Long-term correction of STZ-diabetic rats after short-term i.p. VOSO4 treatment: Persistence of insulin secreting capacities assessed by isolated pancreas studies

We have previously shown that 3 week oral VOSO₄ treatment of streptozotocin (STZ, 60 mg/kg)-induced diabetic rats was able to correct diabetes for 13 weeks after treatment withdrawal. In the present study, we investigated whether a short-term (8 days) i.p. VOSO₄ treatment was similarly able to reverse the diabetic state. Insulin secretory capacities were assessed at distance of treatment using the isolated pancreas preparation. Seven treatment-groups were performed: high dose VOSO₄-treated diabetics (HVD, 1.3 mM/kg/8 days), food-restricted diabetics (FRD, food adjusted to HVD levels), low dose VOSO₄-treated diabetes (LVD, 0.06 mM/kg/day), insulin-treated diabetics (ID, dose adjusted to normalize glycaemia) and VOSO₄ (0.06 mM/kg/day) + insulin (dose adjusted to normalize glycaemia in the presence of vanadium)-treated diabetics (IVD), in addition to the corresponding untreated non-diabetic controls (C) and diabetics (D). Our results indicate that long-term correction of diabetes (a) can be obtained after an 8 day treatment using i.p. VOSO₄ in diabetic animals retaining some degree of pancreatic function, (b) is not obtained with insulin treatment or food restriction although the association of VOSO₄ and insulin was found beneficial, (c) can be prolonged in some individuals for at least 4 months, i.e. in conditions such that tissue vanadium concentrations had returned to values close to pre-treatment levels, (d) is associated with improved and in some cases normalized insulin secretion from isolated pancreas. The protective or corrective role of VOSO₄ on diabetes-related pancreatic alterations, as well as the potential of the VOSO₄-insulin association should be further studied in view of the possible use of vanadium derivatives in the treatment of diabetes.     

Galangin,a dietary flavonoid,improves antioxidant status and reduces hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats

Objective: To examine the effect of galangin on hyperglycemia-mediated oxidative stress in streptozotocin (STZ)-induced diabetic rats.

Methods: Diabetes was induced by intraperitoneal administration of low-dose STZ (40?mg/kg body weight (BW)) into male albino Wistar rats. Galangin (8?mg/kg BW) or glibenclamide (600?µg/kg BW) was given orally, once daily for 45 days to normal and STZ-induced diabetic rats.

Results: Diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes. The levels of insulin and non-enzymatic antioxidants (vitamin C, vitamin E, reduced glutathione) and the activity of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase (GST)) were decreased significantly in diabetic control rats. These altered plasma glucose, insulin, lipid peroxidation products, enzymatic and non-enzymatic antioxidants ions were reverted to near-normal level after the administration of galangin and glibenclamide.

Conclusion: The present study shows that galangin decreased oxidative stress and increased antioxidant status in diabetic rats, which may be due to its antidiabetic and antioxidant potential.     

Thymoquinone ameliorates chemical induced oxidative stress and β-cell damage in experimental hyperglycemic rats

The present study was aimed to investigate the effect of thymoquinone (TQ) on pancreatic insulin levels, tissue antioxidant and lipid peroxidation (LPO) status in streptozotocin (STZ) nicotinamide (NA) induced diabetic rats. Diabetes was induced in experimental rats by a single intraperitoneal (i.p) injection of STZ (45 mg/kg b.w) dissolved in 0.1 mol/L citrate buffer (pH 4.5), 15 min after the i.p administration of NA (110 mg/kg b.w). Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. The activities of antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and the levels of low-molecular weight antioxidants Vitamin C, Vitamin E and reduced glutathione (GSH) were decreased while increases in the levels of lipid peroxidation markers were observed in liver and kidney tissues of diabetic control rats as compared to control rats. In addition, diabetic rats showed an obvious decrease in pancreatic insulin levels. Administration of TQ (80 mg/kg b.w) to diabetic rats for 45 days significantly reversed the damage associated with diabetes. Biochemical findings were supported by histological studies. These results indicated that TQ exerts a protective action on pancreatic beta cell function and overcomes oxidative stress through its antioxidant properties.     

Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress

This study aimed to investigate whether treatments with vitamin E, L-carnitine and melatonin can protect against CCl₄ and diabetes-induced hepatic oxidative stress. Hepatic oxidative stress was performed in rats through 50% v/v carbon tetrachloride (CCl₄) (1 ml/kg/3days, i.p.), and through diabetes mellitus induced by streptozotocin (STZ) (40 mg/kg, i.p.). Vitamin E (100 mg/kg/day, i.p), L-carnitine (300 mg/kg/day, i.p.) and melatonin (10 mg/kg/day, i.p.) were injected for a period of 6 weeks. Thereafter, changes in serum glucose level, liver function tests, hepatic malondialdehyde (MDA) content, hepatic reduced glutathione (GSH) content, hepatic superoxide dismutase (SOD) activity, and serum total antioxidant capacity (TAC) level were evaluated. In CCl₄-induced liver fibrosis, the efficacy order was melatonin > L-carnitine > vitamin E, while in STZ-induced diabetes, the efficacy order was vitamin E ≥ melatonin > L-carnitine. In conclusion, these data indicate that low dose of melatonin is more effective than high doses of vitamin E and L-carnitine in reducing hepatic oxidative stress induced by CCl₄ and diabetes. Moreover, the potent effect of vitamin E in ameliorating diabetes can be linked not only to the antioxidant actions, but also to the superior effect in reducing diabetes-induced hyperglycaemia. Meanwhile, potency of L-carnitine was nearly the same in CCl₄ and diabetes-induced liver damage.     

Effect of sakuranin on carbohydrate-metabolizing enzyme activity modifications in streptozotocin-nicotinamide-induced diabetic wistar rats

This study is to assess the glucose lowering activity of sakuranin in diabetes induced rats by streptozotocin (STZ) and nicotinamide (NA). Diabetic rats were treated sakuranin for 45 days (20, 40, 80 mg/kg) by orally. Sakuranin (80 mg/kg body weight) was normalized the changes of abnormal blood glucose plasma glucose and plasma insulin levels. Hence, we have continued the further research with this active dose of 80 mg/kg sakuranin. The plasma glucose and glycosylated hemoglobin (HbA₁c) reduced and insulin, glycogen and hemoglobin levels increased by Sakuranin administration in diabetic rats. Additionally, hexokinase and glucose-6-phophate dehydrogenase activities increased and glucose-6-phosphatase and fructose-1,6-bisphosphatase activities decreased in diabetic condition while administration of treated compound. In this observed result signified that sakuranin may have potential role of diabetic condition rats by evidenced with reducing glucose and increasing insulin and also protect the carbohydrate metabolic changes.     

Melatonin relieves diabetic complications and regenerates pancreatic beta cells by the reduction in NF-kB expression in streptozotocin induced diabetic rats

Melatonin, a pleiotropic hormone, has many regulatory effects on the circadian and seasonal rhythms, sleep and body immune system. It is used in the treatment of blind circadian rhythm sleep disorders, delayed sleep phase and insomnia. It is a potent antioxidant, anti-inflammatory, free radical scavenger, helpful in fighting infectious disease and cancer treatment. Decreased level of circulating melatonin was associated with an increased blood glucose level, losing the anti-oxidant protection and anti-inflammatory responses. We aimed to evaluate the effect of melatonin administration, in streptozotocin (STZ) induced diabetic rats, on blood glucose level and pancreatic beta (β) cells. Diabetes mellitus was induced in Sprague dawley male rats by the intravenous (i.v) injection of 65 mg/kg of STZ. Diabetic rats received melatonin at a dose of 10 mg/kg daily for 8 weeks by oral routes. The results showed, after 8 weeks of melatonin administration, a reduction in: 1- fasting blood glucose (FBG) and fructosamine (FTA) levels, 2- kidney and liver function parameters, 3- levels of serum triglycerides, cholesterol and LDL-C, 4- malondialdehyde (MDA), 5- NF-κB expression in treated group, 6- pro-inflammatory cytokines (IL-1β and IL-12) and immunoglobulins (IgA, IgE and IgG). Furthermore, an elevation in insulin secretion was noticed in melatonin treated group that indicated β cells regeneration. Therefore, melatonin administration, in STZ induced diabetic rats; reduced hyperglycemia, hyperlipidemia and oxidative stress. Melatonin acted as an anti-inflammatory agent that reduced pro-inflammatory cytokines (IL-1β and IL-12) and oxidative stress biomarkers (MDA). Melatonin succeeded in protecting β cells under severe inflammatory situations, which was apparent by the regeneration of islets of Langerhans in treated diabetic rats. Moreover, these results can open a gate for diabetes management and treatment.     

Impaired duodenal bicarbonate secretion in diabetic rats. Salutary effect of nitric oxide synthase inhibitor

We previously reported the impaired HCO₃⁻ secretion and the increased mucosal susceptibility to acid in the duodenum of streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the salutary effect of the NO synthase inhibitor L-NAME (N^G-nitro-L-arginine methyl ester) on these changes and compared it with those of insulin. Animals were injected streptozotocin (STZ: 70 mg/kg, ip) and used after 1, 3–4, and 5–6 weeks of diabetes with blood glucose levels of > 300 mg/dL. Under urethane anesthesia the HCO₃⁻ secretion was measured in the proximal duodenal loop using a pH-stat method and by adding 10 mM HCl. L-NAME (20 mg/kg × 2) or insulin (4 units/rat) was administered sc for 4–5 weeks, starting 1 week after STZ treatment. The duodenal HCO₃⁻ secretory responses to various stimuli such as mucosal acidification (10 mM HCl for 10 min), 16,16-dimethyl prostaglandin E₂ (dmPGE₂: 10 μg/kg, iv), and vagal stimulation (0.5 mA, 2 ms, 3 Hz) were significantly decreased in STZ-treated rats, depending on the duration of diabetes. Repeated administration of L-NAME, starting from 1 week after STZ treatment, significantly reduced blood glucose levels toward normal values and restored the HCO₃⁻ responses to various stimuli in STZ rats, the effects being similar to those observed after supplementation of insulin. Diabetic rats developed duodenal lesions after perfusion of the duodenum with 150 mM HCl for 4 h, but this ulcerogenic response was significantly inhibited by the repeated treatment with L-NAME as well as insulin. We conclude that L-NAME is effective in ameliorating hyperglycemic conditions in STZ-diabetic rats, similar to insulin, and restores the impaired HCO₃⁻ secretion and the increased mucosal susceptibility to acid in diabetic rat duodenums.     

Blockade of sphingosine 1-phosphate receptor 2 signaling attenuates streptozotocin-induced apoptosis of pancreatic β-cells

Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that acts through five cognate G protein-coupled receptors (S1P₁-S1P₅) and regulates many critical biological processes. Recent studies indicated that S1P at nanomolar concentrations significantly reduces cytokine-induced apoptosis of pancreatic β-cells in which genes for S1P₁-S1P₄ are co-expressed. However, the S1P receptor subtype(s) involved in this effect remains to be clarified. In this study, we investigated the potential role of S1P₂ in streptozotocin (STZ)-induced apoptosis of pancreatic β-cells and progression of diabetes. S1P₂-deficient (S1P₂^-/-) mice displayed a greater survive ability, lower blood glucose levels, and smaller numbers of TUNEL-positive apoptotic β-cells to administration of a high dose of STZ than wild-type (WT) mice. S1P₂^-/- mice showed higher insulin/glucose ratios (an index of relative insulin deficiency) and larger insulin-positive islet areas to administration of a low dose of STZ than WT mice. Moreover, administration of JTE-013, a S1P₂-specific antagonist, to WT mice ameliorated STZ-induced blood glucose elevation and reduced the incidence of diabetes. Our findings indicate that blockade of S1P₂ signaling attenuates STZ-induced apoptosis of pancreatic β-cells and decreases the incidence of diabetes.     

Antioxidant icariside II combined with insulin restores erectile function in streptozotocin‐induced type 1 diabetic rats

Erectile dysfunction (ED) worsens in patients with diabetes mellitus (DM) despite good control of blood glucose level with insulin. Recent studies imply that diabetic vascular stresses (e.g. oxidative stress) persist in spite of glucose normalization, which is defined as metabolic memory. Studies suggest that the interaction between advanced glycation end products (AGEs) and their receptor (RAGE) mediates the development of metabolic memory. To investigate the effects of the antioxidant icariside II plus insulin on erectile function in streptozotocin (STZ)‐ induced type 1 diabetic rats. Fifty 8‐week‐old Sprague‐Dawley rats were randomly distributed into five groups: normal control, diabetic, insulin‐treated diabetic, icariside II‐treated diabetic, and insulin plus icariside II‐treated diabetic. Diabetes was induced by a single intraperitoneal injection of STZ. Eight weeks after induction of diabetes, icariside II was administered by gastric lavage once a day (5 mg/kg) for 6 weeks; and 2–6 units of intermediate‐acting insulin were given to maintain normal glycemia for 6 weeks. The main outcome measures were the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP); histology of penile endothelial cells and smooth muscle cells; neural nitric oxide synthase, AGEs and RAGE expression; malondialdehyde concentration; superoxide dismutase activity; and apoptosis index. Diabetic rats demonstrated a significantly lower ICP/MAP ratio, reduced penile endothelial cells, reduced smooth muscle cells, increased AGEs and RAGE, and increased apoptosis. Insulin and icariside II monotherapy partially restored erectile function and histological changes. However, the combination therapy group showed significantly better erectile parameters, cytological components and biochemistry, similar to those in the normal control group. These results suggest that, although insulin can effectively control glycemic levels, it does not completely alter the pathological changes in erectile tissues. Better efficacy could be expected with tight glycemic control plus the antioxidant icariside II. The proposed combination therapy might have the potential to eliminate metabolic memory by down‐regulating the AGEs‐RAGE‐oxidative stress axis.     

Cortical and hippocampal mitochondria bioenergetics and oxidative status during hyperglycemia and/or insulin-induced hypoglycemia

This study was undertaken to evaluate the effects of streptozotocin (STZ)-induced hyperglycemia and insulin-induced hypoglycemia in cortical and hippocampal mitochondria bioenergetics and oxidative status. For that purpose we used, citrate (vehicle)-treated Wistar rats, STZ-treated rats [i.p., 50 mg/kg body weight] and STZ-treated rats injected with insulin [s.c., dose adjusted to blood glucose levels] 1 h prior to sacrifice to induce an acute episode of hypoglycemia. Several parameters were analyzed: respiratory chain, phosphorylation system, thiobarbituric acid reactive substances (TBARS) levels, hydrogen peroxide (H₂O₂) production rate, and non-enzymatic and enzymatic antioxidant defenses. Cortical mitochondria from insulin-induced hypoglycemic rats present a significant decrease in the ADP/O index, a significant increase in the repolarization lag phase and a decrease in GSH/GSSG ratio when compared with STZ and control mitochondria. Both STZ-induced diabetes and insulin-induced hypoglycemia promote a significant increase in TBARS levels and a decrease in glutathione disulfide reductase activity. Diabetic cortical mitochondria present a significant decrease in glutathione peroxidase (GPx) activity compared to control mitochondria. In turn, insulin-induced hypoglycemia induced a significant increase in GPx and manganese superoxide dismutase (MnSOD) activities. In hippocampal mitochondria, insulin-induced hypoglycemia increases the respiratory control ratio whereas both situations, hyper- and hypoglycemia, potentiate H₂O₂ production and decrease the activity of MnSOD. These results suggest that the poor glycemic control that occurs in type 1 diabetic patients undergoing insulin therapy may have detrimental effects in brain areas involved in learning and memory.     

Ameliorative effect of kaempferol,a flavonoid,on oxidative stress in streptozotocin-induced diabetic rats

Abstract

Objective

The aim of the present study was to evaluate the protective effect of kaempferol against oxidative stress in streptozotocin (STZ)-induced diabetic rats.

Methods

Diabetes was induced in male, adult albino rats of the Wistar strain, by intraperitoneal administration of STZ (40 mg/kg body weight (BW)). Kaempferol (100 mg/kg BW) or glibenclamide (600 µg/kg BW) was administered orally once daily for 45 days to normal and STZ-induced diabetic rats.

Results

The STZ-induced diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes in plasma, liver, kidney, and heart whereas they showed significantly decreased level of plasma insulin. The levels of non-enzymic antioxidants (vitamin C, vitamin E, reduced glutathione) in plasma, liver, kidney, and heart and the activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) in liver, kidney, and heart were significantly decreased in diabetic rats. Administration of kaempferol to diabetic rats was showed brought back in plasma glucose, insulin, lipid peroxidation products, enzymatic, and non-enzymatic antioxidants to near normal.

Conclusion

The present study indicates that kaempferol has a good antioxidant property, as evidenced by its increase of antioxidant status and decrease of lipid peroxidation markers, thus providing protection from the risks of diabetic complications.     

The relationship between nitric oxide and leptin in the lung of rat with streptozotocin-induced diabetes

Lung structural changes and immunoreactivity of endothelial (eNOS)- and inducible nitric oxide synthase (iNOS) were investigated by light microscopy in lungs of treated and untreated diabetic rats. Diabetes was induced by a single intraperitoneal (i.p.) injection of 65 mg kg(-1) streptozotocin (STZ) in Wistar albino male rats. Diabetic rats received daily i.p. doses of dexamethasone (2 mg kg(-1)), leptin (0.5 microg kg(-1)) and intramuscular insulin (20 U kg(-1)) or a combination of these drugs for 1 week starting 4 weeks after the STZ injections. After treatment, the blood levels of glucose, leptin, insulin and nitrate/nitrite (NO(3) (-)/NO(2) (-)) were measured. Dilatation of alveoli and alveolar ducts, partial alveolar wall thickening and increased eNOS- and iNOS characterized the diabetic rat lungs. High blood glucose and nitrate/nitrite levels as well as low insulin and leptin levels were also present. Treatment with insulin, dexamethasone and a combination of these drugs resulted in improvement of the structural and immunohistochemical abnormalities. The most effective treatment was insulin therapy. Leptin administration resulted in increased relative amounts of extracellular material, which led to noticeable respiratory efficiency in the diabetic rat lungs. All treatments except leptin lowered blood glucose levels. The combination of insulin and dexamethasone increased blood leptin and insulin, while the remaining diabetic rats had blood with low leptin and insulin concentrations. These results suggest that therapy with insulin plus dexamethasone but not therapy with leptin is beneficial for diabetics.     

Protective effect of secoisolariciresinol diglucoside against streptozotocin-induced diabetes and its mechanism

Objectives: Reactive oxygen species (ROS) have been implicated in the development of streptozotocin (STZ)-induced diabetes mellitus. Secoisolariciresinol diglucoside (SDG) isolated from flaxseed is an antioxidant. An investigation was made of the effects of SDG on the development of STZ-induced diabetes in rat, to determine if SDG can prevent/reduce the development of diabetes and if this prevention/reduction is associated with reduction in oxidative stress.Design and Methods: The rats were divided into 4 groups: Group I, Control; Group II, SDG (22 mg/kg body wt, orally) for 24 days; Group III, STZ (80 mg/kg intraperitoneally); Group IV, SDG in the dose similar to Group II three days prior to STZ and 21 days thereafter. Oxidative stress was assessed by measuring serum and pancreatic lipid peroxidation product malondialdehyde (MDA), pancreatic antioxidant reserve (pancreatic-CL) and oxygen free radical producing activity of white blood cells (WBC-CL). A diagnosis of diabetes was made on the basis of glucosuria and was confirmed at the time of sacrifice (21 days after STZ treatment) by the presence of hyperglycemia. At the end of the protocol blood samples were collected for estimation of glucose, MDA and WBC-CL, and pancreas were removed for estimation of MDA and antioxidant reserve.Results: Incidence of diabetes was 100% in Group III and 25% in Group IV. SDG prevented the development of diabetes by 75%. Development of diabetes was associated with an increase in serum and pancreatic MDA, and in WBC-CL, and a decrease in pancreatic antioxidant reserve. Prevention of diabetes by SDG was associated with a decrease in serum and pancreatic MDA and WBC-CL and an increase in pancreatic antioxidant reserve.Conclusions: These results suggest that STZ-induced diabetes is mediated through oxidative stress and that SDG is effective in reducing the STZ-induced diabetes mellitus.     

Effect of cerebrocrast, a new long-acting compound on blood glucose and insulin levels in rats when administered before and after STZ-induced diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin secreting pancreatic islets beta-cells. The formation of cytokines (IL-1beta, IL-6, TNF-alpha, etc.) leads to extensive morphological damage of beta-cells, DNA fragmentation, decrease of glucose oxidation, impaired glucose-insulin secretion and decreased insulin action and proinsulin biosynthesis. We examined the protective effect of a 1,4-dihydropyridine (DHP) derivative cerebrocrast (synthesized in the Latvian Institute of Organic Synthesis) on pancreatic beta-cells in rats possessing diabetes induced with the autoimmunogenic compound streptozotocin (STZ). Cerebrocrast administration at doses of 0.05 and 0.5 mg/kg body weight (p.o.) 1 h or 3 days prior to STZ as well as at 24 and 48 h after STZ administration partially prevented pancreatic beta-cells from the toxic effects of STZ, and delayed the development of hyperglycaemia. Administration of cerebrocrast starting 48 h after STZ-induced diabetes in rats for 3 consecutive days at doses of 0.05 and 0.5 mg/kg body weight (p.o.) significantly decreased blood glucose level, and the effect remained 10 days after the last administration. Moreover, in these rats, cerebrocrast evoked an increase of serum immunoreactive insulin (IRI) level during 7 diabetic days as compared to both the control normal rats and the STZ-induced diabetic control rats. The STZ-induced diabetic rats that received cerebrocrast had a significantly high serum IRI level from the 14th to 21st diabetic days in comparison with the STZ-induced diabetic control.The IRI level in serum as well as the glucose disposal rate were significantly increased after stimulation of pancreatic beta-cells with glucose in normal rats that received cerebrocrast, administered 60 min before glucose. Glucose disposal rate in STZ-induced diabetic rats as a result of cerebrocrast administration was also increased in comparison with STZ-diabetic control rats. Administration of cerebrocrast in combination with insulin intensified the effect of insulin. The hypoglycaemic effect of cerebrocrast primarily can be explained by its immunomodulative properties. Moreover, cerebrocrast can act through extrapancreatic mechanisms that favour the expression of glucose transporters, de novo insulin receptors formation in several cell membranes as well as glucose uptake.     

Pre-Clinical Study for the Antidiabetic Potential of Selenium Nanoparticles

This research was delineated to explore the efficacy of selenium nanoparticles delivered in liposomes (L-Se) in the mitigation of type-2 diabetes mellitus. Adult female Wistar rats were assigned into four groups: group I, the normal control group in which the rats received normal saline solution orally; group II, the diabetic control group in which the rats were injected intraperitoneally with a single dose of streptozotocin (STZ) for induction of diabetes; group III, the metformin (Met)-treated group in which the diabetic rats were treated orally with Met; and group IV, the L-Se-treated group in which the diabetic rats were treated orally with L-Se. All treatments were delivered for 21 days. Blood and pancreas tissue samples were obtained for biochemical analysis, immunohistochemical examinations, and histopathological investigation. The L-Se-treated group showed significant drop in serum glucose and pancreatic malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), and prostaglandin F2α (PGF2α) levels associated with significant rise in serum insulin and pancreatic glutathione, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) values, in addition to significant improvement in the immunohistochemical indices (insulin and glucagon). Aforementioned results are appreciated by the histopathological findings of pancreatic tissue. In conclusion, our data have brought about compelling evidence favoring the antidiabetic potency of elemental selenium nanoparticles delivered in liposomes through preservation of pancreatic β cell integrity with consequent increment of insulin secretion and in turn glucose depletion, repression of oxidative stress, potentiation of the antioxidant defense system, and inhibition of pancreatic inflammation.     

Comparative Study of Antidiabetic Activity and Oxidative Stress Induced by Zinc Oxide Nanoparticles and Zinc Sulfate in Diabetic Rats

In the current study, antidiabetic activity and toxic effects of zinc oxide nanoparticles (ZnO) were investigated in diabetic rats compared to zinc sulfate (ZnSO₄) with particular emphasis on oxidative stress parameters. One hundred and twenty male Wistar rats were divided into two healthy and diabetic groups, randomly. Each major group was further subdivided into five subgroups and then orally supplemented with various doses of ZnO (1, 3, and 10 mg/kg) and ZnSO₄ (30 mg/kg) for 56 consecutive days. ZnO showed greater antidiabetic activity compared to ZnSO₄ evidenced by improved glucose disposal, insulin levels, and zinc status. The altered activities of erythrocyte antioxidant enzymes as well as raised levels of lipid peroxidation and a marked reduction of total antioxidant capacity were observed in rats receiving ZnO. ZnO nanoparticles acted as a potent antidiabetic agent, however, severely elicited oxidative stress particularly at higher doses.     

Ameliorative effect of 20-OH ecdysone on streptozotocin induced oxidative stress and β-cell damage in experimental hyperglycemic rats

The present study was to evaluate the effects of 20-OH ecdysone on hyperglycemia mediated oxidative stress in streptozotocin induced diabetic rats. Diabetes was induced in experimental rats by single intraperitoneal injection of STZ (45 mg/kg b.w.) dissolved in 0.1 mol/L citrate buffer (pH 4.5). Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. The activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and the levels of non-enzymic antioxidants vitamin C, vitamin E and reduced glutathione (GSH) were decreased while increases in the levels of LPO markers were observed in liver and kidney tissues of diabetic rats. Moreover, hepatic markers (aspartate aminotransferase and alanine aminotransferase) and renal markers (urea, creatinine) were significantly increased in diabetic rats as compared to control rats. Upon treatment with 20-OH ecdysone to diabetic rats showed significant ameliorative effects on all the biochemical parameters studied. Biochemical findings were supported by histological studies. These results indicated that 20-OH ecdysone exerts a protective action on pancreatic beta cell function and overcomes oxidative stress through its hypoglycemic potential. The effect produced by the 20-OH ecdysone on various parameters was comparable to that of glibenclamide – an antidiabetic drug.     

Anti-hyperglycemic, antioxidant and anti-inflammatory effects of VIP and a VPAC1 agonist on streptozotocin-induced diabetic mice

Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide with potent anti-inflammatory properties, and its receptor, VPAC1, mediates most of the anti-inflammatory effects of VIP. Diabetes mellitus is characterized by increased oxidation and inflammation due to persistent hyperglycemia. This research was performed to investigate the effects of VIP and a VPAC1 agonist on streptozotocin (STZ)-induced type 1 diabetic mice. Intraperitoneal injection of VIP and VPAC1 agonist (50 nmol/kg/day in saline) over a 28-day period (1) decreased food intake, (2) increased body weight, (3) improved visceral index, (4) increased the fasting plasma insulin levels, (5) decreased the fasting plasma glucose, (6) improved the glucose tolerance, (7) decreased pancreas H₂O₂ and malondialdehyde (MDA) and (8) increased total antioxidant activity (T-AOC) in the liver, spleen and pancreas. The results of histopathological and immunohistochemical analysis showed that VIP and the VPAC1 agonist improved the structure and cellularity of islets and ameliorated the insulin-secreting activity of islets. Additionally, administration of VIP or the VPAC1 agonist not only significantly decreased the plasma TNFα and CRP and promoted IL-10 in diabetic mice but also blocked the increased NF-κB activity of pancreatic tissue in diabetic mice. Furthermore, the VPAC1 agonist displayed stronger effects than VIP. These results show that both VIP and VPAC1 agonist ameliorated STZ-induced diabetes and protected mice against oxidative stress and inflammation associated diabetes, with VPAC1 being the receptor most responsible for these positive effects in diabetic mice.     

Effects of exendin-4 and selenium on the expression of GLP-1R,IRS-1, and preproinsulin in the pancreas of diabetic rats

The mechanisms by which exendin-4 and selenium exert their antidiabetic actions are still unclear. Here, we investigated the effects of exendin-4 or selenium administration on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and preproinsulin in the pancreas of diabetic rats. Diabetes was induced by streptozotocin administration. Diabetic rats were injected intraperitoneally with 0.03 μg exendin-4/kg body weight/daily or treated with 5 ppm selenium in drinking water for a period of 4 weeks. GLP-1R and IRS-1 levels were decreased while the level of preproinsulin messenger RNA (mRNA) was increased in the pancreas of diabetic untreated rats, as compared to that in control rats. Treatment of diabetic rats with exendin-4 increased protein and mRNA levels of GLP-1R, and IRS-1, and the mRNA level of preproinsulin in the pancreas, as compared to their levels in diabetic untreated rats. Selenium treatment of diabetic rats increased the pancreatic mRNA levels of GLP-1R, IRS-1, and preproinsulin. Exendin-4 or selenium treatment of diabetic rats also increased the numbers of pancreatic islets and GLP-1R molecules in the pancreas. Therefore, exendin-4 and selenium may exert their antidiabetic effects by increasing GLP-1R, IRS-1, and preproinsulin expression in the pancreas and by increasing the number of pancreatic islets.     

Probucol attenuated hyperglycemia in multiple low-dose streptozotocin-induced diabetic mice.

The present studies were undertaken to examine the effects of probucol on the protection against pancreatic beta-cell damage by multiple low-dose streptozotocin (STZ: 40 mg/kg, ip). The degree of hyperglycemia at 7, 14 and 17 days after STZ injection was attenuated by probucol. Serum immunoreactive insulin (IRI) levels were increased in the rats fed probucol containing diet at Day 14 and 17. Serum IRI levels after intraperitoneal injection of 2.0 g/kg glucose was reduced in STZ mice and the reduction of serum IRI levels was attenuated in the rats fed probucol, accompanied with a significant reduction of the degree of hyperglycemia after bolus of glucose. Probucol attenuated the reduction of pancreatic IRI content by STZ. The percentage of Thy 1.2-positive splenocytes was increased by STZ and probucol reduced the percentage of Thy 1.2-positive splenocytes, although there were no differences in the populations of splenocytes, positive with Lyt 2 or L3/T4. These data suggest that probucol has a protective action against pancreatic insulitis by multiple low-dose STZ administration.