Combination Of Streptozotocin Research Articles

Anti-oxidant effect of nitrite in the pancreatic islets of type 2 diabetic male rats.

Nitrite, a nitric oxide (NO) donor, increases insulin secretion from pancreatic islets and has positive metabolic effects in type 2 diabetes (T2D). Here, we test the hypothesis of whether nitrite-induced insulin secretion is due to blunting of diabetes-induced oxidative stress in the islets. T2D was created in male rats using a combination of streptozotocin at 25 mg/kg and a high-fat diet. Wistar rats were assigned to 3 groups (n=6 in each group), including control, T2D, and T2D+nitrite; the latter group consumed drinking water containing sodium nitrite (50 mg/l) for eight weeks. At the end of the study, mRNA levels of NADPH oxidase (Nox1, 2, 3, and 4), superoxide dismutase (SOD1, 2, and 3), glutathione peroxides (GPX1 and 7), glutathione reductase (GR), catalase, thioredoxin (TXN1 and 2), and thioredoxin reductase (TXNRD1) were measured in the isolated pancreatic islets. In the islets of diabetic rats, mRNA expressions of Nox1, 2, and 4 were higher, whereas expressions of SOD1, 2, catalase, GPX1, 7, GR, and TXN1 were lower than controls. Nitrite significantly (all P-values<0.05) decreased gene expression of Nox1 (0.39-fold) and Nox4 (0.23-fold) and increased gene expression of SOD1 (2.2-fold), SOD2 (2.8-fold), catalase (2.7-fold), GPX1 (2.2-fold), GPX7 (6.0-fold), GR (3.0-fold), TXN1 (2.1-fold), and TXNRD1 (2.3-fold) in diabetic rats. Nitrite decreased oxidative stress in isolated pancreatic islets of rats with T2D by suppressing oxidants and augmenting anti-oxidants. These findings favor the notion that nitrite-induced insulin secretion is partially due to decreased oxidative stress.

1,8 cineole protects type 2 diabetic rats against diabetic nephropathy via inducing the activity of glyoxalase-I and lowering the level of transforming growth factor-1β.

Diabetes leading to the production and circulation of glycation products along with the reduction of the activity of glyoxalase-I (GLO-I) contribute to diabetic nephropathy. Therefore, we studied the effect of 1,8 cineole (Cin) on the formation of diverse glycation products and the activity of GLO-I as well as renal histopathological alterations in the type-2 diabetic rat. Type 2 diabetes was induced in rats with a combination of streptozotocin and nicotinamide (55 + 200mg/kg). Two groups of rats, normal and diabetic, were treated intragastrically with Cin (200mg/kg) once daily for 2months. Fasting blood sugar, insulin resistance index, lipid profile, the activity of GLO-I, glycation products (Glycated albumin, Glycated LDL, Methylglyoxal, and advanced glycation end products), and oxidative stress (Advanced oxidation protein products, malondialdehyde, oxidized LDL, and reduced glutathione), inflammatory markers (Tumor necrosis factor-α and Transforming growth factor-1β), creatinine in the serum (Cre), and proteinuria (PU) in the urine of all rats was determined as well as renal histopathological alterations were investigated. Cin reduced biochemical (Cre and PU) and histopathological (glomerulosclerosis) indicators of renal dysfunction in the diabetic rat compared to untreated diabetic rats. Moreover, the treatment decreased different glycation, oxidative stress, and pro-inflammatory markers (p < 0.001).Further, Cin had an advantageous effect on glucose and lipid metabolism. Cin ameliorated diabetic nephropathy via reduction of TGF-1β following to decrease the formation of different glycation products, oxidative stress, and inflammatory process with the induction of the activity of glyoxalase-I in type 2 diabetic rats.

Comparative Evaluation of the Effect of Metformin and Insulin on Gut Microbiota and Metabolome Profiles of Type 2 Diabetic Rats Induced by the Combination of Streptozotocin and High-Fat Diet.

Lately, an increasing number of studies have investigated the relationship between metformin and gut microbiota, suggesting that metformin exerts part of its hypoglycemic effect through the microbes. However, its underlying mechanism remains largely undetermined. In the present study, we investigated the effects of metformin on gut microbiota and metabolome profiles in serum and compared it with insulin treatment in rats with type 2 diabetes mellitus (T2DM). Diabetic rats (DM group) were induced by a combination of streptozotocin and high-fat diet (HFD). After 7 days, DM rats were treated with metformin (MET group) or insulin (INS group) for 3 weeks. The 16S rRNA sequencing of the gut microbiota and non-targeted metabolomics analysis of serum were conducted. A total of 13 bile acids (BAs) in serum were further determined and compared among different groups. The rat model of T2DM was well established with the typical diabetic symptoms, showing significantly increased blood glucose, AUC of OGTT, HOMA-IR, TC, TG, LDL-C and TBA. Metformin or insulin treatment could ameliorate symptoms of diabetes and partly recover the abnormal biochemical indicators. Compared with DM rats, the relative abundances of 13 genera were significantly changed after metformin treatment, while only three genera were changed after insulin treatment. The metformin and insulin treatments also exhibited different serum metabolome profiles in T2DM rats. Moreover, 64 differential metabolites were identified between MET and DM groups, whereas 206 were identified between INS and DM groups. Insulin treatment showed greater influence on amino acids, glycerophospholipids/glycerolipids, and acylcarnitine compared with the metformin treatment, while metformin had an important impact on BAs. Furthermore, metformin could significantly decrease the serum levels of CA, GCA, UDCA, and GUDCA, but increase the level of TLCA in DM rats. Insulin treatment significantly decreased the levels of CA, UDCA, and CDCA. Besides, several metabolites in serum or microbiota were positively or negatively correlated with some bacteria. Collectively, our findings indicated that metformin had a stronger effect on gut microbiota than insulin, while insulin treatment showed greater influence on serum metabolites, which provided novel insights into the therapeutic effects of metformin on diabetes.

Rubusoside Reduces Blood Glucose and Inhibits Oxidative Stress by Activating the AMPK Signaling Pathway in Type 2 Diabetes Mellitus Mice

The current study aimed at investigating the therapeutic effects of rubusoside on type 2 diabetes mellitus (T2DM) mice models as an alternative hypoglycemic candidate drug. T2DM mice models were established with a combination of streptozotocin (STZ) intraperitoneal injection and high-fat diet. After 10 weeks of rubusoside intragastric administration (100, 200 mg/kg/day) to the mice, the body weight, fasting blood glucose, glucose tolerance, and blood lipids were measured. The liver protein expression levels of p-AMPK, GLUT2, GLUT4 and total antioxidant capacity were also investigated. After 10 weeks of rubusoside administration, the levels of blood glucose and lipids were decreased in T2DM mice. Compared with the model group, rubusoside administration significantly decreased the liver mass-to-body weight ratio, upregulated p-AMPK and GLUT4, and downregulated GLUT2 expression levels in the liver. Activities of superoxide dismutase (SOD), catalase (CAT), and gluathione peroxidase (GSH-Px) were increased, and the concentration of malondialdehyde (MDA) was decreased to reduce oxidative stress in the liver. Liver hematoxylin and eosin (H&amp;E) pathological analysis also showed that rubusoside had a protective effect on T2DM mice liver. These results demonstrate that rubusoside could be used as an anti-diabetic candidate drug, and that its hypoglycemic mechanism might be related to the activation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) to modulate the expression of GLUT2 and GLUT4. Finally, rubusoside could also increase total antioxidant capacity to protect the liver from oxidative stress.

Metformin improves cognitive impairment in diabetic mice induced by a combination of streptozotocin and isoflurane anesthesia

ABSTRACT To investigate the protective effects of metformin on the diabetic mice with cognitive impairment induced by the combination of streptozotocin (STZ) and isoflurane anesthesia. The isoflurane-anesthetized cognitive impairment model mice were established and then observed via behavioral tests and histopathological examination. Then these model mice were randomly assigned to three groups, which received the PBS, low and high doses of metformin, respectively. The body weight, food and water consumption of model mice were measured every other day. The mechanisms of metformin on ameliorating the cognitive dysfunction were further investigated by histomorphological, biochemical and Western blot analysis. After 14-days treatment of metformin, the diabetic symptoms in STZ-induced diabetic mice were significantly alleviated. Metformin could restore the isoflurane- and STZ-induced hippocampal tissue damage, cognitive and memory impairment in exposed space via improving the oxidative stress, upregulating the contents of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in the hippocampus tissues of diabetic mice. Furthermore, chronic treatment of metformin significantly down-regulated the expression of AGEs, RAGE, pNF-κB, iNOS, and COX-2. In conclusion, metformin can improve the isoflurane- and STZ-induced cognitive impairment in diabetic mice via improving oxidative stress and inhibiting the AGEs/RAGE/NF-κB signaling pathway.

In -Vivo Anti-Diabetic Activity of Hydro-Ethanolic Seed Extract of Syzygium Cumini (L.)

Introduction: Diabetes mellitus continues to be a major health problem in India and across the world. Over centuries, numerous herbal extracts have been used in the Indian traditional medicine to control elevated blood sugar levels in patients with diabetes. Different aqueous and organic extracts of Syzygium cumini (L.) Skeels have found widespread use owing to their anti-diabetic activity. A systematic study was undertaken to characterise and evaluate the effects of a hydro-ethanolic seed extract (SCE) of Syzygium cumini in a rodent model of experimental type 2 diabetes mellitus. Methods: An established model of diabetes mellitus with a combination of streptozotocin and high fat diet (over 12 weeks) in adult male Wistar albino rats, was used in this study. The onset of diabetes mellitus in rats was confirmed with a fasting blood glucose (FBG) of &gt;200 mg/dl. The diabetic rats were allocated into five experimental groups and treated as follows: with vehicle alone, pioglitazone (10 mg/kg), 100mg/kg or 200mg/kg or 400 mg/kg of SCE, respectively for 21 days. The pre and post treatment levels of fasting blood glucose, insulin and lipids were measured from serum obtained from the various treatment groups. In order to measure insulin resistance, a homeostasis model assessment of insulin resistance (HOMA IR) and for measuring the beta cell function a homeostasis model assessment were employed. The results obtained from these studies were analysed using the Analysis of variance (ANOVA) method. Results: Our study demonstrates the SCE preparation to induce a statistically significant dose-dependent reduction in FBG, serum lipid levels and HOMA IR with a concomitant increase in the serum insulin levels and HOMA B. Conclusions: Wistar rats dosed with SCE at 100 and 200 mg/kg body weight demonstrated statistically significant anti-diabetic activity by virtue of improving the pancreatic beta cell function and reduction in insulin resistance.

Preventive Effect of Eucalyptol on the Formation of Aorta Lesions in the Diabetic-Atherosclerotic Rat.

Background:Glycation, inflammation, and oxidative stress are the cardinal motivators of diabetes vascular complications. Here, we studied the effect of eucalyptol (EUC) on the formation of atheromatous lesions, glycation, oxidative stress, and inflammatory markers as well as insulin resistance, lipid profile, and activity of glyoxalase-1 (GLO-I) in the atherosclerotic rat model.Methods:Diabetic-atherosclerosis induced in rats with a combination of streptozotocin and atherogenic diet. Two groups of rats, normal and diabetic-atherosclerotic, were treated intragastrically with EUC (200 mg/kg) once daily for 3 months. Fasting blood sugar (FBS), insulin, insulin resistance index, lipid profile, the activity of GLO-I, low-density lipoprotein (LDL) glycation and oxidation markers, inflammatory markers, creatinine in the serum, and proteinuria in the urine of all rats were determined.Results:EUC inhibited the formation of any atheromatous lesions in atherosclerotic rats. Further, EUC displayed the lowering effect on glycemia, insulin resistance, LDL glycation, and oxidation products, and tumor necrosis factor (TNF)-α as well as it exhibited the improving effect on lipid profile, the activity of GLO-I, and renal function in the diabetic rat (P < 0.001).Conclusions:EUC prevented the formation of the atheromatous lesions and improved renal function in the atherosclerotic rat model due to a reduction of glycation, oxidative stress, and inflammatory mediators.

Thiamine pyrophosphate improved vascular complications of diabetes in rats with type 2 diabetes by reducing glycation, oxidative stress, and inflammation markers.

Background: Thiamine deficiency contributes to hyperglycemia and diabetes complications. Thus, in this study, the effect of thiamine pyrophosphate (TPP) on the in vivo and in vitro formation of glycation, oxidative stress, and inflammatory markers (the main contributors of vascular diabetes complications) was examined in type 2 diabetes rat model. Methods: Type 2 diabetes was induced in rats with a combination of streptozotocin and nicotinamide (55+200 mg/kg). Two groups of rats, healthy and diabetic, were treated with 0.1% TPP in drinking water daily for 3 months and the 2 others received water only. The glucose, insulin, early to end glycation products, the activity of glyoxalase system, lipid profile, LDL oxidation markers, inflammatory markers, creatinine in the serum, and proteinuria in the urine of all rats were determined. Moreover, albumin and LDL were incubated with glucose in the presence and absence of TPP, and the samples were investigated for glycation and oxidation products. Different variables in all 4 groups were compared with multiple analysis of variance (MANOVA-Tukey) test using SPSS version 16. Significance level was set at p<0.05. Results: TPP decreased the formation of diverse glycation and oxidation products in both in vivo (glycated LDL= 144.50±3.48 and oxidized LDL= 54.08±2.67 μmol/l) and in vitro (glycated LDL= 107.00±2.82 and oxidized LDL= 50.83±1.22 μmol/l). In addition, the vitamin reduced fasting blood sugar (9.23±0.29), insulin resistance (9.10±0.50), tumor necrosis factor-α (285.43±15.97), interleukin-6 (257.65±13.06), and improved the lipid profile, the activity of Glo system (Glo-I= 31.65±1.06 and Glo-II= 27.01±0.90 U/mL) and renal function in the diabetic rat (p<0.001). Conclusion: TPP decreased the major risk factors for diabetic complications and corrected the alternations of glucose and lipid metabolism in type 2 diabetic rats; thus, it is recommended for diabetes treatment.

Annexin‐A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin‐resistant, but not insulin‐deficient, mice

Arterial stiffness, a characteristic feature of diabetes, increases the risk of cardiovascular complications. Potential mechanisms that promote arterial stiffness in diabetes include oxidative stress, glycation and inflammation. The anti-inflammatory protein annexin-A1 has cardioprotective properties, particularly in the context of ischaemia. However, the role of endogenous annexin-A1 in the vasculature in both normal physiology and pathophysiology remains largely unknown. Hence, this study investigated the role of endogenous annexin-A1 in diabetes-induced remodelling of mouse mesenteric vasculature. Insulin-resistance was induced in male mice (AnxA1+/+ and AnxA1-/- ) with the combination of streptozotocin (55mg/kg i.p. x 3 days) with high fat diet (42% energy from fat) or citrate vehicle with normal chow diet (20-weeks). Insulin-deficiency was induced in a separate cohort of mice using a higher total streptozocin dose (55mg/kg i.p. x 5 days) on chow diet (16-weeks). At study endpoint, mesenteric artery passive mechanics were assessed by pressure myography. Insulin-resistance induced significant outward remodelling but had no impact on passive stiffness. Interestingly, vascular stiffness was significantly increased in AnxA1-/- mice when subjected to insulin-resistance. In contrast, insulin-deficiency induced outward remodelling and increased volume compliance in mesenteric arteries, regardless of genotype. In addition, the annexin-A1 / formyl peptide receptor axis is upregulated in both insulin-resistant and insulin-deficient mice. Our study provided the first evidence that endogenous AnxA1 may play an important vasoprotective role in the context of insulin-resistance. AnxA1-based therapies may provide additional benefits over traditional anti-inflammatory strategies for reducing vascular injury in diabetes.

Antidiabetic Activity of an Ayurvedic Formulation Chaturmukha Rasa: A Mechanism Based Study.

ObjectivesThe objective of this study was to evaluate antidiabetic activity of Chaturmukha rasa based on streptozotocin induced diabetes model, alpha amylase inhibitory activity, alpha Glucosidase inhibitory activity and inhibition of sucrase.MethodsChaturmukha rasa was prepared as per Ayurvedic formulary. Antidiabetic activity was measured in experimentally streptozotocin induced rats. The dose was taken as 45 mg/kg, i.p. The antidiabetic activity of Chaturmukha rasa was compared Triphala Kwatha, a marketed formulation. Further In vitro ά-Amylase Inhibitory Assay, In vitro salivary amylase Inhibitory Assay, In vitro α-Glucosidase Inhibitory Assay and In vitro Sucrase Inhibitory Assay was performed with respect to Chaturmukha rasa. The IC50 value was calculated for all the above activity.ResultsStreptozotocin with Acarbose showed significant decrease in blood glucose level whereas streptozotocin with Triphala kwatha showed more decrease in blood glucose level than Streptozotocin with Acarbose. The combination of Streptozotocin + Triphala kwatha + Chaturmukha rasa showed a significant decrease in blood glucose level on 21st day. In vitro ά-Amylase Inhibitory Assay the Chaturmukha rasa showed IC50 value 495.94 μl when compared with Acarbose 427.33 μl, respectively. In the α-Glucosidase Inhibitory Assay Chaturmukha rasa showed IC50 value 70.93 μl when compared with Acarbose 102.28 μl, respectively. In vitro Sucrase Inhibitory Assay Chaturmukha rasa showed IC50 value 415.4 μl when compared with Acarbose 371.43 μl, respectively.ConclusionThis study supports that Chaturmukha rasa may inhibit diabetes by inhibition of salivary amylase or alpha Glucosidase or sucrase. This may be the mechanism by which Chaturmukha rasa inhibits diabetes. Further this study supports the usage of Chaturmukha rasa for the management of diabetes.

Diabetes sepsis on Wistar rat strain (Rattus norvegicus) induced by streptozotocin and bacteria Staphylococcus aureus.

Background and Aim:Sepsis is characterized by loss of control of the inflammatory response, which can be triggered by various microorganisms and toxic secretions. The mortality rate increases due to impaired endothelial function caused dysfunctional organ systems. Diabetes is closely related to sepsis. The study aimed to determine the method of using animal models of sepsis diabetes through a combination of streptozotocin (STZ) and Staphylococcus aureus infection based on biological marker parameters.Materials and Methods:A total of 30 male Wistar rats of 2.5-3 months old weighing approximately 150-250 g body weight (BW) divided into six treatment groups with five replications per group were used in the study. Treatment A was negative control (healthy rats) and Treatment B was the positive control (with diabetes) where rats were given STZ dose at 45 mg/kg BW on day 8 intraperitoneally (IP). The blood glucose was measured on day 10, Treatment C was a positive control (bacteria), rats inoculated with S. aureus with a concentration of 108 CFU/mL on day 8 given IP and observed sepsis conditions on day 10th. Treatment group (D, E, and F): Rats given STZ dose at 45 mg/kg BW on day 8th by IP and measured blood glucose on day 10th, then inoculated with S. aureus with different concentrations of 105 CFU/mL, 106 CFU/mL, and 107 CFU/mL on the 10th day, respectively, and were later observed the condition of sepsis on day 12th. Data on diabetes bacteremia were quantitative used blood glucose levels, the bacterial count, and C-reactive protein (CRP) and were analyzed using the one-way analysis of variance test with a confidence level of 95%. Physical examination (temperature and respiration) is qualitative.Results:Physical examination showed that all treatments had a normal temperature, an increased pulse in Groups D, E, and F and a decrease in respiratory rate in the treatment of E and F, the bacteria found in the vital organs in all groups, and CRP levels were not significantly different at all.Conclusion:Animal model of diabetes sepsis can be observed through a combination of pancreas damage, and respiration, the bacteria in the vital organs.

Extended cycle streptozotocin/5-FU chemotherapy for maintenance therapy in pancreatic neuroendocrine tumors.

The standard of care treatment for patients with advanced pancreatic neuroendocrine tumors (pNET) is a combination of streptozotocin and 5-FU. Although widely used, little is known about the best long-term strategy with these substances. We here report our experience of 28 patients treated with streptozotocin/5-FU for advanced pNET with special consideration for long-term management using an extended cycle protocol. Standard 6-weekly Moertel protocol resulted in a median progression-free survival of 21 months (range 3-128) and a median overall survival of 69 months (range 3-157+) in the whole cohort. Thirteen of the 28 patients were switched to an extended 3-month cycle protocol for maintenance therapy. Of these 13 patients, 2 achieved complete remission, 1 partial remission, and 8 stable disease as best response while 2 showed progressive disease following switch to the extended protocol, resulting in an additional median progression-free survival of 23 months. Median overall survival after the start of chemotherapy in this patient group was 69 months (21-157+). Patients benefitted from extended periods free of chemotherapy-associated side effects after switching to the extended cycle protocol. Switching to an extended cycle protocol of 3 months for maintenance therapy following initial standard cycles may achieve long-term disease stabilization in selected patients with advanced pNET with good patient acceptance.

REGULATION OF ETHYL ACETATE FRACTION FROM MORINGA OLEIFERA LEAVES TO IMPROVE LIPID METABOLISM AND INSULIN SENSITIVITY IN TYPE 2 DIABETES

Objective: Moringa oleifera is a medicinal plant species that has potential as an antidiabetic. The present study was designed to evaluated molecullar mechanism antidiabetic ethyl acetate fraction of Moringa oleifera leaves (EAFML).Methods: The study was conducted on 30 male wistar rats which were induced with the combination of streptozotocin and nicotinamide by intraperitoneal administration to make a model of type 2 diabetes. After the diabetic induction, all rats were divided into six group and once daily administered orally EAFML in doses standardized quercetine. The treatment was given for ten days, and on the final treatment, all rats were checked their blood glucose level and lipid profile. The skeletal muscles and liver were taken to examine glucose transporter-4 (GLUT4) expression by immunohistochemistry.Results: The result of this study shows that the blood glucose level in diabetic rats with the treatment of EAFML decreased significantly from 355.8±83.7 mg/dL to 177.5±89.3 mg/dL. The cholesterol decreased significantly from 105.2±47.4 mg/dL to 58.6±6.9 mg/dL and low-density lipoprotein (LDL) in diabetic rats with the treatment of EAFML decreased significantly compared to control group from 175.6±41.9 mg/dL to 95.3±8.0 mg/dL. The expression of GLUT4 in skeletal muscles increased from 0.7±1.0 to 3.9±1.1 and in the liver increased significantly from 1.8±1.3 to 2.9±1.9.Conclusion: The EAFML can decrease blood glucose level, cholesterol and low-density lipoprotein in type 2 diabetic rat model. Other than that, this fraction can improve insulin sensitivity by the increase of GLUT4 expressions.

Sodium butyrate mitigates type 2 diabetes by inhibiting PERK-CHOP pathway of endoplasmic reticulum stress

Sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitors, has been reported to attenuate hyperglycemia in rats. Our objective was to explore the effect and underlying mechanism of NaB on islet β-cell dysfunction and apoptosis in type 2 diabetic (T2DM) rats. T2DM models were induced by the combination of streptozotocin (STZ, 40 mg/kg) and high-fat-diet, while NaB (500 mg/kg/d) was intraperitoneally injected for 6 weeks in experimental groups. Our results suggested NaB mitigated hyperglycemia, lowered the levels of serum cholestenone (TC) and low-density lipoprotein (LDL-c), prevented body weight loss, and enhanced insulin resistance and glucose tolerance. NaB also improved diabetes-induced histological alteration of islet and functional damage; moreover, results of TUNEL and western blotting indicated NaB alleviated β-cell apoptosis. Further research showed NaB down-regulated the expression of endoplasmic reticulum stress (ERS) related proteins, including phosphorylated type I transmembrane ER-resident protein kinase (p-PERK), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), activating transcription factor (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP). Consequently, NaB mitigates type 2 diabetes by inhibiting PERK-CHOP pathway of ERS.

Evaluation of type 2 diabetic mellitus animal models via interactions between insulin and mitogen‑activated protein kinase signaling pathways induced by a high fat and sugar diet and streptozotocin.

Type 2 diabetic mellitus (T2DM), which is characterized by insulin resistance (IR), hyperglycemia and hyperlipidemia, is a comprehensive dysfunction of metabolism. The insulin receptor (INSR)/phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is well acknowledged as a predominant pathway associated with glucose uptake; however, the effect of streptozotocin (STZ) plus a high fat and sugar diet (HFSD) on the proteins associated with this pathway requires further elucidation. In order to explore this effect, a T2DM rat model was constructed to investigate T2DM pathogenesis and potential therapeutic advantages. Rats were randomly divided into control and model groups, including normal diet (ND) and HFSD types. ND types were administered intraperitoneal (IP) injections of STZ (35 mg/kg) or a combination of STZ and alloxan monohydrate (AON) (40 mg/kg), whereas HFSD types were composed of HFSD pre-given, post-given and simul-given groups, and were modeled as follows: IP or intramuscular (IM) injection of STZ (35 mg/kg) or a combination of STZ and AON (40 mg/kg). Results indicated that, compared with controls, blood glucose, insulin, homeostatic model assessment-insulin resistance and total triglyceride were significantly elevated in groups with HFSD and modeling agents (P<0.05 or P<0.01), whereas total cholesterol and low-density lipoprotein levels were significantly elevated in groups simultaneously administered HFSD and modeling agents (P<0.05 or P<0.01), in addition to downregulation of the expression of insulin signaling pathway proteins in the liver, including INSR, PI3K, AKT1, phosphatidylinositol-5-phosphate 4-kinase type-2α (PIP5Kα) and glucose transporter (GLUT)2, and increased expression of inflammatory factors, including p38, tumor necrosis factor (TNF)α and interleukin (IL)6. Furthermore, compared with other two HFSD types including pre-given and post-given group, the simul-given group that received IM injection with STZ exhibited decreased expression levels of major insulin signal pathway proteins INSR, PI3K, AKT1, PIP5Kα, GLUT2 or GLUT4 in the liver and pancreas (P<0.05 or P<0.01), whereas the opposite was observed in the skeletal muscle. In addition, the protein expression levels of phosphorylated-p38, p38, IL6 and TNFα in the simul-given group that received IM injection with STZ were increased (P<0.05 or P<0.01), and histopathology also indicated inflammation in pancreas and liver. The present findings suggest that a low dose of STZ may partially impair the β cells of the pancreas, whereas long-term excess intake of HFSD may increase lipid metabolites, inhibit the insulin signaling pathway and activate the mitogen-activated protein kinase p38 signaling pathway. The combined action of STZ and AON may result in insulin resistance, which ultimately results in abnormalities in glucose and lipid metabolism. The present model, analogue to T2DM onset of humans, evaluated the medical effect on metabolic dysfunction and provides an insight into the underlining mechanism of IR.

Neuroprotective role of GABAB receptor modulation against streptozotocin-induced behavioral and biochemical abnormalities in rats

Stimulation as well as inhibition of GABAB (Gamma amino butyric acid) receptors has been reported to show beneficial effects in Alzheimer’s disease (AD). Experimental evidences suggest that the use of GABAergic agents could influence learning and memory. The present study was designed to investigate the possible role of GABAB receptors in streptozotocin (STZ)-induced behavioral and biochemical abnormalities in rats. Herein STZ was infused (3mg/kg) bilaterally on alternate days (day 1 and day 3) to produce experimental dementia in rats. STZ-infused rats were then treated with baclofen (GABABR agonist) 5 and 10mg/kg i.p. and CGP35348 (GABABR antagonist) 25 and 50mg/kg i.p. one week following STZ infusion for 15days. Cognitive functions were assessed by using Morris water maze (MWM) and object recognition task (ORT). Levels of malondialdehyde (MDA.), reduced glutathione (GSH), andacetylcholinesterase (AChE) were determined to evaluate oxidative stress and cholinergic function. STZ-infused rats showed decreased memory retention, elevated levels of MDA, increased AChE activity, reduced GSH levels. The combination of STZ with increasing doses of Baclofen further induced a higher decrease in memory retention and increase in oxidative stress. CGP35348 restored cognitive functions and AChE activity in STZ-infused rats. The cognitive enhancement following CGP35348 may be due to its ability to restore cholinergic, serotonergic and dopaminergic function, and its antioxidant activity. Therefore, it would be safe to conclude that the pharmacological blockade of GABAB receptors would be therapeutic in the management of cognitive disorders such as Alzheimer’s disease.

P-206 Efficacy and tolerance of a simplified combination of Streptozotocin and epi-adriamycin in metastatic foregut neuroendocrine tumor (NET)

P-206 Efficacy and tolerance of a simplified combination of Streptozotocin and epi-adriamycin in metastatic foregut neuroendocrine tumor (NET)

Sitagliptin protects proliferation of neural progenitor cells in diabetic mice.

Sitagliptin (SIT) is a dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances the effects of incretin hormones, such as Glucose-dependent Insulinotropic Peptide (also known as Gastric Inhibitory Polypeptide, GIP) and Glucagon-Like Peptide 1 (GLP-1). We have now evaluated the effect of SIT on proliferation of neural progenitors in diabetic mice. A condition resembling the non-obese type 2 diabetes mellitus (D2) was achieved by a combination of streptozotocin and nicotinamide (NA-STZ), whereas a type 1-like disease (D1) was provoked by STZ without NA. Non-diabetic mice received vehicle injections. Cell proliferation was estimated by bromodeoxyuridine (BrdU) incorporation in two different regions of the subventricular zone (SVZ), the largest reserve of neural stem cells in the adult brain. SIT treatment did not modify the high fasting blood glucose (BG) levels and intraperitoneal glucose tolerance test (IPGTT) of D1 mice. By contrast, in D2 mice, SIT treatment significantly reduced BG and IPGTT. Both D1 and D2 mice showed a substantial reduction of BrdU labeling in the SVZ. Remarkably, SIT treatment improved BrdU labeling in both conditions. Our findings suggest that SIT would protect proliferation of neural progenitor cells even in the presence of non-controlled diabetic alterations.

Reduced epidermal thickness, nerve degeneration and increased pain-related behavior in rats with diabetes type 1 and 2

To examine the mechanisms contributing to pain genesis in diabetic neuropathy, we investigated epidermal thickness and number of intraepidermal nerve fibers in rat foot pad of the animal model of diabetes type 1 and type 2 in relation to pain-related behavior. Male Sprague-Dawley rats were used. Diabetes type 1 was induced with intraperitoneal injection of streptozotocin (STZ) and diabetes type 2 was induced with a combination of STZ and high-fat diet. Control group for diabetes type 1 was fed with regular laboratory chow, while control group for diabetes type 2 received high-fat diet. Body weights and blood glucose levels were monitored to confirm induction of diabetes. Pain-related behavior was analyzed using thermal (hot, cold) and mechanical stimuli (von Frey fibers, number of hyperalgesic responses). Two months after induction of diabetes, glabrous skin samples from plantar surface of the both hind paws were collected. Epidermal thickness was evaluated with hematoxylin and eosin staining. Intraepidermal nerve fibers quantification was performed after staining skin with polyclonal antiserum against protein gene product 9.5. We found that induction of diabetes type 1 and type 2 causes significant epidermal thinning and loss of intraepidermal nerve fibers in a rat model, and both changes were more pronounced in diabetes type 1 model. Significant increase of pain-related behavior two months after induction of diabetes was observed only in a model of diabetes type 1. In conclusion, animal models of diabetes type 1 and diabetes type 2 could be used in pharmacological studies, where cutaneous changes could be used as outcome measures for predegenerative markers of neuropathies.

The Protective Effect of Fasudil on the Structure and Function of Cardiac Mitochondria from Rats with Type 2 Diabetes Induced by Streptozotocin with a High-Fat Diet Is Mediated by the Attenuation of Oxidative Stress

Dysfunction of cardiac mitochondria appears to play a substantial role in cardiomyopathy or myocardial dysfunction and is a promising therapeutic target for many cardiovascular diseases. We investigated the effect of the Rho/Rho-associated protein kinase (ROCK) inhibitor fasudil on cardiac mitochondria from rats in which diabetes was induced by a combination of streptozotocin (STZ) and a sustained high-fat diet. Eight weeks after diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ followed by a sustained high-fat diet, either fasudil (5 mg/kg bid) or equivalent volumes of saline (control) were administered over four weeks. Fasudil significantly protected against the histopathologic changes of cardiac mitochondria in diabetic rats. Fasudil significantly reduced the abundances of the Rho A, ROCK 1, and ROCK 2 proteins, restored the activities of succinate dehydrogenase (SDH) and monoamine oxidase (MAO) in cardiac mitochondria, inhibited the opening of the mitochondrial permeability transition pore, and decreased the total antioxidant capacity, as well as levels of malonyldialdehyde, hydroxy radical, reduced glutathione, and superoxide dismutase in heart. Fasudil improved the structures of cardiac mitochondria and increased both SDH and MAO activities in cardiac mitochondria. These beneficial effects may be associated with the attenuation of oxidative stress caused by fasudil treatment.