Laboratory evaluation of the hypoglycemic effect of Anacardium occidentale Linn (Anacardiaceae) stem-bark extracts in rats

This study evaluated the hypoglycemic effect of stem-bark extracts of Anacardium occidentale Linn., of the Anacardiaceae family, in normal (normoglycemic) and in streptozotocin-treated diabetic rats. Young adult, male Wistar rats weighing 250-300 g were used. Diabetes mellitus was induced in the test rats by intraperitoneal injections of streptozotocin (STZ, 90 mg/kg). In one set of experiments, graded doses of the aqueous and methanolic stem-bark extracts of A. occidentale (100-800 mg/kg p.o.) were separately administered to groups of fasted normal and fasted diabetic rats. In another set of experiments, 800 mg/kg p.o. of the aqueous or methanolic extract of the plant, a dose which produced maximal hypoglycemic effects in both fasted normal and diabetic rats in the previous set of experiments, were used. The hypoglycemic effects of single doses (i.e., 800 mg/kg p.o.) of A. occidentale stem-bark aqueous and methanolic extracts were compared with those of insulin (5 microU/kg s.c.) and glibenclamide (0.2 mg/kg p.o.) in both fasted normal and fasted diabetic rats. Following acute treatment, relatively moderate-to-high doses of A. occidentale stem-bark extracts (100-800 mg/kg p.o.) produced dose-dependent, significant reductions (p< 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. On their own, both insulin (5 microU/kg s.c.) and glibenclamide (0.2 mg/kg p.o.) produced significant reductions (p< 0.01-0.001) in the blood glucose concentrations of the fasted normal and fasted diabetic rats. At single doses of 800 mg/kg p.o., A. occidentale stem-bark aqueous and methanolic extracts significantly reduced (p< 0.001) the mean basal blood glucose concentrations of fasted normal and fasted diabetic rats. The hypoglycemic effect of the methanolic plant extract was found to be slightly more pronounced than that of the aqueous plant extract in both the normal and diabetic rats examined. A. occidentale contains a diverse group of chemical compounds. Since methanol extractives of plants usually contain many chemical compounds, each of which is capable of producing definite biological activities via different mechanisms, it is difficult to draw any logical conclusion on the mechanism of the hypoglycemic effect of such a diverse mixture of chemical compounds contained in the plant extracts used in this study. While it is possible that the hypoglycemic effects of the plant extracts may be due, at least in part, to their terpenoid and/or coumarin contents, the mechanism of their hypoglycemic action remains largely speculative. However, this is unlikely to be due to the stimulation of pancreatic beta-cells and subsequent secretion of insulin. Although A. occidentale stem-bark aqueous or methanolic extract is less potent than insulin as an antidiabetic agent, the results of this experimental animal study indicate that it possesses hypoglycemic activity, and thus lends credence to the folkloric use of the plant in the management and/or control of adult-onset, type-2 diabetes mellitus among the Yoruba-speaking people of Western Nigeria.     

Hypoglycemic effect of Hypoxis hemerocallidea corm (African potato) aqueous extract in rats

Diabetes mellitus has been recognized as a clinical syndrome since ancient times, and remains a crippling global health problem today. It is a group of heterogeneous, autoimmune, hormonal and metabolic disorders, often accompanied by hypertension, hyperlipidemia and obesity. Current estimates suggest that approximately 150 million people worldwide suffer from diabetes mellitus. The present study was undertaken to examine the hypoglycemic effect of aqueous extract of Hypoxis hemerocallidea (family: Hypoxidaceae) corm (locally known as "African Potato") in normal (normoglycemic) and in streptozotocin (STZ)-treated, diabetic rats. Young adult, male Wistar rats weighing 250-300 g were used. Diabetes mellitus was induced in the group of diabetic test rats by intraperitoneal injections of STZ (90 mg/kg). In one set of experiments, graded doses of the aqueous extract of African Potato (100-800 mg/kg p.o.) were administered to 12-h fasted normal and diabetic rats. In another set of experiments, 800 mg/kg of African potato extract, a dose of the plant extract that produced maximal hypoglycemic effects in fasted normal and diabetic rats in our pilot experiments, was used. The hypoglycemic effect of this single dose was compared with those of insulin (5 micro U/kg s.c.) and glibenclamide (5 mg/kg p.o.) in 12-h fasted normal and diabetic rats. Following acute treatment, relatively moderate to high doses of African potato extract (100-800 mg/kg p.o.) produced dose-dependent, significant reductions (p < 0.05-0.001) in the blood glucose concentrations of fasted normal and diabetic rats. Similarly, insulin (5 micro U/kg s. c.) and glibenclamide (5 mg/kg p.o.) produced significant reductions (p < 0.01-0.001) in the blood glucose concentrations of the fasted normal and diabetic rats. At a dose of 800 mg/kg, the plant extract caused 30.20% and 48.54% reductions in the blood glucose concentrations of fasted normal and STZ-treated diabetic rats, respectively. While it is likely that the hypoglycemic effect of the plant extract is largely due to its phytosterols and/or sterolin content, the exact mechanism of its hypoglycemic action is still obscure and will have to await further studies. However, the results of this experimental animal study indicate that African potato possesses hypoglycemic activity; and thus lends credence to the suggested folkloric use of the herb in the control and/or management of adult-onset, type 2 diabetes mellitus in some communities of South Africa.     

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).     

Comparison of the effects of efaroxan and glibenclamide on plasma glucose and insulin levels in rats.

The effect of efaroxan (1 and 5 mg/kg p.o.; a selective alpha 2-adrenoceptor antagonist) was compared to glibenclamide (1 and 5 mg/kg p.o.; a standard sulphonylurea) on basal plasma glucose levels of fed and fasted rats. In addition, the effect of efaroxan (5 mg/kg p.o.) and glibenclamide (2 or 5 mg/kg p.o.), alone and in combination, on the hyperglycaemia and hyperinsulinaemia induced by glucose challenges, were investigated. An intra-arterial (250 mg/kg i.a.) and a subcutaneous (1 g/kg s.c.) glucose challenge were used to stimulate the fast and slow release phases of insulin secretion. Efaroxan increased plasma insulin levels in both conscious fed and fasted rats without greatly affecting plasma glucose levels. Glibenclamide also elevated insulin levels, but was associated with marked hypoglycaemia. Efaroxan and glibenclamide potentiated the slow and fast release of insulin secretion, but glibenclamide had a tendency to produce hypoglycaemia in these test situations, a property not shared by efaroxan. A combination of efaroxan and glibenclamide produced a greater elevation in the slow and fast insulin release phases than either compound alone, but did not enhance the hypoglycaemia seen with glibenclamide alone. These results provide further evidence that pancreatic alpha 2-adrenoceptors are involved in the regulation of insulin secretion.     

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.     

Oral Hypoglycemic Effect of Caesalpinia bonducella

The blood sugar lowering efficacy of the aqueous extract of Caesalpinia bonducella F. (seed shell) was evaluated in fasted, fed, glucose loaded, streptozotocin diabetic, and alloxan diabetic rat models. The extract was administered orally at a dose of 250 mg/kg of rat body weight. It produced very significant blood sugar lowering (at least P &lt; 0.005) in glucose loaded, streptozotocin diabetic, and alloxan diabetic models. However, effects were not so pronounced in fasted and fed models. As a whole, Caesalpinia bonducella can be regarded as a good oral hypoglycemic agent in rat.     

活性糖元保降血糖作用实验研究

目的：观察活性糖元保对糖尿病小鼠或大鼠模型的降血糖作用。方法：ICR小鼠皮下注射四氧嘧啶复制糖尿病小鼠模型，灌胃给予活性糖元保1．0、2．0、4．0g／kg剂量（均折算成生药量，下同），每2周检测一次体重以及空腹血糖，连续8周；SD大鼠以小剂量链脲霉素合并高脂饮食诱发2型糖尿病模型，灌胃给予活性糖元保0．75、1．50、3．00g／kg剂量，每2周检测一次体重以及空腹血糖，连续8周；另采用四氧嘧啶诱发的糖尿病小鼠观察其对糖耐量影响。结果：活性糖元保1．0、2．0、4．0g／kg剂量可降低四氧嘧啶所致糖尿病模型小鼠血糖值，并明显改善该模型小鼠糖耐量，减少其血糖曲线下面积；3．00g／kg剂量对小剂量链脲霉素合并高脂饮食诱发的2型糖尿病大鼠血糖也有一定的降低作用。结论：活性糖元保具有一定的调节血糖和改善糖耐量的作用。     

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.     

Differential anti-diabetic effects and mechanism of action of charantin-rich extract of Taiwanese Momordica charantia between type 1 and type 2 diabetic mice

Momordica charantia Linn. (Cucurbitaceae), also called bitter melon, has traditionally been used as a natural anti-diabetic agent for anti-hyperglycemic activity in several animal models and clinical trials. We investigated the differences in the anti-diabetic properties and mechanism of action of Taiwanese M. charantia (MC) between type 1 diabetic (T1D) and type 2 diabetic (T2D) mice. To clarify the beneficial effects of MC, we measured non-fasting glucose, oral glucose tolerance, and plasma insulin levels in KK/HIJ mice with high-fat diet-induced diabetes (200 mg/kg/day of charantin-rich extract of MC [CEMC]) and in ICR mice with STZ-induced diabetes. After 8 weeks, all the mice were exsanguinated, and the expression of the insulin-signaling-associated proteins in their tissue was evaluated, in coordination with the protective effects of CEMC against pancreatic β-cell toxicity (in vitro). Eight weeks of data indicated that CEMC caused a significant decline in non-fasting blood glucose, plasma glucose intolerance, and insulin resistance in the KK/HIJ mice, but not in the ICR mice. Furthermore, CEMC decreased plasma insulin and promoted the sensitivity of insulin by increasing the expression of GLUT4 in the skeletal muscle and of IRS-1 in the liver of KK/HIJ mice; however, CEMC extract had no effect on the insulin sensitivity of ICR mice. In vitro study showed that CEMC prevented pancreatic β cells from high-glucose-induced cytotoxicity after 24 h of incubation, but the protective effect was not detectable after 72 h. Collectively, the hypoglycemic effects of CEMC suggest that it has potential for increasing insulin sensitivity in patients with T2D rather than for protecting patients with T1D against β-cell dysfunction.     

黄连及小蘖碱降血糖作用的研究

实验证明,黄连水煎剂可以降低正常小鼠血糖,黄连的主要成分小蘖碱可以降低正常小鼠、四氧嘧啶糖尿病小鼠和自发性糖尿病KK小鼠的血糖。给正常小鼠腹腔注射葡萄糖或肾上腺素可以引起血糖升高,小蘖碱可以对抗这两种作用。给小蘖碱后,可以改善KK小鼠的葡萄糖耐量。此外,小蘖碱可以降低喂高胆固醇乳剂小鼠的血清胆固醇水平,在体外可以抑制家兔血小板聚集。     

Fasting and L-364,718 prevent cholecystokinin-induced elevations of plasma insulin levels

Sulfated CCK-8 but not non-sulfated CCK-8 induced a dose-dependent increase in plasma insulin levels in fed mice. In fasted mice, however, the CCK peptides caused a non-significant to minimal elevation of plasma insulin. Refeeding fasted mice for 1 h prior to CCK-8-S administration was sufficient to cause a significant elevation of plasma insulin levels. The peripheral CCK antagonist, L-364,718, prevented the CCK-8-S-induced elevation of plasma insulin observed in fed mice. In conclusion, CCK produces a nutrition-dependent increase in plasma insulin levels in vivo via an action upon peripheral CCK receptors.     

Stachyose extract from Rehmannia glutinosa Libosch. to lower plasma glucose in normal and diabetic rats by oral administration

The hypoglycemic effects of water extract and stachyose extract (Part III) from Rehmannia glutinosa Libosch. were investigated in this paper by oral administration to normal, glucose- and adrenaline-induced hyperglycemic and alloxan-induced diabetic rats. The results showed that Part III had the effect of lowering fasted plasma glucose level and partially preventing hyperglycemia induced by glucose (2.5 g x kg(-1), i.p.) and adrenaline (300 microg x kg(-1), i.p.), respectively, but no obvious dose-dependent effect was found when it was administered at the doses of 100, 200 and 400 mg x kg(-1) for 6 days, i.g. In alloxan-induced diabetic rats, Part III (200 mg x kg(-1) for 15 days, i.g.) gave a significant decrease in blood glucose level. The results suggested that Part III, which is mainly composed of stachyose from Rehmannia glutinosa Libosch., had a significant hypoglycemic effect in glucose- and adrenaline-induced hyperglycemic and alloxan-induced diabetic rats.     

Hypoglycemic activity of aqueous seed extract of Hunteria umbellata in normal and streptozotocin-induced diabetic rats

The present study evaluated the aqueous seed extract of Hunteria umbellata K. Schum (Apocynaceae) for hypoglycemic activity in rats. Diabetes was induced by a single dose of streptozotocin (50?mg/kg i.p.). Daily doses of 400, 800, and 1000?mg/kg of extract were orally administered to fasted normal and diabetic rats. Blood glucose levels were monitored after 0, 2, 4, 8, 12?h and on day 14 post treatment. Liver glycogen levels were also estimated on day 14. In normal rats, only 400?mg/kg of the extract produced a significant reduction in blood glucose at the 4?h (P?<?0.05) which was 22.15?±?4.88%. In diabetic rats, the extract, 400, 800?mg/kg, caused significant reduction (P?<?0.01), 51.87% ± 5.79% and 43.47% ± 8.06% respectively, with maximum effect at 8?h. This reduction in blood glucose was greater than that of glibenclamide (31.03% ± 8.86%). Diabetic rats administered with 400?mg/kg extract produced a significant reduction (P?<?0.01) on day 14 (43.60% ± 8.10%). Liver glycogen levels were significantly increased (P?<?0.05) in diabetic rats administered with doses of 400 and 800?mg/kg extracts and these were comparable to glibenclamide. Acute toxicity data showed no mortality in mice up to 17.5?g/kg. We conclude that the extract possesses marked hypoglycemic effects in diabetic rats possibly through increased glycogenesis, thus justifying its use in herbal medicine for the treatment of diabetes.     

Anti-diabetic and hypolipidemic effects of aqueous-extract from the flower of Inula japonica in alloxan-induced diabetic mice

The anti-diabetic and hypolipidemic effects of aqueous-extract from the flower of Inula japonica (IJ) and its two fractions (IJR and IJP) were investigated in alloxan-induced diabetic mice. An oral glucose tolerance test (OGTT) of IJ was also performed in normal and diabetic mice. The results showed that IJ (1000 mg/kg), IJR (500 mg/kg) and IJP (250 mg/kg) significantly reduced blood glucose levels in diabetic mice by oral administration (p<0.01). IJ and IJP markedly decreased serum triglyceride concentrations (p<0.05) in diabetic mice. Their hypoglycemic activities were better than gliclazide (40 mg/kg) and compared with metformin (250 mg/kg). IJ raised plasma insulin levels in alloxan-induced diabetic mice. IJ, IJR and IJP significantly decreased the consumption of water and food in diabetic mice. OGTT showed that IJ slightly lowered blood glucose levels in normal mice, but significantly decreased blood glucose in diabetic mice between 60-150 min after a glucose load (p<0.05). The data indicated that IJ has both anti-diabetic and hypolipidemic effects.     

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.     

Hypoglycemic and antioxidant effects of Rheum franzenbachii extract in streptozotocin-induced diabetic rats

The hypoglycemic and antioxidant effects of ethanol extract from the roots and rhizomes of Rheum franzenbachii Münt. (Polygonaceae) were evaluated in streptozotocin-induced diabetic rats. Effects of repeated oral administration of ethanol extract (125, 250, and 500?mg/kg body weight) on the plasma glucose level (PGL), oral glucose tolerance test (OGTT), malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in diabetic rats were examined. It was found that administration of ethanol extract (125, 250, and 500?mg/kg) produced a significant fall in PGL, AUC, and MDA, while elevating the GSH levels and SOD and CAT activities in diabetic rats. The dose of 500?mg/kg was identified as the most effective dose, with a decrease of 65.8 and 44.0% in PGL and MDA, and elevation of 72.6, 75.0, and 51.5% in GSH level and SOD and CAT activities, respectively, after 14 days of ERF administration in diabetic rats. Moreover, the OGTT studies showed a maximum reduction in PGL and AUC. From the active extract of Rheum franzenbachii, two stilbenes, desoxyrhapontigenin (1) and desoxyrhaponticin (2), were isolated as major constituents. The present study concludes that the ethanol extract of roots and rhizomes from Rheum franzenbachii had significant hypoglycemic and antioxidant effects.     

Relative hypoglycemic effect of insulin suppositories in diabetic beagle dogs: optimization of various concentrations of sodium salicylate and polyoxyethylene-9-lauryl ether.

The effect of insulin suppositories containing different amounts and concentrations of sodium salicylate (50, 100 mg) and polyoxyethylene-9-lauryl ether (POELE 1, 3, 4%), respectively, on the plasma glucose concentration of diabetic beagle dogs was investigated after rectal administration. Comparison of the effects of these formulations was made with that produced after subcutaneous insulin injections. Insulin suppositories containing sodium salicylate (50 mg) produced a maximum reduction of plasma glucose concentration (Cmax) of 55 +/- 11%, an area under the curve (AUC) of 252 +/- 59% reduction h; and a relative hypoglycemia (RH) of 49 +/- 12% relative to subcutaneous injection of insulin (4 U/kg). Increasing sodium salicylate to 100 mg/suppository did not improve the hypoglycemic effect of insulin suppositories further. Investigation of the influence of insulin suppositories containing different concentrations of the nonionic surfactant POELE (1, 3, 4%) showed that; the suppositories containing the lowest concentration (1%) produced the highest hypoglycemic effect with a Cmax of 68%, AUC of 332 +/- 67% reduction h, and RH of 55 +/- 11%. Incorporation of sodium salicylate 50mg in insulin suppositories containing 1% POELE did not improve further the effects found with these suppositories. In conclusion, a relative hypoglycemic effect of about 50-55% can be achieved using insulin suppositories containing Witepsol W35 as a base, insulin (5 U/kg), and sodium salicylate (50 mg) or POELE (1%) as rectal absorption enhancers.     

Increase in plasma fibrinogen and plasminogen activator inhibitor level in diabetic KK and KK-Ay mice

Coagulation activity in KK mice and KK-Ay mice produced by transferring the yellow obese gene (Ay) into KK mice, was studied to examine whether both mice are useful as a model of diabetic atherosclerosis. Plasma levels of hemoglobin A1c (HbA1c), insulin, fibrinogen, plasminogen activator inhibitor (PAI) and thrombomodulin were significantly high in KK and KK-Ay mice compared with age-matched non-diabetic mice (ddY mice). The changes in the plasma levels of fibrinogen at each time-point correlated with the increases in HbA1c levels. Pathological observation by Oil red O staining of aorta tissue from 4-month-old KK and KK-Ay mice revealed the early stages of atherosclerosis such as lipid deposition. These age-related increases in the plasma level of fibrinogen and PAI suggested that KK-Ay mice may contribute to help elucidate the early stages of diabetic atherosclerosis.     

In vivo evidence that insulin does not inhibit hepatic tryptophan pyrrolase activity in rats

Previous reports have indicated that insulin administration triggers an early increase in plasma tryptophan (TRP) levels in fasted rats. Then, the present study was undertaken to investigate the putative role of liver tryptophan pyrrolase (TPO) in this short-term effect of insulin. In 24 hr fasted rats, doses of insulin that triggered an increase in plasma TRP levels (i.e., 2-3 I.U./kg, 1 hr) did not alter either holoenzyme or total enzyme activity. In another series of experiments, the administration of insulin (2 I.U./kg) to 24 hr fasted rats promoted biphasic time effects on plasma TRP levels and liver TPO activity. Thus, insulin initially triggered a rise in plasma TRP (without any change in liver TPO activity) and then increased liver TPO activity whilst plasma TRP returned toward control levels. In addition, hypercorticosteronemia was evidenced throughout the first phasis. Lastly, the influence of insulin administration (2 I.U./kg) on fasting-induced TPO induction was analysed. Whereas fasting increased liver TPO activity in a time-dependent manner, insulin administration (2 I.U./kg, 30 min) did not modify either plasma TRP or liver TPO activity. The data reported herein bring evidence that the effect of insulin administration on circulating TRP is not mediated by an inhibition of hepatic TPO.     

The hypoglycaemic effect of 5-hydroxytryptophan

1 In nialamide-treated mice, L-5-hydroxytryptophan produced a dose-dependent hypoglycaemic response which was independent of whether the animals had been fed or fasted.2 This response was accompanied by a head-twitching response which was also dose-dependent.3 The hypoglycaemic response was not accompanied by an elevation in plasma immunoreactive insulin levels and was fully manifest in alloxan diabetic animals.4 5-Hydroxytryptophan did not increase the in vitro glucose uptake of adipose tissue or skeletal muscle, either on incubation of the tissues in contact with the drug or on incubation of tissues removed from mice injected with the drug.5 Both the hypoglycaemic and head-twitching responses were prevented by pretreatment with methysergide or cyproheptadine and augmented by mepyramine treatment.