Treatment Of Diabetic Rats Research Articles

Anti-diabetic activity of different oils through their effect on arylsulfatases

BackgroundDiabetes mellitus (DM) is characterized by the overproduction of the reactive oxygen species which affects the integrity of the lysosomal membrane affecting lysosomal enzymes. The effect of these species is blocked by some natural products as antioxidants. In the current study, groups of normal and streptozotocin (STZ)-induced diabetic rats were treated by Nigella sativa (NS), olive and canola oils and subjected to the study of arylsulfatases as a model of lysosomal enzymes. The aim of the present study is to investigate the effect of STZ-induced diabetes on arylsulfatases in presence and absence of NS, olive and canola oils.MethodsDifferent groups of rats were induced by STZ, treated with different oils and compared to their corresponding control group. All groups were subjected for the assays of blood glucose, insulin, catalase and arylsulfatases. A comparative kinetic study of arylsulfatses was performed to detect the alteration of catalytic characterization.ResultsThe results demonstrated that diabetes causes a significant elevation in the level of hepatic arylsulfatase B and a significant reduction of hepatic catalase as an antioxidant enzyme. NS and olive oils returned catalase and arylsulfatase B activities back near to normal by fixing their catalytic properties. Furthermore, the maximum velocity of arylsulfatases A and B was significantly elevated in the induced diabetes, whereas their Km values were significantly changed. The treatment of diabetic rats by NS and olive oils reduced the degree of significance.ConclusionDiabetes induces significant alterations of the catalytic characters of arylsulfatases and some oils decrease this alteration through an antioxidant-mediated effect.

The β-amyloid precursor protein analog P165 improves impaired insulin signal transduction in type 2 diabetic rats.

This study was performed to understand whether P165 improves learning and memory by restoring insulin action using a diabetes mellitus (DM) rat model. A total of 34 male Sprague-Dawley rats were randomly divided into four groups: control group (n = 8), DM group (n = 8), DM group treated with a low dose of P165 (n = 9), and DM group treated with a high dose of P165 (n = 9). After 8 weeks of treatment, the animals were killed and the expression of insulin signaling-related proteins was examined in the hippocampus by Western blot and immunohistochemical staining. Administration of P165 in diabetic rats did not induce a significant effect on the fasting blood glucose level. The expression of IR, IRS-1, AKT, p-CREB, and Bcl-2 proteins was significantly enhanced in the hippocampus in diabetic rats. Treatment of diabetic rats with P165 at both low and high doses significantly attenuated the expression levels of these proteins. Moreover, immunohistochemistry staining showed that IR, IRS-1, AKT, p-CREB, and Bcl-2 were abundantly expressed in the CA1 region of the hippocampus. The number of cells positively stained for the above proteins was significantly higher in diabetic tissues compared to control tissues, whereas P165 treatments induced a significant reduction in the expression of these proteins. The expression of IR, IRS-1, AKT, p-CREB, and Bcl-2 was enhanced in DM rats, and administration of P165 normalized the expression of these molecules, suggesting that P165 can improve impaired insulin signal transduction.

Treatment of Diabetic Rats With Insulin or a Synthetic Insulin Receptor Agonist Peptide Leads to Divergent Metabolic Responses

In addition to lowering of blood glucose, treatment with insulin also induces lipid synthesis and storage. Patients with type 2 diabetes often suffer from lipid-related comorbidities including dyslipidemia, obesity, and fatty liver disease. We examined here in two separate studies changes in lipid dynamics in Zucker diabetic fatty (ZDF) rats, in response to 7 days of treatment with either insulin or the insulin receptor agonist peptide S597. In concert with blood glucose normalization, the treated rats displayed large increases in hepatic de novo lipid synthesis and deposition of newly synthesized lipids in adipose tissue depots, accompanied by weight gain and expansion of adipose depots. In both treatment groups, heavy water labeling revealed that after 2 h (study A), de novo lipogenesis was responsible for 80% of newly stored hepatic triglyceride (TG)-palmitate, and after 5 days (study B), ∼60% of newly deposited TG-palmitate in adipose tissues originated from this pathway. Interestingly, in both studies, treatment with the insulin mimetic peptide resulted in significantly lower blood TG levels, plasma TG production rates, and hepatic de novo synthesized fatty acid in plasma TG compared with insulin. There were no differences in plasma TG turnover (clearance rate) in response to either treatment, consistent with differential actions on the liver. These results show that in ZDF rats, treatment with a synthetic insulin-receptor-activating peptide or with insulin to lower blood glucose is accompanied by different effects on hepatic lipid anabolism and blood TG profiles.

Protective effects of metformin on renal tubular cells.

Dear Editor, Recently, we conducted a preclinical investigation to find the ameliorative properties of metformin on renal biochemical and histologic alterations of gentamicin-induced kidney damage in male Wistar rats (1). In this investigation, attenuation of gentamicin-induced acute kidney injury was found. Likewise, Taheri et al. conducted a study on the effects of metformin on renal tubular cells after unilateral ischemia reperfusion in rats’ kidney. They observed that metformin provided kidney protection against ischemia and reperfusion-induced injury (2). They concluded that metformin has tissue-protective effect through activation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (2). More recently we conducted a study on 70 male Wistar rats to test the efficacy of coadministrating garlic extract and metformin in prevention of gentamicin-induced renal tubular damage in Wistar rats (3). The result of this study showed that metformin, garlic juice, or their combination had both curative and protective effects on gentamicin-induced kidney injury. In addition, Kim et al. conducted a study using metformin for diabetic rats for 17 weeks and found that treatment of diabetic rats with metformin had restored podocyte loss. They suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by metformin through the repression of oxidative injury. They proposed that diabetes-induced podocyte loss in diabetic nephropathy could be reduced by metformin (4). Kim et al. found that the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was decreased in the kidney of diabetic rats and metformin could restore its modification (4). Diabetic nephropathy is one of the most important complications of diabetes mellitus (5-11) and metformin has been broadly used for the treatment of type 2 diabetes (12). Thus, the suggestion of Baradaran et al. further attests our results and those by Taheri et al., which stated metformin protects against tubular injury by restoring the biochemical alterations and modulation of oxidative stress on the tubules (2, 3). Furthermore, according to the study of Kim et al. metformin protects podocytes in diabetic nephropathy (4). On the other hand, there is also tubular cell injury in diabetic nephropathy due to glycosuria (12-18). These findings can more potentiate the clinical use of metformin in the prevention of diabetic nephropathy. Previously, Morales et al. showed that gentamicin-induced renal tubular damage was attenuated by metformin (17). It is evident that metformin treatment significantly attenuates the increase in malondialdehyde and total reactive oxygen species generation and restores both enzymatic and nonenzymatic antioxidants to their physiologic levels (18, 19). These findings advocate the use of metformin in diabetes due to its protective effect on kidney beyond its blood regulatory effects. In fact, it is reasonable to illuminate three different actions of metformin including blood sugar regulatory property, renal tubular cell protection by acting as an effective antioxidant, and finally, protective effect on diabetic nephropathy through saving the podocytes (4, 18, 19). Hence, patients with diabetes might benefit from all of these three distinct protective properties (4, 18, 19). In this regard, more experimental or clinical studies are recommended to improve our knowledge regarding the kidney protective properties of metformin.

High dose of aspirin moderates diabetes-induced changes of heart glycogen/glucose metabolism in rats.

Aspirin (ASA), as a multifunctional drug has been used as a hypoglycaemic agent in the treatment of diabetes and severe hyperglycaemia and has been established as a secondary strategy which may prevent many cardiovascular events. In this study we investigated high dose (100mg/kg b.w./i.p) and time-dependent (2, 7 and 14days) effects of ASA on the heart key enzymes and substrates from glycogen/glucose metabolism in control and diabetic rats. The results accomplished demonstrated that ASA significantly potentiates glycogen accumulation, as well as decreased blood glucose level and heart glycolytic potential in control rats. The treatment of diabetic rats with ASA caused moderation of the diabetic complication-significant inhibition of glycogen accumulation, lowering of blood glucose, as well as elevation of glycolytic potential. In conclusion, we propose that use of high-dose of ASA has anabolic effects in control rats and reduces heart glycogen glucose complications in diabetic rats. The moderation of diabetes-induced changes is time-dependent and involves reduction of glycogenogenesis and inhibited depression of glycolysis, with a tendency to maintenance control values.

The effect of glucagon-like peptide-1 in the management of diabetes mellitus: cellular and molecular mechanisms.

Incretins, such as glucagon-like peptide-1 (GLP)-1, have been shown to elevate plasma insulin concentration. The purpose of this study is to investigate the cellular and molecular basis of the beneficial effects of GLP-1. Normal and diabetic male Wistar rats were treated with GLP-1 (50 ng/kg body weight) for 10 weeks. At the end of the experiment, pancreatic tissues were taken for immunohistochemistry, immunoelectron microscopy and real-time polymerase chain reaction studies. Samples of blood were retrieved from the animals for the measurement of enzymes and insulin. The results show that treatment of diabetic rats with GLP-1 caused significant (P < 0.05) reduction in body weight gain and blood glucose level. GLP-1 (10(-12)-10(-6) M) induced significant (P < 0.01) dose-dependent increases in insulin release from the pancreas of normal and diabetic rats compared to basal. Diabetes-induced abnormal liver (aspartate aminotransferase and alanine aminotransferase) and kidney (blood urea nitrogen and uric acid) parameters were corrected in GLP-1-treated rats compared to controls. GLP-1 treatment induced significant (P < 0.05) elevation in the expression of pancreatic duodenal homeobox-1, heat shock protein-70, glutathione peroxidase, insulin receptor and GLP-1-receptor genes in diabetic animals compared to controls. GLP-1 is present in pancreatic beta cells and significantly (P < 0.05) increased the number of insulin-, glutathione reductase- and catalase-immunoreactive islet cells. The results of this study show that GLP-1 is co-localized with insulin and seems to exert its beneficial effects by increasing cellular concentrations of endogenous antioxidant genes and other genes involved in the maintenance of pancreatic beta cell structure and function.

DPP IV inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats.

Dipeptidyl peptidase IV (DPP IV) modulates protein activity by removing dipeptides. DPP IV inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. DPP IV substrates not only increase insulin secretion but also affect bone metabolism. In this study, the effect of DPP IV inhibitor sitagliptin on bone was evaluated in normal and streptozotocin-induced diabetic rats. This study included 64 male Wistar rats divided into four groups (n = 16): two diabetic and two control groups. One diabetic and one control group received sitagliptin through drinking water. Tibiae were scanned every 3 wk using an in vivo μCT scanner. After 6 and 12 wk, rats were euthanized for histomorphometric analysis of bone parameters. The mechanical resistance of femora to fracture was assessed using a three-point bending test, and serum levels of bone metabolic markers were measured. Efficient DPP IV inhibition was achieved in sitagliptin-treated groups. Trabecular bone loss, the decrease in trabecular number, and the increase in trabecular spacing was attenuated through sitagliptin treatment in diabetic rats, as shown by in vivo μCT. Bone histomorphometry was in line with these results. μCT analysis furthermore showed that sitagliptin prevented cortical bone growth stagnation in diabetic rats, resulting in stronger femora during three-point bending. Finally, the serum levels of the resorption marker CTX-I were significantly lower in sitagliptin-treated diabetic animals compared with untreated diabetic animals. In conclusion, sitagliptin treatment attenuates bone loss and increases bone strength in diabetic rats probably through the reduction of bone resorption and independent of glycemic management.

Вплив продукту декарбоксилювання L-аргініну на морфофункціональні показники еритрону за умов експериментального цукрового діабету у щурів

This paper reports the results of a study of the impact of the agmatine treatment on erythrocyte resistance to acid hemolytic, reticulocyte count and reticulocyte production index, erythrocyte surface architectonics in streptozotocin-induced diabetic rats. Our results indicate that treatment of diabetic rats with agmatine causes a suppression of erythropoiesis and increases the resistance of erythrocytes against HCl-induced hemolysis. It was shown a 10% increase in the number of young red blood cells and 35% reduction in the number of structurally transformed erythrocytes that are capable of restoring normal biconcave disc shape under physiological condition. Our data demonstrate an improvement of morphofunctional state of red blood cells in diabetes and reflect the positive effect of agmatine treatment on erythrone due to the glucose-lowering action.

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

ObjectiveTo 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. MethodsDiabetes mellitus was induced by a single administration of streptozotocin (50 mg/kg) and the rats were treated for 7 weeks. Antioxidant enzymes [catalase (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. ResultsTreatment with RPO, RTE and RPO + RTE significantly (p>0.05) improved liver SOD and plasma ORAC in the diabetic rats. Similarly, diabetic rats treated with RTE and RPO + RTE enhanced liver GPx. A significant (P<0.05) 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 P<0.05 from the normal control group. ConclusionsThe 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.

Pyrrolidine dithiocarbamate protects pancreatic β-cells from oxidative damage through regulation of FoxO1 activity in type 2 diabetes rats.

Pyrrolidine dithiocarbamate (PDTC) can lower the blood glucose level and improve the insulin sensitivity in diabetic rats. However, the mechanisms underlying this effect of PDTC treatment in diabetic rats remained uncertain. In this study, we evaluated the mechanisms by which PDTC conferred protection against oxidative damage to pancreatic islet β-cells in rats with experimental type 2 diabetes mellitus (DM). DM in the rats was elicited by long-term high-fat diet accompanied with a single intraperitoneal (i.p.) injection of a low dose of streptozotocin. After a 7-day administration of PDTC (50 mg/kg/day i.p.), blood glucose levels were measured and pancreatic tissues were collected for the determination of various biochemical and enzymatic activities using immunohistochemistry, immunofluorescence, and western blot techniques. The percentage of apoptotic pancreatic islet β-cells was detected by flow cytometry. The results showed that diabetic rats had elevated blood glucose levels and insulin resistance, accompanied with an increase in malondialdehyde content, nitrotyrosine production, and inducible nitric oxide synthase expression. A decrease in superoxide dismutase and glutathione peroxidase activities was also observed in DM rats, culminating with elevated β-cell apoptosis. PDTC treatment significantly reduced the oxidative damage and the β-cell apoptosis, and also increased the insulin production through down-regulating FoxO1 acetylation and up-regulating nuclear PDX-1 level. These data suggested that PDTC can protect islet β-cells from oxidative damage and improve insulin production through regulation of PDX-1 and FoxO1 in a DM rat model.

Antioxidant potential of bilirubin-accelerated wound healing in streptozotocin-induced diabetic rats.

Oxidative injury is markedly responsible for wound complications in diabetes mellitus. The biological actions of bilirubin may be relevant to prevent oxidant-mediated cell death, as bilirubin application at a low concentration scavenges reactive oxygen species. Hence, we hypothesized that topical bilirubin application might improve wound healing in diabetic rats. Diabetes was induced in adult male Wistar rats, which were divided into two groups, i.e., diabetic control and diabetic treated. Non-diabetic healthy rats were also taken as healthy control group. Wound area was measured on days 3, 7, 14, and 19 post-wounding. The levels of malondialdehyde (MDA) and reduced glutathione (GSH) and the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were estimated in the granulation tissue. There was a significant increase in percent wound closure in healthy control and diabetic treated rats on days 7, 14, and 19, as compared to diabetic control rats on days 7, 14, and 19. There was significant decrease in MDA levels on days 7, 14, and 19 in diabetic treated rats, as compared to diabetic control rats. Levels of GSH were significantly increased on days 3, 7, 14, and 19 in diabetic treated rats, as compared to diabetic control rats. GPx, SOD, and CAT activities were significantly higher on days 3, 7, and 14 in diabetic treated rats, as compared to diabetic control rats. The findings indicate that bilirubin is effective in reducing the oxidant status in wounds of diabetic rats which might have accelerated wound healing in these rats.

Effect of vitamin D3 on behavioural and biochemical parameters in diabetes type 1-induced rats.

Diabetes is associated with long-term complications in the brain and reduced cognitive ability. Vitamin D3 (VD3 ) appears to be involved in the amelioration of hyperglycaemia in streptozotocin (STZ)-induced diabetic rats. Our aim was to analyse the potential of VD3 in avoiding brain damage through evaluation of acetylcholinesterase (AChE), Na(+) K(+) -adenosine triphosphatase (ATPase) and delta aminolevulinate dehydratase (δ-ALA-D) activities and thiobarbituric acid reactive substance (TBARS) levels from cerebral cortex, as well as memory in STZ-induced diabetic rats. Animals were divided into eight groups (n = 5): control/saline, control/metformin (Metf), control/VD3 , control/Metf + VD3 , diabetic/saline, diabetic/Metf, diabetic/VD3 and diabetic/Metf + VD3 . Thirty days after treatment, animals were submitted to contextual fear-conditioning and open-field behavioural tests, after which they were sacrificed and the cerebral cortex was dissected. Our results demonstrate a significant memory deficit, an increase in AChE activity and TBARS levels and a decrease in δ-ALA-D and Na(+) K(+) -ATPase activities in diabetic rats when compared with the controls. Treatment of diabetic rats with Metf and VD3 prevented the increase in AChE activity when compared with the diabetic/saline group. In treated diabetic rats, the decrease in Na(+) K(+) -ATPase was reverted when compared with non-treated rats, but the increase in δ-ALA-D activity was not. VD3 prevented diabetes-induced TBARS level and improved memory. Our results show that VD3 can avoid cognitive deficit through prevention of changes in important enzymes such as Na(+) K(+) -ATPase and AChE in cerebral cortex in type 1 diabetic rats.

English

In diabetes mellitus and insulin resistance, the activity of the enzymes involved in hepatic glucose homeostasis is disturbed. Promoting the physiologic functions of these enzymes and restoring homeostatic control by medicinal plants could be beneficial in the management of diabetes. This study investigates the effects of extract of leaves of Newbouldia laevis on some key enzymes of hepatic glucose metabolism in streptozotocin-induced diabetic rats. Diabetes was induced in rats by intravenous injection of streptozotocin. Diabetic rats were treated orally with N. laevis extract for four weeks. At the end of the treatment, the activities of hepatic glucokinase and glucose 6-phosphatase were evaluated. Effect of N. laevis extract on glucose 6-phosphatase activity was also assessed in vitro using enzyme obtained from rabbit liver. The levels of hepatic glycogen, pancreatic insulin and serum insulin were also determined. Treatment of diabetic rats with N. laevis extract resulted in a significant increase (P &lt; 0.05) in the activity of hepatic glucokinase when compared with diabetic control. Extract of N. laevis showed significant inhibitory effect against the activity of glucose 6-phosphatase in both in vivo and in vitro studies. The level of hepatic glycogen in treated rats significantly increased (P &lt; 0.05) compared to untreated diabetic rats. Although there was a slight increase in serum and pancreatic insulin levels of treated diabetic rats, the difference was not significant (P &gt; 0.05) when compared to diabetic control. Based on the results of this study, we conclude that N. laevis leaf extract stimulates the activity of hepatic glucokinase and inhibits the activity of glucose 6-phosphatase in streptozotocin-induced diabetic rats. It could serve as a good alternative remedy in the management of diabetes mellitus. &nbsp; Key words: Liver, glucokinase, glucose 6-phosphatase, diabetes mellitus, Newbouldia laevis, glucose.

Impaired insulin signaling affects renal organic anion transporter 3 (Oat3) function in streptozotocin-induced diabetic rats.

Organic anion transporter 3 (Oat3) is a major renal Oats expressed in the basolateral membrane of renal proximal tubule cells. We have recently reported decreases in renal Oat3 function and expression in diabetic rats and these changes were recovered after insulin treatment for four weeks. However, the mechanisms by which insulin restored these changes have not been elucidated. In this study, we hypothesized that insulin signaling mediators might play a crucial role in the regulation of renal Oat3 function. Experimental diabetic rats were induced by a single intraperitoneal injection of streptozotocin (65 mg/kg). One week after injection, animals showing blood glucose above 250 mg/dL were considered to be diabetic and used for the experiment in which insulin-treated diabetic rats were subcutaneously injected daily with insulin for four weeks. Estrone sulfate (ES) uptake into renal cortical slices was examined to reflect the renal Oat3 function. The results showed that pre-incubation with insulin for 30 min (short term) stimulated [3H]ES uptake into the renal cortical slices of normal control rats. In the untreated diabetic rats, pre-incubation with insulin for 30 min failed to stimulate renal Oat3 activity. The unresponsiveness of renal Oat3 activity to insulin in the untreated diabetic rats suggests the impairment of insulin signaling. Indeed, pre-incubation with phosphoinositide 3-kinase (PI3K) and protein kinase C zeta (PKCζ) inhibitors inhibited insulin-stimulated renal Oat3 activity. In addition, the expressions of PI3K, Akt and PKCζ in the renal cortex of diabetic rats were markedly decreased. Prolonged insulin treatment in diabetic rats restored these alterations toward normal levels. Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin-induced Akt/PKB activation through PI3K/PKCζ/Akt/PKB signaling pathway.

Efficacy of Ankaferd Blood Stopper on bone healing in diabetic rats: a stereological and histopathological study

We evaluated the effects of Ankaferd Blood Stopper (ABS) and routine antibiotic prophylaxis (AP) on early healing of bone defects in diabetic rats. We used 48 rats in the study. Diabetes was induced in 24 rats using streptozotocin; the remaining 24 healthy untreated rats served as controls. Twelve of the diabetic rats and 12 of the healthy rats were treated with AP for 3 days before surgery. Bilateral bone defects were created in the mandible of all animals. ABS was applied to the defects on the left sides of the mandibles, while nothing was applied to the right sides. Animals were sacrificed on days 7 and 14 after operation and examined for histopathology and by stereology. The volume of newly formed bone was significantly less in the diabetic rats on both days 7 and 14. Local administration of ABS significantly increased the mean volume of newly formed bone in both diabetic and nondiabetic rats at days 7 and 14. No significant difference in new bone formation was found between AP and ABS treatment in diabetic rats. Both AP and local administration of ABS have beneficial effects on bone healing in diabetic animals.

Abstract 398: Tocomin Restores Endothelium-Dependent Relaxation in Diabetic Rat Aorta

Increased superoxide in blood vessels can lead to impaired endothelial function. Tocotrienols, components of vitamin E are effective antioxidants that may have beneficial effects on vascular function particularly in pathologies involving oxidative stress such as diabetes. Tocomin is an extract of palm oil with high tocotrienol content. This study investigated the effect of 4 week treatment with tocomin (composition: tocotrienol rich fraction: 40%, α-tocopherol: 11% and palm olein: 38%) treatment on endothelium-dependent and endothelium-independent relaxation in the diabetic rat aorta. Male Wistar rats were randomly assigned to 4 groups (control, control+tocomin, diabetic and diabetic+tocomin). Diabetes was induced by a single injection of streptozotocin (STZ, 50 mg/kg iv). Rats were treated with tocomin (40 mg/kg per day s.c.) or vehicle (100% peanut oil) for 4 weeks commencing 6 weeks after induction of diabetes. Endothelium-dependent (EDR) to ACh, endothelium-independent relaxation (EIR) to sodium nitroprusside and superoxide production were measured using standard organ bath techniques and lucigenin enhanced chemiluminescence. Diabetes increased blood glucose (control 6.8±0.3 vs diabetic 32.1±1.2 mmol/L, n=7-9) and glycated hemoglobin (HbA1c control 5.6±0.2% vs diabetic 13.3±0.3%, n=7-9). Neither parameter was affected by tocomin treatment (blood glucose control+tocomin 7.3±0.7 mmol/L, diabetic+tocomin 26.3±4 mmol/L, HbA1c control+tocomin 5.5±0.2%, diabetic+tocomin 11.8±1.3%, n=8-10). Diabetes impaired EDR (ACh Rmax control 93±4% vs diabetic 76±4%, n=6-8, p&lt;0.05) without affecting EIR. Tocomin treatment significantly improved EDR (ACh Rmax diabetic 76±4% vs diabetic+tocomin 89±3%, n=6-8, p&lt;0.05) in diabetic rat aortae. Diabetes also significantly increased superoxide production (control 573±75 vs diabetic 1113±90 counts/mg dry tissue, n=4-9, p&lt;0.05), which was alleviated by tocomin treatment (761±71 counts/mg dry tissue, n=4-9, p&lt;0.05, in comparison to diabetic). These findings demonstrate that 4 week treatment of diabetic rats with tocotrienol rich tocomin significantly reduces superoxide production and improves EDR without affecting blood glucose levels.

Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGFβ-1 signaling

The aims of the present study were to investigate, in diabetes mellitus (DM), the mechanism of NOX4 up-regulation, its link with 5′ adenosine monophosphate-activated protein kinase (AMPK) inactivation and transforming growth factor (TGF) ß-1 signaling in determining the accumulation of kidney extracellular matrix (ECM), and the possible action of cocoa enriched with polyphenols (CH) in these events. After 16 weeks of DM, spontaneously hypertensive rats showed increased kidney TGFβ-1 levels and expression of phosphorylated smad2, collagen IV and fibronectin in parallel with elevated NOX4 expression and reduced phosphorylated AMPK. CH treatment in diabetic rats prevented all of these abnormalities. In immortalized human mesangial cells exposed to high glucose (HG), or TGFβ-1, CH, nicotinamide adenine dinucleotide phosphate blocker, or silencing NOX4 ameliorated enhanced phosphorylated smad2 and collagen IV. Reduction in phosphorylated AMPK induced by HG or TGFβ-1 was ameliorated by CH or activation of AMPK, which reduced phosphorylation of smad2 and collagen IV via reduction in NOX4 expression. The effects of CH were abolished by AMPK blockade. These results suggest that inactivation in AMPK leads to NOX4 up-regulation, activation of TGFβ-1 signaling and increased ECM accumulation. Additionally, increased TGF-ß1 per se leads to the amplification of ECM production by reducing AMPK and promoting the activation of NOX4. It is suggested that the activation of AMPK by CH followed by reduction in NOX4/TGFβ-1 signaling may have a therapeutic potential in diabetic nephropathy.

DPP‐4 inhibitor linagliptin restores endothelium‐dependent relaxation in small mesenteric artery from type‐1 diabetic rats (1051.4)

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors which are used to treat hyperglycaemia in type 2 diabetes may exert beneficial cardiovascular effects independently of their glucose lowering action. We hypothesized that linagliptin (LNG) treatment (4 weeks, 2 mg/kg per day orally) would improve relaxation in mesenteric arteries (MA) from STZ‐induced diabetic rats. In MA from diabetic rats there was a significant increase in superoxide levels, assayed by lucigenin chemiluminescence (diabetes, 1448± 108 counts/mg versus normal 644±380 counts/mg, n=7‐9, p&lt;0.01). LNG does not reduce high blood glucose levels in diabetic rats (diabetes, 25±2.2 mM versus diabetes+ LNG, 27±1.7 mM). Acetylcholine (ACh)‐induced relaxation of MA was assessed using wire myography (pEC50=7.26±0.13, n = 8). Diabetes significantly reduced the sensitivity to ACh and treatment with LNG improved endothelial dysfunction (pEC50, diabetic 6.15±0.21 versus diabetic+ LNG, 6.84±0.13, n=8‐10, p&lt;0.05). Diabetes impaired the contribution of both NO and EDHF to ACh‐induced relaxation and LNG treatment significantly enhanced the contribution of both relaxing factors. Our results indicate that the treatment of diabetic rats with LNG significantly reduced vascular superoxide levels and preserved both NO and EDHF mediated relaxation indicating that LNG can improve endothelial function in diabetes independently of any glucose lowering activity.

Effects of vanadium (III, IV, V)-chlorodipicolinate on glycolysis and antioxidant status in the liver of STZ-induced diabetic rats

Vanadium compounds exert various insulin-mimetic and anti-diabetic effects both in vitro and in vivo. Vanadium(III, IV, V)-chlorodipicolinate (Vdipic-Cl) compounds, including H[VIII(dipic-Cl)2]·5H2O (V3dipic-Cl), VIVO(dipic-Cl)(H2O)2 (V4dipic-Cl) and K[VVO2(dipic-Cl)] (V5dipic-Cl), were synthesized with the indicated oxidation states. The present study was conducted to investigate if chemical valence and anti-oxidation effects of vanadium compounds are involved in the anti-diabetic effects observed in streptozotocin (STZ)-induced diabetic rats treated with these vanadium compounds. V3dipic-Cl, V4dipic-Cl, V5dipic-Cl, inorganic vanadium salts vanadyl sulfate (VOSO4) or sodium metavanadate (NaVO3) were orally administered in drinking water (50μgV/ml) to STZ-induced diabetic rats for 28days. The results showed that Vdipic-Cl treatment significantly improved hyperglycemia and glucose intolerance, as well as increased hepatic glycogen synthesis in diabetic rats. The mRNA levels of key glycolytic enzymes in liver, phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GK), and L-pyruvate kinase (L-PK) altered in diabetic animals were significantly restored towards normal values by treatment with some of the vanadium compounds. Moreover, the diabetes elevated activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in serum were significantly decreased after treatment with Vdipic-Cl complexes. Furthermore, treatment of diabetic rats with V4dipic-Cl and V5dipic-Cl compounds significantly reduced malondialdehyde (MDA) production and increased glutathione peroxidase (GSH-Px) and catalase (CAT) activities. These data suggest that vanadium compounds with the indicated chemical valence promote glycogen synthesis and recover suppressed glycolysis in the liver of diabetic rats due to their capacity to reduce oxidative stress by stimulating antioxidant enzymes.

Therapeutic effects of stem cell on hyperglycemia, hyperlipidemia, and oxidative stress in alloxan-treated rats

Diabetes mellitus is the most common endocrine disorder that affects more than 285 million people worldwide. The purpose of this study was to investigate the effect of mesenchymal stem cells (MSCs) from the bone marrow of albino rats, on hyperglycemia, hyperlipidemia, and oxidative stress induced by intraperitoneal injection (i.p.) of alloxan at a dose of 150 mg/kg in rats. Injection of alloxan into rats resulted in a significant increase in serum glucose, total cholesterol, triglyceride, low density lipoprotein cholesterol, and sialic acid level and a significant decrease in serum insulin, high density lipoprotein-cholesterol, vitamin E, and liver glycogen as compared to their corresponding controls. Also, oxidative stress was noticed in pancreatic tissue as evidenced by a significant decrease in glutathione level, superoxide dismutase, glutathione-S-transferase activities, also a significant increase in malondialdehyde and nitric oxide levels when compared to control group. Treatment of diabetic rats with MSCs stem cells significantly prevented these alterations and attenuated alloxan-induced oxidative stress. In conclusion, rat bone marrow harbors cells that have the capacity to differentiate into functional insulin-producing cells capable of controlling hyperglycemia, hyperlipidemia, and oxidative stress in diabetic rats. This may be helpful in the prevention of diabetic complications associated with oxidative stress.