Alloxan-induced Type Research Articles

Thiazolidine-2, 4-Diones as Non-Hepatotoxic Tri-action Drug Candidates: Design, Synthesis, Characterization, Biological Evaluation and Docking Studies

Thiazolidine-2, 4-diones and their derivatives are a well-established chemical class of compounds that express their pharmacological actions through insulin sensitization and enhanced glucose utilization in peripheral tissues. In the current research different approaches have been employed to synthesize thiazolidine-2, 4-dione derivatives and these synthesized compounds were chemically characterized for the establishment of their chemical structures. A series of thiazolidine-2, 4-dione (TZD) derivatives, Scheme 1 (3A-3V) 22 compounds, were synthesized and characterized by FT-IR, 1H NMR and mass spectral analysis. The title compounds were screened for their in vitro and in vivo antidiabetic, antioxidant, and cytotoxicity studies. In vivo antihyperglycemic effect was assessed by measuring plasma glucose (PG) levels in alloxan-induced type II diabetic rat models. The synthesized TZD derivatives were evaluated for hepatotoxicity and pancreatic tissue integrity. Antioxidant activity was evaluated by the DPPH method and H2O2 method. Thiazolidinedione derivatives were subjected to predict free energy of binding towards target PPARγ, using rosiglitazone as the reference compound for molecular docking visualization through the FlexX docking program. Molecular docking studies are also performed for understanding the binding of a ligand to a receptor. The compound 3V 4-(5- (naphthalen-1-ylmethylene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better blood glucoselowering activity than that of the standard drug rosiglitazone. Compound 3T and 3U exhibited potent antioxidant activity. Among the tested compounds for cytotoxicity using an MTT assay, compound 3H 5-(4-chlorobenzylidene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better viability and cytotoxicity activity. From selected anti-diabetic targets, the proposed derivatives exhibited better interaction with PPARγ receptor, for example, while rosiglitazone showed a docking score of -19.891 kJ/mol, compound 3V exhibited highest docking score of -31.6617 kJ/mol. Computational molecular docking study demonstrated the selectivity and provided a binding model for the further refinement of this chemotype. Therefore, this series of thiazolidine-2, 4-diones derivatives (3A-3V) have considerable importance for development as a potential antihyperglycemic and hypolipidemic agents.

Peroxiredoxin 6 Attenuates Alloxan-Induced Type 1 Diabetes Mellitus in Mice and Cytokine-Induced Cytotoxicity in RIN-m5F Beta Cells.

Type 1 diabetes is associated with the destruction of pancreatic beta cells, which is mediated via an autoimmune mechanism and consequent inflammatory processes. In this article, we describe a beneficial effect of peroxiredoxin 6 (PRDX6) in a type 1 diabetes mouse model. The main idea of this study was based on the well-known data that oxidative stress plays an important role in pathogenesis of diabetes and its associated complications. We hypothesised that PRDX6, which is well known for its various biological functions, including antioxidant activity, may provide an antidiabetic effect. It was shown that PRDX6 prevented hyperglycemia, lowered the mortality rate, restored the plasma cytokine profile, reversed the splenic cell apoptosis, and reduced the β cell destruction in Langerhans islets in mice with a severe form of alloxan-induced diabetes. In addition, PRDX6 protected rat insulinoma RIN-m5F β cells, cultured with TNF-α and IL-1β, against the cytokine-induced cytotoxicity and reduced the apoptotic cell death and production of ROS. Signal transduction studies showed that PRDX6 prevented the activation of NF-κB and c-Jun N-terminal kinase signaling cascades in RIN-m5F β cells cultured with cytokines. In conclusion, there is a prospect for therapeutic application of PRDX6 to delay or even prevent β cell apoptosis in type 1 diabetes.

Hypoglycemic Activity and the Mechanisms of Lycium Bark Extract in db/db Mice.

The extract of Lycium bark (LBE), which is the root bark of Lycium chinense, has long been used in China for hypertension, inflammation, and diabetes. LBE has been reported to ameliorate hyperglycemia in mice with alloxan-induced type 1 diabetes, but evidence on the effect of LBE in diabetes had not been enough. Therefore, we investigated the effects of LBE on type 2 diabetes using db/db mice. Nine-week-old male db/db mice were orally administered LBE (425 mg/kg) for 10 weeks. Blood samples were collected under anesthesia for the determination of blood glucose and insulin levels. The blood glucose level was increased in the control group and was unchanged in the LBE group. The blood insulin level was increased in both groups within 4 weeks, but it decreased in the control group and was maintained at a relatively high level in the LBE group thereafter. Furthermore, LBE increased the glucose uptake, which was measured using C2C12 myotubes, in a concentration-dependent manner, independent of the addition of a phosphatidylinositol 3-kinase inhibitor (i.e., LY294002) and an AMP-activated kinase inhibitor (i.e., dorsomorphin). And LBE increased the mRNA expression of glucose transporter (GLUT) 1. These results suggested that LBE decreased the blood glucose level by additive effect such as improvement of the insulin secretion, promoting activity of glucose uptake. These findings suggested that LBE administration can be a novel therapeutic approach for type 2 diabetes.

Antidiabetic and hypolipidemic potentials of Solidago virgaurea extract in alloxan-induced diabetes type 1

Objectives The aim of the current study is to investigate the antidiabetic and hypolipidemic potentials of Solidago virgaurea extract in alloxan-induced diabetic rats. Materials and methods Alloxan-induced diabetic rats were orally administered a dose of Solidago virgaurea extract (250 mg/kg body weight) daily for 15 days. Then blood glucose, insulin, serum lipid profile, amylase, tumour necrosis factor-α (TNF- α), and liver glycogen were determined. Besides, superoxide dismutase (SOD), catalase activities, and malondialdehyde (MDA) levels in pancreatic tissue were assessed. Results Solidago virgaurea extract significantly reduced blood glucose level, serum amylase activity, TNF-α level, and pancreatic MDA level as well as increasing the serum insulin, liver glycogen level, pancreatic SOD, and catalase activities in comparison with their corresponding diabetic rats, p < .05. Conclusion The findings of this study support the ethnomedicinal use of Solidago virgaurea extract as an antidiabetic and antihyperlipidemic in the management of diabetes mellitus.

Superimposition of hypertension on diabetic peripheral neuropathy affects small unmyelinated sensory nerves in the skin and myelinated tibial and sural nerves in rats with alloxan-induced type 1 diabetes.

Diabetic peripheral neuropathy (DPN) is a major complication of diabetes mellitus, and hypertension is considered to be a risk factor for DPN in patients with type 1 diabetes (T1DM). However, the morphological effects of hypertension on DPN are unclear. In this study, we investigated the effect of hypertension on DPN by investigating the changes in unmyelinated and myelinated nerve fibers in hypertensive rats with alloxan (AL)-induced T1DM. Thirteen-week-old WBN/Kob rats with AL-induced diabetes were allocated to receive tap water only (AL group), tap water containing 0.5% saline (0.5AN group), or tap water containing 0.75% saline (0.75AN group) for 15 weeks. Hyperglycemia was maintained for 15 weeks, and the animals were euthanized at 28 weeks. By 23 weeks of age, the systolic blood pressure was significantly higher in the 0.75AN and 0.5AN groups than in the AL group and was unchanged in all groups at 28 weeks. The number of intraepidermal sensory unmyelinated nerve fibers was significantly smaller in the 0.75AN and 0.5AN groups than in the AL group. The axonal size in the myelinated tibial and sural nerve fibers was significantly smaller in the 0.75AN group than in the AL group. Furthermore, luminal narrowing and endothelial hypertrophy were observed in the endoneurial tibial nerve vessels in the 0.75AN group. These findings suggest that superimposing hypertension on hyperglycemia may accelerate a reduction in the number of small unmyelinated sensory nerve fibers in the skin and induce mild axonal atrophy in myelinated tibial and sural nerve fibers in rats with AL-induced T1DM.

Ethnopharmacological activity of Hedera nepalensis K. Koch extracts and lupeol against alloxan-induced type I diabetes

In this study, we investigated the protective effects of Hedera nepalensis crude extract, its fractions and lupeol in alloxan-induced diabetic rats. Lupeol and n-hexane (HNN) fraction significantly reduced the blood glucose level by increasing insulin level in time dependent manner, and also significantly increased amylase and lipase activity in diabetic rats. Elevated levels of alanine transaminases (ALT), aspartate transaminases (AST), thiobarbituric acid reactive substances (TBARS), nitrite, hydrogen peroxide (H2 O2 ), total bilirubin and total protein in blood serum were efficiently restored to normal levels. Suppressed enzymatic activity of catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH) and peroxidase (POD) were also restored to their normal levels. Kidney functions were also restored to normal level after treatment with HNN and lupeol. HNN fraction and lupeol of H. nepalensis prevented oxidative stress in alloxan-induced diabetic rats. This study signifies the importance of H. nepalensis and lupeol in ameliorating diabetes by inducing insulin secretion in diabetic model rats.

SERUM CONCENTRATION OF THYROID HORMONES AND THYROID STIMULATING HORMONE IN ALLOXAN-INDUCED TYPE 1 DIABETIC WISTAR ALBINO RATS

Background: Literature has reported thyroid functional abnormalities in diabetes mellitus. The objectives of this study were to determine and compare the serum concentrations of T3, T4 and TSH in alloxan-induced type 1 diabetic and control Wistar albino rats. Materials &amp; Methods: It was an experimental animal study on 20 Wistar albino rats, extending over a period of eight weeks. Alloxan, a diabetogenic agent, was used to produce animal models of type 1 diabetes. Animals were divided equally into two groups: control and diabetic. The animals in the diabetic group were injected intraperitoneally with 150 mg/kg body weight of 10% alloxan to induce diabetes. After 72 hours, diabetes was confirmed with glucometer (glucose &gt;350mg/dl). During the course of experiment, one rat in control group and 2 rats in diabetic group died. Blood was collected for estimation of serum concentrations of thyroid hormones, thyroid stimulating hormone at the end of experimental period. Serum T3, T4, and TSH were measured using ELISA kits. Results: At the end of eight weeks, the mean concentration of serum T3 was 0.69 ±0.29 ng/ml and 0.44±0.02 ng/ml in control and diabetic groups, respectively. The mean concentration of T4 was 3.78±1.16 μg/dl and 2.24±0.86 μg/dl in control and diabetic groups respectively. The mean concentration of TSH was 0.77±0.20 μU/ml and 1.41±0.23 μU/ml in control and diabetic groups respectively. The mean serum concentrations of T3 (p=.0025) and T4 (p=&lt;.00001) were significantly lower in diabetic and that of TSH (p=&lt;.00001) were significantly higher in diabetic than control group. Conclusion: This study concludes that the serum concentrations of both T3 and T4 are significantly lower and that of TSH is significantly higher in alloxan-induced type 1 diabetic as compared to control group in Wistar albino rats.

Effects of Coriandrum sativum L. in Association with Physical Exercise in Alloxan-Induced Type 1 Diabetes Mellitus in Rats

The treatment of type 1 diabetes mellitus (T1DM) is a health challenge and new approaches to solve this issue have been proposed. This study evaluated the biological effects of a concomitant treatment with Coriandrum sativum (coriander) and whole-body vibration (WBV) exercise on rats with T1DM. It is hypothesized that this concomitant treatment will improve the metabolic state of rats with T1DM. T1DM was induced with alloxan. Male rats (n = 20) were divided into four groups: control (CON), treated with coriander (COR), exposed to 50 Hz of WBV (WBV), and treated with coriander and exposed to 50 Hz of WBV (COR + WBV), weekly for 28 days. No alterations were observed in the metabolic outcome variables relating to the organs, specific biomarkers, body mass, food intake, and stool consistency. Alloxan-induced T1DM resisted desirable therapeutic effects of the proposed concomitant treatment as it inhibited antidiabetic activity of the coriander. Putting together all findings, neither coriander nor WBV exercise were capable of improving the metabolic state of the Wistar rats with T1DM. This data set and the knowledge in the literature about the effects of the concomitant treatment in healthy animals can provide greater reliability concerning the effects of coriander.

Comment on "Anion Gap Toxicity in Alloxan Induced Type 2 Diabetic Rats Treated with Antidiabetic Noncytotoxic Bioactive Compounds of Ethanolic Extract of Moringa oleifera".

Comment on "Anion Gap Toxicity in Alloxan Induced Type 2 Diabetic Rats Treated with Antidiabetic Noncytotoxic Bioactive Compounds of Ethanolic Extract of Moringa oleifera".

Pancreato-protective PANCREATOPROTECTIVE EFFECT OF SILYMARIN ON OXIDATIVE STRESS IN ALLOXAN-INDUCED HYPERGLYCEMIA IN MALE WISTAR RATS

Objective: The objective of the study was to study the silymarin’s pancreatoprotective effect in alloxan-induced Type I diabetes mellitus. Numerous studies have evidence to prove the fact that antioxidant defense mechanism of flavonoids has overcome the progression of chronic diabetic complications.&#x0D; Methods: A total of 24 male Wistar rats were divided into four groups (n=6): Group I normal control, Group II, Group III, and Group IV were induced diabetes with alloxan. Group I and Group II diabetic rats received the vehicle (PO). Group III was treated with silymarin 400 mg/kg (PO). Group IV was treated with glibenclamide 0.5 mg/kg, per orally for 21 days. Fasting blood samples were collected from all four groups of animals at the end of 21 days to evaluate serum glucose and glycosylated hemoglobin (HbA1c). Pancreatic tissue extraction, to perform lipid peroxidation and histopathological study confirms the level of oxidative damage to tissues and recovery after treatment.&#x0D; Results: The serum glucose and HbA1c levels significantly increased in untreated diabetic rats, also a significant rise in lipid peroxidation and necrosis of beta cells in the pancreatic tissue. The rise in serum glucose levels was ameliorated in rats treated with silymarin, pancreatic tissue showed increased antioxidant levels, decreased lipid peroxides, and minimal changes and signs of regeneration of beta cells.&#x0D; Conclusion: This study adds experimental evidence to the fact that silymarin is an effective nutritional supplement to treasure pancreatic beta-cell reserve and to delay diabetic complications.

Glucose consumption assay discovers coptisine with beneficial effect on diabetic mice

Many drugs with anti-diabetic effects regulate glucose consumption in peripheral tissues. Via cellular glucose consumption assays, we identified that coptisine, a main effective constituent from the plant Coptis chinensis, enhanced hepatic and skeletal muscle glucose consumption. We further explored its effects on glucose metabolism in diabetic animals to elucidate its mechanism of action. Our results showed that coptisine did not show cytotoxicity. Intragastric administration of coptisine for ten days in normal ICR mice markedly decreased fasting blood-glucose levels without significant effects on body weight. In alloxan-induced type 1 diabetic mice, intragastric administration of coptisine for 28 days decreased fasting and non-fasting blood-glucose levels as well. In type 2 diabetic KKAy mice, intragastric administration of coptisine for nine weeks improved glucose tolerance. It decreased fasting/non-fasting blood-glucose and fructosamine levels. Coptisine decreased low-density lipoprotein and total cholesterol levels, however, had no significant effect on triglyceride levels. Coptisine increased AMPK phosphorylation while decreasing Akt phosphorylation in HepG2 hepatic cells and C2C12 myotubes. Coptisine also reduced mitochondrial respiration in isolated and cellular mitochondria, suggesting that coptisine lowered cellular energy levels. In particularly, coptisine administration (10−6 M) decreased the mitochondrial oxygen consumption rate (OCR) with a greater extracellular acidification rate (ECAR), resulting in an oxidative-to-glycolysis phosphorylation shifted for cellular energy generation. Our results demonstrate that coptisine acts as an enhancer of peripheral glucose consumption could improve glucose metabolism in diabetic animals. Coptisine may serve as a novel anti-diabetic agent and warrant further evaluation.

Phytochemical composition, antioxidant and in vivo antidiabetic activities of the hydroethanolic extract of Eugenia florida DC. (Myrtaceae) leaves

Some literature studies have shown the popular use of species of Eugenia sp. leaves as an antioxidant, hypoglycemic, hypotensive and antipyretic. However, the species E. florida DC. shows few studies in this field of knowledge. In this way, it becomes a choice for further research. Several chemical compounds, such as phenolic acids, flavonoids, saponins and tannins, have previously been identified in the species and may be related to biological activity. The aim of present work was done to identify the chemical compounds present in the hydroethanolic extract of Eugenia florida DC. leaves by high-performance liquid chromatography coupled to mass spectrometry, as well as to investigate the antioxidant and antidiabetic effects in alloxan-induced type 1 diabetic rats. Initially, the data collection, specimen deposition of leaves of E. florida DC. and the preparation of the hydroethanolic extract were done. The chemical characterization of the major compounds in the extract was done using a liquid chromatograph coupled to the mass spectrometer, in the negative ionization mode. The evaluation of the antioxidant activity of the extracts was done by the DPPH method. To evaluate the biochemical parameters in the Wistar diabetic rats, alloxan was administered at a dose of 140 mg/kg to the diabetic groups, and the extract was diluted in water to 200 mg/mL and administered to all groups for 30 days. After this period, whole blood from the animals was collected for the determination of some biochemical parameters, as well as livers and kidneys for the evaluation of the effects of the extract on the control of lipid peroxidation. The phytochemical analysis of the extract revealed the presence of substances belonging to the classes described in the literature for the genus Eugenia sp., such as flavonoids, tannins and phenolic acids, based on the molecular mass and the fragmentation patterns obtained. The leaf extract presented potential DPPH radical scavenging activity very close to the catechin standard. In the evaluation of the biochemical parameters of diabetic rats treated with the extract, significant decreases in serum levels of glucose, fructosamine and triglycerides (38.0%, 31.0% and 19.7%, respectively) were observed, as well as an increase in HDL cholesterol (10.3%). The administration of the extract had no significant effect on renal function, AST and ALT activity and on the other parameters of the lipid profile. In addition, there was improvement in liver and kidney damage in treated diabetic animals, through reduction of MDA values in livers and kidneys (17.3% and 13.8%, respectively). Thus, the species E. florida DC. presents an interesting biological potential, due mainly to its bioactive secondary metabolites, which showed promising antioxidant activity and biochemical parameters in diabetic rat models.

Antihyperglycemic activity of the leaves from annona diversifolia Safford. and farnesol on normal and alloxan-induced diabetic mice*

Background: Diabetes mellitus (DM) is a chronic disease characterized by high blood glucose levels resulting from insulin resistance or inadequate insulin secretion. In the world, DM is one of the most frequent non-contagious diseases that affect more than 371 million people. Objective: This study aimed to evaluate the antihyperglycemic properties of the ethanol extract, subsequent fractions, and farnesol obtained from the leaves of Annona diversifolia on alloxan-induced diabetic and normal mice. Materials and Methods: Bioassay-guided fractionation of the ethanol extract of the leaves of A. diversifolia (EELAd) was performed on alloxan-induced Type 2 diabetic and normoglycemic (NM) mice. Oral glucose tolerance test (OGTT), oral sucrose tolerance test (OSTT), and oral lactose tolerance test (OLTT) were performed in fast NM mice (FNM). Results: The EELAd, CHCl3 fraction, and farnesol induced a significant reduction of postprandial hyperglycemia in acute and subchronic tests using AITD mice. When EELAd, CHCl3 fraction, and farnesol were tested on NM in subchronic assays, these did not affect glycemic levels. In the case of acute test on NM, only CHCl3 fraction induced a hypoglycemic effect at 2 h after the treatment. OLTT and OSTT showed that the EELAd, CHCl3 fraction, and farnesol induced a significant reduction of hyperglycemia levels in FNM at 2 h after a lactose or sucrose load comparable to acarbose. In the case of OGTT was observed a significant reduction of hyperglycemia levels in FNM mice at 2 h after a glucose load comparable to canagliflozin. Conclusion: The EELAd and farnesol induced a significant reduction of postprandial hyperglycemia on AITD mice in acute and subchronic assays. Our results suggest that the control of postprandial hyperglycemia may be mediated by the regulation of absorption of glucose and inhibition of disaccharide digestion such as sucrose and lactose. Finally, the results explained the use of A. diversifolia in Mexican traditional medicine as an antihyperglycemic agent.

Hypoglycemic and Hypolipidemic Activities of Psychotria sylhetensis Hook in Alloxan-induced Type 2 Diabetic Rats

The current study was carried out to determine the hypoglycemic and hypolipidemic activities of methanolic extract P. silhetensis leaves in alloxan-induced diabetic rats. In this study diabetes was induced in rats by intraperitoneal administration of 150 mg/kg of alloxan. Animals were treated for one week with the plant extract at doses of 250 and 500 mg/kg body weight. Metformin (100 mg/kg b.w.) was used as standard for comparison. The anti-diabetes activity was examined by measuring blood glucose level at 0, 3, 5 and 7 days in diabetic induced animal models. Blood samples were collected at day eight of the treatment and analyzed for triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) after sacrifice. Alloxan-induced diabetic rats exhibited a significant decrease in plasma glucose level when treated with P. silhetensis leaf extract as compared to normal, diabetic control and standard rats. All tested lipid parameters were improved after the treatment with methanolic extract of P. silhetensis and metformin as compared to diabetic rats. The results of the present study showed that P. silhetensis possesses significant anti-diabetic properties and has beneficial effects on diabetic hyperlipidemia. Bangladesh Pharmaceutical Journal 22(1): 41-44, 2019

In vivo antidiabetic and antioxidant potential of Psychotria dalzellii in streptozotocin-induced diabetic rats

Psychotria species have been known for wide array of health benefits as per traditional knowledge and only a few scientific evidences are available. In the current study in vivo antidiabetic property of methanol extract of Psychotria dalzellii (MEPD) was elucidated in alloxan-induced type 1 diabetes in Wistar rats. MEPD, acetone and ethylacetate extracts were examined for potential anti-diabetic properties (α-amylase and α-glucosidase inhibition) in in vitro and the significantly potent extract – MEPD was analyzed for in vivo antioxidant activity. Blood glucose levels, TBARS, antioxidant, creatinine, alkaline phosphatase etc., were measured. Results of the study revealed that, oral intubation of 400 mg kg−1b.w. of MEPD for a period of 20 days prior inducing diabetes resulted in the normalization of blood glucose level (259.83 ± 10.11 mg/dL as opposed to induced 389.5 ± 8.97; healthy animals had 129.16 ± 4.12 mg/dL glucose) suggesting the antidiabetic potency of MEPD. Biochemical analysis substantiated the antidiabetic property of MEPD as revealed by normalization of altered TBARS/oxidant and antioxidant levels. Results were further substantiated by in vitro studies, where MEPD exhibited good antioxidant activity – reducing power activity (IC50–8.81 U/mg vs Ascorbic acid – 6.21 U/mg; MEPD); hydrogen peroxide activity (IC50−26.57 μg/mL vs Ascorbic acid 19.12 μg/mL); MEPD inhibited α-amylase and α-glucosidase activity with (IC50 47.11 ± 2.8 μg/mL vs Acarbose – IC50 40.86 ± 1.7 μg/mL); (IC50 40.34 ± 1.2 μg/mL vs Acarbose – IC50 40.99 ± 2.3 μg/mL); providing evidence for the first time for the antidiabetic property of P. dalzellii. The potent anti-type I diabetic property could be due to antioxidant and inhibition of α-glucosidase/amylase which results in control of release of glucose levels into the circulation. Phytochemical analysis of revealed that MEPD is enriched in phenolics and flavonoids compound. In order to understand its probable mechanism of action, antioxidant status during healthy, diabetic and sample treated groups of animals were also investigated.

Involvement of inducible nitric oxide synthase and estrogen receptor ESR2 (ERβ) in the vascular dysfunction in female type 1 diabetic rats

AimsInflammation is involved in diabetes-related vascular dysfunction. Estrogen receptor ESR2/ERβ induces the expression of inducible nitric oxide (NO) synthase (iNOS) and inflammation. The present study investigated the effect of alloxan-induced type 1 diabetes on the iNOS and ESR2 expression and the effect of the chronic iNOS inhibition on the vascular smooth muscle dysfunction in diabetic female rats. In addition, we evaluated the involvement of ESR2 in iNOS expression. Main methodsAlloxan-induced diabetic female rats were treated or not with iNOS inhibitor (L-NIL). iNOS and ESR2 immunostaining, S-nitrosylated proteins and IL-1β protein expression in aorta and plasmatic NO levels were analyzed. Contractile response to noradrenaline was analyzed in endothelium-denuded aorta. iNOS mRNA expression was analyzed in isolated aortic smooth muscle cells (ASMCs) of female rats, incubated with 22 mM glucose and an ESR2 antagonist. Key findingsAortic iNOS and ESR2 immunostaining, S-nitrosylated proteins, IL-1β protein expression and plasmatic NO levels were all increased, whereas noradrenaline-induced contraction was reduced in aorta of diabetic female rats. With the exception of iNOS and ESR2 immunostaining, all these parameters were corrected by L-NIL treatment. High glucose increased iNOS mRNA expression in ASMCs, which was reduced by an ESR2 antagonist. SignificanceWe demonstrated that increased iNOS-NO contributed to the impairment of the contractile response of aortic smooth muscle cells in female type 1 diabetic rats and that increased expression of iNOS may involve the participation of ESR2/ERβ.

Antihyperglycemic Activity of the Leaves from Annona diversifolia Safford and Farnesol on Alloxan-Induced Type 2 Diabetic Mice

Antihyperglycemic Activity of the Leaves from Annona diversifolia Safford and Farnesol on Alloxan-Induced Type 2 Diabetic Mice

P15 Effects of coptisine on glucose metabolism and the mechanisms

Aim: Coptis chinensis (Chinese goldthread) has been widely used in Traditional Chinese Medicine for centuries and has a variety of pharmacological effects. In this study, we investigated the effect of coptisine on glucose related metabolic regulation in vitro and in vivo . Methods: Normal ICR mice, alloxan-induced type 1 diabetic mice and type 2 diabetic mice (KKay mice) were employed to explore the effect of coptisine on glucose metabolism in vivo . Human hepatoma cells (HepG2) and rat skeletal muscle myotube cells (L6) were used to investigate the effect of coptisine on the glucose metabolism in vitro . Results: In normal ICR mice, coptisine (10 mg/kg) decreased the fasting and fed blood glucose significantly without any significant effect on body weight. In alloxan-induced type 1 diabetic mice, coptisine decreased fasting and fed blood glucose. In type 2 diabetic Kkay mice, coptisine improved insulin tolerance and glucose tolerance but did not change LDL, TG, HDL or CHO level in serum. Our in vitro results showed that coptisine increased the glucose consumption and glucose uptake in HepG2 cells and L6 myotube cells. Coptisine significantly increased ATP level in HepG2 cells and decreased mitochondrial membrane potential in HepG2 cells. Furthermore, coptisine promoted hepatic mitochondrial F0F1-ATPase activity. Conclusion: In summary, coptisine has been shown to be effective in improving glucose metabolism in animal models. The effects of coptisine may be closely related with enhanced function of the mitochondria.

Decreased expression of orexin 1 receptor in adult mice testes during alloxan-induced diabetes mellitus perturbs testicular steroidogenesis and glucose homeostasis

Diabetes mellitus (DM) affects male reproductive system and causes infertility. The male reproductive health is largely dependent upon uptake and proper utilization of glucose by testicular cells. Results show involvement of orexin A (OXA) and its receptor (OX1R) in regulation of steroidogenesis and glucose homeostasis in adult mice testis. However, the role of OX1R in regulation of testicular functions during hyperglycemia has not been investigated so far. The present study, therefore, examined the role of OX1R in regulation of steroidogenesis and glucose homeostasis in testis of adult mice during alloxan-induced type 1 DM. A significant decrease was noted in body weight and testis weight in alloxan-treated mice compared to controls. The blood glucose level, however, was markedly increased in treated animals than in controls. Further, serum and intratesticular level of testosterone, activities of testicular steroidogenic enzymes, and expressions of various steroidogenic markers, OX1R, glucose transporter 3 (GLUT3) and Wilms' tumor gene (WT1) were downregulated in treated mice. The level of glucose, activity of lactate dehydrogenase (LDH) and lactate concentration in the testes of diabetic mice were also decreased; a significant increase in the number of testicular apoptotic cells with concomitant increase in the expression of caspase-3 was noted in these mice. Furthermore, DM affected germ cell proliferation with decreased expression of proliferating cell nuclear antigen (PCNA). Results thus suggest that type 1 DM impairs testicular steroidogenesis and glucose homeostasis through inhibition of OXA/OX1R signaling cascade due to decreased OX1R expression in adult mice, thereby affecting germ cell survival and their proliferation in the testis.

Protective effects of oleuropein against renal injury oxidative damage in alloxan-induced diabetic rats; a histological and biochemical study.

Background: Oleuropein is a potent antioxidant and free-radical scavenger with antiinflammatory properties. Objectives: In the present study, we evaluated the protective effects of oleuropein on myeloperoxidase (MPO) activity, nitrite, urea, creatinine and glomerulosclerosis in alloxan-induced type 1 diabetic rats. Materials and Methods: Thirty Sprague-Dawley male rats were randomly divided into 3 groups: group 1 as control; group 2 as untreated diabetic; and group 3 as treated with oleuropein 15 mg/kg i.p daily. Diabetes was induced in the second and third groups by subcutaneous alloxan injection. After 48 days, the animals were anaesthetized and then the livers and kidneys were removed immediately and used fresh or kept frozen until MPO activity analysis. Blood samples were also collected before sacrificing to measure nitrite, urea, and creatinine. Kidney paraffin sections were prepared to estimate glomerular volume, leukocyte infiltration, and glomerulosclerosis. Results: Oleuropein significantly decreased leukocyte infiltration and glomerulosclerosis in the treated group compared with the diabetic untreated group. Oleuropein significantly decreased the levels of urea, nitrite, and creatinine in the treated group compared with the diabetic untreated group. Moreover, oleuropein significantly decreased MPO activity in the treated group compared with the diabetic untreated group. Conclusions: Oleuropein has antioxidative and antiatherogenic activities and exerts beneficial effects on inflammation and kidney function test and decreases diabetic complication in diabetic rats.