Effects of (-)-(R)-1-(p-hydroxyphenyl)-2-[3,4-dimethoxyphenethyl)amino]ethanol (TA-064), a new cardiotonic agent, on circulating parameters of carbohydrate and lipid metabolism in the rat

Effects of the new cardiotonic and selective beta 1-adrenergic agonist TA-064, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, on circulating concentrations of glucose, lactate, free fatty acids (FFA), glycerol, cyclic AMP and the pancreatic hormones insulin (IRI) and glucagon (IRG) were examined in rats. TA-064, administered orally or intraperitoneally at the dose of 10 mg/kg (ca. 50 times the therapeutic dose) or higher, caused a slight transient rise followed by a persistent lowering of blood glucose concentrations, but it did not affect blood lactate levels at all. The same treatment with TA-064 elevated the concentrations of blood FFA, glycerol and plasma IRI and IRG. These changes induced by TA-064 were inhibited by pretreatment with propranolol (a non-selective beta-adrenergic antagonist) and practolol (a selective beta 1-adrenergic antagonist). The non-selective beta-adrenergic agonist isoproterenol and the selective beta 2-adrenergic agonist terbutaline elevated both blood glucose and lactate when administered intraperitoneally. They also brought about sustained rises in blood glycerol and plasma IRI, but only transiently increased the plasma IRG level. The cardiotonic agent prenalterol, claimed to be a selective beta 1-agonist, elevated blood glucose, lactate, and glycerol only slightly, and plasma IRI significantly, but it had no effect on plasma IRG. The cardiotonic agents dobutamine and amrinone also elevated blood glucose. Thus, TA-064 is unique among the beta-adrenergic and other cardiotonic agents in that it produces sustained hypoglycemia while it has no lactacidemic effect. Since this hypoglycemic action of TA-064 was always preceded by a rise in plasma IRI and abolished in streptozotocin-diabetic rats, we conclude that increased secretion of pancreatic insulin and the lack of hyperglycemic action are responsible for the hypoglycemia by high doses of TA-064.     

Pharmacologic profile and insulin secretagogue effect of linogliride (McN-3935), a new,orally effective hypoglycemic agent

Linogliride (McN-3935) [N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-4-morpholinecarboximidamide] was selected for clinical evaluation as a potential orally effective hypoglycemic agent for treatment of noninsulin-dependent diabetes mellitus. Linogliride is structurally unrelated to sulfonylureas and biguanides. It produced a dose-dependent hypoglycemic effect in nondiabetic rats, mice, and dogs. The minimum effective oral doses that lowered fasting blood glucose levels and improved glucose tolerance were 1–5 mg/kg. Comparison of the dose-response curves from fasting rat studies showed linogliride to be approximately two times more potent than the related compound pirogliride and approximately eight times more potent than tolbutamide. Tolerance to its hypoglycemic effect did not develop in rat and dog 3-day repeat dose studies. Linogliride did not alter plasma lactic acid levels in normal and streptozotocin-induced diabetic rats, and it improved glucose tolerance whether the glucose was administered orally or parenterally. In nondiabetic rats and dogs, decreases in fasting blood glucose levels following linogliride administration were associated with elevated (two- to fourfold) plasma insulin concentrations. Linogliride was inactive in depancreatized diabetic dogs. In genetically diabetic (db/db) mice and streptozotocin-induced diabetic rats, linogliride (25–100 mg/kg p.o.) produced variable, nondose-dependent reductions of blood glucose levels, unlike the sulfonylureas, which were consistently ineffective in these diabetic rodent models. In conclusion, although the observed activity in diabetic rodent models is suggestive of a potential nonpancreatic mechanism, the experimental evidence to date indicates that the acute effectiveness of linogliride as a hypoglycemic agent is due primarily to stimulation of insulin release.     

Sulfonyliminoimidazolidines, a new class of oral hypoglycemic agents. 3. Hypoglycemic activity and mode of action of 1-[p-[2-(crotonylamino)-ethyl]-phenylsulfonyl]-3-cyclohexyl-2-imino- imidazolidine (CGP 11 112)

1-[p-[2-(Crotonylamino)-ethyl]-phenylsulfonyl]-3-cyclohexyl-2-imino- imidazolidine (CGP 11 112) is a representative of a new class of oral hypoglycemic agents. It lowers blood glucose in normal animals and in streptozocin (streptozotocin)-diabetic rats. In normal mice, rats and dogs the hypoglycemic effect is more potent (range 3-30 times) and has a shorter duration than that of tolbutamide. CGP 11 112 increases plasma insulin after oral administration in normal animals and stimulates release of insulin in perifused rat islets in vitro (sulfonylurea-like effect). In streptozocin-diabetic rats CGP 11 112 decreases blood glucose with a potency comparable to that of phenformin. In contrast to phenformin, CGP 11 112 does not increase blood lactate in diabetic rats or inhibit intestinal absorption of glucose. An effect of CGP 11 112 on gluconeogenesis and glycogenolysis could not be demonstrated. It is suggested that the hypoglycemic activity in streptozocin-diabetic rats may be due to stimulation of glucose efflux from the circulation. In vitro, CGP 11 112 inhibits glucose oxidation and lipolysis in isolated rat fat cells.     

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.     

Effects of new hypoglycemic agent 2-piperazinyl-4-methyl-amino-5-methylthieno [2,3-d]pyrimidine dihydrochloride hydrate

The antidiabetic effects of 2-piperazinyl-4-methylamino-5-methylthieno [2,3-d]pyrimidine dihydrochloride hydrate (Compound-(I] were investigated in various animals and in various conditions. Compound-(I) is a new hypoglycemic agent structurally unrelated to sulfonylurea and biguanide. It produced dose dependent hypoglycemic effects (10-100 mg/kg) in rats and mice under fed, fasted and glucose tolerated states. However, it was ineffective in fasted guinea pigs even when given at 100 mg/kg. In normal fed rats and mice, hypoglycemic effects of Compound-(I) were estimated to be 3-19 times and 12-70 times more potent than tolbutamide and phenformin, respectively. Compound-(I) also produced hypoglycemic action in streptozocin diabetic rats and genetically diabetic KK mice. Especially, its hypoglycemic effect was observed at the dose as low as 3 mg/kg p.o. in KK mice. However, elevation of blood lactate was accompanied by lowering of blood glucose after oral administration of Compound-(I) in normal rats and mice and in streptozocin diabetic rats, while these effects were not observed in guinea pigs. In addition, plasma insulin significantly increased after administration of Compound-(I) in both normal and KK mice, while this increase in plasma insulin was not so prominent in fed rats. This elevation in plasma insulin might be produced by alpha 2-adrenergic antagonism at pancreatic B cell as Compound-(I) suppressed epinephrine induced hyperglycemia by elevating plasma insulin. In conclusion, Compound-(I) seems mainly to produce hypoglycemic action through extrapancreatic mechanism which increases blood lactate associated with anaerobic glycolysis or inhibition of gluconeogenesis. In addition, elevation of plasma insulin also might be responsible for hypoglycemic effects.     

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.     

The Pharmacology of a New Hypoglycaemic Agent N-[4-(2-(2,3-dihydrobenzo(b)furan-7-carboxamido)-ethyl) -benzenesulphonyl] -N’-cyclohexylurea (NOVO CS 476). I. Pharmacological Studies on the Hypoglycaemic effect

Abstract 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.     

Promoting effect of the new chymotrypsin inhibitor FK-448 on the intestinal absorption of insulin in rats and dogs

FK-448 is a potent and specific inhibitor of chymotrypsin, which enhances the intestinal absorption of insulin in rats and dogs resulting in a decrease in blood glucose levels in these animals. In dogs, the immunoreactive insulin (IRI) level of plasma rose proportionally to the decrease in blood glucose level. From in-vitro data, insulin was inactivated by pancreatic enzymes or the supernatants of intestine or liver homogenates. FK-448 suppressed the digestion of insulin by pancreatic enzymes and its enhancement of the intestinal absorption of insulin was found to be related to its inhibition of digestive enzymes, especially chymotrypsin.     

Glucose intolerance following cis-platinum treatment in rats

cis-Dichlorodiammineplatinum (cis-Pt) is a heavy metal complex used in cancer chemotherapy. Since this drug has been shown to induce hyperglycemia in rats, these studies were initiated to elucidate the effects of cis-Pt on carbohydrate tolerance and insulin and glucagon secretion. Two days following i.v. cis-Pt (2.5 or 7.5 mg/kg, 5 ml/kg) or vehicle administration to male F-344 rats, plasma glucose, immunoreactive insulin (IRI) and glucagon (IRG) concentrations were determined in the basal state and serially following a glucose load (2 g/kg, i.p.). Since cis-Pt induces a dose-related anorexia, a pair-fed control group was also studied. Administration of 7.5 mg/kg cis-Pt was associated with plasma glucose concentrations 2.5-5 times greater than ad-libitum and pair-fed controls at every time point during the 2-h glucose tolerance test. Although basal plasma IRI concentrations of the 7.5-mg/kg group were comparable to ad-libitum fed controls, they were significantly greater than those of pair-fed partners. Furthermore, the appropriate IRI response to a glucose stimulus observed in both controls and the 2.5-mg/kg group was absent in the 7.5-mg/kg group. Basal plasma IRG concentrations of the 7.5-mg/kg group were approximately 3-4 times greater than ad-libitum and pair-fed controls and were not suppressed following a glucose load. These results suggest that cis-Pt induces marked glucose intolerance in association with an impaired IRI response and abnormal glucagon response to a glucose stimulus.     

Role of glucagon in the hyperglycemic response to catecholamines in fasted baboons.

The hyperglycemic activities of epinephrine (EPI) and isoproterenol (ISO) in baboons correlated with their ability to increase plasma glucagon (IRG) levels relative to insulin (IRI). EPI inhibited IRI release and produced greater increases in plasma glucose and IRG than did ISO. ISO increased plasma IRI levels more than IRG. Infusion of somatostatin blocked IRG release and inhibited hyperglycemic responses to EPI by approximately 50%. These findings indicate that, as in man, IRG release contributes significantly to the hyperglycemic effects of catecholamines in baboons. The baboon thus appears to be a suitable model for predicting effects of drugs on glucose homeostasis in humans.     

Nateglinide, a non-sulfonylurea rapid insulin secretagogue, increases pancreatic islet blood flow in rats

We studied whether the rapid hypoglycemic action of nateglinide is associated with an increase in islet blood flow. Islet blood flow was measured using the two-colour microsphere method. Orally administered nateglinide with glucose acutely increased islet blood flow to levels greater than those after glucose alone or tolbutamide with glucose in conscious Sprague-Dawley rats (percent increase at 10 min after oral administration; nateglinide+glucose, 125+/-25%; glucose, 33+/-11%, p<0.001; tolbutamide+glucose, 42+/-23%, p<0.01). Nateglinide administered with non-metabolisable 3-O-methylglucose also increased islet blood flow (61+/-17%). The stimulated islet blood flow significantly correlated with serum insulin levels. N(G)-monomethyl-L-arginine, a nitric oxide synthase inhibitor, completely inhibited the increase in islet blood flow induced by nateglinide with glucose. Intravenously administered nateglinide did not significantly affect the already increased islet blood flow in diabetic Otsuka Long-Evans Tokushima Fatty rats. Our results indicated that nateglinide acutely increased islet blood flow at least in part through a nitric oxide-dependent mechanism.     

Regulation of plasma insulin level by alpha 2-adrenergic receptors

Phentolamine, yohimbine or dihydroergotamine markedly increased plasma immunoreactive insulin (IRI) and inhibited epinephrine-induced hyperglycemia in fasted mice. On the other hand, phenoxybenzamine or prazosin only slightly increased plasma IRI and enhanced epinephrine-induced hyperglycemia. These results indicate that there is a distinct difference in the effects of alpha-adrenergic blockers on the plasma IRI and glucose levels, and that alpha-adrenergic receptors responsible for the plasma IRI level resemble alpha 2-adrenergic receptors more closely.     

Insulin suppressive effects of aminotetralin analogs and of dopamine

The study concerned the effects of 2-amino-6,7-(OH)2-1,2,3, 4-tetrahydronaphthalene (A-6,7-DTN), dipropyl-A-6,7-DTN and dopamine on plasma levels of immunoreactive insulin (IRI) in cattle. During infusions of A-6,7-DTN, dipropyl-A-6,7-DTN and dopamine, the circulating levels of IRI decreased. In response to A-6,7-DTN, the levels of glucose increased whereas non-esterified fatty acids did not change. The decrease of IRI during additional infusions of A-6,7-DTN was not modified by prolonged administration of A-6,7-DTN. During infusions of A-6,7-DTN there was no increase in response to the administration of glucose and tolbutamide. However, if the beta-adrenergic agonist isoproterenol was infused, IRI increased in the presence of A-6,7-DTN. During, infusions of the alpha-adrenergic blocking agent, phentolamine, levels of IRI increased within minutes while glucose did not change. Concomitant infusions of A-6,7-DTN and phentolamine caused IRI to decrease and the rise in glucose levels seen in the absence of phentolamine was inhibited. In conclusion, enhanced dopaminergic activity inhibited IRI secretion. The suppressive effects of A-6,7-DTN were due primarily to its dopaminergic properties, but A-6,7-DTN also possessed some characteristics of an alpha-adrenergic agonist. beta-Adrenergic stimulation reversed the suppressive effects of A-6,7-DTN on IRI secretion.     

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.     

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.     

口服降糖药联合甘精胰岛素治疗2型糖尿病的疗效观察

目的 观察在口服降糖药的基础上联合甘精胰岛素治疗2型糖尿病（T2DM）的临床效果。方法对49例单用降糖药效果欠佳的T2DM患者联用甘精胰岛素治疗,分别于治疗前及治疗后（3个月）观察空腹血糖（FPG）、餐后2h血糖（2hPG）、血脂、血压、体重指数的变化。结果联用甘精胰岛素治疗后FPG、2hPG、HbA1c较治疗前明显下降（P〈0．01）,而血脂、血压、体重指数影响不大,且无明显低血糖反应。结论口服降糖药联合甘精胰岛素治疗方案具有作用佳、安全性好的特点。     

乌拉坦诱导的高血糖反应(英文)

目的:观察麻醉剂量的乌拉坦对空腹大鼠、葡萄糖负荷大鼠,肾上腺素或四氧嘧啶诱发高血糖大鼠血糖水平的影响,并探讨其对外源性胰岛素降血糖作用的影响。方法:葡萄糖氧化酶法测定血糖含量。结果:麻醉剂量1.5g·kg~(-1)乌拉坦(sc,ip各半)显著升高空腹大鼠和葡萄糖负荷大鼠的血糖水平,但对肾上腺素(胰岛功能正常)或四氧嘧啶(胰岛功能受损)诱发的高血糖大鼠的血糖水平无明显影响。在四氧嘧啶诱发的高血糖大鼠,乌拉坦显著对抗外源性胰岛素的降血糖作用。结论:乌拉坦升高血糖的作用除与已知的释放肾上腺素有关外,抑制胰岛素的降血糖作用也是其升高血糖的机制之一。     

A novel,orally effective hypoglycemic agent,SaRI 59–801, in laboratory animals

SaRl 59-801 (59-801) (α-[dimethylaminomethyl]-2-[3-ethyl-5-methyl-4-isoxazolyl]-1H-indole-3-methanol), is a novel, orally effective hypoglycemic compound which appears to act largely, if not entirely, by stimulation of insulin release. The compound is structurally unrelated to sulfonylurea derivatives. The 2-hr hypoglycemic ED₂₅ in fasting mice was 110 mg/kg; the plasma insulin levels were increased, with an ED₅₀ of 47 mg/kg. Significant hypoglycemic activity was observed 2 hr after oral administration of 59-801 to fasting rats (ED₂₅ = 86 mg/kg), while plasma insulin was elevated by 62% at 100 mg/kg. 59-801 caused an insignificant decrease in plasma lactic acid levels. The hyperglycemic response 30 min after an oral starch load was inhibited by 1-hr pretreatment with 59-801 (ED₅₀ = 37 mg/kg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats. In monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mg/kg and an ED₂₅ of 33 mg/kg for a period of 6 hr after oral administration. In genetically diabetic (db⁺/db⁺) mice, 59-801 was more potent in producing hypoglycemia (ED₂₅ = 47 mg/kg) than their lean littermates (ED₂₅ = 131 mg/kg). In alloxan-diabetic rats or streptozotocin-diabetic mice, this agent was inactive at 200 mg/kg, but at 400 mg/kg, it caused reduction of blood glucose levels of 29–39 and 21%, respectively, possibly the result of stimulation of residual β-cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59-801.     

ANTI-OBESITY AND ANTI-DIABETIC EFFECTS OF CARTEOLOL IN NON-INSULIN-DEPENDENT DIABETIC MICE

1. When carteolol, a β-adrenergic blocker, was administered to KK-A^y/Ta Jcl mice that are obese and develop spontaneously non-insulin dependent diabetes, their increase in bodyweight was arrested from the age of 16 weeks. Since their intake of food and water was not influenced by carteolol treatment, compared with the control KK-A^y/Ta Jcl mice, abolition of the weight gain might be attributed to increased energy metabolism. 2. Non-fasting serum glucose levels in carteolol-treated mice at the age of 17 weeks were within normal range (118±4 vs 186±12 mg/dL). An intraperitoneal glucose-tolerance test revealed that the carteolol treatment markedly restored glucose metabolism; fasting plasma glucose (88±6 mg/dL) was within normal range, and immunoreactive insulin (IRI; 5.8±0.8 vs 33.3 ± 10.5 ng/mL) and plasma glucose levels at 60 min post glucose (361±44 vs 541 ±32 mg/dL) were significantly lower in carteolol-treated mice than those in the control group at the age of 20 weeks. 3. From these findings, carteolol is considered to have little effect on the growth of mice but to correct the obesity that develops after age 16 weeks, when their growth terminates. In addition, the normalization of blood glucose and marked decrease in IRI levels suggests that carteolol improves glucose tolerance by increasing the insulin sensitivity. 4. Since brown adipose tissue (BAT) is closely associated with thermogenesis and energy consumption, we tested whether carteolol may affect BAT, When the regional blood flow was measured by radioactive microspheres in rats, blood flow in BAT and white adipose tissue was markedly increased by carteolol. 5. These findings indicate that carteolol blocks β₁- and β₂-adrenoceptors, but may stimulate β-receptors particularly in the adipose tissue to promote lipolysis and thermogenesis, and to consume excess energy in mice. Thus, carteolol does not influence mouse growth, but may prevent obesity leading to increases in insulin sensitivity.     

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.