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.     

Combined effect of nicotinamide and streptozotocin on diabetic status in partially pancreatectomized adult BALB/c mice.

Pancreatic regeneration after pancreatectomy has been well documented in the animal models. We have recently reported that STZ diabetic animals operated for partial pancreatectomy showed normoglycemic status after the operation as compared to uncontrolled hyperglycemia and even death in the diabetic sham operated animals. In drug and virus-induced experimental diabetic models there is a high mortality of animals due to uncontrolled destruction of the beta-cells. In order to destroy sufficient beta-cell mass so as to induce diabetes but prevent mortality, we designed present studies to investigate the combined effect of pancreatectomy, nicotinamide, and streptozotocin (STZ) on diabetic status of BALB/c mice. BALB/c mice of either sex were subjected to 50% pancreatectomy. These were then treated with nicotinamide (350 mg/kg body weight) before and after streptozotocin (200 mg/kg body weight) administration. The changes in body weight, blood glucose levels, serum and pancreatic insulin contents of these animals were monitored in experimental and control group for 12 weeks, and follow up studies were made of these animals for further 12 weeks. It was found that there was a drastic loss of body weight, decreased serum and pancreatic insulin levels coupled with sustained and low levels of hyperglycemia in the experimental group as opposed to the control group. The results indicate that partial pancreatectomy followed by nicotinamide and streptozotocin treatment leads to a long-lasting hyperglycemic state, depicting the clinical symptom of NIDDM without mortality. The study probably reveals a new model for experimental diabetes.     

Low dose streptozotocin diabetes after partial pancreatectomy in dogs. Histological findings in a new type of experimental diabetes

Permanent diabetes was produced in 16 out of 55 dogs by partial pancreatectomy (77% of the calculated organ weight) and simultaneous infusion of 2 mg/kg streptozotocin into the superior pancreaticoduodenal artery. The animals exhibited hyperglycemia, absolute lack of endogenous B-cell function, and ketosis, but no exocrine pancreatic insufficiency. 21 animals needed up to 7 additional subsequent intravenous streptozotocin injections (15 mg/kg each at intervals of 3 days). In 18 animals the procedure failed to render them diabetic; they died mainly from toxic effects of the drug. There were severe pathohistological changes in all streptozotocin-treated animals. Besides the well known alterations of the islets of Langerhans, lymphocytic inflammations were found in numerous organs including the exocrine pancreas. In most cases they were combined with degenerative changes of the organ parenchyma, particularly in kidney and liver. These findings were not correlated to the sex of the animals, to the occurrence and severity if diabetes, to the time of survival, or to the streptozotocin dose applied. But they were obviously related to the clinical picture existing besides diabetes. It is concluded that the model of experimental diabetes presented might be useful in a carnivorous big animal species but that toxic streptozotocin effects are to be expected when the dose administered exceeds 2 mg/kg.     

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.     

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.     

Muscle collagen content in diabetic rats

Collagen content (mg/dl of dry weight) was measured biochemically in the extensor digitorum longus and the soleus muscle in rats. Comparison of muscles from diabetic (induced by intraperitoneal streptozotocin injection /60 mg/kg body weight/) and non diabetic controls showed an increase in the collagen content of the extensor digitorum longus, and little change in the soleus. The differences did not attain statistical significance indicating that the accelerated collagen ageing attributed to diabetes may not necessarily be true in all tissues.     

Beneficial effect of vitamin E on the metabolic parameters of diabetic rats

The role of vitamin E in the pathogenesis of diabetes mellitus is unknown. The purpose of this study was to examine the effect of oral administration of vitamin E on some of the metabolic parameters of experimental diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (60 mg/kg body weight at 12 weeks of age). Vitamin E (0.2, 0.4, 0.8 mg/kg body weight) was administered orally for a period of 3 weeks to normal and diabetic Wistar rats. In some experiments, Vitamin E was given either before or after the induction of diabetes mellitus. Blood glucose level and weight were recorded for each rat in different groups on a weekly basis. Oral glucose tolerance test (OGTT) was performed on fasted normal, diabetic and vitamin E treated rats at the end of the experiment. Vitamin E significantly (p < 0.01) reduced blood glucose levels in experimental diabetes mellitus at all doses as compared to untreated rats. Vitamin E induced weight loss in normal as well as in diabetic rats. The beneficial effect of vitamin E on the hyperglycaemia of diabetic rats was dose-dependent. Moreover, vitamin E also improved OGTT in diabetic rats compared to untreated diabetics. In conclusion, vitamin E may play a role in glucose metabolism and thus be a useful adjuvant therapy in type I diabetes. (Mol Cell Biochem 261: 35–42, 2004)     

Ameliorating effect of eugenol on hyperglycemia by attenuating the key enzymes of glucose metabolism in streptozotocin-induced diabetic rats

Epidemiological studies have demonstrated that diabetes mellitus is a serious health burden for both governments and healthcare providers. This study was hypothesized to evaluate the antihyperglycemic potential of eugenol by determine the activities of key enzymes of glucose metabolism in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced into male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg body weight (b.w.)). Eugenol was administered to diabetic rats intragastrically at 2.5, 5, and 10 mg/kg b.w. for 30 days. The dose 10 mg/kg b.w. significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and liver marker enzymes (AST, ALT, and ALP), creatine kinase and blood urea nitrogen in serum and blood of diabetic rats were significantly reverted to near normal levels by the administration of eugenol. Further, eugenol administration to diabetic rats improved body weight and hepatic glycogen content demonstrated the antihyperglycemic potential of eugenol in diabetic rats. The present findings suggest that eugenol can potentially ameliorate key enzymes of glucose metabolism in experimental diabetes, and it is sensible to broaden the scale of use of eugenol in a trial to alleviate the adverse effects of diabetes.     

Induction of experimental diabetes in frog (author's transl)]

The effect of diabetogenic agents, alloxan and streptozotocin, in frogs has been studied. These drugs were administered to the animals by injection into the dorsal lymph sac. Alloxan did not exert any effect at non-lethal doses. At 300 mg/kg alloxan caused death of most of the animals in an hyperglycemic state in less than 72 hours. Streptozotocin at doses lower than 1 g/kg was ineffective. At 1.5 g/kg, a non-lethal dose, about half of the animals became diabetic.     

Impact of experimental diabetes and insulin replacement on epididymal secretory products and sperm maturation in albino rats

The present study is aimed to explore the impact of experimental diabetes and insulin replacement on epididymal secretory products, sperm count, motility, and fertilizing ability in albino rats. Prepubertal and adult male Wistar strain rats were made diabetic with a single intraperitoneal injection of streptozotocin (STZ), at 120 and 65 mg/kg body weight for prepubertal and adult rats, respectively. After 3 days of STZ administration, insulin was given to a group of diabetic rats at a dose of 3 U/100 g body weight, subcutaneously and killed after 20 days of treatment. STZ‐diabetes significantly reduced the epididymal tissue concentrations of testosterone, androgen‐binding protein, sialic acid, glycerylphosphoryl choline, and carnitine, suggesting its adverse effects on the secretory activity and concentrating capacity of epididymal epithelium. Impaired cauda epididymidal sperm motility and fertility (in vivo) of STZ‐diabetic rats imply the defective sperm maturation. Insulin replacement prevented these changes either partially or completely. From the above findings, it is evident that STZ‐diabetes has an adverse effect on sperm maturation, which may be due to the decrease in the bioavailability of testosterone and epididymal secretory products. J. Cell. Biochem. 108: 1094–1101, 2009. © 2009 Wiley‐Liss, Inc.     

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.     

Antihyperglycemic effect of fraxetin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats

Epidemiological studies have demonstrated that the diabetes mellitus is a serious health burden for both governments and healthcare providers. The present study was hypothesized to evaluate the antihyperglycemic potential of fraxetin by determining the activities of key enzymes of carbohydrate metabolism in streptozotocin (STZ) – induced diabetic rats. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg b.w). Fraxetin was administered to diabetic rats intra gastrically at 20, 40, 80 mg/kg b.w for 30 days. The dose 80 mg/kg b.w, significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as glucokinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and hepatic enzymes (aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)) in the liver tissues of diabetic rats were significantly reverted to near normal levels by the administration of fraxetin. Further, fraxetin administration to diabetic rats improved body weight and hepatic glycogen content demonstrated its antihyperglycemic potential. The present findings suggest that fraxetin may be useful in the treatment of diabetes even though clinical studies to evaluate this possibility may be warranted.     

Prevention of nicotine and streptozotocin treatment induced circulatory oxidative stress by bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione in diabetic rats

Diabetes and smoking have been considered as major health problems individually and their seriousness related to health hazard has been well reported. The role of nicotine in causing or worsening effect on diabetes is not well understood. The aim of our study was to investigate the effect of nicotine on experimental diabetes and to analyze the effect of bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione a bisdemethoxy curcumin analog (BDMCA) in streptozotocin and nicotine induced toxicity. Group I: control rats; Group II: nicotine (2.5 mg/kg b.wt); Group III: streptozotocin (STZ) (40 mg/kg b.wt); Group IV: STZ (40 mg/kg b.wt) + nicotine (2.5 mg/kg b.wt); Group V: STZ + nicotine + BDMCA (40 mg/kg b.wt); Group VI: STZ + nicotine + BDMCA (80 mg/kg b.wt). Efficacy of BDMCA was determined by evaluating blood glucose, thiobarbituric acid reactive substances (TBARS), hydroperoxides (HP), activities of marker enzymes alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) and activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). From our study, we have observed that nicotine not only aggravates diabetic complications but also increased the risk for diabetes. BDMCA, at a dose 80 mg/kg body weight was found to be more effective in decreasing toxic effects induced by nicotine and STZ.     

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.     

Antihypertensive treatment in spontaneously hypertensive rats with streptozotocin-induced diabetes mellitus

Recent clinical reports have suggested that hypertension accelerates the progress of diabetic nephropathy and retinopathy, whereas antihypertensive treatments may retard them. Thus, the effect of antihypertensive treatment in diabetes mellitus with hypertension was evaluated in rats. A model of diabetes mellitus with hypertension has been developed in spontaneously hypertensive (SHR) rats by unilateral nephrectomy and streptozotocin (STZ, 30 mg/kg, i.v. treatment). The rats were treated with four antihypertensive drugs orally for 12 weeks thereafter. STZ treatment induced chronic hypeglycaemia (300-400 mg/dl), decreased body weight and heart rate, and caused vascular changes of ophthalmic fundi and cataracta. The kidney of these rats showed proliferative changes such as periarteritis nodosa, hyperplasia, or fibronecrosis of the arterioles, exudative changes, mesangial proliferation, or thickening of the basement membrane of the glomeruli. Enalapril (10 mg/kg per day) and remipril (Hoe 498) (1 mg/kg per day), converting enzyme inhibitors, or arotinolol (20 mg/kg per day), a beta-adrenoceptor blocking drug, decreased blood pressure, prevented the development of renal and ocular lesions, and tended to increase creatinine clearance. Nisoldipine (3 mg/kg per day), a calcium-entry blocking drug, tended to decrease blood glucose, and prevented the decrease of body weight and development of ocular lesions. In conclusion, antihypertensive treatments were effective in preventing the progress of diabetic retinopathy and nephropathy, and renal insufficiency in this animal model.     

Effects of vanadate on plasma lipoprotein profiles in experimental diabetic rats

The insulin-like effects of vanadate have been intensively studied in the biological system. Lipids and lipoprotein profiles are altered in diabetes. Rats were made diabetic by a single i.v. injection of streptozotocin (55 mg/kg body weight) in citrate buffer. After the overt of diabetes, the diabetic rats were treated with sodium orthovanadate (0.3 mg/ml) for fifteen days. The altered cholesterol, phospholipids and triglycerides in plasma lipoprotein fractions (HDL, LDL and VLDL) were found to be reverted back to near normal levels in vanadate treated diabetic rats.     

Effect of chronic treatment with losartan on streptozotocin-induced renal dysfunction

The present investigation was undertaken to study the effect of chronic treatment with angiotensin (AT₁) receptor antagonist losartan (2 mg/kg, p.o., 6 weeks) on streptozotocin (STZ) induced (45 mg/kg, i.v., single dose) renal dysfunctions in diabetic rats. Injection of streptozotocin produced not only the cardinal symptoms of diabetes mellitus like loss of body weight, hyperglycemia, and hypoinsulinemia but also the renal dysfunctions. Losartan treatment significantly prevented all these changes except STZ-induced hypoinsulinemia. There was a significant elevation of blood pressure in diabetic rats and treatment with losartan significantly brought it back to normal. Renal dysfunction in diabetic rats was characterized by a significant decrease in creatinine clearance, elevated levels of electrolytes and renal hypertrophy. Treatment with losartan prevented these changes. A good correlation was found between biochemical parameters and histopathological abnormalities. Our data suggests that, losartan may be considered as the drug of choice when there is a co-existence of diabetes mellitus and hypertension with compromised kidney function.     

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.     

Effect of streptozotocin diabetes on the pituitary-testicular axis in the rat

The pituitary-testicular axis was investigated in the streptozotocin diabetic male rat to determine the relationship between hormonal alterations and steroidogenic activity. Male Sprague-Dawley rats weighing 250-300 g were used in all experiments. Diabetes was induced by intraperitoneal injection (40 mg/kg body wt.) of streptozotocin and they were studied with non-diabetic controls. The observations on these animals were compared to those from diabetic rats treated with 1-5 IU protamine zinc insulin. Steroidogenic activity was determined by measuring the per cent of [4-14C]-cholesterol converted to [4-14C]-pregnenolone and [4-14C]-progesterone. Plasma concentrations of LH, FSH and prolactin were measured by RIA. Streptozotocin induced diabetes resulted in significantly reduced plasma LH (34%, p less than 0.20) and prolactin (53%, p less than 0.001) but did not modify FSH concentrations. Insulin treatment completely and partially restored abnormal LH and prolactin release. The activity of the enzyme cleaving the side-chain of cholesterol (rate limiting step in steroidogenesis) was considerably reduced in the diabetic state (59%, p less than 0.002) and insulin treatment restored it to even supranormal levels (not significant). Our findings suggest that insulin may play a physiological and differential role in regulating the secretory activity of the anterior pituitary. The insulin is needed for normal LH and prolactin release and Leydig cells function but its role in FSH release and Sertoli cells function is not clear.     

Hypoglycemic effect of Sclerocarya birrea {(A. Rich.) Hochst.} [Anacardiaceae] stem-bark aqueous extract in rats

This study was undertaken to evaluate the hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] subspecies caffra (Sond.) Kokwaro [family: Anacardiaceae] stem-bark aqueous extract in normal (normoglycemic) and in streptozotocin (STZ)-treated, diabetic Wistar rats. In one set of experiments, graded doses of S. birrea stem-bark aqueous extract (SB, 100-800 mg/kg p.o.) were separately administered to groups of fasted normal and fasted diabetic rats. In another set of experiments, a single dose of the plant aqueous extract (SB, 800 mg/kg p.o.) was used. The hypoglycemic effect of this single dose (SB, 800 mg/kg p.o.) of S. birrea stem-bark aqueous extract was compared with that of chlorpropamide (250 mg/kg p.o.) in both fasted normal and fasted diabetic rats. Following acute treatment, relatively moderate to high doses of S. birrea stem-bark extract (SB, 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. Chlorpropamide (250 mg/kg p.o.) also produced significant reductions (P < 0.05-0.001) in the blood glucose concentrations of the fasted normal and fasted diabetic rats. Administrations of the single dose of S. birrea stem-bark aqueous extract (SB, 800 mg/kg p.o.) significantly reduced (P 0.01 < 0.001) the blood glucose levels of both fasted normal (normoglycemic) and fasted STZ-treated, diabetic rats. The results of this experimental animal study indicate that aqueous extract of Sclerocarya birrea possesses hypoglycemic activity, and thus lend credence to the suggested folkloric use of the plant in the management and/or control of adult-onset, type-2 diabetes mellitus in some African communities.