Decreased expression of liver epidermal growth factor receptors in rats with alloxan and streptozotocin diabetes

Male rats (200 g) were rendered diabetic with one intraperitoneal injection of alloxan (150 mg/kg) or streptozotocin (60 mg/kg). In hyperglycemic animals within 3 hours after the injection, the binding of EGF to liver membranes decreased by 43-52%; the maximal drop was by 70% and persisted for the 20 days of the experiment. EGF receptors decreased in number with almost no changes in their affinity. Autophosphorylation of the receptors decreased parallel to the ligand binding. In animals that received lower doses and did not develop diabetes and in animals in whom diabetes was prevented by the injections of glucose (before alloxan) or nicotinamide (before streptozotocin) the binding of EGF to liver receptors remained normal. We conclude that the decreased expression of EGF receptors was caused by diabetes and not by the toxic effects of the diabetogenic compounds on the liver.     

Modification of renal tumorigenic effect of streptozotocin by nicotinamide: spontaneous reversibility of streptozotocin diabetes.

The renal oncogenic activity of streptozotocin in male Holtzman rats was significantly decreased by nicotinamide. Adenomas of the kidney were noted in 77% (21/28) of the animals treated with single iv dose of the streptozotocin, 50 mg/kg, while only 18% (5/28) of animals given nicotinamide ip, 350 mg/kg, 10 min before and 180 min after the same dose of streptozotocin had demonstrable renal tumors. Moreover, the renal adenomas induced by streptozotocin alone occurred sooner and were generally larger when compared with those in the animals treated with the nicotinamide-streptozotocin combination. The 50 mg/kg dose of streptozotocin was diabetogenic in all rats, but the diabetic state was not permanent. Spontaneous recovery from the diabetes was first noted after 8 and 10 months of followup, and after 16 months none of the surviving rats were diabetic.     

Streptozotocin diabetes in juvenile pigs. Evaluation of an experimental model

Spontaneous diabetes in the domestic pig, an animal suitable for metabolic and endocrine studies and for experimental surgery, is extremely rare. In this study we have compared the diabetogenic response of various doses of streptozotocin in comparison to surgically induced diabetes. Streptozotocin in a low dose, 35 mg/kg body weight did not influence glucose metabolism while an intermediate dose, 85 mg/kg, resulted in a transient diabetic reaction. Streptozotocin, 100-150 mg/kg body weight, caused a complete and permanent diabetes. Animals made diabetic by means of pancreatectomy did not survive more than 10 days due to their poor general condition and diabetes. Streptozotocin induced diabetic animals survived with insulin treatment up to seven months. The results show that juvenile pigs made diabetic with 100-150 mg/kg body weight of streptozotocin may be useful in experimental work on glucose-, insulin- and C-peptide-metabolism in a large animal. Therefore it is potentially useful in pancreatic transplantation research.     

Dietary caloric restriction improves the redox status at the onset of diabetes in hepatocytes of streptozotocin-induced diabetic rats

Enhanced production of free radicals and oxidative stress induced by hyperglycemia play a central role in the pathogenesis of diabetes and its complications. This study assessed the attenuation by dietary caloric restriction on the oxidative and lipid peroxidative effects of diabetes in the liver through reduction in body and organ weights and concomitant metabolic changes. Three-month-old male Wistar rats were subjected to ad libitum feeding and 30% caloric restriction for 9 weeks before induction of diabetes by intraperitoneal injection of 35 mg/kg body weight streptozotocin. The animals were sacrificed 2 weeks after streptozotocin treatment depicting the onset of diabetes. Caloric restriction significantly reduced the organ weights (p<0.01), malondialdehyde (p<0.01) and catalase activity (p<0.01), but significantly increased glutathione reductase activity (p<0.01), and GSH/GSSG ratios (p<0.05). Caloric restriction also non-significantly reduced reactive oxygen species, superoxide dismutase and oxidized glutathione but increased glutathione peroxidase activity and reduced glutathione levels in the diabetic rats. Our data indicate a decrease in lipid peroxidation, improvement in the antioxidant defense systems and restoration of the redox status in the liver by caloric restriction. Therefore, this could provide a non-invasive antioxidant therapy early in diabetes to prevent the development of the complications associated with the disease.     

Effect of probucol on recovery from streptozotocin diabetes in rats.

The present study was conducted to see the effect of probucol on streptozotocin diabetes in rats. After 2 weeks of a 1% probucol diet, 35 or 50 mg/kg of streptozotocin were intravenously injected into male Wistar rats. All the rats became diabetic 2 days after treatment. Thereafter, in order to see the effect of probucol on spontaneous recovery from streptozotocin diabetes, 25 mg/kg of streptozotocin was injected into rats after two weeks of probucol diet and the diet was continued for additional two weeks. All the rats with a standard diet (group CS, n = 13) and 12 of 13 rats with probucol diet (group PS) became diabetic 2 days after streptozotocin injection. One rate from group PS did not develop diabetes. Two weeks after injection, only 4 of 13 rats in groups CS showed recovery, while 11 of 12 rats in group PS showed recovery from streptozotocin diabetes (p less than 0.05). The average blood glucose levels in group PS were significantly lower than group CS (10.5 +/- 4.6 vs 18.5 +/- 0.6 mM, p less than 0.05). In addition, the pancreatic insulin content of group PS was 8 times greater than that of group CS (0.75 +/- 0.24 vs 0.09 +/- 0.03 mmol/pancreas, p less than 0.01). Thus, the in vivo diabetogenic action of streptozotocin could not be reduced by pretreatment with probucol. However, recovery from streptozotocin diabetes was induced by subsequent treatment with probucol. The precise mechanisms for this phenomenon were not known; but the present findings suggest the protective effect of probucol on beta-cell damage induced by small dose of streptozotocin.     

Resistance of cats to the diabetogenic effect of alloxan

Experimental diabetes mellitus can be induced chemically in many species of animals with streptozotocin or alloxan. However, the cat is known to be resistant to the diabetogenic effect of streptozotocin. The purpose of this study was to find the optimal dose and rate of injection of alloxan to consistently produce hyperglycemia (blood sugar levels greater than 300 mg/dl) in cats. Alloxan was administered to 22 cats at various concentrations (50, 100 and 150 mg/kg) and different rates of injection (0.5, 1.0 and 1.5 ml/min). No hyperglycemic effect was observed at any of the concentrations or different rates of injection. Cats receiving high concentrations and/or high rates of injection of alloxan died due to kidney damage. The results of this study suggest that the cat is resistant to the diabetogenic effect of alloxan, but is susceptible to its toxic side effects.     

Effects of vanadyl sulfate on kidney in experimental diabetes

The aim of this work was to investigate the biochemical and histological effects of vanadyl sulfate on blood glucose, urea, and creatinine in serum and nonenzymatic glycosylation and glutathione levels in kidney tissue of normal and streptozotocin (65 mg/kg) diabetic rats. Vanadyl sulfate was administered by gavage at a dose of 100 mg/kg. After 60 d of treatment, serum urea, creatinine, and blood glucose levels significantly increased in the diabetic group but not so in the vanadyl sulfate, which showed significantly reduced serum urea and blood glucose levels and a nonsignificant reduction of serum creatinine levels. Nonenzymatic glycosylation was increased and the glutathione level was decreased in the kidney tissue of diabetic rats. Treatment with vanadyl sulfate reversed these effects. Degenerative changes were detected in diabetic animals by electron and light microscopy. Although there are individual differences in diabetic animals given vanadium, some reduction of degenerative changes were observed.     

Early induction of diabetes in NOD mice by streptozotocin

To clarify whether the non-obese diabetes prone (NOD) mouse has an unusual pancreatic sensitivity to damage, mice were administered streptozotocin in high dose (direct beta cell toxic) or multiple low-dose (autoimmune-insulitis generating) regimen. NOD mice were found to be less sensitive to the diabetogenic effects of high-dose streptozotocin than C57BL/6 mice, but were exquisitely responsive to the multiple low dose regimen when compared to C57BL/6 or C3H/HeJ mice. These results suggest that the basic defect in NOD mice resides in the immune system and that the NOD mouse may be a useful model to investigate the relationships between environmental factors and intrinsic genetic predisposition to diabetes.     

Streptozotocin and alloxan produce alterations in rat brain monoamines independently of pancreatic beta cells destruction.

In recent years the effect of experimental diabetes mellitus on brain neurochemistry has been under an intensive investigation. In most of these studies diabetes was produced by a peripheral administration of streptozotocin or alloxan. In line with previous reports, a week after such an application of alloxan (200 mg/kg s.c.) we found the concentration of serotonin, dopamine and norepinephrine to be increased in the brain of a diabetic rat. Accumulation of these monoamines, produced by inhibition of monoamine oxydase with pargyline (100 mg/kg i.p.) decreased in animals made diabetic by alloxan or streptozotocin (100 mg/kg i.p.) suggesting a decrease in deamination rate. Surprisingly, however, one week after an intracerebroventricular administration of non-diabetogenic doses of streptozotocin (5-20 mg/kg) or alloxan (20 mg/kg), changes in brain monoamines were similar to those observed in diabetic animals. This observation apparently suggests that the CNS effect of streptozotocin or alloxan is not necessarily related to a diabetogenic, beta-cytotoxic action of these substances.     

Protection by thymosin fraction 5 from streptozotocin-induced diabetes in mice

Protection by thymosin fraction 5 (TF5) from subdiabetogenic-dose streptozotocin (STZ)-induced type I diabetes in CD-1 mice was investigated. Mice which received multiple subdiabetogenic-dose (35 mg/kg) injections of STZ became hyperglycemia within two weeks. Hyperglycemia was also induced in those treated with low dose of TF5 (0.01 mg/day) in addition to STZ, though it was somewhat mild. In contrast, animals given STZ plus high dose of TF5 (0.1 mg/day) remained normoglycemic throughout the whole observation period (within 4 weeks). In the pancreatic islets from these animals, histologically, the well-granulated beta cells were observed and the infiltration of lymphoid cells was absent or mild. These results suggest that the administration of TF5 prevents the induction of insulitis and hyperglycemia in the subdiabetogenic-dose STZ-treated mice.     

Autoradiographic studies on protein metabolism and histochemical demonstration of the brain zinc content in diabetes mellitus. 1. Comparison in experimental streptozotocin-induced diabetes]

By application of streptozotocin diabetes mellitus is induced in rats: 40 mg/kg body weight streptozotocin produce a fairly serious diabetes with minimal ketosis, 125 mg/kg body weight streptozotocin cause a severe diabetic keto-acidosis. After 72 hours these animals and also a group of control animals receive 8.33 mCi/animal 3H-leucine intraperitoneally. By means of stripping film autoradiograms the rates of uptake of 3H-leucine in different areas of the rat brain are measured. The values of the control animals are compared with those of a fairly serious diabetes and those of a severe diabetic keto-acidosis. In the regions of the neocortex parietalis and of the thalamus the 3H-leucine values of the diabetic animals are considerably lower in comparison with the controls, and that irrespective of the degree of severity of the diabetic disease. Compared with the control animals the 3H-leucine values of diabetic animals decrease according to the degree of severity of the disease within the Ammon's horn and the dentate fascia. Within the Ammon's horn and dentate fascia also the zinc contents change very specifically in different areas with the degree of severity of diabetes mellitus. The zinc is identified on H2S-alcohol fixed brains by means of a photographic development. The particular significance of the Ammon's horn and the dentate fascia concerning diabetic metabolic conditions is discussed.     

Changes in the function and ultrastructure of vessels in the rat model of multiple low dose streptozotocin-induced diabetes

In this study we investigated functional changes in the femoral artery and ultrastructural alterations in mesenteric vessels and capillaries in the rat model of multiple low dose streptozotocin (STZ)-induced diabetes. Participation of oxidative stress in this model of diabetes was established by studying the effect of the pyridoindole antioxidant stobadine (STB) on diabetes-induced impairment. Experimental diabetes was induced by i.v. bolus of STZ (20 mg/kg) given for three consecutive days to male rats. At the 12(th) week following STZ administration, the animals revealed typical signs of diabetes, such as polyphagia, polydypsia and polyuria. There was no weight gain in the diabetic groups throughout the experiment. No exitus occurred in any group. Diabetes was characterised with high levels of plasma glucose, no significant changes in lipid metabolism, decreased serum levels of glutathione, increased serum levels of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase (NAGA), injured endothelial relaxant capacity of the femoral artery and alterations in ultrastructure of mesenteric arteries and capillaries. Antioxidant STB in the dose of 25 mg/kg body weight i.p. (5 times per week) did not influence glucose levels, however, it mitigated biochemical, functional and ultrastructural changes induced by diabetes, suggesting a role of reactive oxygen species in diabetes-induced tissue damage.     

Effect of nickel chloride on streptozotocin-induced diabetes in rats

The potential of nickel chloride to prevent streptozotocin-induced hyperglycemia was tested in rats in vivo. To induce diabetes, streptozotocin (100 mg/kg body weight) was injected as a single dose. Streptozotocin treatment resulted in a significant decrease in plasma insulin and ceruloplasmin, and pancreatic Cu, protein, and Cu-Zn superoxide dismutase activity. In rats treated with nickel chloride (10 mg/kg body weight) and streptozotocin, these values were comparable with those observed in control rats. The results indicate that nickel chloride injected before streptozotocin prevented streptozotocin-induced hyperglycemia, and suggest that the protective effect was related to Cu-Zn superoxide dismutase activity, mediated by copper.     

Increase of pancreatic somatostatin concentration in early phases of streptozotocin diabetes in rats

A small yet significant increase of immunoassayable pancreatic somatostatin concentration (0.107 +/- 0.005 vs. 0.156 +/- 0.017 microgram/g at 24 hr, p less than 0.05) was found in rats, 24 hr as well as 7 days after treatment with a diabetogenic dose of streptozotocin (65 mg/kg BW). These animals were characterized by marked decreases of insulin in the pancreas without any significant changes in pancreatic glucagon concentration. These results suggest that an abrupt deprivation of insulin from islets results in an elevation of pancreatic somatostatin concentration, and that glucagon in the pancreas plays a minor role in determining pancreatic somatostatin concentration in rats with insulin-deprived diabetes of short duration.     

Renin-angiotensin blockade attenuates cardiac myofibrillar remodelling in chronic diabetes

Previous studies have shown that the renin-angiotensin system (RAS) is activated in diabetes and this may contribute to the subcellular remodelling and heart dysfunction in this disease. Therefore, we examined the effects of RAS blockade by enalapril, an angiotensin-converting enzyme inhibitor, and losartan, an angiotensin receptor AT1 antagonist, on cardiac function, myofibrillar and myosin ATPase activity as well as myosin heavy chain (MHC) isozyme expression in diabetic hearts. Diabetes was induced in rats by a single injection of streptozotocin (65 mg/kg; i.v.) and these animals were treated with and without enalapril (10 mg/kg/day; oral) or losartan (20 mg/kg/day; oral) for 8 weeks. Enalapril or losartan prevented the depressions in left ventricular rate of pressure development, rate of pressure decay and ventricular weight seen in diabetic animals. Both drugs also attenuated the decrease in myofibrillar Ca2+-ATPase, Mg2+-ATPase and myosin ATPase activity seen in diabetic rats. The diabetes-induced increase in beta-MHC content and gene expression as well as the decrease in alpha-MHC content and mRNA levels were also prevented by enalapril and losartan. These results suggest the occurrence of myofibrillar remodelling in diabetic cardiomyopathy and provide evidence that the beneficial effects of RAS blockade in diabetes may be associated with attenuation of myofibrillar remodelling in the heart.     

Influence of age on the sensitivity of the rat to streptozotocin.

The relationship between age and sensitivity to the diabetogenic effect of streptozotocin was investigated. Changes in the serum levels of several parameters (glucose, immunoreactive insulin, lipids), as well as changes of the pancreatic insulin content were monitored at 2, 4, 8, 24 and 48 h after the intravenous administration of different doses of streptozotocin in rats of various weights. Different concentrations of blood glucose and lipid and different amounts of pancreatic immunoreactive insulin could be found in rats of different ages 24 and 48 h after injection of the same dose of the drug (in mg/kg body weight). Also, age-dependent changes of serum immunoreactive insulin could be observed as early as 4 h after streptozotocin administration. All these changes indicate that the sensitivity of the rat to the diabetogenic effect of streptozotocin is inversely related to the age of the animals. Most likely, age-dependent pancreatic factors have an important role. In fact, the changes of the minimum dose of streptozotocin required to cause diabetes in rats of different weights closely parallel the age-related changes of the total immunoreactive insulin content of the pancreas of the intact rats. The role of other age-related factors which may influence the effectiveness of streptozotocin action is briefly discussed.     

Effects of streptozotocin in the male guinea pig: a potential animal model for studying diabetes

The effects of acutely administered streptozotocin in the male guinea pig were studied for a period of 18 days following treatment. A single intracardiac injection of streptozotocin (150 mg/kg) was administered on Day 0. On Day 2, plasma glucose concentrations were not significantly different from control levels. On Day 7 and 18, an oral glucose tolerance test was performed with streptozotocin-treated animals receiving an acute injection of either insulin (18 U/kg, i.m.) or saline 90 minutes prior to glucose loading. On Day 7, streptozotocin-treated animals receiving saline had significantly elevated plasma and urine glucose concentrations at 3 hours after glucose loading when compared to controls. Streptozotocin-treated animals receiving insulin however, had significantly lower plasma glucose concentrations at 3 hours while urinary glucose was equal to control values. The second glucose tolerance test performed on Day 18 yielded similar results. Necropsies were performed on animals that died after Day 6. Lesions found in the streptozotocin-treated animals included: small and irregular pancreatic islets, pyknotic nuclei and degranulation of beta cells, renal proximal tubule swelling and vacuolization, adrenal cortical hyperplasia, hepatocyte vacuolization, and visceral fat atrophy. Animals surviving until Day 18 were sacrificed and found to have significantly elevated kidney and adrenal weights compared to controls. These changes illustrate the effectiveness of streptozotocin in the acute chemical induction of diabetes in an animal model (guinea pig) which, like humans, requires a dietary source of ascorbic acid.     

The antidiabetic effects of cysteinyl metformin, a newly synthesized agent, in alloxan- and streptozocin-induced diabetic rats

In this paper, the antidiabetic effects of cysteinyl metformin (CM), a newly synthesized agent, were investigated to evaluate the hypoglycemic/hypolipidemic effects by measuring blood glucose, triglyceride and insulin levels in CM- and metformin-treated diabetic rats. Two diabetic models were used: (1) an alloxan-induced model in which diabetes was produced by alloxan (200 mg/kg, i.p.), then rats were treated with CM (300, 100 and 33 mg/kg) for 14 days; (2) a streptozocin-induced model in which diabetes was produced by streptozocin (30 mg/kg, i.p.) and a sustained high lipid diet, then rats were treated with CM for 8 weeks. The hypoglycemic effect of CM exceeded that of metformin while the hypolipidemic effect was similar. In addition, CM increased the blood insulin level of the alloxan-induced experimental animals (which had an insulin deficiency), but reduced the insulin level of the streptozocin-induced animals (which had an insulin excess), suggesting that CM improves pancreatic beta-cell function. The effects of CM, metformin and cysteine on the antioxidant defense system in alloxan-induced rats were also studied. The serum malondialdehyde (MDA) level was determined to provide evidence for lipid peroxidation, All the groups of animals given CM, metformin and cysteine exhibited less severe oxidative stress than the diabetic group. Then, several key antioxidants such as superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and the pancreatic exocrine enzyme amylase (AMS) were measured. CM restored the activity of all these agents to nearly normal values while metformin and cysteine merely restored the activity of SOD. At the end of our study, the animals were sacrificed by decapitation and the liver, kidney and pancreas were weighed to allow investigation of organ edema. The results obtained showed that CM corrected the organ edema of the diabetic rats. All these findings suggested that CM has a protective effect on the antioxidant defense system and beta-cell dysfunction in alloxan-induced diabetic rats. All these results suggest that CM is a potential candidate for the future treatment of both type 1 and type 2 diabetes.     

Gastric mucosal susceptibility for ulcerogenic effect of indometacin at different time points of streptozotocin-induced diabetes development

In the study, we examined the gastric mucosal susceptibility for ulcerogenic effect of indometacin at different time points of streptozotocin-induced diabetes development. Indometacin was injected at ulcerogenic dose (35 mg/kg, s. c.) on days 3, 7 and 30 after streptozotocin administration (60 mg/kg, i. v.) or its vehicle to fasted rats. Typical diabetic hyperglicaemia was observed as early as in 3 days after streptozotocin administration and accompanied with enhanced mucosal susceptibility for indometacin as compared with that of control group. In 7 and 30 days after streptozotocin administration, when hyperglicaemia was still present, the average areas of indometacin-induced erosion increased 2- and 3-fold, respectively, as compared with those observed in 3 day after streptozotocin administration. The data obtained demonstrate that gastric mucosal susceptibility for the ulcerogenic effect of indometacin is increased at the early stages of diabetes development and then aggravates along with further development of the pathological condition.     

STZ诱导恒河猴糖尿病动物模型的建立

目的复制稳定的链脲佐菌素诱导糖尿病恒河猴动物模型。方法健康恒河猴5只,小剂量（30mg/kg）多次静脉注射链脲佐菌素,分别在注射后2、3个月进行葡萄糖耐量实验并连续观察血糖、胰岛素、C肽的变化。连续观察12个月。结果随着时间推移,动物出现典型的糖尿病症状。3只动物的血糖静脉注射1次后持续10周稳定,另外2只分别进行了第2、3次注射。动物血糖在12个月内平稳上升、胰岛素、C肽分泌持续下降。2个月时葡萄糖耐量减低明显（P〈0.01）。结论小剂量多次注射STZ后恒河猴可出现持续、稳定的糖尿病表现,可作为相关研究的动物模型。