The mechanisms of alloxan- and streptozotocin-induced diabetes

Alloxan and streptozotocin are toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter. In the presence of intracellular thiols, especially glutathione, alloxan generates reactive oxygen species (ROS) in a cyclic redox reaction with its reduction product, dialuric acid. Autoxidation of dialuric acid generates superoxide radicals, hydrogen peroxide and, in a final iron-catalysed reaction step, hydroxyl radicals. These hydroxyl radicals are ultimately responsible for the death of the beta cells, which have a particularly low antioxidative defence capacity, and the ensuing state of insulin-dependent ‘alloxan diabetes’. As a thiol reagent, alloxan also selectively inhibits glucose-induced insulin secretion through its ability to inhibit the beta cell glucose sensor glucokinase. Following its uptake into the beta cells, streptozotocin is split into its glucose and methylnitrosourea moiety. Owing to its alkylating properties, the latter modifies biological macromolecules, fragments DNA and destroys the beta cells, causing a state of insulin-dependent diabetes. The targeting of mitochondrial DNA, thereby impairing the signalling function of beta cell mitochondrial metabolism, also explains how streptozotocin is able to inhibit glucose-induced insulin secretion.     

Antidiabetic and antihyperlipidaemic activity of ethanol extract of Melastoma malabathricum Linn. leaf in alloxan induced diabetic rats

ObjectiveTo evaluate the antidiabetic and antihyperlipidaemic effect of ethanol extract of Melastoma malabathricum (M. malabathricum) Linn. leaf in alloxan induced diabetic rats.MethodsDiabetes was induced in albino rats by administration of alloxan monohydrate (150 mg/kg i.p). the ethanol extracts of M. malabathricum at a dose of 150 and 300 mg/kg of body weight were administrated at a single dose per day to diabetes induced rats for a period of 14 d. The effect of ethanol extract of M. malabathricum leaf extract on blood glucose, plasma insulin, creatinine, glycosylated haemoglobin, urea serum lipid profile [total cholesterol, triglycerides, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, high density lipoprotein-cholesterol and phospholipid, serum protein, albumin, globulin, serum enzymes (serum glutamate pyruvate transaminases), serum glutamate oxaloacetate transaminases, and alkaline phosphatase] were measured in the diabetic rats.ResultsIn the acute toxicity study, ethanol extract of M. malabathricum leaf was non-toxic at 2 000 mg/kg in rats. The increased body weight, decreased blood glucose, glycosylated haemoglobin and other biochemical parameters level were observed in diabetic rats treated with both doses of ethanol extract of M. malabathricum leaf compared to diabetic control rats. In diabetic rats, ethanol extract of M. malabathricum leaf administration, altered lipid profiles were reversed to near normal than diabetic control rats.ConclusionsEthanol extract of M. malabathricum leaf possesses significant antidiabetic and antihyperlipidaemic activity in diabetic rats.     

Anti-Diabetic Activities of the Methanol Leaf Extracts of Hymenocardia Acida (Tul.) in Alloxan-Induced Diabetic Rats

The effect of methanolic extract of Hymenocardia acida leaves on diabetes and associated lipidemia were investigated on experimentally-induced diabetic rats. The extract did not demonstrate any acutely toxic effect in rats within the dose range (250 mg/kg – 2000 mg/kg) employed in the study; hence it was well tolerated by the rats. In all experiments, the anti-diabetic effects were dose-dependent and comparable to that of glibenclamide (2 mg/kg) standard. At a dose of 500 mg/kg, lipid profile markers such as the serum total cholesterol (TC) levels, LDL-C, triglycerides and HDL-C were significantly lower (p <0.05) than those of both the treated and untreated controls.     

Increased intestinal absorption of insulin in a micellar solution: Water-in-oil-in-water insulin micelles

Summary Water-in-oil-in-water (W/O/W) insulin micelles were prepared, and the possibility of insulin absorption in a micellar form was examined. In this preparation, insulin was trapped in oil droplets of oleic acid in glyceryl-α-monooleate. (1) W/O/W insulin micelles were absorbed from the ligated jejunal loop of rabbits to the order of 12.3 to 58.5% of the dose given (10 U/kg body weight) during the 3-h experimental period. (2) Alloxan diabetic rats were treated with intrajejunal administration of W/O/W insulin micelles at a dosage of either 25 or 50 U/100 g body weight, three times daily for as longs as 14 days. During treatment, a significant reduction in the daily excretion of urinary glucose was observed, concomitant with a decrease in fasting blood glucose. Quantitative estimates suggested that the effectiveness of 25 U/100 g of intrajejunal W/O/W insulin micelles was comparable to that of regular insulin at a dosage of 1 U/100 g i.m. These results would indicate that W/O/W insulin micelles, when given enterally, are more effective in lowering blood and urinary glucose levels than W/O/W insulin emulsions in which insulin was trapped in oil droplets of triglyceride.     

L'effet d'une surcharge lipidique et du butylbiguanide chez les rats alloxano-diabétiques aux changements différentes de poids corporel

Résumé Nous avons entrepris ces recherches à partir de travaux antérieurs concernants les changements différents du poids corporel chez des rats alloxano-diabétiques, qui sont en outre atteints de diabète de même gravité. Dans ce présent travail, la teneur en lipides totaux sériques a été mesurée 2 hrs après une surcharge lipidique orale chez des rats qui avaient perdu en moyenne 35 g depuis l'alloxanisation, ainsi que chez des rats qui avaient pris en moyenne 51 g. Le taux de lipides sériques était significativement plus élevé chez les rats qui avaient perdu du poids que chez ceux qui en avaient gagné. Dans les deux groupes, cependant, le taux de lipides sériques était diminué dans la même proportion par l'injection s.c. du butylbiguanide (100 mg/kg) succédant à la surcharge lipidique.

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Summary Previous investigations concerning the different changes in body weight in alloxan diabetic rats showed no differences in the severity of diabetes. Therefore, the following experiments were carried out: rats which had lost an average weight of 35 g after alloxanisation as well as rats with an average weight gain of 51 g, received lard by stomach tube and 2 hrs later total serum lipid concentration was determined. In rats with weight loss a significantly more marked increase in the total serum lipid level was found than in those with weight gain. Butylbiguanide (100 mg/kg) administered s.c. immediately after fat feeding lowered the serum lipid levels in both groups by a proportionally similar degree.

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Zusammenfassung In früheren Untersuchungen wurde ein unterschiedliches Verhalten des Körpergewichtes bei alloxandiabetischen Ratten mit gleich stark ausgeprägtem Diabetes festgestellt. In der vorliegenden Arbeit wurden chronisch diabetische Ratten in eine Gruppe mit einer durchschnittlichen Gewichtsabnahme von 35 g und in eine zweite mit einer mittleren Gewichtszunahme von 51 g eingeteilt. Die Tiere erhielten mittels Schlundsonde zerlassenes Schweineschmalz. Zwei Stunden später wurde im Serum der Gesamtlipoidgehalt bestimmt. Bei den Ratten mit Gewichtsabnahme war der Serumgesamtlipoidgehalt signifikant höher als bei denen mit Gewichtszunahme. Durch die s.c. Verabreichung von Butylbiguanid unmittelbar nach der Fettbelastung erfolgte hingegen bei beiden Gruppen eine prozentuell ungefähr gleiche Verminderung des Serumlipidgehaltes.

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Resumen Basándonos en trabajos anteriores hemos continuado nuestra investigación sobre los diversos cambios de peso corporal de ratas aloxán-diabéticas, afectas también de otros procesos diabéticos de la misma gravedad. En el presente trabajo hemos calculado el porcentaje máximo de lípidos séricos a las dos horas de suministrar oralmente una dosis de carga de lípidos a ratas que habían perdido en promedio 35 g después de aloxanación, y a ratas que habían ganado un promedio de 51 g. El porcentaje de lípidos séricos era notablemente más alto en las ratas que habían perdido peso que en las que lo habían ganado. Sin embargo, en ambos grupos el porcentaje de lípidos séricos había disminuido en la misma proporción tras inyección de butylbiguanida (100 mg/kg) con posterioridad al suministro de la dosis de carga lipídica.

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Riassunto Riprendendo i risultati di precedenti studî condotti in ratti con diabete da allossana di uguale gravità e relativi alle modificazioni del peso corporeo, abbiamo esaminato, nella presente ricerca, il comportamento della lipemia totale, a 2 h di distanza da un carico lipidico orale, in due gruppi di animali che, dopo l'allossanizzazione, avevano subìto rispettivamente una riduzione ponderale media di 35 g o un aumento medio di 51 g. I valori della lipemia totale sono risultati significativamente maggiori nei primi che nei secondi. Tuttavia, una diminuzione dei livelli lipemici è stata osservata in entrambi i gruppi, quando il carico lipidico era immediatamente seguìto dalla somministrazione s. c. di butilbiguanide (100 mg/kg).

     

The effect of acute alloxan diabetes on the sensitivity of the rat skeletal neuromuscular junction to drugs

Summary Preparations from alloxan diabetic rats showed a reduced sensitivity to the neuromuscular blocking action of (+)-tubocurarine but no alteration in sensitivity to the deplolarizing neuromuscular blocking drug decamethonium. Physostigmine was less effective in augmenting twitch height in preparations from alloxan diabetic rats and such preparations had a significantly lowered total cholinesterase activity compared with control preparations. An additional observation was a reduction in the effectiveness of the pre-junctionally active agent β-bungarotoxin in producing neuromuscular blockade in physostigmine-treated preparations from alloxan diabetic rats. All the changes produced by alloxan administration were prevented by treatment with insulin.     

仙蜜果植物茎花果降血糖作用研究

目的:研究仙蜜果植物茎、花及果实的降血糖作用。方法:分别制得仙蜜果植物茎、花及果实的乙醇提物和茎、花的水提物;采用给予小鼠腹腔注射四氧嘧啶法建立糖尿病模型,并按体质量随机分成14组。各组小鼠给药7d后测定血糖含量、体质量、胰腺指数及胸腺指数。结果:与模型组比较,各种提取物均可降低糖尿病小鼠的血糖水平,果实85%乙醇提物和花水提物的降糖作用有极显著性差异;各种提取物对胰腺均有保护和改善作用,对免疫系统的影响不明显。结论:仙蜜果植物具有降低血糖作用,是潜在的治疗糖尿病辅助药物。     

Biochemical study on the effects of some Egyptian herbs in alloxan-induced diabetic rats

The present study was carried out to investigate the effects of Lupinus albus, L. (Lupinus termis), family L. leguminosae, Cymbopogon proximus, (Halfa barr), family Gramineae, and Zygophyllum coccineum L. (Kammun quaramany), family L. Zygophyllacae on biochemical parameters in alloxan-induced diabetic rats. A dose of 1.5 ml of aqueous suspension of each herb/100 g body weight (equivalent to 75 mg/100 g b.wt.) was orally administered daily to alloxan-diabetic rats for 4 weeks. The levels of glucose, urea, creatinine and bilirubin were significantly (P<0.05) increased in plasma of alloxan-diabetic rats compared with the control group. In contrast, total protein and albumin were significantly decreased by 25 and 46%, respectively, versus control. Treatment of the diabetic rats with repeated doses of any one of the three herb suspensions could restore the changes of the above parameters to their normal levels after 4 weeks of treatment. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and alkaline phosphatase (AlP) activities were significantly (P<0.05) increased in the plasma of alloxan-diabetic rats. However, acetylcholinesterase activity was significantly (P<0.05) decreased in the plasma compared with the control group, whereas, such activity did not change in brain. The activities of AST, ALT and LDH were significantly (P<0.05) decreased in the liver of alloxan-diabetic rats by 58, 21 and 40%, respectively, and such activities increased in testes by 39, 26 and 26%, respectively, compared with the control group. Also, brain LDH was significantly (P<0.05) increased. Treatment of the diabetic rats with the aqueous suspension of the tested herbs restored the activities of the above enzymes to their normal level in plasma, liver and testes. The present results showed that the herb suspensions exerted antihyperglycemic effects and consequently may alleviate liver and renal damage caused by alloxan-induced diabetes.     

土牛膝提取物对正常及四氧嘧啶糖尿病模型小鼠血糖的影响

目的研究土牛膝提取物齐墩果酸、牛膝多糖对正常及四氧嘧啶糖尿病模型小鼠血糖的影响。方法采用正常小鼠和四氧嘧啶糖尿病模型小鼠,用邻甲苯胺法测定血糖值。结果土牛膝提取物齐墩果酸、牛膝多糖对正常小鼠空腹血糖无明显降低作用,能明显降低四氧嘧啶糖尿病模型小鼠的空腹血糖水平。结论土牛膝提取物齐墩果酸、牛膝多糖对糖尿病模型小鼠有较好的降糖作用。     

土牛膝水煮液对正常及四氧嘧啶糖尿病模型小鼠血糖的影响

目的研究了土牛膝水煮液对正常及四氧嘧啶糖尿病模型小鼠血糖的影响。方法采用正常小鼠和四氧嘧啶糖尿病模型小鼠,用邻甲苯胺法测定血糖值。结果土牛膝水煮液对正常小鼠空腹血糖无明显降低作用,能降低四氧嘧啶糖尿病模型小鼠的空腹血糖水平。结论土牛膝水煮液对糖尿病小鼠有较好的降糖作用。