Attenuation of streptozotocin diabetes with superoxide dismutase-like copper(II)(3,5-diisopropylsalicylate)2 in the rat

Summary Experimental diabetes can be produced by agents with specific toxicity for pancreatic islet B cells. This effect has been reported to be modified both in vitro and in vivo by various radical scavengers including the enzyme Superoxide dismutase. Copper(II)(3,5-diisopropylsalicylate)₂ is lipophilic and possesses Superoxide dismutase bioactivity. Prior administration of this compound to male rats appeared to attenuate the severity of streptozotocin-induced diabetes as assessed by glycosuria and glucose tolerance. Diisopropylsalicylate, which has no Superoxide dismutase activity, did not alter the severity of streptozotocin-induced diabetes. Rats treated with the copper complex, with Streptozotocin or with a combination of the two agents gained 50% less weight than untreated controls, or rats treated with diisopropylsalicylate. The attenuation of diabetes by the copper-complex may represent partial protection of the B cells against Streptozotocin damage, although an extrapancreatic, toxic effect cannot be ruled out.     

Effects of Folic Acid on Cardiac Myocyte Apoptosis in Rats with Streptozotocin-induced Diabetes Mellitus

BACKGROUNDS: The effect of folic acid on cardiac myocyte apoptosis secondary to diabetes is unknown. METHODS: Diabetic rats were divided into diabetic control (DC, n = 11), low-dose (LDF, 0.4 mg/kg/day, n = 12) and high-dose (HDF, 1.2 mg/kg/day, n = 12) folic acid groups. Non-diabetic rats (n = 11) were used as the normal control (NC). RESULTS: After 11 weeks of treatment, compared with the NC group, the DC group showed a reduced blood levels of reactive oxygen species (ROS, P < 0.01). The rate of cardiac myocyte apoptosis in the diabetic control group was also greater than in the non-diabetic control group (P < 0.01). In folic acid-treated rats, the blood levels of ROS was higher than in the diabetic control group (P < 0.05). There was a dose-dependent reduction in the rate of cardiac myocyte apoptosis in the folic acid groups (P < 0.01), and this was accompanied by an increased level of anti-apoptotic protein Bcl-2 and decreased level of pro-apoptotic protein Bax and Fas (P < 0.01). CONCLUSIONS: Dietary folic acid supplementation diminishes the cardiac myocyte apoptosis in streptozotocin-induced diabetes. The apoptosis suppression is accompanied by an increase in the expression of Bcl-2 and a decrease in Bax and Fas.     

Restricted effect of formycin A and non-glucidic nutrients upon insulin release in islets from rats with hereditary or acquired non-insulin-dependent diabetes

Pancreatic islets isolated from control rats, Goto-Kakizaki rats and adult rats that were injected with streptozotocin during the neonatal period were incubated for two successive periods of 90 min each in the presence ofd-glucose (11.1 mM) with or without formycin A (1.0 mM), and in the presence of the dimethyl ester of succinic acid (SAD, 10.0 mM) with or without palmitate (1.0 mM). Although formycin A augmented glucose-stimulated insulin release in both control and diabetic rats, it failed to compensate for the impaired secretory response tod-glucose in the latter animals. Likewise, non-glucidic nutrients such as SAD and/or palmitate failed to display a more efficient insulinotropic action, relative to basal insulin output, in diabetic than control rats. These results indicate that both formycin A and non-glucidic nutrients are unable, through their immediate insulinotropic action, to restore a normal output of insulin in islets of animals with inherited or acquired non-insulin-dependent diabetes.     

Destruction of the blood-retina barrier in diabetic retinopathy depends on angiotensin-converting enzyme-mediated TGF-β1/Smad signaling pathway activation

Diabetes mellitus (DM) is a systemic, chronic metabolic disease that is related to heredity and autoimmunity and is often accompanied by complications of retinopathy. However, the causative mechanism involved in the pathological process remains unclear. In this research, treatment with fosinopril or LY2109761 was found to be responsible for the improvement of the pathological processes, serum biochemical indexes and retinopathy in rats with streptozotocin-induced diabetes. In addition, the upregulation of angiotensin-converting enzyme (ACE) in the serum and the increased expression of TGF-β1 in the pathological outer nuclear layer (ONL) and inner nuclear layer (INL) of the retina were also reduced. In vitro experiments demonstrated that ACE enhanced cell damage and TGF-β1/Smad signaling pathway activation in retinal capillary endothelial cells (RCECs) under high glucose conditions. In addition, the activity of ACE was also considered to be related to the increasing levels of activated TGF-β1 in both rat retinal Müller cells (RMCs) and RCECs, but ACE activity had no effect on the high glucose-mediated upregulation of total TGF-β1 in RMCs. Coculture experiments with RCECs and RMCs showed that the barrier that was established under normal conditions was significantly impaired when exposed to high glucose combined with ACE, and damage of barrier can be prevented by adding fosinopril or LY2109761. Finally, a similar auxiliary effect of ACE was also observed in the activated TGF-β1-mediated barrier damage in blood-retinal barrier model in vitro. In summary, ACE-mediated TGF-β1/Smad signaling pathway activation was found to be involved in the destruction of the blood-retina barrier during diabetic retinopathy in a model of streptozotocin-induced diabetes, and these data may provide evidence to guide the treatment of the complications of diabetes mellitus.     

Modulation of antioxidant status in streptozotocin-induced diabetic male wistar rats following intake of red palm oil and/or rooibos

Objective:To investigate the role of red palm oil(RPO),rooibos tea extract(RTE)and their combined treatment(RPO+RTE)on antioxidant status in streptozotocin(STZ)-induced diabetic rats.Methods:Diabetes mellitus was induced by a single administration of streptozotocin(50 mg/kg)and the rats were treated for 7 weeks.Antioxidant enzymes[calalase(CAT),glutathione peroxidase(GPx),superoxide dismutase(SOD)],antioxidant capacity[trolox equivalence antioxidant capacity(TEAC),oxygen radical absorbance capacity(ORAC)]as well as total protein,albumin,globulin,total glutathione,conjugated diene and thiobarbituric acid reactive substances(TBARS)were investigated.Results:Treatment with RPO,RTE and RPO+RTE significantly(p0.05)improved liver SOD and plasma ORAC in the diabetic rats.Similarly,diabetic rats treated with RTE and RPO+RTE enhanced liver GPx.A significant(P0.05)increase in the plasma TBARS in the diabetic control group was observed when compared with the normal control group.Treatment of diabetic rats with RTE and RPO+RTE reduced plasma TBARS to a level not significantly different at P0.05 from the normal control group.Conclusions:The results revealed the anti-oxidative potentials of red palm oil,rooibos and their combination in diabetic conditions and hence,they could be useful in the management of diabetes and its complications.     

Modeling type 2 diabetes in rats using high fat diet and streptozotocin

The pathology of type 2 diabetes is complex, with multiple stages culminating in a functional β‐cell mass that is insufficient to meet the body's needs. Although the broad outlines of the disease etiology are known, many critical questions remain to be answered before next‐generation therapeutics can be developed. In order to further elucidate the pathobiology of this disease, animal models mimicking the pathology of human type 2 diabetes are of great value. One example of a type 2 diabetes animal model is the high‐fat diet‐fed, streptozotocin (HFD/STZ)‐treated rat model. The present review first summarizes the current understanding of the metabolic profile and pathology involved in the different stages of the type 2 diabetes disease progression in humans. Second, the known characteristics of the HFD/STZ rat model are reviewed and compared with the pathophysiology of human type 2 diabetes. Next, the suitability of the HFD/STZ model as a model of type 2 diabetes with a focus on identifying critical caveats and unanswered questions about the model is discussed. The improved understanding of refined animal models will hopefully lead to more relevant preclinical studies and development of improved therapeutics for diabetes. Depending on the amount of residual functional β‐cells mass, the HFD/STZ rat model might be a suitable animal model of the final stage of type 2 diabetes.     

Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer's disease by exendin-4

Growing evidence suggests that type 2 diabetes mellitus (DM) is associated with age-dependent Alzheimer's disease (AD), the latter of which has even been considered as type 3 diabetes. Several physiopathological features including hyperglycemia, oxidative stress, and dysfunctional insulin signaling relate DM to AD. In this study, high glucose-, oxidative stress-induced neuronal injury and intracerebroventricular-streptozotocin (ICV-STZ) animals as the possible models for diabetes-related AD were employed to investigate the effects of exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, on diabetes-associated Alzheimer-like changes as well as the molecular mechanisms involved. Our study demonstrated that GLP-1/Ex-4 could exert a protective effect against reduced viability of PC12 cells caused by high glucose and that this protective effect was mediated via the PI3-kinase pathway. In addition, GLP-1/Ex-4 ameliorated oxidative stress-induced injury in PC12 cells. In rat models, bilateral ICV-STZ administration was used to produce impaired insulin signaling in the brain. Fourteen days following ICV-STZ injection, rats treated with twice-daily Ex-4 had better learning and memory performance in the Morris water maze test compared with rats treated with saline. Additionally, histopathological evaluation confirmed the protective effects of Ex-4 treatment on hippocampal neurons against degeneration. Furthermore, we demonstrated that Ex-4 reversed ICV-STZ-induced tau hyperphosphorylation through downregulation of GSK-3β activity, a key kinase in both DM and AD. Our findings suggests that Ex-4 can protect neurons from diabetes-associated glucose metabolic dysregulation insults in vitro and from ICV-STZ insult in vivo, and that Ex-4 may prove of therapeutic value in the treatment of AD especially DM-related AD.     

Antidiabetic and enzymatic antioxidant properties from methanol extract of Ficus talboti bark on diabetic rats induced by streptozotocin

ObjectiveTo explore scientifically, the type–I anti-diabetic potential of Ficus talboti bark (FTB).MethodsThe HPLC analysis was carried out to identify the phenolic compounds. Effect of two doses of methanol extract of FTB (100 mg/kg and 200 mg/kg body wt.) was orally administered to STZ (Streptozotocin) induced diabetic rats for 21 days. The various parameters were studied including body weight, fasting blood glucose levels, plasma insulin, lipid profile, glycogen content, total protein, serum enzymes levels, and antioxidant activities in normal, treated and diabetic rats. Histochemical analysis of liver and pancreas were also carried out in normal, treated and diabetic rats.ResultsThe HPLC analysis showed the presence of antidiabetic responsible compounds of Rutin, Quercetin and Kaemfeorl. The treatment group with the extract at two dose levels showed a significant increase in the liver, muscle glycogen and serum insulin level and a significant decrease in fasting blood glucose and serum marker enzyme levels. The total cholesterol and serum triglycerides levels were also significantly reduced and the high density lipoprotein and plasma enzymes level was significantly increased upon treatment with the FTB methanol extract. Histochemical study of pancreas also confirmed the biochemical findings. Acute toxicity studies revealed the non-toxic nature of the FTB methanol extract.ConclusionThe results of the experiments presented here suggest that methanol extract of FTB exerts significant antidiabetic and antioxidant effect in STZ induced diabetic rats.     

Chronic effects of streptozotocin diabetes on myocardial sensitivity in the rat

Summary One month after streptozotocin treatment, basal rate in spontaneously beating right atria was decreased and basal developed force in electrically-driven right ventricular tissue was increased. Atrial sensitivity to the chronotropic effects of isoproterenol was not altered. In contrast, sensitivity in ventricular tissue to the inotropic effects of isoproterenol was decreased while sensitivity to calcium was increased. Associated with these changes was a decrease in myocardial-adrenoceptor density. Data obtained 3 and 6 months after streptozotocin treatment were similar to the observed alterations at 1 month. These results suggest that alterations in the chronotropic and inotropic responses that are expressed within 1 month after streptozotocin treatment do not significantly progress during the 6 months following induction of diabetes. They therefore reveal the independence of myocardial alterations from age of the animal and duration of diabetes (up to 6 months).     

Beneficial Antioxidative and Antiperoxidative Effect of Cinnamaldehyde Protect Streptozotocin-Induced Pancreatic β-Cells Damage in Wistar Rats

The present study was aimed to evaluate the antioxidant defense system of cinnamaldehyde in normal, diabetic rats and its possible protection of pancreatic β-cells against its gradual loss under diabetic conditions. In vitro free radical scavenging effect of cinnamaldehyde was determined using DPPH (1,1-diphenyl-2-dipicrylhydrazyl), superoxide radical, and nitric oxide radical. Streptozotocin (STZ) diabetic rats were orally administered with cinnamaldehyde at concentrations of 5, 10 and 20 mg/kg body weight for 45 days. At the end of the experiment, the levels of plasma lipid peroxides and antioxidants such as vitamin C, vitamin E, ceruloplasmin, catalase, superoxide dismutase, reduced glutathione and glutathione peroxidase were determined. A significant increase in the levels of plasma glucose, vitamin E, ceruloplasmin, and lipid peroxides and significant decrease in the levels of plasma insulin and reduced glutathione were observed in the diabetic rats. Also the activities of pancreatic antioxidant enzymes were altered in the STZ-induced diabetic rats. The altered enzyme activities were reverted to near-normal levels after treatment with cinnamaldehyde and glibenclamide. Histopathological studies also revealed a protective effect of cinnamaldehyde on pancreatic β-cells. Cinnamaldehyde enhances the antioxidant defense against reactive oxygen species produced under hyperglycemic conditions and thus protects pancreatic β-cells against their loss and exhibits antidiabetic properties.