclamide (1-3 mg/kg) caused a persistent decrease in fasting blood glucose levels, and tolbutamide only improved glucose tolerance at 10-100 mg/kg. Furthermore, JTT-608 (3-30 mg/kg) enhanced insulin secretion only with glucose stimulation, but tolbutamide (10-100 mg/kg) enhanced it both with and without glucose stimulation. In neonatally streptozotocin-treated rats, JTT-608 (10-100 mg/kg) improved glucose tolerance with enhanced insulin secretion in the oral glucose tolerance test and meal tolerance test. Additionally, JTT-608 improved glucose tolerance dose dependently, but the effect of tolbutamide reached a plateau. We conclude that JTT-608 is an enhancer of glucose-stimulated insulin secretion.     

Alterations of insulin secretion from mouse islets treated with sulphonylureas: perturbations of Ca2+ regulation prevail over changes in insulin content.

1. To determine how pretreatment with sulphonylureas alters the beta cell function, mouse islets were cultured (18 - 20 h) without (controls) or with (test) 0.01 microM glibenclamide. Acute responses to glucose were then determined in the absence of glibenclamide. 2. Test islets were insensitive to drugs (sulphonylureas and diazoxide) acting on K+-ATP channels, and their [Ca2+]i was already elevated in the absence of stimulation. 3. Insulin secretion was increased in the absence of glucose, and mainly stimulated between 0 - 10 instead of 7 - 20 mM glucose in controls. The maximum response was halved, but this difference disappeared after correction for the 45% decrease in the islet insulin content. 4. The first phase of glucose-induced insulin secretion was abrogated because of a paradoxical decrease of the high basal [Ca2+]i in beta cells. The second phase was preserved but occurred with little rise of [Ca2+]i. These abnormalities did not result from alterations of glucose metabolism (NADPH fluorescence). 5. In islets cultured with 50 microM tolbutamide, glucose induced biphasic increases in [Ca2+]i and insulin secretion. The decrease in the secretory response was matched by the decrease in insulin content (45%) except at maximal glucose concentrations. Islets pretreated with tolbutamide, however, behaved like those cultured with glibenclamide if tolbutamide was also present during the acute functional tests. 6. In conclusion, treatment with a low glibenclamide concentration causes long-lasting blockade of K+-ATP channels and rise of [Ca2+]i in beta cells. Glucose-induced insulin secretion occurs at lower concentrations, is delayed and is largely mediated by a modulation of Ca2+ action on exocytosis. It is suggested that glucose regulation of insulin secretion mainly depends on a K+-ATP channel-independent pathway during in vivo sulphonylurea treatment.     

Antihyperlipidemic effect of Garlip, a polyherbal formulation in streptozotocin induced diabetic rats

This study was undertaken to investigate the effect of Garlip, a polyherbal drug composed of aqueous extract of six medicinal plants on blood glucose, plasma insulin, tissue lipid profile, and lipidperoxidation in streptozotocin induced diabetic rats. Aqueous extract of Garlip a, polyherbal drug was administered orally (200 mg/kg body weight) for 30 days. The different doses of Garlip on blood glucose and plasma insulin in diabetic rats were studied and the levels of lipid peroxides (TBARS and Hydroperoxide) and tissue lipids (cholesterol, triglyceride, phospholipids and free fatty acids) were also estimated in streptozotocin induced diabetic rats. The effects were compared with tolbutamide. Treatment with Garlip and tolbutamide resulted in a significant reduction of blood glucose and increase in plasma insulin. Garlip also resulted in a significant decrease in tissue lipids and lipid peroxide formation. The effect produced by Garlip was comparable with that of tolbutamide. The decreased lipid peroxides and tissue lipids clearly showed the antihyperlipidemic and antiperoxidative effect of Garlip apart from its antidiabetic effect.     

Influence of food and age on the single-dose kinetics and effects of tolbutamide and chlorpropamide

Summary The influence of food intake (standardized breakfast) on the oral single-dose kinetics and effects of tolbutamide (0.5 g) and chlorpropamide (250 mg) was investigated in young, healthy volunteers. The single-dose kinetics of the two drugs was also studied in elderly healthy subjects. There was great interindividual variation in the elimination rate of both drugs, but food intake influenced neither their AUCs nor their rates of absorption and elimination. The peak concentration of chlorpropamide, but not that of tolbutamide, was reduced by food intake. The peak concentrations of serum tolbutamide were approximately doubled by an increase in dose from 0.5 to 1.0 g, and from 1.0 to 2.0 g. At no time did tolbutamide 0.5 g affect the plasma insulin level, neither in the fasting nor in the non-fasting state. However, this dose did reduce the blood glucose level during fasting and the increase in blood glucose in response to the meal. The latter effect was recorded within 30 min, when the serum level of tolbutamide still was close to zero. Plasma insulin concentrations did increase within 30 min after a higher dose of tolbutamide (1.0 g), when the serum concentration of tolbutamide was about 50 µmol/l. Between 2.5 and 8 h after administration of chlorpropamide 250 mg, serum drug concentrations were lower than those following tolbutamide 0.5 g. The blood glucose response was smaller and occurred later, being significant at 2 h, when the serum concentration of the drug was about 70 µmol/l. There was no significant change in plasma insulin. There was no significant pharmacokinetic difference between young and elderly subjects, except that the peak concentration of tolbutamide was higher in the latter. It appears that both for tolbutamide and chlorpropamide there is great interindividual variation in drug disposition, but food intake does not influence the bioavailability of either drug. The effect of any particular drug concentration seems dependent upon the blood glucose level and hence upon the elapsed time since the last meal. Both drugs can reduce blood glucose without an alteration in the peripheral blood concentration of insulin. This may reflect an extrapancreatic effect of the drugs, but it could also be an expression of increased insulin secretion, which is not detected because of enhanced hepatic degradation of the hormone released into the portal circulation. The observations made in young individuals are also probably relevant for elderly subjects.     

Serum Growth Hormone,Serum Immunoreactive Insulin and Blood Glucose Response to Intravenous Tolbutamide in Postmenopausal Women with and without Natural Oestrogen Therapy

Abstract The response of serum growth hormone, serum immunoreactive insulin and blood glucose to intravenously administered tolbutamide was studied in twenty non-obese and four obese healthy volunteer postmenopausal women with or without oestrogen therapy. Fasting blood glucose and the maximal fall in blood glucose during the test (44 % and 45 %) was normal in the non-obese control and oestrogen groups, and the two groups did not differ significantly from each other. Even the four obese women, two on oestrogen therapy and two without, showed a normal blood glucose response to tolbutamide. Moreover the response of serum immunoreactive insulin to tolbutamide was normal in subjects both with and without oestrogen therapy and there were no significant differences between the two groups. The response of serum growth hormone to tolbutamide was small in both groups, but slightly more pronounced in the non-obese women undergoing oestrogen therapy than in the controls. It is concluded that a postmenopausal period of five years leads to no impairment in carbohydrate metabolism in healthy women, and an oestrogen therapy for 3–7 years has no effects on glucose tolerance in healthy postmenopausal subjects.     

The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes

Summary It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The interrelationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group).In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration.In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response.In the subset with a fasting blood glucose concentration of less than 8 mmol·l^–1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.     

Chronopharmacological assessment identified GLUT4 as a factor responsible for the circadian variation of the hypoglycemic effect of tolbutamide in rats

The circadian relationship between the pharmacokinetics and pharmacodynamics of tolbutamide in rats was analyzed using a compartment model. The basal concentration of plasma glucose had a circadian rhythm with the acrophase at 15:19 h. After intravenous administration of tolbutamide at 06:00, 14:00, or 18:00 h, the hypoglycemic effect showed a circadian variation, with the greatest effect at 18:00 h and the lowest effect at 06:00 h. The time courses of unbound tolbutamide concentration in plasma after intravenous administration were predicted using the model-estimated total concentration of tolbutamide and the albumin concentration and resulted in profiles that did not vary with the time of administration. Significant low insulin resistance was observed at 18:00 h to i.v. glucose and insulin loads. There was no obvious time dependency in the expression of glucose transporter 4 (GLUT4) in epididymal adipocytes. The hypoglycemic rate estimated from the plasma glucose concentration was described by the conventional pharmacokinetic-pharmacodynamic model with an effect compartment. The time courses of theoretical signals in the effect compartment described the observed circadian changes in the increased expression profile of GLUT4 normalized by the increased plasma insulin (IRI) concentration (ΔGLUT4/ΔIRI) after dosing. Thus, the time dependency in glucose uptake is responsible for the circadian variation of the hypoglycemic effect of tolbutamide.     

Mechanism of chlorpromazine action on plasma glucose and cyclic AMP levels

The s.c. administration of chlorpromazine (CPZ) caused an elevation of plasma glucose and cyclic AMP levels in fed intact mice, but not in fed adrenalectomized mice. The pretreatment with reserpine partially blocked the elevation of plasma glucose and cyclic AMP. The pretreatment with 6-hydroxydopamine or alpha-methyl-p-tyrosine failed to inhibit the increase of plasma glucose and cyclic AMP induced by CPZ. These findings suggest that CPZ acts on the central nervous system and increases plasma glucose and cyclic AMP through epinephrine release from the adrenal medulla. The elevations of plasma glucose and cyclic AMP induced by epinephrine were enhanced by CPZ. CPZ increased plasma glucose and cyclic AMP significantly at high room temperatures (28 and 33 degrees C) at which CPZ did not decrease body temperature. The mechanism of CPZ action is discussed in relation to the increase in the plasma glucose and cyclic AMP levels.     

Potentiation of the insulin-releasing capacity of tolbutamide by thiols: Studies on the isolated perfused pancreas

Summary It has been suggested that the islet thiol redox status plays a role in the regulation of -cell sensitivity in response to insulin secretagogues. Employing the isolated perfused rat pancreas, the effect of reduced glutathione (1 mM) and L-cysteine (5 mM) on insulin release induced by tolbutamide (0.2 mg/ml), glucose (5.6 and 11.1 mM) and tolbutamide (0.1 mg/ml) in the presence of 5.6 mM glucose was studied.In the absence of glucose or in the presence of 5.6 mM of glucose neither glutathione nor L-cysteine stimulated the release of insulin. Reduced glutathione potentiated the secretion induced by glucose (11.1 mM) during the first and the second phase. L-Cysteine potentiated only the first phase of glucose-induced insulin release, whereas the second phase was depressed. Both of the tested thiols potentiated the insulin secretory action of either tolbutamide (0.2 mg/ml) alone or tolbutamide (01. mg/ml) in the presence of glucose (5.6 mM).The data suggest that supplementation of thiols to the pancreatic -cells perse cannot initiate the insulin secretory process. It is also suggested that GSH and L-cysteine increase the sensitivity of -cells to the stimulatory action of tolbutamide and/or glucose.This study was reported previously and published as an abstract (Abdel-hamid and Ammon 1980)