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.     

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.     

Effects of nifedipine on insulin secretion and glucose metabolism in rats and in hypertensive type 2 (non-insulin dependent) diabetics

The effects of nifedipine (Adalat) on glucose metabolism and insulin release were studied in rats and in patients with type 2 diabetes mellitus complicated with hypertension. 1. In rats, 2.5-50 micrograms/kg of intravenous nifedipine reduced glucose tolerance and insulin release after intravenous glucose in a dose related fashion, although fasting blood sugar and insulin were not affected at 50 micrograms/kg of nifedipine. 2. Daily 20 to 60 mg of oral nifedipine for 12-75 weeks to 14 type 2 diabetics with hypertension did not affect their fasting blood glucose or hemoglobin A1. Mean glucose tolerance curve after the treatment was significantly ameliorated, although insulin response during the oral glucose loading did not show any significant change. Those results suggest firstly that there may be a difference in insulinopenic effect of nifedipine between the species, and secondly that long-term administration of nifedipine produced no adverse influence on glucose metabolism in type 2 diabetics.     

Impairment of insulin secretion in man by nifedipine

Summary The effect of nifedipine, a calcium antagonist, on carbohydrate metabolism and insulin secretion was evaluated in patients who required treatment with this drug. 20 subjects underwent two oral glucose tolerance tests (100 g), one under basal conditions, and the other after ten days of treatment with nifedipine 30 mg/day by mouth, in three divided doses. 10 subjects had normal glucose tolerance; in them nifedipine administration reduced the insulin response to oral glucose in the first 60 min, but improved glucose tolerance. The other 10 subjects had impaired glucose tolerance and nifedipine treatment resulted in a further reduction both of insulin secretion and glucose tolerance. No such effects were seen in the placebo (weight- and disease-matched) group. The mechanism by which nifedipine influences carbohydrate metabolism and insulin secretion is discussed.     

The effect of fourteen day treatment with diuretics on mouse blood sugar and glucose tolerance

Treatment of mice for 14 days with ethacrynic acid or frusemide (100 mg/kg daily orally) increased the fasting blood sugar and liver glycogen. Oral glucose tolerance was altered so that blood sugar concentrations in drug-treated groups were significantly above control values. The failure of the drugs to affect intravenous glucose tolerance and sensitivity to insulin or to tolbutamide suggested that the decrease in the oral glucose tolerance was attributable to some effect of the drug treatments on the rate of absorption of glucose from the gastrointestinal tract. Treatment with hydrochlorothiazide (100 mg/kg daily orally) exerted no effect on blood sugar, liver glycogen or glucose tolerance.     

Glucose intolerance in thiamine-deficient rats

The mechanism of glucose intolerance in thiamine-deficient rats has been examined. Deficient rats showed marked glucose intolerance. However, the hypoglycaemic effect of insulin (1 i.u. kg^?1, i.p.) was similar in the deficient, pair-fed and normal groups, though somewhat weaker in the normal group than in the other two groups. After injection of tolbutamide (40 mg kg^?1, i.p.), the hypoglycaemic effects in the three groups were the same. Tyramine (10 mg kg^?1, s.c.) restored the impaired glucose tolerance of deficient rats to normal, but not that of alloxan diabetic rats. Furthermore, tyramine did not restore the intolerance of deficient rats pretreated with alloxan. These results suggest that the main factor causing glucose intolerance in the deficient rats may be suppressed insulin secretion.     

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.     

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).     

异搏定对大鼠四氧嘧啶引起的糖耐量和胰岛素改变的影响

本实验以糖耐量为背景,观察四氧嘧啶(allxan,AXN)对大鼠胰岛B细胞的破坏作用以及异搏定(verapamil,VAP)的预防作用。尾静脉注射AXN(50mg/kg,iv)后的第48h经口灌注葡萄糖(5g/kg),则血糖急剧升高,并在120min时仍然持续上升,这51.05±3.18mmol/L。血清胰岛素在葡萄糖刺激后无明显升高,未出现正常的分泌高峰。在AXN注射前30min,预先注射VAP(40mg/kg,ip)则给药48h台的糖耐量曲线和血清胰岛素反应均与正常对照组相类似:在第60min时,血糖呈现高峰,并在灌糖后的120min逐渐趋于基础水平。在口服葡萄糖负荷后第30min,异搏定预防组大鼠血清胰岛素分泌显著增多,出现了正常的胰岛素分泌峰。本实验结果提示异搏定具有防止有害物质损伤胰岛B细胞的作用。     

Effect of chlorpromazine on glucose and tolbutamide-stimulated insulin release in the adrenalectomized rat

The influence of chlorpromazine pretreatment on the insulin response to glucose and tolbutamide was investigated in adrenalectomized rats. Chlorpromazine pretreatment (10 mg/kg, ip) reduced the capacity of the animals to secrete insulin in response to intravenously administered glucose and tolbutamide. Furthermore, it appeared that in the adrenalectomized rat, the insulin response to tolbutamide was not transient but multiphasic and prolonged. The data suggest that the reduction in glucose tolerance in rats following chlorpromazine pretreatment may be due, in part, to a reduced beta cell responsiveness.     

Hypoglycemic and hypotriglyceridemic effects of tolbutamide in triphenyltin chloride-induced diabetic rabbits

Triphenyltin (TPT) induces transient hyperglycemia and hypertriglyceridemia in rabbits and hamsters through inhibition of the insulin release stimulated by glucose. The disturbed site in TPT-diabetes is a result of signal transduction occurring before the voltage-dependent Ca2+ channel. The ATP-sensitive K channel (KATP channel) is located immediately at the upstream signal of voltage dependent Ca2+ channels on the signaling pathway of insulin secretion. KATP channel produces depolarization by a signal of ATP through glucose metabolism and by stimulation from sulfonylurea drugs (tolbutamide, glibenclamide). To clarify if the insulin secretion that a KATP channel mediates is inhibited in vivo, we studied the effects of tolbutamide (a sulfonylurea) on changes in plasma glucose, triglyceride and insulin in TPT-diabetic rabbits prepared by po administration of 100 mg TPT-chloride/kg bw. In TPT-diabetic rabbits, plasma glucose decreased to a minimum at about 50% and plasma triglyceride levels also decreased. Insulin release was detected after injecting = 10 mg tolbutamide/kg, and insulin was secreted much higher than in normal rabbits. These findings suggest that the insulin released by tolbutamide stimulus decreased the plasma glucose and triglyceride levels in the TPT-diabetic rabbits. Moreover, a possible mechanism to be considered is as follows: tolbutamide combines with sulfonylurea receptor; membrane depolarization is induced by a KATP channel with the signal of a sulfonylurea receptor; insulin is released. The inhibition of insulin secretion by TPT may be caused by a glucose metabolic disorder in beta cells before the occurrence of membrane depolarization due to closed KATP channels interacting directly with a sulfonylurea receptor.     

The calcium channel blocker LAS 30538, unlike nifedipine, verapamil, diltiazem or flunarizine, potently inhibits insulin secretion in-vivo in rats and dogs.

The effects of a novel calcium channel blocker, LAS 30538 (1-[2-(2,6-dimethylphenoxy)ethyl]-alpha,alpha-bis-(p-fluorophenyl)-4- piperidine methanol), were studied on glucose tolerance and insulin secretion in rats and dogs in-vitro and in-vivo. Some comparisons were made with nifedipine, verapamil, diltiazem, flunarizine, diazoxide, cromakalim and minoxidil. LAS 30538, like a number of calcium channel blockers, was found to inhibit insulin secretion in-vitro, but was 1000-fold more potent than verapamil or diltiazem in this respect. LAS 30538 differed from the other calcium channel blockers studied in that it also potently inhibited insulin secretion and impaired glucose tolerance in-vivo. The evidence that LAS 30538 is more potent than diazoxide as a hyperglycaemic agent in-vivo suggests that this could be a useful drug for the treatment of hyperinsulinaemia in man.     

Inhibition effect of dehydroascorbic acid on insulin secretion from mouse pancreatic islets.

Intravenous doses of 200 mg/kg dehydroascorbic acid (DHA) produced hyperglycemia, hypoinsulinemia, and decreased glucose tolerance in mice. This effect of DHA is mediated, at least in part, through a direct inhibition of pancreatic insulin release. Exposure of isolated pancreatic islets to a concentration of 2.0 mg/dl DHA reduces the responsiveness of the islets to both glucose (300 mg/dl) and tolbutamide (6±10^?3m). Exposure of isolated islets to DHA in a high concentration of d-glucose (300 mg/dl) partially protected them against the inhibitory effect of DHA. Exposure of islets to 4.0 mg/dl of DHA causes a leakage of insulin. Similarly, islets isolated from mice which had been treated with 300 mg/kg DHA iv exhibited increased insulin release in the presence of only 60 mg/dl glucose. Intravenous administration of either 200 or 300 mg/kg DHA prior to islet isolation results in increased insulin secretion in response to 300 mg/dl glucose. The results show that the pancreatic effects of DHA are similar to those of the diabetogen, alloxan.     

Modification of glybenclamide hypoglycaemia by verapamil in rabbits

The study was designed to demonstrate the interaction between verapamil and glybenclamide on blood glucose in rabbits. Glybenclamide (0.05 mg/kg, po) induced hypoglycaemia was observed 1 h after treatment and persisted till 3 h. Verapamil (8 mg/kg, sc) per se produced hyperglycaemia which lasted for 2 1/2 hr. Concurrent administration of verapamil was found to impair significantly the hypoglycaemic response of glybenclamide.     

Effects of combination of mitiglinide with various oral antidiabetic drugs in streptozotocin‐nicotinamide‐induced type 2 diabetic rats and Zucker fatty rats

We examined the effects of combining the rapid insulin secretagogue, mitiglinide, with various oral hypoglycaemic drugs including biguanides, pioglitazone, α‐glucosidase inhibitors, and sodium‐glucose co‐transporter 2 inhibitors in a rat model of type 2 diabetes. The oral glucose tolerance test (OGTT) using glucose, sucrose, or a liquid meal was used to compare the effects of mitiglinide with those of the four oral hypoglycaemic drugs and examine their combined effects on blood glucose levels and insulin secretion in the rat model. The combination of mitiglinide with other oral hypoglycaemic drugs suppressed the plasma glucose levels more than either agent did alone. Furthermore, the combination of these agents decreased insulin secretion more than mitiglinide did alone. These results indicate that mitiglinide is suitable for use in combination with other hypoglycaemic drugs because it inhibits postprandial hyperglycaemia by rapidly stimulating insulin secretion.     

The pharmacology of a new hypoglycaemic agent N-[4-(2-(2,3-dihydrobenzo(b)furan-m-carboxamido)-ethyl)-benzenesulphonyl]-N'-cyclohexylurea (NOVO CS 476). I. Pharmacological studies on the hypoglycaemic effect.

The new sulphonylurea CS 476 has been shown to be a potent hypoglycaemic agent. In normal fasting dogs, rabbits, rats and mice the maximal hypoglycaemia produced by intravenous administration of CS 476 was comparable on a weight basis to that produced by glibenclamide. Randomized Latin square experiments in dogs showed that 0.03 mg/kg orally of CS 476 and of glibenclamide caused the same maximal decrease of blood glucose and that CS 476 had the shorter duration of action. CS 476 had no hypoglycaemic effect in totally pancreatectomized dogs nor in streptozotocin diabetic dogs and rats. The insulin releasing activity was studied in dogs after intravenous and oral administration of equipotent doses of CS 476, tolbutamide and glibenclamide. It was found that the insulin curves after CS 476 tended to have a plateau-like maximum like those after glibenclamide although the duration of effect was shorter.     

Influence of diftalone on tolbutamide test and i.v. glucose tolerance test.

In 16 healthy volunteers tolbutamide tests or i.v. glucose tolerance tests were performed with and without previous oral administration of 1000 mg diftalone. Blood sugar and serum insulin were assayed in regular intervals. Both with and without previous administration of diftalone blood glucose after tolbutamide did not show any difference. IRI response to tolbutamide, measured by planimetrical integration showed a statistically significant augmentation (0.05 greater than p greater than 0.01) after diftalone. Glucose assimilation (K-value) after diftalone was decreased (0.05 greater than p greater than 0.01) yet within normal range. For the accompanying insulin levels however no statistically significant difference was observed. In addition a normalisation of pathological tolbutamide test after diftalone could be noted in five patients with subclinical diabetes. Our results indicate that diftalone seems to have the following three actions: 1. Enhancement of the tolbutamide action. 2. direct augmentation of IRI secretion, 3. a peripheral action on glucose metabolism.     

Different effects of bombesin on glucose- and tolbutamide-induced insulin release in man.

1. The effect of bombesin, a neurogastrointestinal peptide, on basal and stimulated insulin release was studied in man. 2. Two different stimuli were used, hyperglycaemic (20 g glucose) and hypoglycaemic (1 g tolbutamide). They were injected intravenously to two groups of male healthy volunteers during saline or bombesin (5 ng kg-1 min-1 for 60 min) infusion. 3. The peptide had no significant effect on basal levels of glucose and insulin. However, the insulin response to intravenous glucose was strongly potentiated by bombesin, the integrated insulin response being 2.23 +/- 0.59 mu ml-1 . 90 min and 0.98 +/- 0.19 mu ml-1 . 90 min during infusion of bombesin and saline, respectively (P less than 0.05). The behaviour of plasma glucose was not significantly modified by the peptide. Indeed, the glucose disappearance rate (K of Conard, mg min 10(-2)) changed from 2.5 +/- 0.3 during saline to 2.4 +/- 0.4 during bombesin infusion. 4. When the hypoglycaemic stimulus (i.e. tolbutamide) was used, no effect of the peptide on insulin release could be detected. Here again, the drop in plasma glucose (expressed as Marigo's coefficient) was not affected by the peptide, with a value of 92.8 +/- 12.6 and 84.0 +/- 10.9 during bombesin and saline administration. 5. These data therefore show that, at normal or low blood glucose levels, the dose of bombesin used is unable to modify insulin release and suggest that this peptide might be regarded as a glucose-dependent insulinotropic peptide.     

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.     

Insulin and pro-insulin secretion following intravenous administration of tolbutamide, glisoxepide and glibenclamide]

12 metabolically healthy subjects were i.v. administered equipotent doses (ED30) of tolbutamide (7.5 mg/kg), glisoxepide (0.02 mg/kg) and glibenclamide (0.006 mg/kg). Prior to and 2, 5, 8, 10, 20, 40, 60 and 120 min after the injection the following serum parameters were determined: blood glucose, immunologically measurable insulin (IMI) with the double-antibody method (Hales and Randle) and proinsulin (IMP) enzymatically (ISP-method). The maximum level of insulin follows the injection of tolbutamide with a value of 70.5 micronU/ml after 2 min, of glisoxepide after 5 min (67.0 micronU/ml) and of glibenclamide after 20 min (32.3 micronU/ml). The proinsulin fraction of the total insulin shows a level of 12.5 micronU/ml before the test. After the administration of the three compounds proinsulin increases, too, but reaches only 20-40% of the total immunoreactive insulin. The amount of secreted insulin and proinsulin during the 120-min test is rather the same for the three substances. The average increase of insulin is nearly identical for tolbutamide and glisoxepide, whereas it is less for glibenclamide. Both the mean blood sugar depression and the highest mean increase of proinsulin is reached after glisoxepide. The significance of the one-chain precursor of insulin as a part of the sulfonylurea stimulated total insulin for glucose depression is discussed.