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1

Hypoglycemic effect of astaxanthin from shrimp waste in alloxan-induced diabetic mice  

Microsoft Academic Search

Hypoglycemic effect of astaxanthin obtained from shrimp waste was assessed in alloxan-induced diabetic and normal mice. Animals\\u000a received oral administration of astaxanthin in dose of 5 and 10 mg\\/kg. The plasma glucose levels were examined and compared\\u000a with that of metformin and gliclazide. Administration of astaxanthin (5 and 10 mg\\/kg) produced significantly fall on plasma\\u000a glucose in alloxan-induced diabetic mice, while a

Juan-juan Wang; Zhi-qiang Chen; Wen-qing Lu

2

Ghrelin improves delayed gastrointestinal transit in alloxan-induced diabetic mice  

Microsoft Academic Search

AIM: To investigate the effects of ghrelin on delayed gastrointestinal transit in alloxan-induced diabetic mice. METHODS: A diabetic mouse model was established by intraperitoneal injection with alloxan. Mice were randomized into two main groups: normal mice group and diabetic mice group treated with ghrelin at doses of 0, 20, 50, 100 and 200 ?g\\/kg ip. Gastric emptying (GE), intestinal transit

Wen-Cai Qiu; Zhi-Gang Wang; Ran Lv; Wei-Gang Wang; Xiao-Dong Han; Jun Yan; Yu Wang; Qi Zheng; Kai-Xing Ai; Qiu WC; Wang WG; Wang ZG; Han XD; Yan J

2008-01-01

3

Antihyperglycemic Effects of Fermented and Nonfermented Mung Bean Extracts on Alloxan-Induced-Diabetic Mice  

PubMed Central

Mung bean was reported as a potential antidiabetic agent while fermented food has been proposed as one of the major contributors that can reduce the risk of diabetes in Asian populations. In this study, we have compared the normoglycemic effect, glucose-induced hyperglycemic effect, and alloxan-induced hyperglycemic effect of fermented and nonfermented mung bean extracts. Our results showed that fermented mung bean extracts did not induce hypoglycemic effect on normal mice but significantly reduced the blood sugar levels of glucose- and alloxan-induced hyperglycemic mice. The serum levels of cholesterol, triglyceride (TG), and low-density lipoprotein (LDL) were also lowered while insulin secretion and antioxidant level as measured by malonaldehyde (MDA) assays were significantly improved in the plasma of the fermented mung bean-treated group in alloxan-induced hyperglycemic mouse. These results indicated that fermentation using Mardi Rhizopus sp. strain 5351 inoculums could enhance the antihyperglycemic and the antioxidant effects of mung bean in alloxan-treated mice. The improvement in the antihyperglycemic effect may also be contributed by the increased content of GABA and the free amino acid that are present in the fermented mung bean extracts.

Yeap, Swee Keong; Mohd Ali, Norlaily; Mohd Yusof, Hamidah; Alitheen, Noorjahan Banu; Beh, Boon Kee; Ho, Wan Yong; Koh, Soo Peng; Long, Kamariah

2012-01-01

4

Effect of Potentilla fulgens on lipid peroxidation and antioxidant status in alloxan-induced diabetic mice  

PubMed Central

Potentilla fulgens (Rosaceae) root traditionally used as a folk remedy by local health practitioners of Khasi Hills, Meghalaya was investigated for its effects on lipid peroxidation and antioxidant status in alloxan-induced diabetic mice. Significant increase in levels of thiobarbituric acid reactive substances (TBARS) and decrease in activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were observed under diabetic condition. Intraperitoneal administration of methanol extract of P. fulgens roots at a dose of 250 mg/kg body weight to male swiss albino diabetic mice for 14 days caused significant reduction in the elevated TBARS level, while increasing the activities of the antioxidant enzymes in diabetic mice. Maximum reduction in TBARS level was observed in liver tissue (75%, p<0.001). Kidney exhibited the highest elevation in the activity for catalase (68%, p<0.001) and superoxide dismutase (29%, p<0.001) while maximum increase in glutathione peroxidase activity was seen in brain (50%, p<0.001). The effects of P. fulgens was compared against known antioxidant, vitamin C. Results indicate that Potentilla fulgens methanolic root extract can reduce free radical mediated oxidative stress in experimental diabetes mellitus.

Saio, Valrielyn; Syiem, Donkupar; Sharma, Ramesh

2012-01-01

5

Methanolic Root Extract of Rauwolfia serpentina Benth Improves the Glycemic, Antiatherogenic, and Cardioprotective Indices in Alloxan-Induced Diabetic Mice  

PubMed Central

The aim of the study was to evaluate the phytochemistry and the effect of methanolic root extract (MREt) of Rauwolfia serpentina on alloxan-induced diabetic Wister male mice. Mice were divided in control (distilled water at 1?mL/kg) and alloxan-induced diabetic mice which subdivided into diabetic (distilled water at 1?mL/kg), negative (0.05% dimethyl sulfoxide at 1?mL/kg), positive (glibenclamide at 5?mg/kg) controls, and three test groups (MREt at 10, 30, and 60?mg/kg). All treatments were given orally for 14 days. Qualitatively MREt showed the presence of alkaloids, carbohydrates, flavonoids, glycosides, cardiac glycosides, phlobatannins, resins, saponins, steroids, tannins, and triterpenoids, while quantitatively extract was rich in total phenols. The flavonoids, saponins and alkaloids were also determined in root powder. MREt found effective in improving the body weights, glucose and insulin levels, insulin/glucose ratio, glycosylated and total hemoglobin in test groups as compared to diabetic control. Similarly, significantly decreased levels of total cholesterol, triglycerides, low-density lipoprotein (LDL-c), and very low-density lipoprotein (VLDL-c) cholesterols were found in test groups. Significant lipolysis with improved glycogenesis was also found in liver tissues of all test groups. ALT levels were found normal in all groups. Thus, MREt improves the glycemic, antiatherogenic, coronary risk, and cardioprotective indices in alloxan-induced diabetic mice.

Azmi, Muhammad Bilal; Qureshi, Shamim A.

2012-01-01

6

Hypoglycemic Properties of Oxovanadium (IV) Coordination Compounds with Carboxymethyl-Carrageenan and Carboxymethyl-Chitosan in Alloxan-Induced Diabetic Mice  

PubMed Central

In order to avoid low absorption, incorporation, and undesirable side effects of inorganic oxovanadium compounds, the antidiabetic activities of organic oxovanadium (IV) compounds in alloxan-induced diabetic mice were investigated. Vanadyl carboxymethyl carrageenan (VOCCA) and vanadyl carboxymethyl chitosan (VOCCH) were synthesized and administrated through intragastric administration in different doses for 20 days in alloxan-induced diabetic mice. Glibenclamide was administrated as the positive control. Our results showed that low-dose group, middle-dose group, and high-dose group of VOCCA and VOCCH could significantly reduce the levels of blood glucose (P < 0.05) compared with untreated group, but not in normal mice. Besides, high-dose groups of VOCCA and VOCCH exhibited more significant hypoglycemic activities (P < 0.01). After treated with VOCCH, the oral glucose tolerance of high-dose group of VOCCH was improved compared with model control group (P < 0.05).

Zhang, Hongyu; Yi, Yuetao; Feng, Dawei; Wang, Yipeng; Qin, Song

2011-01-01

7

Interaction of Aqueous Extract of Pleurotus pulmonarius (Fr.) Quel-Champ. with Glyburide in Alloxan Induced Diabetic Mice  

PubMed Central

Mushrooms are low calorie food with very little fat and are highly suitable for obese persons. With no starch and very low sugars, they are the ‘delight of the diabetics’. Combination of herbal drugs (or isolated phytochemicals) is found to be beneficial in certain diseases when given along with conventional drugs. The aim of the present study was to evaluate the effects of aqueous extract of Pleurotus pulmonarius (Lentinaceae) (called as PP-aqu) and its interaction with glyburide in alloxan induced diabetic mice. The diabetic mice treated were with PP-aqu (500?mg/kg, p.o.) alone or combination with glyburide (10?mg/kg, p.o.) for 28 days. Blood samples were collected by orbital sinus puncture using heparinized capillary glass tubes and were analyzed for serum glucose on 0, 7th, 14th, 21st and 28th days. Body weights and mortality were noted during the study period. In oral glucose tolerance test (OGTT), glucose (2.5?g/kg, p.o.) was administered with either vehicle, PP-aqu alone or in combination with glyburide and serum glucose level analyzed at 0, 30, 60 and 120?min after drug administration. Administration of PP-aqu (500?mg/kg) and its combination with glyburide (10?mg/kg) significantly (P < 0.001) decreased serum glucose level in diabetic mice. In OGTT, glyburide or PP-aqu treatment alone or their combination produced significant (P < 0.001) increase in glucose threshold. Thus we suggest that P. pulmonarius showed potent and synergistic antihyperglycemic effect in combination with glyburide.

Patel, Naimesh M.; Thakurdesai, Prasad A.; Bodhankar, Subhash L.

2008-01-01

8

Mogrosides extract from Siraitia grosvenori scavenges free radicals in vitro and lowers oxidative stress, serum glucose, and lipid levels in alloxan-induced diabetic mice.  

PubMed

This study evaluated the supplementation of a mogrosides extract (MG) from fruits of Siraitia grosvenori on reducing oxidative stress, hyperglycemia, and hyperlipidemia in alloxan-induced diabetic mice. The oxygen free radical scavenging activity of MG was also assessed in vitro. After induction of diabetes, a significant increase in the levels of serum glucose, total cholesterol (TC), triacylglycerol (TG), and hepatic malondialdehyde (MDA) as well as a reduction in the level of hepatic high-density lipoprotein cholesterol (HDL-C) associated with diminution of the corresponding antioxidant enzymes, such as glutathione peroxidase (GSH-Px) and superoxide dismutase, were observed in all diabetic mice. Treatment of diabetic mice with MG (100, 300, and 500 mg/kg ) for 4 weeks significantly decreased serum glucose, TC, TG, and hepatic MDA levels (P < .05), whereas it increased serum HDL-C level and reactivated the hepatic antioxidant enzymes (P < .05) in alloxan-induced diabetic mice (P < .05). The hypoglycemic, hypolipidemic, and antioxidative activities of MG (100 mg/kg treatment) were all higher compared with all other diabetic groups and were similar to that observed for XiaoKeWan-pill (894 mg/kg; Guangzhou Zhongyi Pharmaceutical Co., Ltd., Guangzhou, China), a Chinese traditional antidiabetic drug. Antioxidant capacity evaluated in vitro showed that MG and mogroside V, which was the main component of MG, possessed strong oxygen free radical scavenging activities. These results demonstrate that the extract may have capacity to inhibiting hyperglycemia induced by diabetes, and the data suggest that administration of the extract may be helpful in the prevention of diabetic complications associated with oxidative stress and hyperlipidemia. We conclude that the extract should be evaluated as a candidate for future studies on diabetes mellitus. PMID:19083420

Qi, Xiang-Yang; Chen, Wei-Jun; Zhang, Li-Qin; Xie, Bi-Jun

2008-04-01

9

Antihyperglycemic Effect of Stephania Glabra Tubers in Alloxan Induced Diabetic Mice  

Microsoft Academic Search

Diabetes mellitus is a chronic, worldwide heterogeneous and life-threatening disease which is most common metabolic disorder, characterized by hyperglycemia, glycosuria, hyperlipemia, negative nitrogen balance and some times by ketonemia. The prevalence of diabetes will be 5.4% by the year 2025, with the global diabetic population reaching to 300 million. Among all the WHO regions, South East Asian region are highest

Deepak Kumar Semwal; Usha Rawat; Ruchi Badoni; Ravindra Semwal; Randhir Singh

2010-01-01

10

DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice  

Microsoft Academic Search

Diabetes mellitus is associated with a high production of reactive oxygen species, which may cause oxidative DNA damage. High levels of genomic damage have been associated with liver and renal failure as well as immune-system decline. Flavonoids are effective antioxidants and may protect against several chronic diseases including diabetes. This study used the comet assay to assess the levels of

Nada Oršoli?; Goran Gajski; Vera Garaj-Vrhovac; Domagoj ?iki?; Zvjezdana Špacir Prskalo; Damir Sirovina

2011-01-01

11

Comparative study of antidiabetic activity of Cajanus cajan and Tamarindus indica in alloxan-induced diabetic mice with a reference to in vitro antioxidant activity  

PubMed Central

Background: Oxidative stress not only develops complications in diabetic (type 1 and type 2) but also contributes to beta cell destruction in type 2 diabetes in insulin resistance hyperglycemia. Glucose control plays an important role in the pro-oxidant/antioxidant balance. Some antidiabetic agents may by themselves have antioxidant properties independently of their role on glucose control. Objective: The present investigation draws a comparison of the protective antioxidant activity, total phenol content and the antihyperglycemic activity of the methanolic extract of Cajanus cajan root (MCC) and Tamarindus indica seeds (MTI). Materials and Methods: Antidiabetic potentials of the plant extracts were evaluated in alloxan-induced diabetic Swiss albino mice. The plant extracts at the doses of 200 and 400 mg/kg body weight was orally administered for glucose tolerance test during 1-hour study and hypoglycemic effect during 5-day study period in comparison with reference drug Metformin HCl (50 mg/kg). In vitro antioxidant potential of MCC and MTI was investigated by using 1, 1- diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity at 517 nm. Total phenolic content, total antioxidant capacity and reducing power activity was also assayed. Results: There was a significant decrease in fasting serum glucose level (P < 0.001), reduction in blood glucose level (P < 0.001) in 5-days study, observed in the alloxan-induced diabetic mice. The reduction efficacy of blood glucose level of both the extracts is proportional to their dose but MCC is more potent than MTI. Antioxidant study and quantification of phenolic compound of both the extracts revealed that they have high antioxidant capacity. Conclusion: These studies showed that MCC and MTI have both hypoglycemic and antioxidant potential but MCC is more potent than MTI. The present study suggests that both MCC and MTI could be used in managing oxidative stress.

Nahar, Laizuman; Nasrin, Fatema; Zahan, Ronok; Haque, Anamul; Haque, Ekramul; Mosaddik, Ashik

2014-01-01

12

Isolation, purification, and structural features of a polysaccharide from Phellinus linteus and its hypoglycemic effect in alloxan-induced diabetic mice.  

PubMed

Phellinus linteus is a medicinal mushroom that has been used in Oriental countries for centuries for its antitumor, antioxidant, immunomodulatory, and biological activity on hyperglycemia. A water-soluble crude polysaccharide was extracted using hot water from P. linteus mycelia grown under submerged culture. An orthogonal experiment was used to optimize the extraction conditions of P. linteus mycelia polysaccharides (PLP). The crude polysaccharide was purified using DEAE Sephadex A-50 and Sephadex G-200 chromatography. Fourier transform infrared (FT-IR) spectroscopy and nuclear magnetic resonance ((1) H NMR) spectroscopy were used to investigate the structure of the purified P. linteus polysaccharide (PLP-I), revealing that it was mainly a branched-type glycan with both ?- and ?-linkages and a pyranoid sugar ring conformation. PLP orally administered at 100 mg/kg body weight/d could significantly reduce the blood glucose level by 35.60% in alloxan-induced diabetic mice. The results of an oral glucose tolerance test (OGTT) revealed that PLP had an effect on glucose disposal after 28 d of treatment. The result revealed that PLP from a submerged culture of P. linteus mycelia possessed potent hypoglycemic properties. The polysaccharide may be useful as a functional food additive and a hypoglycemic agent. PMID:24761950

Zhao, Chao; Liao, Zunsheng; Wu, Xiaoqi; Liu, Yanling; Liu, Xiaoyan; Lin, Zhanxi; Huang, Yifan; Liu, Bin

2014-05-01

13

[The irradiation consequencees of animals with alloxan-induced diabetes].  

PubMed

The effects of external acute irradiation at dose 1.0 Gy on biologic, haematologic and metabolic changes in blood of alloxan-induced diabetic rats were studied. It was found that the deterioration of diabetic animals occurs in different terms after irradiation exposure, resulting in considerable body weight decrease, well-marked hyperglycemia, abrupt falling of leukocytic system parameters, intensification energetic processes of extant lymphocytes, imbalance of lipid metabolism and thyroid state, as well as significant inhibition of 5'-deiodinase activity in liver tissue. PMID:17953435

Konoplia, E F; Vereshchako, G G; Gorokh, G A; Andronov, E V; Luk'ianenko, O V

2007-01-01

14

Effect of Momordica grosvenori on oxidative stress pathways in renal mitochondria of normal and alloxan-induced diabetic mice  

Microsoft Academic Search

Background  Oxidative stress plays an important role in the pathogenesis of diabetes and diabetic nephropathy. Momordica grosvenori (MG), a traditional medicinal herb used as substitute sugar for obese and diabetes, exhibits anti-oxidative activity in vitro.\\u000a \\u000a \\u000a \\u000a Aim of the study  This study investigated the effect of MG on renal mitochondrial lipid peroxidation, anti-oxidative defense system, and a potent\\u000a oxidative stress–responsive protein, heme oxygenase-1

Fangfang Song; Xiangyang Qi; Weijun Chen; Wenbo Jia; Ping Yao; Andreas K. Nussler; Xiufa Sun; Liegang Liu

2007-01-01

15

Antidiabetic potentials of Momordica charantia and Andrographis paniculata and their effects on estrous cyclicity of alloxan-induced diabetic rats  

Microsoft Academic Search

Momordica charantia and Andrographis paniculata are the commonly used herbs by the diabetic patients in Pampanga, Philippines. While the anti-diabetic potential of Momordica charantia is well established in streptozocin- or alloxan-induced diabetic animals, the anti-diabetic potential of Andrographis paniculata in alloxan-induced diabetic rat is not known. Neither the effects of these herbs on estrous cyclicity of alloxan-induced diabetic rats are

B. A. S. Reyes; N. D. Bautista; N. C. Tanquilut; R. V. Anunciado; A. B. Leung; G. C. Sanchez; R. L. Magtoto; P. Castronuevo; H. Tsukamura; K.-I. Maeda

2006-01-01

16

Antioxidant effect of Boerhavia diffusa L. in tissues of alloxan induced diabetic rats.  

PubMed

Administration of B. diffusa leaf extract (BLEt; 200 mg/kg) for 4 weeks resulted in a significant reduction in thiobarbutric acid reactive substances and hydroperoxides, with a significant increase in reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione--S-transferase in liver and kidney of alloxan induced diabetic rats. The results suggest that BLEt has remarkable antidiabetic activity and can improve antioxidant status in alloxan induced diabetic rats. PMID:15511002

Satheesh, M Amarnath; Pari, L

2004-10-01

17

Antioxidant Effect of Tinospora cordifolia Extract in Alloxan-induced Diabetic Rats.  

PubMed

Many plants are claimed to possess antidiabetic and antioxidant activity. In practice, it is being increasingly recognized to be an alternative approach to modern medicine. This study assess the antioxidant capacity of Tinospora cordifolia stem methanol extract in daily oral administration of 500 mg/kg of body weight for 40 days in alloxan induced diabetic rats. The erythrocytes membrane lipid peroxide and catalase activity was increased where as the activities of superoxide dismutase, glutathione peroxidase were found to be decreased significantly (P<0.01) in alloxan-induced diabetic rats. The levels of lipid peroxide in liver of diabetic rats increased significantly (P<0.01) and catalase, superoxide dismutase, glutathione peroxidase in liver was significantly decreased in alloxan-induced diabetic rats, when compared to normal rats. After treatment of methanol Tinospora cordifolia stem extract brings back to normal (P<0.01) in the erythrocytes membrane and liver cell enzymes activities. PMID:21969757

Sivakumar, V; Rajan, M S Dhana

2010-11-01

18

Antioxidant Effect of Tinospora cordifolia Extract in Alloxan-induced Diabetic Rats  

PubMed Central

Many plants are claimed to possess antidiabetic and antioxidant activity. In practice, it is being increasingly recognized to be an alternative approach to modern medicine. This study assess the antioxidant capacity of Tinospora cordifolia stem methanol extract in daily oral administration of 500 mg/kg of body weight for 40 days in alloxan induced diabetic rats. The erythrocytes membrane lipid peroxide and catalase activity was increased where as the activities of superoxide dismutase, glutathione peroxidase were found to be decreased significantly (P<0.01) in alloxan-induced diabetic rats. The levels of lipid peroxide in liver of diabetic rats increased significantly (P<0.01) and catalase, superoxide dismutase, glutathione peroxidase in liver was significantly decreased in alloxan-induced diabetic rats, when compared to normal rats. After treatment of methanol Tinospora cordifolia stem extract brings back to normal (P<0.01) in the erythrocytes membrane and liver cell enzymes activities.

Sivakumar, V.; Rajan, M. S. Dhana

2010-01-01

19

Antidiabetic activity of Cassia occidentalis (Linn) in normal and alloxan-induced diabetic rats  

PubMed Central

Objective: To evaluate the hypoglycemic activity of various extracts, petroleum ether, chloroform and aqueous extract of Cassia occidentalis in normal and alloxan-induced diabetic rats. Materials and Methods: Petroleum ether, chloroform and aqueous extract of whole plant of Cassia occidentalis were orally tested at the dose of 200 mg/kg for hypoglycemic effect in normal and alloxan-induced diabetic rats. In addition, changes in body weight, serum cholesterol, triglyceride and total protein levels, assessed in the ethanol extract-treated diabetic rats, were compared with diabetic control and normal animals. Histopathological observations during 21 days treatment were also evaluated. Results: Aqueous extract of C. occidentalis produced a significant reduction in fasting blood glucose levels in the normal and alloxan-induced diabetic rats. Apart from aqueous extract, petroleum ether extract showed activity from day 14 and chloroform extract showed activity from 7 days. Significant differences were observed in serum lipid profiles (cholesterol and triglyceride), serum protein, and changes in body weight by aqueous extract treated-diabetic animals, when compared with the diabetic control and normal animals. Concurrent histopathological studies of the pancreas of these animals showed comparable regeneration by extract which were earlier necrosed by alloxan. Conclusion: Aqueous extract of C. occidentalis exhibited significant antihyperglycemic activity in normal and alloxan-induced diabetic rats. They also showed improvement in parameters like body weight and serum lipid profiles as well as histopathological studies showed regeneration of ?-cells of pancreas and so might be of value in diabetes treatment.

Verma, Laxmi; Khatri, Anirudh; Kaushik, Basant; Patil, Umesh K.; Pawar, Rajesh S.

2010-01-01

20

Antihyperglycemic and antihyperlipidemic effects of Clitoria ternatea Linn. in alloxan-induced diabetic rats  

Microsoft Academic Search

This study aims to investigate the therapeutic effects of Clitoria ternatea Linn. leaves and flowers extract on alloxan-induced diabetic rats. The effect of aqueous extract of C. ternatea leaves and flowers on serum glucose, glycosylated hemoglobin, insulin, total cholesterol, triglycerides, HDL-cholesterol, protein, urea, creatinine were examined in control and extract treated diabetic rats. Glycogen was examined both in the liver

P. Daisy; Kanakappan Santosh; M. Rajathi

21

Antihyperglycemic and antilipidperoxidative effects of Pongamia pinnata (Linn.) Pierre flowers in alloxan induced diabetic rats.  

PubMed

Our aim was to evaluate the antihyperglycemic and antilipid peroxidative effect of ethanolic extract of Pongamia pinnata (Linn.) Pierre (Leguminosae) flowers (PpEt) in normal rats and alloxan induced diabetic rats. Hyperglycemia, elevated lipid peroxidation [thiobarbituric acid reactive substances (TBARS)] and disturbed nonenzymatic [Vitamin E, Vitamin C and glutathione] and enzymatic antioxidants status were noticed in alloxan induced diabetic rats. The oral administration of ethanolic extract of Pongamia pinnata flowers (300 mg/kg bw) showed significant antihyperglycemic, and antilipidperoxidative effects and enhancement in antioxidants defense system in alloxan induced diabetic rats. However, no significant characteristic changes were noticed in blood glucose level as well as in lipid peroxidation and antioxidant status in normal rats treated with "PpEt" alone. We have also observed that the "PpEt" considerably reduced the blood glucose concentration in a similar extent to that of the reference drug glibenclamide (600 microg/kg bw) in alloxan induced diabetic rats. Our results thus suggested that the "PpEt" could be used as a safe alternative antihyperglycemic drug for diabetic patients. PMID:16271443

Punitha, R; Manoharan, S

2006-04-21

22

Hypoglycemic and Hypolipidemic effect of Coccinia indica Wight & Arn in alloxan induced diabetic rats  

PubMed Central

Diabetes Mellitus is characterized by elevated plasma glucose concentrations resulting from insufficient insulin. The present study was aimed to investigate the hypolipidemic effect of Coccinia indica aqueous leaf extract in alloxan induced diabetic rats. The results of this study revealed that a continuous administration of Coccinia indica extract for 21 days prevents the elevation of the level of serum lipids secondary to the diabetes state

Manjula, S.; Ragavan, B

2007-01-01

23

Hypoglycemic and Hypolipidemic effect of Coccinia indica Wight & Arn in alloxan induced diabetic rats.  

PubMed

Diabetes Mellitus is characterized by elevated plasma glucose concentrations resulting from insufficient insulin. The present study was aimed to investigate the hypolipidemic effect of Coccinia indica aqueous leaf extract in alloxan induced diabetic rats. The results of this study revealed that a continuous administration of Coccinia indica extract for 21 days prevents the elevation of the level of serum lipids secondary to the diabetes state. PMID:22557267

Manjula, S; Ragavan, B

2007-10-01

24

Suppressive effects of electrolyzed reduced water on alloxan-induced apoptosis and type 1 diabetes mellitus  

Microsoft Academic Search

Electrolyzed reduced water, which is capable of scavenging reactive oxygen species, is attracting recent attention because\\u000a it has shown improved efficacy against several types of diseases including diabetes mellitus. Alloxan produces reactive oxygen\\u000a species and causes type 1 diabetes mellitus in experimental animals by irreversible oxidative damage to insulin-producing\\u000a ?-cells. Here, we showed that electrolyzed reduced water prevented alloxan-induced DNA

Yupin Li; Takeki Hamasaki; Noboru Nakamichi; Taichi Kashiwagi; Takaaki Komatsu; Jun Ye; Kiichiro Teruya; Masumi Abe; Hanxu Yan; Tomoya Kinjo; Shigeru Kabayama; Munenori Kawamura; Sanetaka Shirahata

2011-01-01

25

Effect of Artemisia santonicum L. on blood glucose in normal and alloxan-induced diabetic rabbits.  

PubMed

The hypoglycaemic effect of panicles of Artemisia santonicum L. in normal and alloxan-induced diabetic rabbits was investigated. Blood glucose levels were determined after oral administration of an aqueous extract of Artemisia santonicum L. In normal and diabetic rabbits, 2 mL/kg (0.42 g/kg) aqueous extract significantly (p < 0.01) reduced blood glucose levels 6 h after administration, which was consistent and time-dependent. PMID:12410552

Korkmaz, H; Gürdal, A

2002-11-01

26

Antihyperglycemic and Antihyperlipidemic Activity of Plectranthus Amboinicus on Normal and Alloxan-Induced Diabetic Rats  

PubMed Central

The present study was undertaken to investigate the antihyperglycemic and antihyperlipidemic effects of ethanol extract of Plectranthus amboinicus in normal and alloxan-induced diabetic rats. Diabetes was induced in Wistar rats by single intraperitoneal administration of alloxan monohydrate (150 mg/kg). Normal as well as diabetic rats were divided into groups (n=6) receiving different treatments. Graded doses (200 mg/kg and 400 mg/kg) of ethanol extract of Plectranthus amboinicus were studied in both normal and alloxan-induced diabetic rats for a period of 15 days. Glibenclamide (600 ?g/kg) was used as a reference drug. Oral administration with graded doses of ethanol extract of Plectranthus amboinicus exhibited hypoglycemic effect in normal rats and significantly reduced the peak glucose levels after 120 min of glucose loading. In alloxan-induced diabetic rats, the daily oral treatment with ethanol extract of Plectranthus amboinicus showed a significant reduction in blood glucose. Besides, administration of ethanol extract of Plectranthus amboinicus for 15 days significantly decreased serum contents of total cholesterol, triglycerides whereas HDL-cholesterol, total proteins and calcium were effectively increased. Furthermore, effect of ethanol extract of Plectranthus amboinicus showed profound elevation of serum amylase and reduction of serum lipase. Histology examination showed ethanol extract of Plectranthus amboinicus exhibited almost normalization of damaged pancreatic architecture in rats with diabetes mellitus. Studies clearly demonstrated that ethanol extract of Plectranthus amboinicus leaves possesses hypoglycemic and antihyperlipidemic effects mediated through the restoration of the functions of pancreatic tissues and insulinotropic effect.

Viswanathaswamy, A. H. M.; Koti, B. C.; Gore, Aparna; Thippeswamy, A. H. M.; Kulkarni, R. V.

2011-01-01

27

The Control of Hyperglycemia by Estriol and Progesterone in Alloxan induced Type I Diabetes Mellitus Mice Model through Hepatic Insulin Synthesis  

PubMed Central

As much as 20% of the women in menopause are reported to develop type I diabetes mellitus. The cessation of the ovarian syntheses of the female sex hormones is known to cause menopause in women, and the roles of estriol (one of the most abundant estrogens) and progesterone were investigated for hepatic insulin synthesis through estriol and progesterone induced synthesis of nitric oxide in the liver cells. Type 1 Diabetic mellitus mice were prepared by alloxan treatment, Nitric oxide was determined by methemoglobin method. Insulin was determined by enzyme linked immunosorbant assay. Injection of either 3.5 µM estriol or 3.5 nM progesterone to the diabetic mice which cannot synthesize pancreatic insulin, reduced the blood glucose level from 600 mg/dl to 120 mg/dl and 500 ± 25 mg/dl to 120 ± 6 mg/dl in 6 and 10 h respectively with simultaneous increase of the plasma insulin from 0 µunits/ml to 40 µunits/ml and 0 µunits/ml to 9.5 µunits/ml in the case of estriol and progesterone respectively with stimulated NO synthesis. The inhibition of the steroids induced NO synthesis by using NAME (NG-methyl-l-arginine acetate ester) in the reaction mixture resulted in the inhibition of hepatic insulin synthesis. Use of pure NO solution in 0.9% NaCl instead of either estriol or progesterone in the reaction mixture was found to stimulate the hepatic insulin synthesis. Both estriol and progesterone might be involved in the prevention of type 1 diabetes mellitus through the hepatic insulin synthesis even when the pancreatic insulin synthesis was impaired.

Bhattacharya, Suman; Bank, Sarbashri; Maiti, Smarajit; Sinha, Asru K.

2014-01-01

28

Effect of Red Hogweed (Boerhavia diffusa L.) on Plasma Antioxidants in Alloxan-Induced Diabetes  

Microsoft Academic Search

The present study was designed to evaluate the antioxidant activity of an aqueous Boerhavia diffusa leaf extract (BLEt) (200 mg\\/kg) in rats with alloxan-induced diabetes mellitus. Administration of BLEt for four weeks resulted in a significant reduction in plasma thio-barbituric acid reactive substances (TBARS), lipid peroxides, cerulo-plasmin, and ?-tocopherol and a significant elevation in plasma of reduced glutathione and vitamin

M. Amarnath Satheesh; L. Pari

2004-01-01

29

Antioxidant activity of Cassia fistula (Linn.) flowers in alloxan induced diabetic rats.  

PubMed

Aqueous extract of Cassia fistula (Linn.) flowers (ACF) was screened for its antioxidant effect in alloxan induced diabetic rats. An appreciable decrease in peroxidation products viz thiobarbituric acid reactive substances, conjugated dienes, hydroperoxides was observed in heart tissues of ACF treated diabetic rats. The decreased activities of key antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione in diabetic rats were brought back to near normal range upon ACF treatment. These results suggest that ACF has got promising antioxidative activity in alloxan diabetic rats. PMID:15652272

Manonmani, G; Bhavapriya, V; Kalpana, S; Govindasamy, S; Apparanantham, T

2005-02-10

30

Antidiabetic Activity of Vinca rosea Extracts in Alloxan-Induced Diabetic Rats  

PubMed Central

The present study was carried out to evaluate the antidiabetic activity of Vinca rosea methanolic whole plant extracts in alloxan induced diabetic rats for 14 days. The methanolic whole plant extract at high dose (500?mg/kg) exhibited significant anti-hyperglycemic activity than whole plant extract at low dose (300?mg/kg) in diabetic rats. The methanolic extracts also showed improvement in parameters like body weight and lipid profile as well as regeneration of ?-cells of pancreas in diabetic rats. Histopathological studies reinforce the healing of pancreas, by methanolic Vinca rosea extracts, as a possible mechanism of their antidiabetic activity.

Ahmed, Mohammed Fazil; Kazim, Syed Mohammed; Ghori, Syed Safiullah; Mehjabeen, Syeda Sughra; Ahmed, Shaik Rasheed; Ali, Shaik Mehboob; Ibrahim, Mohammed

2010-01-01

31

Hypoglycemic effect of Gymnema sylvestre (retz.,) R.Br leaf in normal and alloxan induced diabetic rats.  

PubMed

The water extract of Gymnema sylvestre R.Br leaf was tested for hypoglycemic activity in normal and alloxan induced diabetic rats. Grated amount (2ml/kg) of the water extract of Gymnema sylvestre leaf was given to both normal and alloxan induced diabetic rats. A significant reduction of glucose concentration was noticed in normal rats, blood glucose level was significantly reduced in diabetic rats. Protein level is also decreased in diabetic rats. Urea, uric acid and creatinine levels were increased in diabetic condition. After the herbal treatment the levels were altered near to normal level. PMID:22557305

Sathya, S; Kokilavani, R; Gurusamy, K

2008-10-01

32

Anti-diabetic activity of Ferula assafoetida extract in normal and alloxan-induced diabetic rats.  

PubMed

The aim of the present study was to evaluate the possible anti-diabetic potential of Asafetida extract against the pancreatic beta-cells damage from alloxan-induced diabetes in rats and some hormones related to diabetes mellitus. Asafetida induced significant reduction in blood glucose and increasing of serum insulin, our data indicate that the level of glucose in the animals that subjected with alloxan was 10.28 +/- 0.85 mmol L(-1) p < 0.05 comparing with control group 3.27 +/- 0.25 p < 0.05, the level of blood glucose in diabetic group when subjected with Asafetida extract decreasing to 6.75 +/- 0.31 p < 0.05. There was significant amount of insulin secretion in diabetic animals when subjected with Asafetida extract 0.48 +/- 0.05 p < 0.05 in comparison with diabetic animal's 0.33 +/- 0.06 p < 0.05. These findings suggested that Asafetida extract treatment exerts therapeutic protective effect in diabetes by preserving pancreatic beta-cells integrity and significant activity extract, which supports traditional usage to prevent diabetic complications. PMID:20415145

Abu-Zaiton, Ahmed Saber

2010-01-15

33

Antidiabetic and antihyperlipidemic effects of Thespesia populnea fruit pulp extracts on alloxan-induced diabetic rats  

PubMed Central

Present study was carried to find out the antihyperglycemic and antihyperlipidemic activity of ethanol and aqueous extract of Thespesia populnea fruit pulp on alloxan-induced diabetic rats. Diabetes was induced in rats by administration of alloxan (150 mg/kg, i.p.). After the successful induction of experimental diabetes, the rats were divided into five groups each comprising a minimum of six rats. Phytochemical analysis and acute toxicity study of extracts was also done. The effects of extracts and metformin on fasting blood glucose and plasma lipid were examined for 28 days. Statistical analysis was carried out by using analysis of variance followed by Dunnet's multiple comparison test and paired t-test were done as the test of significance using GraphPad Prism. P?0.05 was considered as the minimal level of statistical significance. Therapeutic dose of extract was found to be 200 mg/kg on the basis of acute toxicity study. Aqueous and alcoholic extract showed a significant reduction in blood glucose levels as well as a lipid profile of diabetic rats at the end of 28th day of treatment. However, in groups treated with plant extract the reduction in the blood glucose and improvement in lipid profile was slightly less than that achieved with the standard group (metformin). From this study, it can be concluded that ethanol and aqueous extract of Thespesia populnea exhibited significant antihyperglycemic and antihyperlipidemic effects on alloxan-induced diabetic rats.

Belhekar, S. N.; Chaudhari, P. D.; Saryawanshi, J. S.; Mali, K. K.; Pandhare, R. B.

2013-01-01

34

Early Renal Histological Changes in Alloxan-Induced Diabetic Rats  

PubMed Central

Diabetes mellitus is a progressive disease. Most investigators have focused on glomerular changes in diabetic kidney and non-glomerular alterations have been less attended. The present study has been conducted to find early non-glomerular histological changes in diabetic renal tissue. Twenty male Wistar rats weighting 200-250 g were used for the diabetic group. Diabetes mellitus was induced by single injection of Alloxan. After 8 weeks, paraffin embedded blocks of kidneys were prepared for evaluating the histological changes due to diabetes. Histological study showed the deposit of eosinophilic materials in the intermediate substantial of medulla and thickening of renal arterial wall in the kidney of 70% of diabetic rats. The average weight of kidneys increased when compared to non diabetic animals. Furthermore, the amount of blood flow in arteries of all diabetic kidneys has been enhanced. The present study demonstrates some early renal histological changes in diabetes mellitus which were earlier compared to those reported previously. Diabetic nephropathy is a progressive disease and renal care design can help better prognosis achievement.

Pourghasem, Mohsen; Nasiri, Ebrahim; Shafi, Hamid

2014-01-01

35

Antihyperglycemic and hypolipidemic effects of Hibiscus schizopetalus (Mast) Hook in alloxan-induced diabetic rats.  

PubMed

The antihyperglycemic and hypolipidemic activities of Hibiscus schizopetalus (Mast) Hook (Malvaceae) flower and leaves extracts were investigated in alloxan-induced diabetic rats. The hypoglycemic activity of both the extracts (100mg/kg, body weight) was tested in fasting normal rat, glucose loaded rats. Observation on body weight was also recorded. The extracts showed a significant (p<0.001) reduction in blood glucose level in normal fasting rats. In glucose tolerance test, significant (p<0.01) decreased observed in all glucose loaded animals. While in alloxan induced diabetic rats, the percent blood glucose reduction was 59.94% and 45.14% in extracts treated groups. The results obtained were compared with the reference standard drug Tolbutamide (100mg/kg, body weight). The diabetic rats showed sign of decreased in their body weight during the treatment period. Cholesterol and triglycerides levels were significantly decreased (p<0.001) by HFE. The results obtained demonstrated the potential hypoglycemic activity of methanolic extracts of H. schizopetalus. There is need of bioassay-directed assay of the active principles responsible for the anti-diabetic activity. The methanolic extracts showed the presence of carbohydrates, alkaloids, steroids, terpenes, saponins and glycosides. PMID:24374457

Zahid, Hina; Rizwani, Ghazala H; Shareef, Huma; Khursheed, Raheela; Huma, Ambreen; Hasan, S M Farid

2014-01-01

36

Histological changes and antidiabetic activities of Icacina trichantha tuber extract in beta-cells of alloxan induced diabetic rats  

PubMed Central

Objective To investigate the antidiabetic, hypolipidaemic activities and histopathological changes of Icacina trichantha (I. trichantha) tuber extract in alloxan induced diabetic rats. Methods In the present study, 80% methanol extract of I. trichantha tuber was tested on alloxan induced diabetic rats. They were randomly grouped into control (distilled water and glibenclamide) and experimental (200, 400 and 600 mg/kg body weight). Diabetes was induced by a single intraperitoneal injection of 160 mg/kg body weight of alloxan. Blood glucose levels were measured using blood glucose test strips with AccuCheck Advantage II glucometer at 1, 3, 6, and 24 h on the first day and 1 h after treatment on Day 7, 14 and 21. Blood samples were collected and centrifuged to separate serum for estimation of lipid profile and other biochemical parameters. Histopathological changes in diabetic rats pancreas were also studied after extract treatment. Results Daily oral administration of I. trichantha tuber extract (200, 400, and 600 mg/kg body weight) and glibenclamide (2 mg/kg) showed beneficial effects on blood glucose level (P<0.01) as well as improving liver, kidney functions and hyperlipidaemia due to diabetes. The extract had a favourable effect on the histopathological changes of the pancreas in alloxan induced diabetes. Conclusions I. trichantha tuber extracts posses antidiabetic activities as well as improve liver and renal profile and total lipids levels. I. trichantha tuber extracts also have favourable effects to inhibit the histopathological changes of the pancreas in alloxan induced diabetes.

Monday, Onakpa Michael; Uzoma, Asuzu Isaac

2013-01-01

37

Effect of ethanolic extract of Cassia occidentalis Linn. for the management of alloxan-induced diabetic rats  

PubMed Central

Aim: As per traditional claims, root, bark, leaf and flower of the plant Cassia occidentalis Linn. (Caesalpiniaceae) have been reported to possess antidiabetic activity. Based on this traditional indication, the aim of this study was to evaluate the antidiabetic activity of ethanolic extract of C. occidentalis in normal and alloxan induced diabetic rats. Materials and Methods: Ethanolic extract of the whole plant of C. occidentalis was orally tested at doses of 100 and 200 mg/kg for evaluating the hypoglycemic effect in normal and alloxan-induced diabetic rats. In addition, changes in body weight, serum cholesterol, triglyceride and total protein levels, assessed in the ethanol extract treated diabetic rats were compared with diabetic control and normal animals. Histopathologic observations during 21 days of treatment were also evaluated. Results: Ethanolic extract of C. occidentalis produced a significant reduction in fasting blood glucose levels in the normal and alloxan-induced diabetic rats at doses of 100 and 200 mg/kg body weight. Treatment with ethanolic extract of C. occidentalis in normal and alloxan-induced diabetic rats led to a dose-dependent fall in blood sugar levels. Significant differences were observed in serum lipid profiles (cholesterol and triglyceride), serum protein and changes in body weight in ethanolic extract treated diabetic animals, when compared with the diabetic control and normal animals. Concurrent histopathologic studies of the pancreas of these animals showed comparable regeneration by ethanolic extract, which were earlier necrosed by alloxan. Conclusion: Ethanolic extract of C. occidentalis exhibited significant antidiabetic activity in normal and alloxan-induced diabetic rats. The rats also showed improvement in parameters like body weight and lipid profiles and also, histopathologic studies showed regeneration of ?-cells of pancreas and so it might be of value in the treatment of diabetes.

Verma, Laxmi; Singour, P. K.; Chaurasiya, P. K.; Rajak, H.; Pawar, R. S.; Patil, U. K.

2010-01-01

38

Study of antihyperglycaemic activity of medicinal plant extracts in alloxan induced diabetic rats  

PubMed Central

Background: Diabetes mellitus, for a long time, has been treated with plant derived medicines in Sri Lanka. Aim: The aim of this study is to determine the efficacy and dose response of oral antihyperglycaemic activity of eight Sri Lankan medicinal plant extracts, which are used to treat diabetes in traditional medicine in diabetic rats. Materials and Methods: Medicinal plants selected for the study on the basis of documented effectiveness and wide use among traditional Ayurveda physicians in the Southern region of Sri Lanka for the treatment of diabetes mellitus. The effect of different doses of aqueous stem bark extracts of Spondias pinnata (Anacardiaceae), Kokoona zeylanica (Celastraceae), Syzygium caryophyllatum (Myrtaceae), Gmelina arborea (Verbenaceae), aerial part extracts of Scoparia dulcis (Scrophulariaceae), Sida alnifolia (Malvaceae), leaf extract of Coccinia grandis (Cucurbitaceae) and root extract of Languas galanga (Zingiberaceae) on oral glucose tolerance test was evaluated. A single dose of 0.25, 0.50, 0.75, 1.00, 1.25, 2.00 g/kg of plant extract was administered orally to alloxan induced (150 mg/kg, ip) diabetic Wistar rats (n = 6). Glibenclamide (0.50 mg/kg) was used as the standard drug. The acute effect was evaluated over a 4 h period using area under the oral glucose tolerance curve. Statistical Analysis: The results were evaluated by analysis of variance followed by Dunnett's test. Results: The eight plant extracts showed statistically significant dose dependent improvement on glucose tolerance (P < 0.05). The optimum effective dose on glucose tolerance for six extracts was found to be 1.00 g/kg in diabetic rats with the exception of C. grandis: 0.75 g/kg and L. galanga: 1.25 g/kg. Conclusion: The aqueous extract of G. arborea, S. pinnata, K. zeylanica, S. caryophyllatum, S. dulcis, S. alnifolia, L. galanga and C. grandis possess potent acute antihyperglycaemic activity in alloxan induced diabetic rats.

Attanayake, Anoja P.; Jayatilaka, Kamani A. P. W.; Pathirana, Chitra; Mudduwa, Lakmini K. B.

2013-01-01

39

Hybrid of 1-deoxynojirimycin and polysaccharide from mulberry leaves treat diabetes mellitus by activating PDX-1\\/insulin-1 signaling pathway and regulating the expression of glucokinase, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in alloxan-induced diabetic mice  

Microsoft Academic Search

Ethnopharmacological relevance1-Deoxynojirimycin (DNJ) discovered from mulberry trees has been reported to be a potent inhibitor of intestinal ?-glycosidases (sucrase, maltase, glucoamylase), and many polysaccharides were useful in protecting against alloxan-induced pancreatic islets damage through their scavenging ability. This study was aimed to evaluate the therapeutic effect and potential mechanism(s) of the hybrid of DNJ and polysaccharide (HDP) from mulberry leaves

You-Gui Li; Dong-Feng Ji; Shi Zhong; Zhi-Qiang Lv; Tian-Bao Lin; Shi Chen; Gui-Yan Hu

2011-01-01

40

Lactobacillus plantarum TN627 significantly reduces complications of alloxan-induced diabetes in rats.  

PubMed

This study aimed to assess the potential of the probiotic strain Lactobacillus plantarum TN627 for preventing alloxan-induced diabetes in rats. The oral administration of this probiotic was noted to significantly improve the immunological parameters, protect the pancreatic tissues, and reduce the pancreatic and plasmatic ?-amylase activities and level of plasma glucose in the treated as compared to the control group of rats. Furthermore, this probiotic treatment was observed to markedly reduce pancreatic and plasmatic lipase activities and serum triglyceride and LDL-cholesterol rates and to increase the level of HDL-Cholesterol. It also exerted efficient protective effects on the liver and kidney functions evidenced by significant decreases in serum aspartate transaminase, alanine transaminase, lactate dehydrogenase, and gamma-glutamyl transpeptidase activities, as well as creatinine and urea contents. Taken together, the findings indicate that L. plantarum TN627 exhibits attractive in vivo antidiabetic effects that may be helpful in preventing diabetic complications in adult rats. PMID:23999246

Bejar, Wacim; Hamden, Khaled; Ben Salah, Riadh; Chouayekh, Hichem

2013-12-01

41

Alcoholic leaf extract of Plectranthus amboinicus regulates carbohydrate metabolism in alloxan-induced diabetic rats  

PubMed Central

Objective: The present investigation was undertaken to explore the possible mechanisms of Plectranthus amboinicus leaf extract in alloxan-induced diabetic rats. Materials and Methods: Control and alloxan-induced diabetic albino rats received different treatments; orally control (vehicle), 200 mg/kg and 400 mg/kg of ethanol extract of Plectranthus amboinicus (PAEE) and 600 ?g/kg of glibenclamide (standard) for 15 days. At the end of the experiment, the animals were sacrificed and enzyme activities of carbohydrate metabolism were measured in the liver. Results: Diabetic control rats showed a significant elevation (P < 0.001) in fasting blood glucose on successive days of the experiment as compared with their basal values, which was maintained over a period of 2 weeks. Daily oral treatment with PAEE showed a significant reduction (P < 0.001) in the blood glucose levels on successive days of the experiment as compared with their basal values. The most pronounced antihyperglycemic effect was obtained with the dose of 400 mg/kg. PAEE shows a dose-dependent reduction in gluconeogenic enzymes like glucose-6-phosphatase and fructose-1,6-disphosphatase. After 15 days of treatment with PAEE, glycolytic enzymes like phosphoglucoisomerase resulted in a significant increase with a concomitant significant decrease in the activities of aldolase. On the other hand, glucose-6-phosphate dehydrogenase was significantly improved in diabetic rats on administration of PAEE; the 400 mg/kg dose of PAEE elicited a more potent effect compared with the 200 mg/kg dose. Conclusion: The results obtained in this study provide evidence of the antidiabetic activity of PAEE, mediated through the regulation of carbohydrate metabolic enzyme activities.

Koti, B. C.; Gore, Aparna; Thippeswamy, A. H. M.; Swamy, A. H. M. Viswanatha; Kulkarni, Rucha

2011-01-01

42

Antidiabetic activity of Crateva nurvala stem bark extracts in alloxan-induced diabetic rats  

PubMed Central

Objectives: The aim of this study was to investigate the antidiabetic activity of Crateva nurvala stem bark (family: Capparidaceae) extracts in alloxan-induced diabetic albino rats. A comparison was made between the action of different extracts of C. nurvala and a known antidiabetic drug glibenclamide (600 ?g/kg b. wt.). An oral glucose tolerance test (OGTT) was also performed in diabetic rats. Materials and Methods: The petroleum ether, chloroform, alcohol, and aqueous extracts of C. nurvala stem bark were obtained by simple maceration method and were subjected to standardization by following pharmacognostical and phytochemical screening methods. Dose selection was made on the basis of acute oral toxicity study (50–5000 mg/kg b. wt.) as per Organization for Economic Co-operation and Development (OECD) guidelines. Results and Conclusions: C. nurvala petroleum ether extract (CNPEE) and ethanolic extract (CNEE) showed significant (P< 0.001) antidiabetic activities. In alloxan-induced model, blood glucose level of these extracts on seventh day of study were CNPEE (126.33±13.703 mg/dl) and CNEE (126.66±13.012 mg/dl) when compared with diabetic control (413.50±4.752 mg/dl) and chloroform extract (320.83±13.516 mg/dl). In OGGT model (glucose loaded rats), CNPEE showed a glucose level of 178.83±3.070 mg/dl after 30 min and 131.66±2.486 mg/dl after 90 min, whereas CNEE showed 173.66±4.224 mg/dl after 30 min and 115.50±3.394 mg/dl after 90 min. These extracts also prevented body weight loss in diabetic rats. The drug has the potential to act as an antidiabetic drug.

Sikarwar, Mukesh S.; Patil, M. B.

2010-01-01

43

Antidiabetic activity of Pongamia pinnata leaf extracts in alloxan-induced diabetic rats  

PubMed Central

The antidiabetic activity of Pongamia pinnata ( Family: Leguminosae) leaf extracts was investigated in alloxan-induced diabetic albino rats. A comparison was made between the action of different extracts of P. pinnata and a known antidiabetic drug glibenclamide (600 ?g/kg b. wt.). An oral glucose tolerance test (OGTT) was also performed in experimental diabetic rats. The petroleum ether, chloroform, alcohol and aqueous extracts of P. pinnata were obtained by simple maceration method and were subjected to standardization using pharmacognostical and phytochemical screening methods. Dose selection was made on the basis of acute oral toxicity study (50-5000 mg/kg b. w.) as per OECD guidelines. P. pinnata ethanolic extract (PPEE) and aqueous extract (PPAE) showed significant (P < 0.001) antidiabetic activity. In alloxan-induced model, blood glucose levels of these extracts on 7th day of the study were 155.83 ± 11.211mg/dl (PPEE) and 132.00 ± 4.955mg/dl (PPAE) in comparison of diabetic control (413.50 ± 4.752mg/dl) and chloroform extract (210.83 ± 14.912mg/dl). In glucose loaded rats, PPEE exhibited glucose level of 164.50 ± 6.350mg/dl after 30 min and 156.50 ± 4.089mg/dl after 90 min, whereas the levels in PPAE treated animals were 176 ± 3.724mg/dl after 30 min and 110.33 ± 6.687mg/dl after 90 min. These extracts also prevented body weight loss in diabetic rats. The drug has the potential to act as an antidiabetic drug.

Sikarwar, Mukesh S.; Patil, M.B.

2010-01-01

44

Effect of atorvastatin and hydroxychloroquine combination on blood glucose in alloxan-induced diabetic rats  

PubMed Central

Objective: To evaluate the antihyperglycemic activity of atorvastatin and hydroxychloroquine combination in alloxan-induced diabetic rats. Materials and Methods: Alloxan induced diabetic Wistar male rats were randomized into six groups of 6 rats each. (Normal rats, diabetic control, atorvastatin (ATV), hydroxychloroquine (HCQ), ATV 5 mg /kg + HCQ 100 mg/kg, and ATV 10 mg/kg + HCQ 200 mg/kg). The rats were treated for 9 days and blood samples were collected at baseline and end of therapy. These samples were analyzed for plasma glucose by autoanalyzer. Changes in body weight, water, food intakes and total protein content were also recorded. Results: Atorvastatin and hydroxychloroquine alone and in combination reported significant fall in blood glucose level from baseline. Fall in glucose level was significantly more in high dose combination of atorvastatin and hydroxychloroquine (ATV: 10 mg/kg + HCQ: 200 mg/kg) as compared to other study treatment groups (ATV: 17% Vs HCQ: 7% Vs ATV 5mg/kg + HCQ 100mg /kg: 14% Vs ATV 10mg/kg + HCQ 200mg /kg: 21%; p<0.01). ATV and HCQ individually and in combination also improved the body weight loss. The weight gain was significantly more in combination treated rats as compared to positive control group and greater than those who received atorvastatin and hydroxychloroquine alone. Rats treated with the combination also reported significant decrease in food intake and significant increase in total protein. Conclusion: Increased hypoglycemic effect in combination may be due to potentiation or synergism between HCQ and ATV. Further studies are required to demonstrate clinically significant antidiabetic effect.

Pareek, Anil; Yeole, P.G.; Tenpe, C.R.; Chandurkar, Nitin; Payghan, Ravikiran

2009-01-01

45

Wound healing activity of Malva sylvestris and Punica granatum in alloxan-induced diabetic rats.  

PubMed

The flowers of Malva sylvestris Linn. (Malvaceae) and Punica granatum Linn. (Punicaceae) are important medicinal plants in Iranian traditional medicine (Unani) whose have been used as remedy against edema, bum, wound and for their carminative, antimicrobial and anti-inflammatory activities. The diethyl ether extract of M. sylvestris and P. granatum flowers were used to evaluate the wound healing activity at 200 mg/kg/day dose in alloxan-induced diabetic rats. Wounds were induced in Wister rats divided into six groups as following; Group I, normal rats were treated with simple ointment base. Group II, diabetic rats were treated with simple ointment base (control). Groups III and IV, diabetic rats were treated with simple ointment base containing of extracts (diabetic animals), Groups V, diabetic rats were treated with simple ointment base containing of mixed extracts (1:1), Group VI, diabetic rats received the standard drug (nitrofurazone). The efficacy of treatment was evaluated based on wound area relative and histopathological characteristics. The extract-treated diabetic animals showed significant reduction in the wound area when compared with control. Also, histological studies of the tissue obtained on days 9th and 18th from the extract-treated by extract of M. sylvestris showed increased well organized bands of collagen, more fibroblasts and few inflammatory cells. These findings demonstrate that extract of M. sylvestis effectively stimulates wound contraction as compared to control group and other groups. M. sylvestris accelerated wound healing in rats and thus supports its traditional use. PMID:20873419

Pirbalouti, Abdollah Ghasemi; Azizi, Shahrzad; Koohpayeh, Abed; Hamedi, Behzad

2010-01-01

46

Antidiabetic and antioxidant effects of oleanolic acid from Ligustrum lucidum Ait in alloxan-induced diabetic rats.  

PubMed

The present study evaluated the antidiabetic and antioxidant effects of oleanolic acid (OA) from Ligustrum lucidum Ait (LLA) in alloxan-induced diabetic rats. OA in the alloxan-induced diabetic rats showed significant hypoglycemic activity by lowering blood glucose (at doses of 60 and 100 mg/kg for 40 days). The levels of serum total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-c) in the OA-treated diabetic rats were lower, and the high-density lipoprotein cholesterol (HDL-c) level was higher than in the control diabetic rats. A significant reduction in the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels of diabetic rats following OA treatment was also observed. Furthermore, OA treatment decreased the malondialdehyde (MDA) level, but increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activities of the liver and kidney in diabetic rats. These results indicate that OA could protect the liver function avoiding alloxan-induced damage; OA had hypoglycemic, hypolipidemic and antioxidant efficacy in the diabetic rats. The antioxidant ability of OA might be one of the mechanisms of its hypoglycemic and hypolipidemic effects. PMID:19274687

Gao, Dawei; Li, Qingwang; Li, Ying; Liu, Zhihua; Fan, Yusheng; Liu, Zhiwei; Zhao, Hongwei; Li, Jian; Han, Zengsheng

2009-09-01

47

Nutritional and Hypoglycemic Effect of Fruit Pulp of Annona squamosa in Normal Healthy and Alloxan-Induced Diabetic Rabbits  

Microsoft Academic Search

Thenutritive value of the pulp of the edible fruit of Annona squamosa and its effect on various biochemical parameters has been assessed in normal and alloxan-induced diabetic rats. Different doses (2.5, 5.0, 10.0 g\\/kg b.w.) of fresh fruit pulp of A. squamosa were given to the three groups each of normal healthy and diabetic rabbits orally daily for 1 month.

Rajesh Kumar Gupta; Achyut Narayan Kesari; Geeta Watal; P. S. Murthy; Ramesh Chandra; Vibha Tandon

2005-01-01

48

Evaluation of hypoglycemic and antihyperglycemic effects of Datura metel (Linn.) seeds in normal and alloxan-induced diabetic rats  

Microsoft Academic Search

The seed powder of Datura metel was tested for its hypoglycemic activity in normal and alloxan-induced diabetic rats. Graded doses (25, 50 and 75mg\\/kg, p.o.) of the seed powder when given to both normal and diabetic rats produced significant reduction in blood glucose at the 8h. The effect was found to be dose dependent with all treatments at the doses

B Krishna Murthy; S Nammi; M. K Kota; R. V Krishna Rao; N Koteswara Rao; A Annapurna

2004-01-01

49

Evaluation of hypoglycemic and antihyperglycemic effects of Datura metel (Linn.) seeds in normal and alloxan-induced diabetic rats.  

PubMed

The seed powder of Datura metel was tested for its hypoglycemic activity in normal and alloxan-induced diabetic rats. Graded doses (25, 50 and 75 mg/kg, p.o.) of the seed powder when given to both normal and diabetic rats produced significant reduction in blood glucose at the 8 h. The effect was found to be dose dependent with all treatments at the doses administered. PMID:15036475

Krishna Murthy, B; Nammi, S; Kota, M K; Krishna Rao, R V; Koteswara Rao, N; Annapurna, A

2004-03-01

50

Effects of Aqueous Extract of Triplochiton scleroxylon on Red Blood Cells and Associated Parameters in Alloxan - Induced Diabetic Rabbits  

Microsoft Academic Search

2 Abstract: The effect of aqueous extract of Triplochiton scleroxylon on the body weight, plasma glucose concentration and some hematological parameters in alloxan-induc ed diabetic rabbits were investigated. Rabbits of the same strain (New Zealand) weighing between 1.20 and 1.68kg were used. At least 100ml of the aqueous extract of the plant was administered to a set of test rabbits

2006-01-01

51

Anti-hyperglycemic activity of chromium(III) malate complex in alloxan-induced diabetic rats.  

PubMed

The synthesis, characterization, anti-hyperglycemic activity, oxidative DNA damage capacity, and acute toxicity of chromium(III) malate complex [Cr2(LMA)3] were described. [Cr2(LMA)3] was synthesized in a single-step reaction by chelating chromium(III) with L-malic acid in aqueous solution. Based on elemental analysis, thermodynamic analysis, and spectroscopy studies, the molecular formula of [Cr2(LMA)3] was inferred as Cr2(C4H4O5)3·5H2O. Daily treatment with 2.85-17.10 mg/kg body mass of [Cr2(LMA)3] in alloxan-induced diabetic rats for 2 weeks indicated that low-molecular-weight organic chromium complex [Cr2(LMA)3] had better bioavailability and more beneficial influences on the improvement of controlling blood glucose, serum lipid, and liver glycogen levels compared with CrCl3·6H2O. [Cr2(LMA)3] did not cause oxidative DNA damage under physiologically relevant conditions. Acute toxicity studies revealed no-measurable toxicity of the [Cr2(LMA)3]. Collectively, these results suggest that [Cr2(LMA)3] may represent a novel, proper chromium supplement with potential therapeutic value to control blood glucose and serum lipid in diabetes. PMID:21161430

Wu, Xiang-Yang; Li, Fang; Xu, Wei-Dong; Zhao, Jiang-Li; Zhao, Ting; Liang, Ling-Hong; Yang, Liu-Qing

2011-11-01

52

Blood glucose lowering activity of aloe based composition, UP780, in alloxan induced insulin dependent mouse diabetes model  

PubMed Central

Background There are a few nutritional approaches to address the increased needs of managing diabetic conditions. Previously it has been reported that UP780, a standardized composition of aloe chromone formulated with an aloe polysaccharide, has a significant impact in reducing HbA1C, fasting blood glucose, fructosamine and plasma insulin level in humans and improved impaired glucose and insulin resistance in high-fat diet-induced and db/db non-insulin dependent diabetic mouse models. Here we describe activity of UP780 and its constituents to improve insulin sensitivity in alloxan induced insulin dependent diabetic mouse model. Materials and method Insulin dependent diabetes was induced by administering a single intraperitoneal injection of alloxan monohydrate at a dose of 150 mg/kg to CD-1 mice. Aloesin (UP394) was formulated with an Aloe vera inner leaf gel powder polysaccharide (Qmatrix) to yield a composition designated UP780. Efficacy of oral administration of UP780 at 2000 mg/kg and its constituents (aloesin at 80 mg/kg and Qmatrix at 1920 mg/kg) were evaluated in this model. Glyburide, a sulfonylurea drug used in the treatment of type 2 diabetes, was used at 5 mg/kg as a positive control. Effect of UP780 on non-diabetic normal mice was also addressed. Results Mice administered intraperitoneal alloxan monohydrate developed progressive type-1 diabetes like symptom. After 4 weeks of daily oral administration, reductions of 35.9%, 17.2% and 11.6% in fasting blood glucose levels were observed for UP780, the UP780 Aloe vera inner leaf gel polysaccharide preparation without chromone (Qmatrix), and Aloesin (UP394), treated animals respectively, compared to vehicle treated animals. UP780 has no impact on blood glucose level of non-diabetic healthy mice. UP780 showed statistically significant improvement for blood glucose clearance in oral glucose tolerance tests. Similarly, enhanced improvement in plasma insulin level and statistically significant reduction in triglyceride level was also observed for animals treated with the composition. Conclusion These findings suggest that UP780, a chromone standardized Aloe based composition, could possibly be used as a natural supplement alternative to facilitate maintenance of healthy blood glucose levels.

2014-01-01

53

Antiradical activity of different copper(II) Schiff base complexes and their effect on alloxan-induced diabetes.  

PubMed

Considering the important role of antioxidants in biological systems, the group of copper(II) complexes derived from salicylaldehyde and alpha- or beta-alanine and its thiourea derivative and copper(II) complexes derived from pyruvic acid and beta-alanine were studied. The antiradical activity of the tested compounds was studied by both in vitro and in vivo methods. The chemical methods based on inhibition of INT-formazane or 3-nitrotyrosine formation were used for the evaluation of SOD-mimic and antiperoxynitrite activity, respectively. In the case of in vivo activity evaluation, an alloxan-induced diabetes mellitus model in mice was used, the mechanism of action of alloxan being closely connected with the formation of free radicals selectively damaging the pancreatic beta-cells. Since all the substances studied showed different positive effects, it is obvious that they have not acted only as a source of copper(II) ions but their effect is related to their specific chelate structure. The obtained results are a contribution to the knowledge of copper(II) Schiff base complexes with ligands of aldimine or ketimine type and form the basis for further preclinical tests of these bioactive agents in biological models of oxidative stress. PMID:15646262

Vanco, Ján; Svajlenová, Ol'ga; Ramanská, Eva; Muselík, Jan; Valentová, Jindra

2004-01-01

54

Effect of clonidine on blood glucose levels in euglycemic and alloxan-induced diabetic rats and its interaction with glibenclamide  

PubMed Central

Objectives: Clonidine, a known antihypertensive, is currently used for many purposes including diabetic gastroparesis, postmenopausal hot flushes, opioid/nicotine/alcohol withdrawal. Its effects on carbohydrate metabolism appear to be variable. Hence, the present study was undertaken to evaluate the influence of clonidine on euglycemic and alloxan -induced diabetic rats and its interaction with glibenclamide. Materials and Methods: Alloxan - induced (150 mg/kg, i.p) diabetic rats were divided into six groups of six animals each. Group I - Normal Control; Group II - Nondiabetic + Clonidine (25 ?g/kg); Group III - Diabetic Control; Group IV - Diabetic + Glibenclamide (5 mg/kg); Group V - Diabetic + Glibenclamide + Clonidine. All drugs were given orally once daily. Blood glucose was estimated from rat tail vein using glucometer before start of the experiment and at the end of 30 days. Results: After 30 days of treatment, clonidine (25 ?g/kg) produced significant hyperglycemia in both euglycemic and diabetic rats. It also reduced the hypoglycemic effect of glibenclamide in diabetic rats. Conclusion: The results of present study indicate that clonidine has hyperglycemic effect and it also interacts with glibenclamide to reduce its hypoglycemic activity. If these findings are true to human beings then clonidine should not be used in diabetic patients on sulfonylureas.

Manjunath, S.; Kugali, Santosh N.; Deodurg, Priyadarshani M.

2009-01-01

55

Antihyperglycemic and hypolipidemic activities of aqueous extract of Carica papaya Linn. leaves in alloxan-induced diabetic rats  

PubMed Central

Background: India is considered as the diabetic capital of the world. The study of plants having antihyperglycemic and hypolipidemic activities may give a new approach in the treatment of diabetes mellitus. Objective: The study was intended to evaluate the antihyperglycemic and hypolipidemic activity of aqueous extract of leaves of Carica papaya Linn. (AECPL) in alloxan-induced diabetic albino rats. Materials and Methods: Diabetes was induced in albino rats by administration of alloxan monohydrate (120 mg/kg, i.p.). Rats were divided into 6 groups of 6 animals each. First group served as non-diabetic control, second group as diabetic control, third group as standard and was treated with 0.1 mg/kg/day of glibenclamide. Group 4, 5, and 6 received 100, 200, and 400 mg/kg body weight of AECPL. Blood samples were analyzed for blood glucose on day 0, 1, 7, 14, 21 and lipid profile on day 21. Results: The AECPL showed significant reduction (P<0.01) in blood glucose level and serum lipid profile levels with 400 mg/kg body weight in alloxan-induced diabetic rats as compared with the control. Conclusion: It is concluded that AECPL is effective in controlling blood glucose levels and in improving lipid profile in diabetic rats.

Maniyar, Yasmeen; Bhixavatimath, Prabhu

2012-01-01

56

Hypoglycaemic and Hypolipidaemic Effects of Withania somnifera Root and Leaf Extracts on Alloxan-Induced Diabetic Rats  

PubMed Central

Withania somnifera is an important medicinal plant, which is used in traditional medicine to cure many diseases. Flavonoids were determined in the extracts of W. somnifera root (WSREt) and leaf (WSLEt). The amounts of total flavonoids found in WSREt and WSLEt were 530 and 520 mg/100 g dry weight (DW), respectively. Hypoglycaemic and hypolipidaemic effects of WSREt and WSLEt were also investigated in alloxan-induced diabetic rats. WSREt and WSLEt and the standard drug glibenclamide were orally administered daily to diabetic rats for eight weeks. After the treatment period, urine sugar, blood glucose, haemoglobin (Hb), glycosylated haemoglobin (HbA1C), liver glycogen, serum and tissues lipids, serum and tissues proteins, liver glucose-6-phosphatase (G6P) and serum enzymes like aspartate transaminase (AST), alanine transaminase (ALT), acid phosphatase (ACP) and alkaline phosphatase (ALP) levels were determined. The levels of urine sugar, blood glucose, HbA1C, G6P, AST, ALT, ACP, ALP, serum lipids except high density lipoprotein-bound cholesterol (HDL-c) and tissues like liver, kidney and heart lipids were significantly (p < 0.05) increased, however Hb, total protein, albumin, albumin:globulin (A:G) ratio, tissues protein and glycogen were significantly (p < 0.05) decreased in alloxan-induced diabetic rats. Treatment of the diabetic rats with WSREt, WSLEt and glibenclamide restored the changes of the above parameters to their normal level after eight weeks of treatment, indicating that WSREt and WSLEt possess hypoglycaemic and hypolipidaemic activities in alloxan-induced diabetes mellitus (DM) rats.

Udayakumar, Rajangam; Kasthurirengan, Sampath; Mariashibu, Thankaraj Salammal; Rajesh, Manoharan; Anbazhagan, Vasudevan Ramesh; Kim, Sei Chang; Ganapathi, Andy; Choi, Chang Won

2009-01-01

57

Beneficial Effects of Pentanema vestitum Linn. Whole Plant on the Glucose and Other Biochemical Parameters of Alloxan Induced Diabetic Rabbits  

PubMed Central

The residents of Lower Dir and Malakand agency, Khyber Pakhtunkhwa, Pakistan, use the dry powder of whole plant of Pentanema vestitum for the treatment of asthma and diabetes. No documented reports are available about the therapeutic action of Pentanema vestitum. The present study was aimed to explore the antihyperglycemic effect of 70% methanol extract of Pentanema vestitum whole plant in glucose-induced nondiabetic hyperglycemic and alloxan-induced diabetic rabbits. During this study, the effects of plant extract on the serum lipid profile, GPT, ALP, bilirubin and creatinine of diabetic rabbits were also studied. The extract of Pentanema vestitum whole plant exhibited significant (P < 0.05) antihyperglycemic activity in glucose-induced hyperglycemic rabbits. Treatment of alloxan-induced diabetic rabbits with extract significantly (P < 0.05) reduced the elevated levels of serum glucose, GPT, ALP, bilirubin and creatinine. During the study of lipid profile, the extract proved to be antihyperlipidemic and HDL boosting in diabetic rabbit models. From the finding of the present research, it was concluded that the 70% methanol extract of Pentanema vestitum whole plant has beneficial effects on serum levels of glucose, lipid profile, GPT, ALP, bilirubin, and creatinine of diabetic rabbits.

Ilahi, Ikram; Asghar, Ali; Ali, Shujat; Khan, Murad; Khan, Nasrullah

2012-01-01

58

Are there structural alterations in the enamel organ of offspring of rats with alloxan-induced diabetes mellitus?  

PubMed

Enamel hypoplasia is the most common developmental defect of human teeth that may be seen in deciduous teeth of babies born to diabetic women. In the present experimental study, we analyzed the enamel organ of the mandibular incisors of the offspring of rats with alloxan-induced diabetes. By light microscopy, no alterations could be found in the enamel organ of rats born to diabetic mothers compared to normal ones, except in one case. In contrast, significant differences were detected with computer-aided morphometry. In the rats born to treated and untreated diabetic mothers, there was thinning of the enamel matrix and of the ameloblasts and the nuclear area of the latter was smaller. In the rats born to treated diabetic mothers, the nuclei of the ameloblasts were more elliptical and there was enlargement of the interstitial area of the stellate reticulum. These results indicate that there are structural defects in the enamel organ of rats born to mothers with alloxan-induced diabetes which could induce the enamel hypoplasia observed by scanning electron microscopy and which may reflect the metabolic alterations seen in this condition. Future studies are needed to determine whether these effects are transitory or permanent. PMID:15057390

Silva-Sousa, Yara Teresinha Corrêa; Peres, Luiz Cesar; Foss, Milton César

2003-01-01

59

Hepatoprotective and Hypolipidemic Effects of Satureja Khuzestanica Essential Oil in Alloxan-induced Type 1 Diabetic Rats  

PubMed Central

In the present study, we examined the antioxidative activities of Satureja khuzestanica essential oil (SKE) and possible protective effect of SKE on lipid profile, atherogenic index and liver enzyme markers in Alloxan-induced Type 1 diabetic rats. Thirty male rats were randomly divided into three groups; group one as control, group two diabetic untreatment, and group three treatments with SKE by 500 ppm in drinking water, respectively. Diabetes was induced in the second and third groups by alloxan injection subcutaneously. After 8 weeks, the levels of fasting blood glucose (FBG), triglyceride (TG), cholesterol (C), low density lipoprotein (LDL), very low density lipoprotein (VLDL), high density lipoprotein (HDL), atherogenic index and the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) of all groups were analyzed. Data were analyzed through non-parametric Man Whitney test (using SPSS 13 software) and p < 0.05 was considered significant. SKE inhibited significantly the activities of ALT and ALP and decrease FBG, TG, C, LDL and VLDL. HDL level was significantly increased when treated with the extract. The activities of AST stayed unaltered. Moreover, total antioxidant capacity of SKE was 3.20 ± 0.40 nmol of ascorbic acid equivalents/g SKE. This study showed that SKE is a source of potent antioxidants. The findings of the present study also suggest that SKE exert beneficial effects on the lipid profile, atherogenic index and liver enzymes activity in Alloxan-induced Type 1 diabetic rats.

Ahmadvand, Hassan; Tavafi, Majid; Khalatbary, Ali Reza

2012-01-01

60

Anti-diabetic property of Methanol extract of Musa sapientum leaves and its fractions in alloxan-induced diabetic rats.  

PubMed

Diabetes mellitus is a metabolic disorder resulting from necrosis of ?-cell and insulin resistance at the cellular level. Musa sapientum has been shown to possess anti-diabetic properties, however, the mechanism of its action is unknown. The effect of Methanolic extract of Musa sapientum leaves (MEMSL) and its fractions were assessed for in vitro inhibitory activity of ?-amylase enzyme, in vivo hypoglycemic properties and liver glycogen content in alloxan-induced diabetic rats. Dried plant powder of Musa sapientum was successively extracted using n-hexane, ethyl acetate, dichloromethane and methanol respectively. The filtrate obtained was evaporated using rotary evaporator and the extract was stored at 4°C until use. The methanolic extract obtained was further fractionated using column chromatography. In vitro alpha amylase inhibitory activity of the methanolic extract at different doses (2.5mg/ml, 5mg/ml, 10mg/ml, 25mg/ml and 50mg/ml) and column fractions (100ug/ml) were assessed and compared with that of acarbose (5mg/ml), a standard oral ?-amylase inhibitor. Hypoglycemic activity and liver glycogen content was studied using alloxan -induced diabetic male rats treated with MEMSL (250mg/kg and 500mg/kg), column fractions F2 and F5 (100?g/kg) for 14 days respectively. Results obtained showed a dose -dependent increase in ?-amylase inhibitory activity of the methanolic extract at 5, 10, 25 and 50mg/ml exhibiting 29%, 61%, and 72% and 80% inhibitory activities respectively. Column fractions 2 and 5 showed the highest ?-amylase inhibitory activity of 79% and 74% respectively. The MEMSL at 250mg/kg and 500mg/kg exhibited 66% and 59% hypoglycemic activities respectively compared with diabetic controls. Fractions 2 and 5 showed 48% and 75% reduction in blood glucose level respectively. Liver glycogen in diabetic animals treated with MEMSL (250mg/kg and 500mg/kg), F2 and F5 were significantly increased (5.5±0.5, 5.9±0.7, 3.6±0.5, 8.0±0.4 mg/100gwt. liver) compared with Diabetic controls (1.2±0.3 mg/100gwt. liver) respectively suggesting an increase in glucose storage or reduction in glycogen breakdown. It seems possible that the anti-diabetic properties in the leaf extract of Musa sapientum and its fractions maybe due to the inhibition of ?-amylase, increased storage of glucose as glycogen in the liver and/or reduced breakdown of liver glycogen stores. PMID:23955414

Adewoye, E O; Ige, A O

2013-01-01

61

Hypoglycaemic and anti-diabetic activity of stem bark extracts Erythrina indica in normal and alloxan-induced diabetic rats  

PubMed Central

The objective of the study is to investigate the alcoholic (AlcE) and aqueous (AqsE) extracts of stem bark of Erythrina indica (Papilionaceae) for hypoglycaemic effects in normal and diabetic rats. Diabetes was induced in rats by a single dose administration of alloxan (120 mg/kg, i.p.) or by injecting dexamethasone (10 mg/kg, i.p.) for 10 days. In normal rats, AlcE and AqsE had significantly decreased the blood glucose level (BGL) in a dose dependent manner after repeated administration for 7 days. In alloxan-induced diabetic rats, both the extracts decreased blood sugar levels with significant improvement in glucose tolerance and body weight at the end of 1st, 2nd and 3rd week after test extract treatment. In case of dexamethasone induced insulin resistant diabetic rats, repeated administration of AlcE and AqsE inhibited the increase in blood glucose level and improved glucose tolerance induced by dexamethasone as compared to dexamethasone induced diabetic rats. These results suggest that both extracts possess hypoglycaemic activity in normal as well as in diabetic rats. Among AlcE and AqsE, AqsE possesses better hypoglycaemic activity than AlcE in all the models. Preliminary phytochemical investigations revealed that alcoholic extracts contain carbohydrates, alkaloids, flavonoids, saponins, phytosterols, phenolics and tannins. Aqueous extract contains carbohydrates, alkaloids, flavonoids, glycosides, phytosterols and triterpenoids. These phytoconstituents may be responsible for the hypoglycaemic activity of the plant.

Yashwant Kumar, A.; Nandakumar, K.; Handral, M.; Talwar, Sahil; Dhayabaran, Daniel

2010-01-01

62

Antioxidant, antihyperglycemic, and antihyperlipidemic effects of Coriandrum sativum leaf and stem in alloxan-induced diabetic rats.  

PubMed

In India's indigenous system of medicine, Coriandrum sativum (CS), commonly used as a food ingredient, is claimed to be useful for various ailments. To establish its utility in diabetes mellitus, the present study evaluated the antidiabetic and antioxidant effects of CS in alloxan-induced diabetic rats. The extracts were shown to contain bioactive compounds including phenolics, flavonoids, steroids, and tannins. The extracts of CS in alloxan-induced diabetic rats were found to significantly lower blood glucose levels. Antidiabetic activity of the CS extracts was compared with the clinically available drug glibenclamide. The levels of serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol were lower in the extract-treated group and high-density lipoprotein cholesterol was higher than the diabetic control rats. The extracts of CS exhibited strong scavenging effect on 2, 2-diphenyl-2-picrylhydrazyl free radical and inhibition of lipid peroxidation. The free radical scavenging effect of the extracts was comparable with that of the reference antioxidants. Furthermore, it also showed an improved antioxidant potential as evidenced by decreased lipid peroxidation and a significant increase in the activity of various antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase in the liver of diabetic rats. These results indicate that the extracts could protect liver function and exhibited hypoglycemic, hypolipidemic, and antioxidant efficacies in the diabetic rats. These results support the use of this plant extract to manage diabetes mellitus. PRACTICAL APPLICATIONS: The leaves and stem of this plant Coriandrum sativum if used in cuisine would be a remedy for diabetes. PMID:22671941

Sreelatha, S; Inbavalli, R

2012-07-01

63

Antidiabetic and antihyperlipidaemic activity of ethanol extract of Melastoma malabathricum Linn. leaf in alloxan induced diabetic rats  

PubMed Central

Objective To evaluate the antidiabetic and antihyperlipidaemic effect of ethanol extract of Melastoma malabathricum (M. malabathricum) Linn. leaf in alloxan induced diabetic rats. Methods Diabetes was induced in albino rats by administration of alloxan monohydrate (150 mg/kg i.p). the ethanol extracts of M. malabathricum at a dose of 150 and 300 mg/kg of body weight were administrated at a single dose per day to diabetes induced rats for a period of 14 d. The effect of ethanol extract of M. malabathricum leaf extract on blood glucose, plasma insulin, creatinine, glycosylated haemoglobin, urea serum lipid profile [total cholesterol, triglycerides, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, high density lipoprotein-cholesterol and phospholipid, serum protein, albumin, globulin, serum enzymes (serum glutamate pyruvate transaminases), serum glutamate oxaloacetate transaminases, and alkaline phosphatase] were measured in the diabetic rats. Results In the acute toxicity study, ethanol extract of M. malabathricum leaf was non-toxic at 2?000 mg/kg in rats. The increased body weight, decreased blood glucose, glycosylated haemoglobin and other biochemical parameters level were observed in diabetic rats treated with both doses of ethanol extract of M. malabathricum leaf compared to diabetic control rats. In diabetic rats, ethanol extract of M. malabathricum leaf administration, altered lipid profiles were reversed to near normal than diabetic control rats. Conclusions Ethanol extract of M. malabathricum leaf possesses significant antidiabetic and antihyperlipidaemic activity in diabetic rats.

Balamurugan, Karuppasamy; Nishanthini, Antony; Mohan, Veerabahu Ramasamy

2014-01-01

64

Acute effect of Bauhinia forficata on serum glucose levels in normal and alloxan-induced diabetic rats.  

PubMed

Experimental diabetes was used to study the acute effect of the n-butanol fraction of Bauhinia forficata Link (Leguminosae) (BF) leaves on the serum glucose levels of rats. Body weight was measured on the day of diabetes induction and on the day of the experiment. Levels of glucose were determined at different doses and times following treatment with BF or with vehicle in normal, diabetic and hyperglycemic normal rats. Oral administration of n-BuOH fraction led to a significant blood glucose-lowering effect in normal and diabetic rats. However, in glucose-fed hyperglycemic normal rats, the maximum dose of this fraction failed to decrease blood glucose levels. The hypoglycemic effect was observed at doses of 500 and 600 mg/kg after 1 and 2 h treatment respectively, in normal rats. The maximum effect of BF was detected at 1 h with 800 mg/kg in diabetic animals and this profile was maintained for the next 3 h. Treatment of normal and alloxan-induced diabetic rats with BF decreased glucose levels, while this fraction was devoid of hypoglycemic effect in glucose-fed hyperglycemic normal rats. PMID:12413705

Silva, Fátima Regina Mena Barreto; Szpoganicz, Bruno; Pizzolatti, Moacir Geraldo; Willrich, Maria Alice Vieira; de Sousa, Eliandra

2002-11-01

65

EFFECTS OF Artemisia sieberi Besser (A. herba-alba) ON HEART RATE AND SOME HEMATOLOGICAL VALUES IN NORMAL AND ALLOXAN-INDUCED DIABETIC RATS  

Microsoft Academic Search

The present study was designed to evaluate the effects of oral administration of Artemisia sieberi Besser on heart rate and some hematological values in normal and alloxan-induced diabetic rats. It was found that water extract of Artemisia sieberi produced significant (p<0.05) reduction in blood glucose level in diabetic rats after 10 days of treatment; however, there was a significant (p<0.05)

Kamal Mansi; Jamil Lahham

66

Anti-oxidant and anti-hyperglycemic activities of musa sapientum root extracts in alloxan-induced diabetic rats.  

PubMed

Anti-hyperglycemic and anti-oxidant properties of methanolic (MEMS) and aqueous (AEMS) extracts of Musa sapientum roots were investigated in alloxan-induced diabetic rats. Thirty adult male Wistar albino rats divided into five groups of 6 rats each were used: group 1--non-diabetic untreated (controls), group 2--diabetic untreated, and groups 3, 4 and 5--diabetic rats treated with 250 mg/kg bodyweight MEMS and AEMS, and 500 mg/kg bodyweight glibenclamide (a standard anti-diabetic drug), respectively. There was severe progressive weight loss in the untreated diabetic rats, while the rats in all the treated diabetic groups gained weight. While there was progressive hyperglycaemia in untreated diabetic rats; with blood glucose levels reaching a peak of 335.5 +/- 1.1 mg/dl on day 7 post-induction, compared to 76.8 +/- 0.8 mg/dl on day 0, these values were reduced to 80.7 +/- 0.5, 86.6 +/- 0.6 and 86.8 +/- 0.5 in MEMS, AEMS and glibenclamide-treated diabetic rats 15 days post-treatment. Also there were decreases in serum lipid peroxidation and increases in serum superoxide dismutase activities in MEMS, AEMS and glibenclamide-treated diabetic rats 15 days post-treatment. Lesions observed in the organs of untreated diabetic rats include selective necrosis of pancreatic beta islet cells, hepatocellular degeneration and necrosis, glomerulonephrosis and cardiovascular degeneration. Treatment of diabetic rats with AEMS and glibenclamide caused a total mitigation, while treatment with the MEMS achieved partial but considerable reduction in the severity of the lesions. It is concluded that aqueous and methanolic extracts of Musa sapientum roots possess anti-diabetic activities comparable to glibenclamide. PMID:20175413

Adewoye, E O; Taiwo, V O; Olayioye, F A

2009-06-01

67

Hypoglycemic effect of ethanolic extract of Musa sapientum on alloxan induced diabetes mellitus in rats and its relation with antioxidant potential.  

PubMed

The antihyperglycemic effect of ethanolic extract of flowers of Musa sapientum (Musaceae), a herb (used in Indian folklore medicine for the treatment of diabetes mellitus) in alloxan induced diabetic rats. Oral administration of the ethanolic extract showed significant (p < 0.001) blood glucose lowering effect at 200 mg/kg in alloxan induced diabetic rats (120 mg/kg, i.p.) and the extract was also found to significantly (p < 0.001) scavenge oxygen free radicals, viz., superoxide dismutase (SOD), catalase (CAT) and also protein, malondialdehyde and ascorbic acid in vivo. Musa sapientum induced blood sugar reduction may be due to possible inhibition of free radicals and subsequent inhibition of tissue damage induced by alloxan. The antidiabetic activity observed in this plant may be attributed to the presence of flavonoids, alkaloids, steroid and glycoside principles. PMID:16260406

Dhanabal, S P; Sureshkumar, M; Ramanathan, M; Suresh, B

2005-01-01

68

The Protective Effect of Cordymin, a Peptide Purified from the Medicinal Mushroom Cordyceps sinensis, on Diabetic Osteopenia in Alloxan-Induced Diabetic Rats.  

PubMed

The aim of this study was to investigate the protective effect of cordymin on diabetic osteopenia in alloxan-induced diabetic rats and the possible mechanisms involved. The diabetic rats received daily intraperitoneal injection with cordymin (20, 50, and 100?mg/kg/day) for 5 weeks. Cordymin could restore the circulating blood glucose, glycosylated hemoglobin (HbA1c), serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), and insulin levels in a dose-dependent manner. Also, the treatment of diabetic rats with cordymin could partially reverse the ? cells death and decrease the total antioxidant status (TAOS) in the diabetic rats. The results may directly and indirectly account for the possible mechanism of the beneficial effect of cordymin on diabetic osteopenia, which was confirmed with the increased bone mineral content (BMC) and bone mineral density (BMD) in diabetic rats (P < 0.05). All those findings indicate that cordymin may play a protective role in diabetic osteoporosis. PMID:24174985

Qi, Wei; Zhang, Yang; Yan, Ya-Bo; Lei, Wei; Wu, Zi-Xiang; Liu, Ning; Liu, Shuai; Shi, Lei; Fan, Yong

2013-01-01

69

The Protective Effect of Cordymin, a Peptide Purified from the Medicinal Mushroom Cordyceps sinensis, on Diabetic Osteopenia in Alloxan-Induced Diabetic Rats  

PubMed Central

The aim of this study was to investigate the protective effect of cordymin on diabetic osteopenia in alloxan-induced diabetic rats and the possible mechanisms involved. The diabetic rats received daily intraperitoneal injection with cordymin (20, 50, and 100?mg/kg/day) for 5 weeks. Cordymin could restore the circulating blood glucose, glycosylated hemoglobin (HbA1c), serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), and insulin levels in a dose-dependent manner. Also, the treatment of diabetic rats with cordymin could partially reverse the ? cells death and decrease the total antioxidant status (TAOS) in the diabetic rats. The results may directly and indirectly account for the possible mechanism of the beneficial effect of cordymin on diabetic osteopenia, which was confirmed with the increased bone mineral content (BMC) and bone mineral density (BMD) in diabetic rats (P < 0.05). All those findings indicate that cordymin may play a protective role in diabetic osteoporosis.

Qi, Wei; Zhang, Yang; Yan, Ya-bo; Lei, Wei; Wu, Zi-xiang; Liu, Ning; Liu, Shuai; Shi, Lei; Fan, Yong

2013-01-01

70

Maternal zinc intake of Wistar rats has a protective effect in the alloxan-induced diabetic offspring.  

PubMed

Zinc has a role in the synthesis, storage, and secretion of insulin, and has been suggested to be beneficial when used in the diabetic state. Effect of zinc intake in pregnant rats has been studied here on diabetized offspring. Pregnant rats were divided in two groups; the control group received normal food and water, and the experimental group received zinc sulfate during pregnancy and 3 weeks after offspring birth. Male offspring from the control (C) and experimental (E) groups were divided each in three groups: C1, fed with normal food and water; C2, diabetized with alloxan; C3, received zinc sulfate; E1, fed with normal food and water; E2, diabetized with alloxan; and E3, receiving zinc sulfate. After 30 days, the histological changes of pancreatic tissues were investigated by light microscopy. Body weight, blood glucose, serum insulin levels, food intake, water intake, and urine quantity were also compared between the groups. Water intake and urine quantity were decreased significantly (p?diabetic group) in comparison with C2 (control diabetic group), but there was no significant difference in the body weight in C2 in comparison with E2, while blood glucose was decreased significantly (p?alloxan-induced beta-cell degeneration. In conclusion, this work showed that maternal zinc intake may influence subsequent deleterious effects of diabetes on alloxan-diabetized offspring. PMID:22730079

Yaghmaei, Parichehreh; Esfahani-Nejad, Hamideh; Ahmadi, Ramesh; Hayati-Roodbari, Nasim; Ebrahim-Habibi, Azadeh

2013-03-01

71

Anti-diabetic properties of chromium citrate complex in alloxan-induced diabetic rats.  

PubMed

The chromium citrate complex [CrCIT] was synthesized and its structure was determined by infrared, UV-visible and atomic absorption spectroscopy, elemental and thermodynamic analysis. Anti-diabetic activity, oxidative DNA damage capacity and acute oral toxicity of [CrCIT] were investigated and compared with that of chromium trichloride hexahydrate. [CrCIT] was synthesized in a single step reaction by chelating chromium(III) with citric acid in aqueous solution. The molecular formula of [CrCIT] was inferred as CrC(6)H(5)O(7)·4H(2)O. The anti-diabetic activity of the complex [CrCIT] was assessed in alloxan-diabetic rats by daily oral gavage for 3 weeks. The biological activity results showed that the complex at the dose of 0.25-0.75 mg Cr/kg body weight could decrease the blood glucose level and increase liver glycogen level in alloxan-diabetic rats. [CrCIT] had more beneficial influences on the improvement of controlling blood glucose, serum lipid and liver glycogen levels compared with CrCl(3)·6H(2)O. Furthermore, [CrCIT] did not cause oxidative DNA damage under physiologically relevant conditions, and [CrCIT] did not produce any hazardous symptoms or deaths in acute oral toxicity test, showing the LD(50) value for female and male rats were higher than 15.1 g/kg body weight. The results suggested that [CrCIT] might represent a novel and proper chromium supplement with potential therapeutic value to control blood glucose in diabetes. PMID:21924886

Li, Fang; Wu, Xiangyang; Zhao, Ting; Zhang, Min; Zhao, Jiangli; Mao, Guanghua; Yang, Liuqing

2011-12-01

72

The hypoglycemic effect of the aqueous extract of the fruits of Balanites aegypticea in Alloxan-induced diabetic rats  

PubMed Central

Background: Balanites aegypticea is used medically for many purposes e.g. anti-spasmodic, stomach pain, malaria, and yellow fever. The extract of the fruit is also used to reduce the blood glucose levels. Objectives: The objective of this study was to investigate the hypoglycemic effects of the aqueous extract of the fruits of the Balanites aegypticea in alloxan-induced diabetic rats. Materials and Methods: Twenty-five adult male Vistar rats were used in this study. The rats were randomly collected and divided into 5 groups (5 rats in each group). The untreated rats (negative control group) received basal diet and tap water only for 15 days. The experimental rats became diabetic by intraperitoneal injection of alloxan (150 mg/kg body weight). The fruit of Balanites aegypticea was powdered, extracted, and dried using organic solvents. The diabetic rats received aqueous extract 200 mg/kg, 400 mg/kg, and 800 mg/kg, respectively, for 2 weeks. Plasma glucose levels were measured by using Glucose GOD-PAP method through spectrophotometer. Results: The results showed that 800 mg/kg aqueous extract decrease significantly the plasma glucose level (P ? 0.05) in diabetic rats, and there is a considerable gain in body weight (P ? 0.05) compared to the diabetic control group. Four-hundred mg/kg aqueous extract has a mild effect on body weights and plasma glucose levels, while 200 mg/kg aqueous extract has no significant effect on plasma glucose level and a little effect on body weight. Conclusions: The results of the presented study revealed that the aqueous extract of Balanites aegypticea has hypoglycemic properties. It can decrease the plasma glucose level and can improve weight in diabetic experimental animals.

Baragob, Abdella Emam Abdella; AlMalki, Waleed Hassan; Shahid, Imran; Bakhdhar, Fatimah Abdullah; Bafhaid, Hanouf Saeed; Eldeen, Omar Muhammad Izz

2014-01-01

73

Biochemical Evaluation of the Hypoglycemic Effects of Extract and Fraction of Cassia fistula Linn. in Alloxan-induced Diabetic Rats  

PubMed Central

Various extracts of flowers of Cassia fistula Linn (Leguminosae) such as petroleum ether (60-80°), chloroform, acetone, ethanol, aqueous, and crude aqueous extracts and two fractions of ethanol extract were tested for antihyperglycemic activity in glucose-overloaded hyperglycemic rats. The effective antihyperglycemic extracts and fraction were tested for their hypoglycemic activity at two dose levels, 200 and 400 mg/kg, respectively. To confirm their utility in higher models, the effective extracts and fraction of C. fistula were subjected to antidiabetic study in an alloxan-induced diabetic model at two dose levels, 200 and 400 mg/kg, respectively. Biochemical parameters like glucose, urea, creatinine, serum cholesterol, serum triglyceride, high-density lipoprotein, low-density lipoprotein, hemoglobin, and glycosylated hemoglobin were also assessed in experimental animals. The petroleum ether and ethanol extracts of C. fistula and the water-soluble fraction of ethanol extract were found to exhibit significant antihyperglycemic activity. The extracts, at the given doses, did not produce hypoglycemia in fasted normal rats, and the fraction exhibited weak hypoglycemic effect after 2 h of the treatment. Treatment of diabetic rats with ethanol extract and water-soluble fraction of this plant restored the elevated biochemical parameters significantly (P<0.05) to the normal level. No activity was found in the petroleum ether extract of the plant. Comparatively, the water-soluble fraction of ethanol extract was found to be more effective than the ethanol extract, and the activity was comparable with that of the standard, glibenclamide (5 mg/kg).

Jarald, E. E.; Joshi, S. B.; Jain, D. C.; Edwin, S.

2013-01-01

74

Biochemical Evaluation of the Hypoglycemic Effects of Extract and Fraction of Cassia fistula Linn. in Alloxan-induced Diabetic Rats.  

PubMed

Various extracts of flowers of Cassia fistula Linn (Leguminosae) such as petroleum ether (60-80°), chloroform, acetone, ethanol, aqueous, and crude aqueous extracts and two fractions of ethanol extract were tested for antihyperglycemic activity in glucose-overloaded hyperglycemic rats. The effective antihyperglycemic extracts and fraction were tested for their hypoglycemic activity at two dose levels, 200 and 400 mg/kg, respectively. To confirm their utility in higher models, the effective extracts and fraction of C. fistula were subjected to antidiabetic study in an alloxan-induced diabetic model at two dose levels, 200 and 400 mg/kg, respectively. Biochemical parameters like glucose, urea, creatinine, serum cholesterol, serum triglyceride, high-density lipoprotein, low-density lipoprotein, hemoglobin, and glycosylated hemoglobin were also assessed in experimental animals. The petroleum ether and ethanol extracts of C. fistula and the water-soluble fraction of ethanol extract were found to exhibit significant antihyperglycemic activity. The extracts, at the given doses, did not produce hypoglycemia in fasted normal rats, and the fraction exhibited weak hypoglycemic effect after 2 h of the treatment. Treatment of diabetic rats with ethanol extract and water-soluble fraction of this plant restored the elevated biochemical parameters significantly (P<0.05) to the normal level. No activity was found in the petroleum ether extract of the plant. Comparatively, the water-soluble fraction of ethanol extract was found to be more effective than the ethanol extract, and the activity was comparable with that of the standard, glibenclamide (5 mg/kg). PMID:24302797

Jarald, E E; Joshi, S B; Jain, D C; Edwin, S

2013-07-01

75

Evaluation of the Antidiabetic and Antilipaemic Activities of the Hydroalcoholic Extract of Phoenix Dactylifera Palm Leaves and Its Fractions in Alloxan-Induced Diabetic Rats  

PubMed Central

Background: The antidiabetic and antilipaemic effects of Phoenix dactylifera leaf extract (PDE) and its fractions were investigated in various rat models. Methods: Diabetes was induced in male Wistar rats by alloxan monohydrate. Diabetic animals were randomly divided into 8 groups (1 diabetic control and 7 treated groups). Diabetic control animals received saline (5 mL/kg) orally, whereas the treatment groups received different doses of PDE (100, 200, and 400 mg/kg), PDE fractions (50, 100, and 200 mg/kg), or glibenclamide (4 mg/kg) orally once a day for 14 days. Blood was withdrawn for glucose determination on the 1st, 6th, 10th, and 14th days. The rats were fasted overnight and then sacrificed on the 14th day; blood was collected for biochemical evaluation, including the levels of blood glucose, plasma insulin, serum triglyceride, and cholesterol. Results: Subacute administration of PDE or its fractions in alloxan-induced diabetic rats significantly reduced blood glucose (P < 0.01). Water intake, serum triglyceride, and cholesterol also decreased in treated animals compared with the control group (P < 0.01). Plasma insulin level increased in the treated groups relative to the control group (P < 0.01). Conclusion: The results suggested that PDE exhibits antidiabetic and antilipaemic effects in alloxan-induced diabetic rats.

Mard, Seyyed Ali; Jalalvand, Kowthar; Jafarinejad, Masoumeh; Balochi, Hoda; Naseri, Mohammad Kazem Gharib

2010-01-01

76

Alloxan-Induced Diabetes Triggers the Development of Periodontal Disease in Rats  

PubMed Central

Background Periodontal disease in diabetic patients presents higher severity and prevalence; and increased severity of ligature-induced periodontal disease has been verified in diabetic rats. However, in absence of aggressive stimuli such as ligatures, the influence of diabetes on rat periodontal tissues is incompletely explored. The aim of this study was to evaluate the establishment and progression of periodontal diseases in rats only with diabetes induction. Methodology/Principal Findings Diabetes was induced in Wistar rats (n?=?25) by intravenous administration of alloxan (42 mg/kg) and were analyzed at 1, 3, 6, 9 and 12 months after diabetes induction. The hemimandibles were removed and submitted to radiographical and histopathological procedures. A significant reduction was observed in height of bone crest in diabetic animals at 3, 6, 9 and 12 months, which was associated with increased numbers of osteoclasts and inflammatory cells. The histopathological analyses of diabetic rats also showed a reduction in density of collagen fibers, fibroblasts and blood vessels. Severe caries were also detected in the diabetic group. Conclusions/Significance The results demonstrate that diabetes induction triggers, or even co-induces the onset of alterations which are typical of periodontal diseases even in the absence of aggressive factors such as ligatures. Therefore, diabetes induction renders a previously resistant host into a susceptible phenotype, and hence diabetes can be considered a very important risk factor to the development of periodontal disease.

Claudino, Marcela; Ceolin, Danielle Santi; Alberti, Sandra; Cestari, Tania Mary; Spadella, Cesar Tadeu; Rubira-Bullen, Izabel Regina Fischer; Garlet, Gustavo Pompermaier; de Assis, Gerson Francisco

2007-01-01

77

In vitro alpha-amylase inhibition and in vivo antioxidant potential of Amaranthus spinosus in alloxan-induced oxidative stress in diabetic rats  

PubMed Central

Amaranthus spinosus Linn. (Amaranthaceae), commonly known as “Mulluharivesoppu” in Kannada, is used in the Indian traditional system of medicine for the treatment of diabetes. The present study deals with the scientific evaluation of alpha amylase and the antioxidant potential of methanol extract of A. spinosus (MEAS). The aim of this study was to investigate in vitro alpha-amylase enzyme inhibition by CNPG3 (2-chloro-4-nitrophenol ?-d-maltotrioside) and in vivo antioxidant potential of malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and total thiols (TT) in alloxan-induced diabetic rats of a methanolic extract of A. spinosus. Blood sugar was also determined in MEAS-treated alloxan-induced diabetic rats. MEAS showed significant inhibition of alpha-amylase activity and IC50 46.02 ?g/ml. Oral administration of MEAS (200 and 400 mg/kg) for 15 days showed significant reduction in the elevated blood glucose, MDA and restores GSH, CAT and TT levels as compared with a diabetic control. The present study provides evidence that the methanolic extract of A. spinosus has potent alpha amylase, anti-diabetic and antioxidant activities.

Ashok Kumar, B.S.; Lakshman, K.; Nandeesh, R.; Arun Kumar, P.A.; Manoj, B.; Kumar, Vinod; Sheshadri Shekar, D.

2010-01-01

78

Does telmisartan prevent hepatic fibrosis in rats with alloxan-induced diabetes?  

Microsoft Academic Search

Background\\/aimsThis study evaluated the effect of telmisartan on the livers of diabetic rats and also aimed to determine the hepatic distribution and role of transforming growth factor ? (TGF-?) in diabetes-related hepatic degeneration while taking into account the possible protective effects of telmisartan.

Zekai Halici; Habip Bilen; Fatih Albayrak; Abdullah Uyanik; Ramazan Cetinkaya; Halis Suleyman; Osman Nuri Keles; Bunyami Unal

2009-01-01

79

HYPOLIPIDEMIC EFFECT OF CUMINUM CYMINUM L. ON ALLOXAN-INDUCED DIABETIC RATS  

Microsoft Academic Search

Hyperlipidemia is an associated complication of diabetes mellitus. Many spices and herbs are known to be hypoglycaemic. Cuminum cyminum belonging to the family Apiaceae is widely used in Ayurvedic medicine for the treatment of dyspepsia, diarrhoea and jaundice.The present work was done to study the role of C. cyminum supplementation on the plasma and tissue lipids in alloxan diabetic rats.

SURYA DHANDAPANI; VIJAYAKUMAR RAMASAMY SUBRAMANIAN; SENTHILKUMAR RAJAGOPAL; NALINI NAMASIVAYAM

2002-01-01

80

Immunomodulatory, beta-cell, and neuroprotective actions of fenugreek oil from alloxan-induced diabetes.  

PubMed

Immunological disorders and nephropathy are among the most frequent and serious complications of diabetes mellitus. This shows that fewer infiltrated inflammatory cells evidenced by reverted back to near the normal value of white blood cell, mean corpuscular volume, and lymphocytes counts as interleukin-6 in pancreas. Also, fenugreek oil significantly improved blood glucose levels, glucose intolerance, and insulin sensitivity compared to the diabetic group. The pancreatic islet and less beta-cells damage were observed after the administration of fenugreek oil to diabetic rats. Moreover, diabetic rats showed low activities of superoxide dismutase, catalase, glutathione peroxidase, and reduced glutathione content in kidney, which were restored to near normal levels by treatment with fenugreek oil. The increased levels of lipid peroxidation, creatinine, albumin, and urea in diabetic rats decreased significantly in diabetic rats treated with fenugreek oil. Diabetic rats treated with fenugreek oil restored almost a normal architecture of pancreas and kidney. In conclusion, this study reveals the efficacy of fenugreek oil in the amelioration of diabetes, hematological status, and renal toxicity which may be attributed to its immunomodulatory activity and insulin stimulation action along with its antioxidant potential. PMID:20100065

Hamden, Khaled; Masmoudi, Hatem; Carreau, Serge; Elfeki, Abdalfattah

2010-09-01

81

Glucose lowering effect of aqueous extract of Bauhinia tomentosa L. on alloxan induced type 2 diabetes mellitus in wistar albino rats  

PubMed Central

The study was designed to evaluate the anti-diabetic effect of aqueous extract of Bauhinia tomentosa L. leaf on alloxan induced Wistar albino rats. Diabetes was induced in albino rat models with alloxan monohydrate (150mg/kg body weight). Aqueous leaf extract of Bauhinia tomentosa at the dose of 300 mg/kg was orally administered once a day for 30 days to the diabetic animals. In this study, glycemic parameters, lipid parameters and serum enzymes were reduced whereas the level of high-density lipoprotein-cholesterol was elevated. The extract significantly increased the total protein and glycogen level in the liver of diabetic rats. Furthermore, the liver carbohydrate metabolizing enzymes were normalized by the administration of the extracts. Histopatholgical examination results of liver, pancreas and kidney were normal in general. The above results indicated the anti-diabetic efficacy of the B.tomentosa leaf extract

Devaki, K.; Beulah, U.; Akila, G.; Narmadha, R.; Gopalakrishnan, V. K.

2011-01-01

82

Coconut kernel-derived proteins enhance hypolipidemic and antioxidant activity in alloxan-induced diabetic rats.  

PubMed

Impaired lipid levels and oxidative stress are indicative of malfunction of endogenous antioxidant capacity. The aim of this study was to determine the effect of coconut kernel protein (CKP) on the lipid peroxides and antioxidant enzyme activities in diabetic rats. Diabetes was induced prior to feeding by injecting a single dose of alloxan (150 mg/kg body weight) intraperitoneally. CKP (8% w/w) was administered to these rats along with a semi-synthetic diet for 45 days. After the experimental period, peroxide products and antioxidant enzyme activities were determined. Results show that CKP maintained the antioxidant enzyme activities and levels of peroxides to the normal levels in treated group compared to diabetic rats. This study clearly show that CKP has potential effect in lowering oxidative stress associated with diabetes. This beneficial effect of CKP may be due to the high amount of biologically potent arginine present in it. PMID:23113582

Salil, Gopalakrishnan; Nevin, Kottayath Govindan; Rajamohan, Thankappan

2013-05-01

83

Hypolipidemic effect of Cuminum cyminum L. on alloxan-induced diabetic rats.  

PubMed

Hyperlipidemia is an associated complication of diabetes mellitus. Many spices and herbs are known to be hypoglycaemic. Cuminum cyminum belonging to the family Apiaceae is widely used in Ayurvedic medicine for the treatment of dyspepsia, diarrhoea and jaundice. The present work was done to study the role of C. cyminum supplementation on the plasma and tissue lipids in alloxan diabetic rats. Oral administration of 0.25 g kg(-1) body weight of C. cyminum for 6 weeks to diabetic rats resulted in significant reduction in blood glucose and an increase in total haemoglobin and glycosylated haemoglobin. It also prevented a decrease in body weight. C. cyminum treatment also resulted in a significant reduction in plasma and tissue cholesterol, phospholipids, free fatty acids and triglycerides. Histological observations demonstrated significant fatty changes and inflammatory cell infiltrates in diabetic rat pancreas. But supplementation with C. cyminum to diabetic rats significantly reduced the fatty changes and inflammatory cell infiltrates. Moreover, C. cyminum supplementation was found to be more effective than glibenclamide in the treatment of diabetes mellitus. PMID:12220968

Dhandapani, Surya; Subramanian, Vijayakumar Ramasamy; Rajagopal, Senthilkumar; Namasivayam, Nalini

2002-09-01

84

Biochemical and histopathological study of the anti-hyperglycemic and anti-hyperlipidemic effects of cornelian cherry (Cornus mas L.) in alloxan-induced diabetic rats.  

PubMed

Abstract Background: Anthocyanins are phytochemicals with a multitude of pharmacological actions including anti-diabetic and anti-hyperlipidemic effects. This study was undertaken to evaluate the anti-hyperglycemic and anti-hyperlipidemic effects of cornelian cherry (Cornus mas L., CM) fruits - that are rich in anthocyanins and known to have medicinal properties- in alloxan-induced diabetic rats. Methods: Twenty-eight adult male rats were randomly assigned to four groups of seven animals each: non-diabetic control, diabetic control, glibenclamide-treated (0.6 mg/kg/day; 4 weeks) and CM fruit-treated (2 g/day; 4 weeks) group. Diabetes was induced by a single injection of alloxan (120 mg/kg). Fasting serum levels of glucose, total cholesterol (TC), low- (LDL-C) and high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), aspartate (AST) and alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were measured at the end of study period. Results: Diabetic rats had significantly elevated levels of serum glucose, LDL-C, TG, AST, ALP and ALT and decreased levels of HDL-C compared to the non-diabetic group (p<0.05). Treatment with either glibenclamide or CM counterbalanced the above-mentioned abnormalities. The effects of CM were comparable to those of glibenclamide at the doses tested in this study. Serum glucose, TG, ALP and HDL concentrations in the normal group were significantly changed compared to the diabetic control group (p<0.05). There were no significant changes in evaluated biochemical parameters between the glibenclamide and CM groups with normal group. Histopathological examinations revealed a less severe hepatic portal inflammation in the CM-treated vs. other study groups. Results: Dietary supplementation with CM fruits effectively prevents the development of diabetes mellitus, dyslipidemia and hepatic inflammation in alloxan-induced diabetes. PMID:24710636

Asgary, Sedigheh; Rafieian-Kopaei, Mahmoud; Shamsi, Fatemeh; Najafi, Somayeh; Sahebkar, Amirhossein

2014-06-01

85

Hypoglycaemic effect of Musa sapientum L. in alloxan-induced diabetic rats.  

PubMed

Musa sapientum L. ('Ney Poovan') commonly known as 'banana' is mainly used in Indian folk medicine for the treatment of diabetes mellitus. Oral administration of 0.15, 0.20 and 0.25 g/kg of chloroform extract of the Musa sapientum flowers (MSFEt) for 30 days resulted in a significant reduction in blood glucose, glycosylated haemoglobin and an increase in total haemoglobin, but in the case of 0.25 g/kg the effect was highly significant. It also prevents decrease in body weight. Oral glucose tolerance test was also performed in experimental diabetic rats in which there was a significant improvement in glucose tolerance in animals treated with MSFEt and the effect was compared with glibenclamide. Thus the study shows that MSFEt has hypoglycaemic action. PMID:10624895

Pari, L; Maheswari, J U

1999-12-15

86

Hypoglycaemic effect of Musa sapientum L. in alloxan-induced diabetic rats  

Microsoft Academic Search

Musa sapientum L. (‘Ney Poovan’) commonly known as ‘banana’ is mainly used in Indian folk medicine for the treatment of diabetes mellitus. Oral administration of 0.15, 0.20 and 0.25 g\\/kg of chloroform extract of the Musa sapientum flowers (MSFEt) for 30 days resulted in a significant reduction in blood glucose, glycosylated haemoglobin and an increase in total haemoglobin, but in

L Pari; J Uma Maheswari

1999-01-01

87

Antidiabetic properties of chromium citrate complex in alloxan-induced diabetic rats  

Microsoft Academic Search

The chromium citrate complex [CrCIT] was synthesized and its structure was determined by infrared, UV–visible and atomic absorption spectroscopy, elemental and thermodynamic analysis. Anti-diabetic activity, oxidative DNA damage capacity and acute oral toxicity of [CrCIT] were investigated and compared with that of chromium trichloride hexahydrate. [CrCIT] was synthesized in a single step reaction by chelating chromium(III) with citric acid in

Fang Li; Xiangyang Wu; Ting Zhao; Min Zhang; Jiangli Zhao; Guanghua Mao; Liuqing Yang

88

Antihyperglycaemic Effect of Tetracarpidium Conophorum Nuts in Alloxan Induced Diabetic Female Albino Rats  

PubMed Central

The antihyperglycaemic activity of Tetracarpidium conophorum nut (walnut) was investigated in albino rats. A total of 20 albino rats were used for the study. The rats were divided into five groups (A–E) of four rats each. Diabetes were induced in the rats except four which served as the positive control group A. Groups B (negative control), C, D, and E contain diabetic rats each with blood sugar level ?17.00?mmol/L. Groups A and B were fed on 85.2?g of top feed grower over the test period. Test groups C, D, and E were fed on 21.3?g, 42.6?g, and 85.2?g of walnuts, respectively, and their fasting blood sugar (FBS) levels were checked on daily basis. Fasting blood glucose levels of the test groups were significantly lower than negative control P < 0.05, for 3rd, 7th, and 10th days of the test. There were also significant increase in the body weight and hemoglobin concentration and a decreased urine output of the test group compared with the controls. These results indicate that Tetracarpidium conophorum nut (walnut) has an antihyperglycemic effect in diabetic rats.

Onwuli, Donatus Onukwufor; Brown, Holy; Ozoani, Harrison Anaezichukwuolu

2014-01-01

89

Effect of 50% Hydro-Ethanolic Leaf Extracts of Ruellia Tuberosa L. and Dipteracanthus Patulus (Jacq.) on Lipid Profile in Alloxan Induced Diabetic Rats  

PubMed Central

Background: The study was undertaken to investigate the effect of 50% hydro -ethanolic leaf extracts of Ruellia tuberosa L. and Dipteracanthus patulus (Jacq.) on lipid profile in alloxan induced diabetic rats. Method: In lipid profile the parameters studied were serum total cholesterol, phospholipids, triglycerides, HDL-c, LDL-c and VLDL-c level. Extracts were orally administered daily for 30 days at a dosage of 250 and 500 mg/kg bodyweight to alloxan induced diabetic rats. Results: The levels of phospholipids, triglycerides, LDL-c and VLDL-c were significantly (P < 0.05) reduced. The HDL-c level was found to be increased in the treatment groups. Total cholesterol level was found to be significantly (P < 0.05) decreased at 500 mg/kg bodyweight of both the plant extracts treated groups. Conclusion: The results further suggests that the effect of plant extract treated groups was found to be lower in reducing the lipid levels in serum when compared to the drug (Glibenclamide 600 ?g/kg body weight) treated group.

Ananthakrishnan, Manikandan; Doss, Victor Arokia

2013-01-01

90

Antihyperglycemic activity of extracts from Boldoa purpurascens leaves in alloxan-induced diabetic rats.  

PubMed

In order to investigate the potential use of Boldoa purpurascens against diabetes, the antihyperglycemic effect of an ethanol extract obtained from its leaves was evaluated at doses of 50, 100 and 200 mg/kg in rats after induction of hyperglycemia by alloxan. Insulin 5 IU/kg was used as positive control and NaCl 0.9% as negative control. A similar experiment was performed with the aqueous extract used at doses of 50 and 100 mg/kg using metformin at a dose of 50mg/kg as positive control. Statistical analysis was carried using the Kruskal-Wallis test with an interval of trust of 99%. The ethanolic and aqueous extract of B. purpurascens showed a significant decrease of blood glucose levels 72 h after administration. Phytochemical analysis of the ethanol extract showed the presence of D-pinitol, a compound known for its hypoglycemic properties. In conclusion, ethanolic as well as aqueous extracts of B. purpurascens leaves show antihyperglycemic activity, possibly due to the presence of D-pinitol and flavonoids. PMID:22807273

González Mosquera, D M; Hernandez Ortega, Y; By, B; Vicet Muro, L; Saucedo Hernandez, Y; Grau Ábalos, R; Dehaen, W; Pieters, L; Apers, S

2013-05-01

91

Effects of hydro-ethanol extract of Citrullus colocynthis on blood glucose levels and pathology of organs in alloxan-induced diabetic rats  

PubMed Central

Objective To evaluated the differential effects of ethanol extraction of Citrullus colocynthis (C. colocynthis) on the blood glucose concentration and pathology of pancreas, liver, lungs, kidney and gastrointestinal tract in the alloxan induced diabetes in rats. Methods Diabetes mellitus was induced in 20 adult female Albino rats, using intraperitoneal injection of 120 mg/kg alloxan. The diabetic rats were randomly assigned into two equal groups. The first group was treated with the extract of C. colocynthis seed (300 mg/kg) and the rats of the second group, as an untreated diabetic group, received ordinary diet. Ten non diabetic rats remained as a normal control group. Results The results of this study indicate that C. colocynthis was able to reduce blood glucose significantly compared with the control diabetic group (P<0.05). Histopathologically, alloxan resulted in severe necrotic changes in the pancreatic islets, especially in the central area of the islets. Tissue sections of the pancreas in the treated rats demonstrated enhanced regeneration of B cells and increased size of pancreatic islets. Liver of the treated diabetic rats revealed significant improvement of the hepatic tissue compared to those of the untreated diabetic rats. Conclusions The present study indicated a significant anti-hyperglycemic effect of C. colocynthis seed and supported its traditional usage in treatment of diabetes mellitus.

Oryan, Ahmad; Hashemnia, Mohammad; Hamidi, Ahmad-Reza; Mohammadalipour, Adel

2014-01-01

92

Hydro-alcoholic extract of the root of Prangos ferulacea (L.) Lindl can improve serum glucose and lipids in alloxan-induced diabetic rats  

PubMed Central

Objectives: Diabetes mellitus manifests itself in a wide variety of complications and the symptoms of this disease are multifactorial. Previous studies proved that this disease is directly related to hyperglycemia and hyperlipidemia. The aim of this study was to investigate the hypoglycemic and hypolipidemic effects of hydroalcoholic extract of Prangos frulacea (L.) Lindl in alloxan-induced diabetic rats. Materials and Methods: Forty female Wistar rats with body weight of 200±20 g were randomly divided into five groups with eight rats per group. Diabetes was induced in rats by alloxan monohydrate at dose of 120 mg/kg body weight (BW) injected intraperitoneally. Hydro-alcoholic extract of the root and leaves with stems of P. frulacea at 100 mg/kg BW were given orally to diabetic rats daily for 4 weeks. Result: Diabetic rats (D) exhibited a significant (p<0.05) increase in the levels of the serum glucose, Total Cholesterol (TC), Triglycerides (TG), and LDL in comparison with the control group whereas their BW and serum HDL levels were decreased. In diabetic rats treated by root extract of P. frulacea, these parameters were reversed to the normal levels compared with diabetic group. Conclusion: According to the results obtained, it was concluded that Root´s hydro-alcoholic extract of P. frulacea can be used in diabetics for the purpose of glucose and lipid profile reduction.

Kafash Farkhad, Najme; Farokhi, Farah; Tukmacki, Amir; Soltani band, Khosro

2012-01-01

93

Effect of aqueous extracts of alligator pear seed (Persea americana mill) on blood glucose and histopathology of pancreas in alloxan-induced diabetic rats.  

PubMed

Effects of aqueous extract of alligator pear seed on normal and alloxan-induced diabetic rats were investigated in 6 groups of rats (5 rats per group). Test groups were made diabetic with intra-peritoneal injection of alloxan and treated with 300 mg and 600 mg/kg body weight of alligator pear seed extract. Two non-diabetic groups were also administered with 300 mg and 600 mg/kg body weight extract. The levels of blood glucose were examined in all 6 experimental groups. In diabetic rats, blood glucose levels were significantly reduced (p<0.05) by 73.26-78.24% on consumption of the extracts, with greater effect exhibited by the 600 mg/kg extract. In normal rats, blood glucose levels were significantly reduced (p<0.05) by 34.68-38.9% on consumption of the seed extract. Histological studies showed a degenerative effect on the pancreatic islet cells of diabetic rats. The result suggested restorative (protective) effect of the extract on pancreatic islet cells. Administration of aqueous extract of alligator pear seed may contribute significantly to the reduction of blood glucose levels and can be useful in the treatment of diabetes. PMID:19553173

Edem, Do; Ekanem, Is; Ebong, Pe

2009-07-01

94

Beneficial effects of the ethanol extract from the dry matter of a culture broth of Inonotus obliquus in submerged culture on the antioxidant defence system and regeneration of pancreatic ?-cells in experimental diabetes in mice  

Microsoft Academic Search

The antihyperglycaemic and antilipidperoxidative effects of the ethanol extract from the dry matter of a culture broth (DMCB) of Inonotus obliquus were investigated in alloxan-induced diabetic mice and the possible mechanism of action was also discussed. In alloxan-induced diabetic mice, treatment with the ethanol extract from DMCB of I. obliquus (30 and 60 mg kg body weight (b.w.) for 21

Hong-Yu Xu; Jun-En Sun; Zhen-Ming Lu; Xiao-Mei Zhang; Wen-Fang Dou; Zheng-Hong Xu

2010-01-01

95

Antidiabetic activity of medium-polar extract from the leaves of Stevia rebaudiana Bert. (Bertoni) on alloxan-induced diabetic rats  

PubMed Central

Objective: To investigate the medicative effects of medium-polar (benzene:acetone, 1:1, v/v) extract of leaves from Stevia rebaudiana (family Asteraceae) on alloxan-induced diabetic rats. Materials and Methods: Diabetes was induced in adult albino Wistar rats by intraperitoneal (i.p.) injection of alloxan (180 mg/kg). Medium-polar extract was administered orally at daily dose of 200 and 400 mg/kg body wt. basis for 10 days. The control group received normal saline (0.9%) for the same duration. Glibenclamide was used as positive control reference drug against Stevia extract. Results: Medium-polar leaf extract of S. rebaudiana (200 and 400 mg/kg) produced a delayed but significant (P < 0.01) decrease in the blood glucose level, without producing condition of hypoglycemia after treatment, together with lesser loss in the body weight as compared with standard positive control drug glibenclamide. Conclusions: Treatment of diabetes with sulfonylurea drugs (glibenclamide) causes hypoglycemia followed by greater reduction in body weight, which are the most worrisome effects of these drugs. Stevia extract was found to antagonize the necrotic action of alloxan and thus had a re-vitalizing effect on ?-cells of pancreas.

Misra, Himanshu; Soni, Manish; Silawat, Narendra; Mehta, Darshana; Mehta, B. K.; Jain, D. C.

2011-01-01

96

Anti-diabetic properties of flavonoid compounds isolated from Hyphaene thebaica epicarp on alloxan induced diabetic rats  

PubMed Central

Background: Diabetes mellitus, becoming the third killer of mankind after cancer and cardiovascular diseases, is one of the most challenging diseases facing health care professionals today. That is why; there has been a growing interest in the therapeutic use of natural products for diabetes, especially those derived from plants. Aim: To evaluate the anti-diabetic activity together with the accompanying biological effects of the fractions and the new natural compounds of Hyphaene thebaica (HT) epicarp. Materials and Methods: 500 g of coarsely powdered of (HT) fruits epicarp were extracted by acetone. The acetone crude extract was fractionated with methanol and ethyl acetate leaving a residual water-soluble fraction WF. The anti-diabetic effects of the WF and one of its compounds of the acetone extract of the (HT) epicarp were investigated in this study using 40 adult male rats. Results: Phytochemical investigation of active WF revealed the presence of ten different flavonoids, among which two new natural compounds luteolin 7-O-[6”-O-?-Lrhamnopyranosyl]-?-D-galactopyranoside 3 and chrysoeriol 7-O-?-D-galactopyranosyl(1?2)-?-L-arabinofuranoside 5 were isolated. Supplementation of the WF improved glucose and insulin tolerance and significantly lowered blood glycosylated hemoglobin levels. On the other hand, compound 5 significantly reduced AST and ALT levels of liver, respectively. Likewise, the kidney functions were improved for both WF and compound 5, whereby both urea and creatinine levels in serum were highly significant Conclusion: The results justify the use of WF and compound 5 of the (HT) epicarp as anti-diabetic agent, taking into consideration that the contents of WF were mainly flavonoids

Salib, Josline Y.; Michael, Helana N.; Eskande, Emad Fawzy

2013-01-01

97

Dietary comparison of conjugated linolenic acid (9 cis , 11 trans , 13 trans ) and ?-tocopherol effects on blood lipids and lipid peroxidation in alloxan-induced diabetes mellitus in rats  

Microsoft Academic Search

The present study investigated the dietary effect of conjugated linolenic acid (CLnA) on lipid profiles and lipid peroxidations\\u000a in alloxan-induced diabetes mellitus in rats. Diabetic rats were fed with 20% sunflower oil (diabetic control), sunflower\\u000a oil supplemented with 0.5% CLnA, sunflower oil supplemented with 0.15% ?-tocopherol, and sunflower oil containing 0.25% CLnA+0.15%\\u000a ?-tocopherol. The results demonstrated that 0.5% CLnA, 0.15%

P. Dhar; D. Bhattacharyya; S. Ghosh

2006-01-01

98

Antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of Punica granatum in alloxan-induced non-insulin-dependent diabetes mellitus albino rats  

PubMed Central

Objectives: Punica granatum L., (Family: Punicaceae) is used in Indian Unani medicine for treatment of diabetes mellitus. Therefore, the present study was done to evaluate the antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of P. granatum in alloxan-induced diabetic rats. Materials and Methods: Healthy Wistar albino rats (100-150 g) were divided into four groups of six animals each. Groups A and B received normal saline [(10 ml/kg/day/per oral (p.o.)]; group C received ethanolic extract of leaves of P. granatum (500 mg/kg/p.o.); and group D received glibenclamide (0.5 mg/kg/day/p.o.). The extracts were given for 1 week in all groups. To induce diabetes, alloxan 150 mg/kg, intraperitoneal (i.p.) single dose was administered to groups B, C, and D. Blood glucose and serum lipids [Total Cholesterol (TC), Triglycerides (TG), Low Density Lipoproteins (LDL), and High Density Lipoproteins (HDL)] and the atherogenic index were estimated after one week. For mechanism of antidiabetic action glycogen estimation on the liver, cardiac and skeletal muscle, and intestinal glucose absorption was done. Results: Group B showed a significant (P<0.01) increase in blood glucose as compared to group A. Groups C and D showed significant decrease (P<0.01) in blood glucose level in comparison to group B. The test drug showed a significant (P<0.01) increase in glycogen content in the liver, cardiac, and skeletal muscle; it significantly (P<0.01) reduced intestinal glucose absorption. Groups C and D showed significant (P<0.01) decrease in serum TC, TG, LDL, and AI as compared to Group B, which showed a significant (P<0.01) increase. Groups C and D showed significant (P<0.01) increase in serum HDL as compared to Group B, which showed a significant (P<0.01) decrease in all values. Conclusion: P. granatum leaves possess significant antidiabetic and antihyperlipidemic activity.

Das, Swarnamoni; Barman, Sarajita

2012-01-01

99

The effect of cadmium on visual evoked potentials in alloxane-induced diabetic rats: relation to lipid peroxidation  

Microsoft Academic Search

Fifty-two healthy male Swiss albino rats, aged three months, were used in this study. They were divided into four groups:\\u000a control (c), diabetic (D), cadmium (Cd), and diabetic + Cd (D+Cd). A diabetic condition was induced in D and D + Cd groups\\u000a by administration of alloxane (5 mg\\/100 g). After this treatment, Cd and D + Cd groups were

P. Yargiço?lu; A. A?ar; M. Edremitlio?lu; Y. O?uz; C. Apaydin

1999-01-01

100

Increased oxidative stress and imbalance in antioxidant enzymes in the brains of alloxan-induced diabetic rats.  

PubMed

Diabetes Mellitus (DM) is associated with pathological changes in the central nervous system (SNC) as well as alterations in oxidative stress. Thus, the main objective of this study was to evaluate the effects of the animal model of diabetes induced by alloxan on memory and oxidative stress. Diabetes was induced in Wistar rats by using a single injection of alloxan (150 mg/kg), and fifteen days after induction, the rats memory was evaluated through the use of the object recognition task. The oxidative stress parameters and the activity of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT) were measured in the rat brain. The results showed that diabetic rats did not have alterations in their recognition memory. However, the results did show that diabetic rats had increases in the levels of superoxide in the prefrontal cortex, and in thiobarbituric acid reactive species (TBARS) production in the prefrontal cortex and in the amygdala in submitochondrial particles. Also, there was an increase in protein oxidation in the hippocampus and striatum, and in TBARS oxidation in the striatum and amygdala. The SOD activity was decreased in diabetic rats in the striatum and amygdala. However, the CAT activity was increased in the hippocampus taken from diabetic rats. In conclusion, our findings illustrate that the animal model of diabetes induced by alloxan did not cause alterations in the animals' recognition memory, but it produced oxidants and an imbalance between SOD and CAT activities, which could contribute to the pathophysiology of diabetes. PMID:22645603

Ceretta, Luciane B; Réus, Gislaine Z; Abelaira, Helena M; Ribeiro, Karine F; Zappellini, Giovanni; Felisbino, Francine F; Steckert, Amanda V; Dal-Pizzol, Felipe; Quevedo, João

2012-01-01

101

Increased Oxidative Stress and Imbalance in Antioxidant Enzymes in the Brains of Alloxan-Induced Diabetic Rats  

PubMed Central

Diabetes Mellitus (DM) is associated with pathological changes in the central nervous system (SNC) as well as alterations in oxidative stress. Thus, the main objective of this study was to evaluate the effects of the animal model of diabetes induced by alloxan on memory and oxidative stress. Diabetes was induced in Wistar rats by using a single injection of alloxan (150?mg/kg), and fifteen days after induction, the rats memory was evaluated through the use of the object recognition task. The oxidative stress parameters and the activity of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT) were measured in the rat brain. The results showed that diabetic rats did not have alterations in their recognition memory. However, the results did show that diabetic rats had increases in the levels of superoxide in the prefrontal cortex, and in thiobarbituric acid reactive species (TBARS) production in the prefrontal cortex and in the amygdala in submitochondrial particles. Also, there was an increase in protein oxidation in the hippocampus and striatum, and in TBARS oxidation in the striatum and amygdala. The SOD activity was decreased in diabetic rats in the striatum and amygdala. However, the CAT activity was increased in the hippocampus taken from diabetic rats. In conclusion, our findings illustrate that the animal model of diabetes induced by alloxan did not cause alterations in the animals' recognition memory, but it produced oxidants and an imbalance between SOD and CAT activities, which could contribute to the pathophysiology of diabetes.

Ceretta, Luciane B.; Reus, Gislaine Z.; Abelaira, Helena M.; Ribeiro, Karine F.; Zappellini, Giovanni; Felisbino, Francine F.; Steckert, Amanda V.; Dal-Pizzol, Felipe; Quevedo, Joao

2012-01-01

102

Acute effect of Bauhinia forficata on serum glucose levels in normal and alloxan-induced diabetic rats  

Microsoft Academic Search

Experimental diabetes was used to study the acute effect of the n-butanol fraction of Bauhinia forficata Link (Leguminosae) (BF) leaves on the serum glucose levels of rats. Body weight was measured on the day of diabetes induction and on the day of the experiment. Levels of glucose were determined at different doses and times following treatment with BF or with

Fátima Regina Mena Barreto Silva; Bruno Szpoganicz; Moacir Geraldo Pizzolatti; Maria Alice Vieira Willrich; Eliandra de Sousa

2002-01-01

103

Comprehensive Evaluation of Anti-hyperglycemic Activity of Fractionated Momordica charantia Seed Extract in Alloxan-Induced Diabetic Rats  

PubMed Central

The present study evaluates anti-hyperglycemic activity of fractionated Momordica charantia (bitter gourd) seed extracts. Fasting blood glucose levels were evaluated before and after administration of different fractions of the seed extract. Among the three fractions tested, fraction Mc-3 (15?mg/kg b.wt.) showed the maximum anti-hyperglycemic activity and reduced blood glucose levels in experimental diabetic rats significantly. The activities of the key regulatory enzymes of glucose metabolism (hexokinase, pyruvate kinase, lactate dehydrogenase, and glucose-6-phosphate dehydrogenase) were determined in Mc-3-treated diabetic animals. Once-daily administration of the fraction Mc-3 for prolonged period of 18 days to the experimental diabetic animals did not result in any nephrotoxicity or hepatotoxicity as evident from insignificant changes in biochemical parameters indicative of liver and kidney functions. Further fractionation of the fraction Mc-3 by size exclusion chromatography resulted in a fraction, designated Mc-3.2, possessing anti-hyperglycemic activity. The fraction Mc-3.2 showed the presence of a predominant protein band of ~11?kDa on SDS-PAGE. Loss in anti-hyperglycemic activity of the Mc-3.2 upon protease treatment indicates the proteinaceous nature of the anti-hyperglycemic principles. Overall, the results suggest that Momordica charantia seeds contain an effective anti-hyperglycemic protein(s) which may find application in treatment of diabetes without evident toxic effects.

Choudhary, Shailesh Kumar; Chhabra, Gagan; Sharma, Dipali; Vashishta, Aruna; Ohri, Sujata; Dixit, Aparna

2012-01-01

104

Comprehensive Evaluation of Anti-hyperglycemic Activity of Fractionated Momordica charantia Seed Extract in Alloxan-Induced Diabetic Rats.  

PubMed

The present study evaluates anti-hyperglycemic activity of fractionated Momordica charantia (bitter gourd) seed extracts. Fasting blood glucose levels were evaluated before and after administration of different fractions of the seed extract. Among the three fractions tested, fraction Mc-3 (15?mg/kg b.wt.) showed the maximum anti-hyperglycemic activity and reduced blood glucose levels in experimental diabetic rats significantly. The activities of the key regulatory enzymes of glucose metabolism (hexokinase, pyruvate kinase, lactate dehydrogenase, and glucose-6-phosphate dehydrogenase) were determined in Mc-3-treated diabetic animals. Once-daily administration of the fraction Mc-3 for prolonged period of 18 days to the experimental diabetic animals did not result in any nephrotoxicity or hepatotoxicity as evident from insignificant changes in biochemical parameters indicative of liver and kidney functions. Further fractionation of the fraction Mc-3 by size exclusion chromatography resulted in a fraction, designated Mc-3.2, possessing anti-hyperglycemic activity. The fraction Mc-3.2 showed the presence of a predominant protein band of ~11?kDa on SDS-PAGE. Loss in anti-hyperglycemic activity of the Mc-3.2 upon protease treatment indicates the proteinaceous nature of the anti-hyperglycemic principles. Overall, the results suggest that Momordica charantia seeds contain an effective anti-hyperglycemic protein(s) which may find application in treatment of diabetes without evident toxic effects. PMID:23320026

Choudhary, Shailesh Kumar; Chhabra, Gagan; Sharma, Dipali; Vashishta, Aruna; Ohri, Sujata; Dixit, Aparna

2012-01-01

105

Hypoglycemic and antioxidant effects of leaf essential oil of Pelargonium graveolens L'H?r. in alloxan induced diabetic rats  

PubMed Central

Background Rose-scented geranium (Pelargonium graveolens L’Hér.), which is used in traditional Tunisian folk medicine for the treatment of hyperglycaemia, is widely known as one of the medicinal herbs with the highest antioxidant activity. The present paper is conducted to test the hypoglycemic and antioxidative activities of the leaf essential oil of P. graveolens. Methods The essential oil P. graveolens was administered daily and orally to the rats at two doses of 75?mg/kg and 150?mg/kg body weight (b.w.) for 30?days. The chemical composition of P. graveolens essential oil, body weight, serum glucose, hepatic glycogen, thiobarbituric acid-reactive substances (TBARS), the components of hepatic, and renal and serum antioxidant systems were evaluated. The hypoglycemic effect of rose-scented geranium was compared to that of the known anti-diabetic drug glibenclamide (600??g/kg b.w.). Results After the administration of two doses of essential oil of Pelargonium graveolens L’Hér. together with glibenclamide which is known by its antidiabetic activities and used as reference (600??g/kg b.w.), for four weeks, the serum glucose significantly decreased and antioxidant perturbations were restored. The hypoglycemic effect of P. graveolens at the dose of 150?mg/kg b.w. was significantly (pdiabetic rats that these beneficial effects of geranium oils were confirmed. Conclusions It suggests that administration of essential oil of P. graveolens may be helpful in the prevention of diabetic complications associated with oxidative stress. Our results, therefore, suggest that the rose-scented geranium could be used as a safe alternative antihyperglycemic drug for diabetic patients.

2012-01-01

106

Antidiabetic activity and phytochemical screening of crude extract of Stevia rebaudiana in alloxan-induced diabetic rats  

PubMed Central

Background: Stevia rebaudiana regulates blood sugar, prevents hypertension and tooth decay. Other studies have shown that it has antibacterial as well as antiviral property. Methods: Preliminary phytochemical screening of aqueous, ether and methanolic extracts of S. rebaudiana was done. Acute and sub-acute toxicity were conducted on twenty four Albino rats, divided into one control (Group I) and three treatment groups viz. aqueous extract (Group II), ether extract (Group III) and methanolic extract (Group IV). For the study of antidiabetic effect of S. rebaudiana rats were divided into seven groups (n=6). Diabetes was induced by a single dose of 5% alloxan monohydrate (125 mg/kg, i.p.) after 24 hour fasting.Blood samples were analysed on day 0, 1, 5, 7, 14 and 28. Results: Phytochemical tests showed presence of different kinds of phyto-constituents in aqueous, ether and methanol extract of Stevia rebaudiana leaves. Daily single dose (2.0 g/kg) administration of aqueous extract (A.E.) , ether extract (E.E.) and methanol extract (M.E.) for 28 days of S. rebaudiana could not show any significant change in ALT and AST levels in rats. Blood sugar level was found to be decreased on day 28 in groups of rats treated with A.E., E.E. and M.E. of S. rebaudiana. Conclusion: The extracts of Stevioside rebaudiana could decrease the blood glucose level in diabetic rats in time dependent manner.

Kujur, R. S.; Singh, Vishakha; Ram, Mahendra; Yadava, Harlokesh Narayan; Singh, K. K.; Kumari, Suruchi; Roy, B. K.

2010-01-01

107

HYPOGLYCEMIC EFFECTS OF FRUIT JUICE OF MURRAYA KOENIGII (L) IN ALLOXAN INDUCED DIABETIC MICE  

Microsoft Academic Search

Oxidative stress has been defined as a disturbance in the balance the production of reactive oxygen species (ROS) and antioxidant defence system, which can lead to tissue injury. Antioxidant level in the tissue is an important factor for sensitivity of individual tissue to oxidative stress. It has been suggested that oxidative stress can play an important role in tissue damage

108

Effect of methanolic extract of Tetrapleura tetraptera (Schum and Thonn) Taub leaves on hyperglycemia and indices of diabetic complications in alloxan-induced diabetic rats  

PubMed Central

Objective To investigate the ameliorative role of Tetrapleura tetraptera (Schum and Thonn) Taub (T. tetraptera) leaf in hyperglycemia with associated conditions like oxidative stress, kidney damage and disorders in lipid metabolism. Methods Five groups of five rats each intraperitoneally received the following treatment schedules for 7 d: untreated normal control, untreated alloxan-diabetic control, diabetic treated with glibenclamide, normal rats treated with extract (50 mg/kg) and diabetic rats treated with the extract. Evaluations were made for fasting blood sugar, body weight changes, malondialdehyde, aspartate aminotransferase, alanine aminotransferase, bilirubin, superoxide dismutase, catalase, lipid profile, packed cell volume, hemoglobin, urea and creatinine in all the rats. Results Whereas the untreated diabetic rats showed a significant decrease (P<0.05) in packed cell volume, superoxide dismutase, catalase and high-density lipoprotein-cholesterol with a concomitant increase in the levels of malondialdehyde, fasting blood sugar, aspartate aminotransferase, alanine aminotransferase, bilirubin, urea and creatinine, administration of methanolic extract of T. tetraptera leaf or glibenclamide alleviated these altered parameters in the treated rats. Conclusions Methanolic extract of T. tetraptera leaves possesses a potent capacity for treatment of diabetes and the accompanying complications, including oxidative stress and hyperlipidemia.

Atawodi, Sunday Ene-Ojo; Yakubu, Ojochenemi Ejeh; Liman, Mubarak Labaran; Iliemene, Dorothy Uju

2014-01-01

109

Effect of a Siraitia grosvenori extract containing mogrosides on the cellular immune system of type 1 diabetes mellitus mice.  

PubMed

The purpose of this study was to observe the islet changes of pancreas in insulin-dependent diabetes mellitus (IDDM) mice in comparison to normal mice after application of an extract from Siraitia grosvenori fruits containing mogrosides, in particular, mogroside V. We hypothesized that mogroside extract (MG) attenuates the severity of alloxan-induced IDDM by effects on the immune system. Our data show that IDDM mice exhibited significant injury to pancreatic islets cells, which were atrophic. In addition, alloxan induced a notable increase in the expression of CD8+ lymphocytes to form a dramatic decrease in CD4+/CD8+ ratio (while CD4+ was unchanged). MG, administered to normal and experimental diabetic mice for 4 wk, effectively attenuated the early clinical symptoms, biochemical abnormalities, and pathological damages in pancreatic islets. Furthermore, at low dose, MG regulated the immune imbalance observed in alloxan-induced IDDM mice by up-regulating the CD4+ T-lymphocyte subsets and CD4/CD8 ratio, and altering the intracellular cytokine profiles. The expression of the pro-inflammatory Th1 cytokines: IFN-gamma, TNF-alpha in splenic lymphocytes was altered toward a beneficial Th2 pattern. MG therapy had no effect on normal mice, except that low dosage MG could up-regulate the IL-4 expression levels. The results revealed that MG exhibited antidiabetic effects presumably due to the presence of mogrosides. PMID:16835866

Xiangyang, Qi; Weijun, Chen; Liegang, Liu; Ping, Yao; Bijun, Xie

2006-08-01

110

D-saccharic acid-1,4-lactone ameliorates alloxan-induced diabetes mellitus and oxidative stress in rats through inhibiting pancreatic beta-cells from apoptosis via mitochondrial dependent pathway  

SciTech Connect

Oxidative stress plays a vital role in diabetic complications. To suppress the oxidative stress mediated damage in diabetic pathophysiology, a special focus has been given on naturally occurring antioxidants present in normal diet. D-saccharic acid 1,4-lactone (DSL), a derivative of D-glucaric acid, is present in many dietary plants and is known for its detoxifying and antioxidant properties. The aim of the present study was to evaluate the beneficial role of DSL against alloxan (ALX) induced diabetes in the pancreas tissue of Swiss albino rats. A dose-dependent study for DSL (20-120 mg/kg body weight) was carried out to find the effective dose of the compound in ALX-induced diabetic rats. ALX exposure elevated the blood glucose, glycosylated Hb, decreased the plasma insulin and disturbed the intra-cellular antioxidant machineries whereas oral administration of DSL at a dose of 80 mg/kg body weight restored these alterations close to normal. Investigating the mechanism of the protective activity of DSL we observed that it prevented the pancreatic {beta}-cell apoptosis via mitochondria-dependent pathway. Results showed decreased mitochondrial membrane potential, enhanced cytochrome c release in the cytosol and reciprocal regulation of Bcl-2 family proteins in the diabetic rats. These events were also found to be associated with increased level of Apaf-1, caspase 9, and caspase 3 that ultimately led to pancreatic {beta}-cell apoptosis. DSL treatment, however, counteracted these changes. In conclusion, DSL possesses the capability of ameliorating the oxidative stress in ALX-induced diabetes and thus could be a promising approach in lessening diabetic complications. Highlights: Black-Right-Pointing-Pointer Oxidative stress is suggested as a key event in the pathogenesis of diabetes. Black-Right-Pointing-Pointer D-saccharic acid 1,4-lactone (DSL) reduces the alloxan-induced diabetes mellitus. Black-Right-Pointing-Pointer DSL normalizes cellular antioxidant machineries disturbed due to alloxan toxicity. Black-Right-Pointing-Pointer DSL inhibits pancreatic {beta}-cells apoptosis via mitochondria-dependent pathway. Black-Right-Pointing-Pointer DSL could be a promising approach for the treatment of diabetes mellitus.

Bhattacharya, Semantee [Department of Life Sciences and Biotechnology, Jadavpur University, 188, Raja S C Mullick Road, Kolkata 700 032 (India)] [Department of Life Sciences and Biotechnology, Jadavpur University, 188, Raja S C Mullick Road, Kolkata 700 032 (India); Manna, Prasenjit [Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054 (India)] [Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054 (India); Gachhui, Ratan [Department of Life Sciences and Biotechnology, Jadavpur University, 188, Raja S C Mullick Road, Kolkata 700 032 (India)] [Department of Life Sciences and Biotechnology, Jadavpur University, 188, Raja S C Mullick Road, Kolkata 700 032 (India); Sil, Parames C., E-mail: parames@bosemain.boseinst.ac.in [Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054 (India)

2011-12-15

111

Beneficial effects of the ethanol extract from the dry matter of a culture broth of Inonotus obliquus in submerged culture on the antioxidant defence system and regeneration of pancreatic beta-cells in experimental diabetes in mice.  

PubMed

The antihyperglycaemic and antilipidperoxidative effects of the ethanol extract from the dry matter of a culture broth (DMCB) of Inonotus obliquus were investigated in alloxan-induced diabetic mice and the possible mechanism of action was also discussed. In alloxan-induced diabetic mice, treatment with the ethanol extract from DMCB of I. obliquus (30 and 60 mg kg(-1) body weight (b.w.) for 21 days) showed a significant decrease in blood glucose level: the percentage reductions on the 7th day were 11.54 and 11.15%, respectively. However, feeding of this drug for three weeks produced reduction of 22.51 and 24.32%. Furthermore, the ethanol extract from the DMCB of I. obliquus treatment significantly decreased serum contents of free fatty acids, total cholesterol, triglycerides and low-density lipoprotein-cholesterol, whereas it effectively increased high-density lipoprotein-cholesterol, insulin levels and hepatic glycogen contents in livers of diabetic mice. Besides this, the ethanol extracts from the DMCB treatment significantly increased catalase, superoxide dismutase and glutathione peroxidase activities, except for decreasing the maleic dialdehyde level in diabetic mice. Histological morphology examination showed that the ethanol extract from the DMCB of I. obliquus restored the damage of pancreatic tissues in mice with diabetes mellitus. The results showed that the ethanol extract from the DMCB of I. obliquus possesses significant antihyperglycaemic, antilipidperoxidative and antioxidant effects in alloxan-induced diabetic mice. PMID:20397104

Xu, Hong-Yu; Sun, Jun-En; Lu, Zhen-Ming; Zhang, Xiao-Mei; Dou, Wen-Fang; Xu, Zheng-Hong

2010-04-01

112

Anti-hyperglycemic and anti-oxidative effect of aqueous extract of Momordica charantia pulp and Trigonella foenum graecum seed in alloxan-induced diabetic rats.  

PubMed

Diabetes is an oxidative stress disorder and oxidative damage to tissues such as heart, kidney, liver and other organs may be a contributory factor to several diabetic complications. Momordica charantia (family: Cucurbitaceae) and Trigonella foenum graecum (family: Fabaceae) are used traditionally in Indian folk medicine to manage diabetes mellitus. In the present study, the anti-hyperglycemic and anti-oxidative potential of aqueous extracts of M. charantia pulp and seed powder of T. foenum graecum were assessed in alloxan (150 mg/kg body weight) induced diabetic rats. Alloxan treatment to the rats could induce diabetes as the fasting blood glucose (FBG) levels were > 280 mg/dl. Treatment of diabetic rats for 30 days with M. charantia and T. foenum graecum could significantly (p < 0.001) improve the FBG levels to near normal glucose levels. Antioxidant activities (superoxide dismutase, catalase, reduced glutathione content and glutathione-s-transferase) and lipid peroxidation levels were measured in heart, kidney and liver tissues of normal, diabetic and experimental animals (diabetics + treatment). TBARS levels were significantly (p < 0.001) higher and anti-oxidative activities were found low in diabetic group, as compared to the control group. Significant (p < 0.001) improvement in both the TBARS levels and antioxidant activities were observed when M. charantia and T. foenum graecum were given to diabetic rats. Our results clearly demonstrate that M. charantia and T. foenum graecum are not only useful in controlling the blood glucose levels, but also have antioxidant potential to protect vital organs such as heart and kidney against damage caused due to diabetes induced oxidative stress. PMID:21174950

Tripathi, Uma Nath; Chandra, Deepak

2010-08-01

113

Taurine exerts hypoglycemic effect in alloxan-induced diabetic rats, improves insulin-mediated glucose transport signaling pathway in heart and ameliorates cardiac oxidative stress and apoptosis  

SciTech Connect

Hyperlipidemia, inflammation and altered antioxidant profiles are the usual complications in diabetes mellitus. In the present study, we investigated the therapeutic potential of taurine in diabetes associated cardiac complications using a rat model. Rats were made diabetic by alloxan (ALX) (single i.p. dose of 120 mg/kg body weight) and left untreated or treated with taurine (1% w/v, orally, in water) for three weeks either from the day of ALX exposure or after the onset of diabetes. Animals were euthanized after three weeks. ALX-induced diabetes decreased body weight, increased glucose level, decreased insulin content, enhanced the levels of cardiac damage markers and altered lipid profile in the plasma. Moreover, it increased oxidative stress (decreased antioxidant enzyme activities and GSH/GSSG ratio, increased xanthine oxidase enzyme activity, lipid peroxidation, protein carbonylation and ROS generation) and enhanced the proinflammatory cytokines levels, activity of myeloperoxidase and nuclear translocation of NF?B in the cardiac tissue of the experimental animals. Taurine treatment could, however, result to a decrease in the elevated blood glucose and proinflammatory cytokine levels, diabetes-evoked oxidative stress, lipid profiles and NF?B translocation. In addition, taurine increased GLUT 4 translocation to the cardiac membrane by enhanced phosphorylation of IR and IRS1 at tyrosine and Akt at serine residue in the heart. Results also suggest that taurine could protect cardiac tissue from ALX induced apoptosis via the regulation of Bcl2 family and caspase 9/3 proteins. Taken together, taurine supplementation in regular diet could play a beneficial role in regulating diabetes and its associated complications in the heart. Highlights: ? Taurine controls blood glucose via protection of pancreatic ? cells in diabetic rat. ? Taurine controls blood glucose via increasing the insulin level in diabetic rat. ? Taurine improves cardiac AKT/GLUT4 signaling pathways in diabetic conditions. ? Taurine exerts antioxidant, antihyperlipidemic and antiinflammatory activities. ? It protects cardiac apoptosis by regulating Bcl2 family and caspase 9/3 proteins.

Das, Joydeep; Vasan, Vandana; Sil, Parames C., E-mail: parames@bosemain.boseinst.ac.in

2012-01-15

114

Evaluation of Mallotus oppositifolius Methanol Leaf Extract on the Glycaemia and Lipid Peroxidation in Alloxan-Induced Diabetic Rats: A Preliminary Study.  

PubMed

Objective. Mallotus oppositifolius (Geiseler) Müll. Arg. (Euphorbiaceae) is folklorically used to "treat" diabetic conditions in some parts of Nigeria therefore the study, to investigate the extract of the leaves for activities on hyperglycaemia, lipid peroxidation, and increased cholesterol levels in vivo in alloxan diabetic rats as well as its potential antioxidant activity in vitro. Methods. Albino rats (240-280?g) were given an injection of 120?mg/kg body weight, i.p. of alloxan monohydrate. After 8 days, diabetic animals with elevated fasting blood glucose levels (>9?mmol/L) were considered and selected for the study. Results. Oral treatment with the extract administered every 12?h by gavage at doses of 100, 200, and 400?mg/kg of the extract to the test rats, for 14 days, resulted in a significant dose-dependent decrease in blood glucose levels from 12.82 ± 1.02?mmol/dL to 4.92 ± 2.01?mmol/dL at the highest dose of 400?mg/kg compared to the control drug and glibenclamide as well as attendant significant decline in diabetic rats employed in the study. Conclusion. The extract also showed in vitro concentration-dependent antioxidant activity following the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and ferric reducing assays. Findings further suggest the presence of active antidiabetic and antioxidant principles in M. oppositifolius leaves. PMID:24224091

Nwaehujor, C O; Ezeigbo, I I; Nwinyi, F C

2013-01-01

115

Evaluation of Mallotus oppositifolius Methanol Leaf Extract on the Glycaemia and Lipid Peroxidation in Alloxan-Induced Diabetic Rats: A Preliminary Study  

PubMed Central

Objective. Mallotus oppositifolius (Geiseler) Müll. Arg. (Euphorbiaceae) is folklorically used to “treat” diabetic conditions in some parts of Nigeria therefore the study, to investigate the extract of the leaves for activities on hyperglycaemia, lipid peroxidation, and increased cholesterol levels in vivo in alloxan diabetic rats as well as its potential antioxidant activity in vitro. Methods. Albino rats (240–280?g) were given an injection of 120?mg/kg body weight, i.p. of alloxan monohydrate. After 8 days, diabetic animals with elevated fasting blood glucose levels (>9?mmol/L) were considered and selected for the study. Results. Oral treatment with the extract administered every 12?h by gavage at doses of 100, 200, and 400?mg/kg of the extract to the test rats, for 14 days, resulted in a significant dose-dependent decrease in blood glucose levels from 12.82 ± 1.02?mmol/dL to 4.92 ± 2.01?mmol/dL at the highest dose of 400?mg/kg compared to the control drug and glibenclamide as well as attendant significant decline in diabetic rats employed in the study. Conclusion. The extract also showed in vitro concentration-dependent antioxidant activity following the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and ferric reducing assays. Findings further suggest the presence of active antidiabetic and antioxidant principles in M. oppositifolius leaves.

Nwaehujor, C. O.; Ezeigbo, I. I.; Nwinyi, F. C.

2013-01-01

116

Effect of methanolic extract of Musa sapientum leaves on gastrointestinal transit time in normal and alloxan induced diabetic rats: possible mechanism of action.  

PubMed

Disorders of gastrointestinal motility have been associated with diabetes mellitus. Hyperglycaemia particularly has been reported to inhibit gastrointestinal transit time while glibenclamide, a sulphonylurea and insulin, both increased transit time. Musa sapientum has also been reported as an antidiabetic agent but there is dearth of information on the effect of this plant on gastrointestinal motility. This study was therefore carried out to investigate the effect of methanolic extract of Musa sapientum leaves (MEMSL) on gastrointestinal transit time (GITT) in male albino rats with and without hyperglycaemia and to elucidate possible mechanism by which this extract functions. Fifty five albino rats were divided into 11 groups of five animals each. All animals were fasted for 24hrs before the begining of the experiment. Group 1 served as control; while the remaining groups (2 - 11) were treated with 250mg/kg; 500mg/kg MEMSL; diabetic control; diabetic treated with 250mg/kg; 500mg/kg MEMSL; diabetic treated with glibenclamide (5mg/kg); normal rats treated with nifedipine (50mg/kg); normal rats treated with calcium chloride (CaCl2) only (10mg/kg); groups 10 and 11 were both pretreated with CaCl2 and subsequently treated with 250mg/kg and 500mg/kg MEMSL respectively. All plant extracts used for treatments were dissolved in normal saline and administered orally using orogastric tube. Charcoal meal was used as marker in the estimation of GITT. The study showed significant decrease in GITT in the normal rats treated with 250mg/kg and 500mg/kg of extract. However, in the diabetic rats treated with 500mg/kg MEMSL, there was significant increase in GITT and this is comparable with the gut response to glibenclamide (5mg/kg). Musa sapientum extract produced significant decrease in transit time in the calcium chloride pre-treated normal rats and this is comparable to the effect observed in Nifedipine treated group. The significant reduction in GITT produced by MEMSL in the normal rats reflects a strong possibility of MEMSL acting as calcium channel antagonist through the voltage gated calcium channel which may be due to the presence of alkaloids, saponins, cardenolides. There is the possibility of the extract acting as an inhibitor of potassium channel at higher concentration as observed in glibenclamide treated groups. PMID:22314993

Adewoye, E O; Ige, A O; Latona, C T

2011-06-01

117

Hypoglycemic effect of methanol extract of Phyllanthus amarus Schum & Thonn on alloxan induced diabetes mellitus in rats and its relation with antioxidant potential.  

PubMed

Methanolic extract of P. amarus was found to have potential anti-oxidant activity as it could inhibit lipid peroxidation, and scavenge hydroxyl and superoxide radicals in vitro. The amount required for 50% inhibition of lipid peroxide formation was 104 microg/ml and the concentrations needed to scavenge hydroxyl and superoxide radicals were 117 and 19 microg/ml respectively. The extract was found to reduce the blood sugar in alloxan diabetic rats at 4th hr by 6% at a dose level of 200 mg/kg body wt and 18.7% at a concentration of 1000 mg/kg body wt. Continued administration of the extract for 15 days produced significant (P < 0.001) reduction in blood sugar. On 18th day after alloxan administration values were almost similar to normal in the group taking 1000 mg/kg body wt. PMID:12597020

Raphael, K Regi; Sabu, M C; Kuttan, Ramadasan

2002-08-01

118

Protective and curative effects of Cocos nucifera inflorescence on alloxan-induced pancreatic cytotoxicity in rats  

PubMed Central

Objectives: This study was planned to investigate the effects of pre and post-treatment of young inflorescence of Cocos nucifera (CnI) on alloxan-induced diabetic rats. Materials and Methods: Male albino Sprague Dawely rats were divided into five groups of six animals each. Group I was normal control, Group II was diabetic control, Cocos nucifera Inflorescence (CnI) was fed along with diet [20% (w/w)] orally (Group III) for a period of 11 days prior to alloxan injection (150 mg/kg i.p.). The curative effect of CnI was evaluated at the same feeding levels in alloxan-induced diabetic rats (Group IV) for a period of 30 days. The effects of both pretreatment and post-treatment (Group V) were also evaluated. Biochemical parameters such serum glucose, hepatic glycogen, and enzymes involving carbohydrate metabolism (hexokinase, phosphoglucomutase, pyruvate kinase, glucose-6-phosphatase, fructose 1, 6-diphosphatase, glucose-6 phosphate dehydrogenase, and glycogen phosphorylase) were assayed along with pancreatic histopathology. Data were analyzed using one-way analysis of variance followed by Duncan's post hoc multiple variance test. P < 0.05 was considered statistical significant. Results: Diabetic control rats showed significant increase in serum glucose (P < 0.05) and decrease in hepatic glycogen levels (P < 0.05) compared to normal rats, which was reversed to near normal in both CnI pretreated and post-treated rats. Treatment with CnI resulted in significant decrease (P < 0.05) in activities of gluconeogenic enzymes in Group III and IV on compared to the diabetic control group, while glycolytic enzyme activities were improved in these groups. The cytotoxicity of pancreatic islets also ameliorated by treatment with CnI on histopathological examination. Conclusion: The results obtained in the study indicate the protective and curative effects of CnI on alloxan-induced pancreatic cytotoxicity, which is mediated through the regulation of carbohydrate metabolic enzyme activities and islets cell repair.

Renjith, Raveendran S.; Rajamohan, Thankappan

2012-01-01

119

Diabetes attenuates the inhibitory effects of endomorphin-2, but not endomorphin-1 on gastrointestinal transit in mice.  

PubMed

Diabetes affects the entire gastrointestinal tract from the esophagus to the anus. In the present study, the charcoal meal test was undertaken to evaluate and compare the effects of intracerebroventricular (i.c.v.) administration of endomorphins (EMs) on gastrointestinal transit in non-diabetic and diabetic mice. Significantly delayed gastrointestinal transit was found in both 4 and 8 weeks alloxan-induced diabetes compared to non-diabetes. Moreover, i.c.v. EM-1 and EM-2 dose-dependently delayed gastrointestinal transit in non-diabetes and diabetes. The EM-1-induced inhibitory effects of gastrointestinal transit in 4 weeks diabetes were qualitatively similar to those of non-diabetes. However, at higher doses, the EM-1-induced effects in 8 weeks diabetes were largely enhanced. Different to EM-1, the EM-2-induced inhibition of gastrointestinal transit in diabetic mice was significantly attenuated compared to non-diabetic mice. Moreover, these effects were further decreased in 8 weeks diabetes. The delayed gastrointestinal transit effects caused by EM-1 may be primarily mediated by ?2-opioid receptor in both non-diabetes and 4 weeks diabetes. Interestingly, in 8 weeks diabetes, these effects were mediated by ?2- and ?-receptors. However, the inhibitory effects of EM-2 were mediated by ?1-opioid receptor, which exerted a reduced function in diabetes. Also, poor blood glucose control might result in the attenuated effects of EM-2. Our present results demonstrated that diabetes attenuates the inhibitory effects of EM-2, but not EM-1 on gastrointestinal transit in mice. The different effects of EM-1 and EM-2 on gastrointestinal transit in diabetes may be due to changes of opioid receptor subtypes and their functional responses. PMID:24876054

Wang, Chang-Lin; Diao, Yu-Xiang; Xiang, Qiong; Ren, Yu-Kun; Gu, Ning

2014-09-01

120

Protective role of D-saccharic acid-1,4-lactone in alloxan induced oxidative stress in the spleen tissue of diabetic rats is mediated by suppressing mitochondria dependent apoptotic pathway.  

PubMed

The present study investigated the role of D-saccharic acid 1,4-lactone (DSL) in the spleen tissue of alloxan (ALX) induced diabetic rats. Diabetes was induced in rats by injecting ALX (at a dose of 120 mg/kg body weight) intraperitoneally in sterile normal saline. Elevated levels of blood glucose, glycosylated Hb and TNF? decreased levels of plasma insulin and disturbed intra-cellular antioxidant machineries were detected in ALX exposed animals. Oral administration of DSL at a dose of 80 mg/kg body weight, however, restored these alterations in diabetic rats. Studies on the mechanism of ALX-induced diabetes showed that hyperglycemia caused disruption of mitochondrial membrane potential in the spleen, released cytochrome C in the cytosol, activated caspase 3 and ultimately led to apoptotic cell death. Results suggest that DSL possesses the ability of protecting the spleen tissue from ALX-induced hyperglycemia and thus could act as an anti-diabetic agent in lessening diabetes associated spleen dysfunction. PMID:22239106

Rashid, Kahkashan; Bhattacharya, Semantee; Sil, Parames C

2012-03-01

121

D-saccharic acid-1,4-lactone ameliorates alloxan-induced diabetes mellitus and oxidative stress in rats through inhibiting pancreatic ?-cells from apoptosis via mitochondrial dependent pathway.  

PubMed

Oxidative stress plays a vital role in diabetic complications. To suppress the oxidative stress mediated damage in diabetic pathophysiology, a special focus has been given on naturally occurring antioxidants present in normal diet. D-saccharic acid 1,4-lactone (DSL), a derivative of D-glucaric acid, is present in many dietary plants and is known for its detoxifying and antioxidant properties. The aim of the present study was to evaluate the beneficial role of DSL against alloxan (ALX) induced diabetes in the pancreas tissue of Swiss albino rats. A dose-dependent study for DSL (20-120 mg/kg body weight) was carried out to find the effective dose of the compound in ALX-induced diabetic rats. ALX exposure elevated the blood glucose, glycosylated Hb, decreased the plasma insulin and disturbed the intra-cellular antioxidant machineries whereas oral administration of DSL at a dose of 80 mg/kg body weight restored these alterations close to normal. Investigating the mechanism of the protective activity of DSL we observed that it prevented the pancreatic ?-cell apoptosis via mitochondria-dependent pathway. Results showed decreased mitochondrial membrane potential, enhanced cytochrome c release in the cytosol and reciprocal regulation of Bcl-2 family proteins in the diabetic rats. These events were also found to be associated with increased level of Apaf-1, caspase 9, and caspase 3 that ultimately led to pancreatic ?-cell apoptosis. DSL treatment, however, counteracted these changes. In conclusion, DSL possesses the capability of ameliorating the oxidative stress in ALX-induced diabetes and thus could be a promising approach in lessening diabetic complications. PMID:21982801

Bhattacharya, Semantee; Manna, Prasenjit; Gachhui, Ratan; Sil, Parames C

2011-12-01

122

Possible signaling cascades involved in attenuation of alloxan-induced oxidative stress and hyperglycemia in mice by ethanolic extract of Syzygium jambolanum: Drug-DNA interaction with calf thymus DNA as target  

Microsoft Academic Search

We injected alloxan (100mg\\/kgb.w.) in mice (Mus musculus) intra-peritoneally to induce hyperglycemia and divided the hyperglycemic mice into two sub-groups: one was fed ethanolic extract of Syzygium jambolanum (EESJ) (20mg\\/kgb.w. for 8weeks) and the other 85% ethyl alcohol (“vehicle”-control). Chromatographic and mass spectroscopic studies of EESJ revealed two principal components, one corresponding to an iridoid glycoside. We estimated blood glucose,

Asmita Samadder; Debrup Chakraborty; Arnab De; Soumya Sundar Bhattacharyya; Kakali Bhadra; Anisur Rahman Khuda-Bukhsh

2011-01-01

123

Diabetic state-induced modifications of succinyl-choline binding mode in the microsomal fractions of mouse skeletal muscles  

SciTech Connect

The skeletal muscles of alloxan-induced diabetic mice and genetically diabetic KK-CA/sup Y/ mice are hypersensitive to a depolarizing blocker, succinylcholine (SuCh) but not to the competitive antagonist, d-tubocurarine (d-TC). The mechanism by which the action of the depolarizing blocker is modified in the diabetic state was investigated on the binding of /sup 14/C-SuCh to the microsomal fraction isolated from mouse skeletal muscles. The Scatchard plot of microsomal preparations from normal ddY mice showed positive cooperativity in SuCh binding, whereas that of the preparations from alloxan-induced diabetic mice as well as genetically diabetic KK-CA/sup Y/ mice lost the positive cooperative interactions. The dissociation constant (K/sub d/) of high affinity site in diabetic muscles was significantly lower than that in non-diabetic ddY muscle. The microsomal fractions from denervated muscles of normal ddY mice maintained weakly positive cooperativity in SuCh binding, and the affinity of SuCh binding in denervated muscles was lower than that of non-denervated muscles. 17 references, 2 figures, 1 table.

Kimura, M.; Kimura, I.; Fujihara, M.; Hoshino, N.

1988-01-01

124

Antihyperglycemic and antioxidant activity of water extract from Anoectochilus roxburghii in experimental diabetes.  

PubMed

The hypoglycemic and antioxidant effects of the water extract from Anoectochilus roxburghii in alloxan-induced diabetic mice were examined. Compared with untreated diabetic mice, the daily oral administration of the water extract from A. roxburghii at 0.5 or 2 g/kg for 14 days caused a significant decrease (p<.05) in blood glucose levels with similar effect but no evidence of dose-related effect. Simultaneously, the alteration in lipid metabolism was partially attenuated as evidenced by decreased serum total cholesterol and triglyceride levels and by increased high-density lipoprotein cholesterol concentration in diabetic mice (p<.05) but no dose-related effect was observed. In addition, the water extract from A. roxburghii caused a significant increase (p<.05) in the activities of enzymic antioxidants and the levels of vitamin E in liver and kidney of diabetic mice. Our results suggest that water extract from A. roxburghii possesses hypoglycemic and antioxidant properties after oral administration to mice showing alloxan-induced diabetes. PMID:22440113

Cui, Shi-Chao; Yu, Jie; Zhang, Xiao-Hui; Cheng, Mei-Zhen; Yang, La-Wei; Xu, Jing-Yan

2013-07-01

125

The medicinal cracked-cap polypore mushroom Phellinus rimosus (higher Basidiomycetes) attenuates alloxan-induced hyperglycemia and oxidative stress in rats.  

PubMed

Diabetes is usually associated with increased production of reactive oxygen species (ROS), impaired antioxidant defense systems, or both, which result in oxidative damage and lead to ROS-mediated diabetic pathogenesis. This investigation was undertaken to evaluate the role of extract from the wood-inhabiting polypore medicinal mushroom Phellinus rimosus in an alloxan-induced diabetic model and the oral glucose tolerance test in rats. Oral administration of extract at doses of 50 and 250 mg/kg body weight/day for 10 days to rats with alloxan-induced diabetes was found to possess significant dose-dependent hypoglycemic activity. In the oral glucose tolerance test, hypoglycemic effect of P. rimosus (250 mg/kg) was significant (P < 0.01) and maximum at 90 minutes after the glucose challenge when compared with that of control group. The effect of extract on antioxidant status in the pancreas, liver, and kidney was estimated. The diabetic control rats exhibited elevated levels of lipid peroxidation and lower activities of copper/zinc superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) content in pancreatic, hepatic, and renal tissues compared with normal tissues. The activities of SOD, CAT, GPx, and GSH were found to be increased in diabetic rats treated with the extract. The increased level of lipid peroxidation in diabetic rats also was found to revert to near-normal status in groups treated with the extract. The findings thus suggest the therapeutic efficiency of Ph. Rimosus against declined antioxidant status as well as hyperglycemia associated with diabetes. PMID:23662616

Rony, Kuttikkadan A; Ajith, Thekkuttuparambil A; Mathew, John; Janardhanan, Kainoor K

2013-01-01

126

The protective effect of vanadium against diabetic cataracts in diabetic rat model.  

PubMed

The present study was designed to investigate the effect of vanadium in alloxan-induced diabetes and cataract in rats. Different doses of vanadium was administered once daily for 8 weeks to alloxan-induced diabetic rats. To know the mechanism of action of vanadium, lens malondialdehyde (MDA), protein carbonyl content, activity of superoxide dismutase (SOD), activities of aldose reductase (AR), and sorbitol levels were assayed, respectively. Supplementation of vanadium to alloxan-induced diabetic rats decreased the blood glucose levels due to hyperglycemia, inhibited the AR activity, and delayed cataract progression in a dose-dependent manner. The observed beneficial effects may be attributed to polyol pathway activation but not decreased oxidative stress. Overall, the results of this study demonstrate that vanadium could effectively reduce the alloxan-induced hyperglycemia and diabetic cataracts in rats. PMID:24604151

Sun, Lei; Shi, De-Jing; Gao, Xiang-Chun; Mi, Shu-Yong; Yu, Ying; Han, Qing

2014-05-01

127

In vitro and in vivo protective effect of Ganoderma lucidum polysaccharides on alloxan-induced pancreatic islets damage  

Microsoft Academic Search

This study was undertaken to investigate the protective effect against alloxan-induced pancreatic islets damage by Ganoderma lucidum Polysaccharides (Gl-PS) isolated from the fruiting body of Ganoderma lucidum (Leyss. ex Fr.) Karst. In vitro, alloxan caused dose-dependent toxicity on the isolated pancreatic islets. Pre-treatment of islets with Gl-PS for 12 h and 24 h significantly reversed alloxan-induced islets viability loss. Gl-PS

Hui-Na Zhang; Jing-Hua He; Lan Yuan; Zhi-Bin Lin

2003-01-01

128

Scientists Reverse Type 1 Diabetes in Mice  

MedlinePLUS

... this page, please enable JavaScript. Scientists Reverse Type 1 Diabetes in Mice Finding might lead one day to new ways to treat humans with ... June 16, 2014 Related MedlinePlus Page Diabetes Type 1 SATURDAY, June 14, 2014 (HealthDay News) -- Scientists who ...

129

Ghrelin reverses experimental diabetic neuropathy in mice  

SciTech Connect

Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. We investigated the pharmacological potential of ghrelin in the treatment of polyneuropathy in uncontrolled streptozotocin (STZ)-induced diabetes in mice. Ghrelin or desacyl-ghrelin was administered daily for 4 weeks after STZ-induced diabetic polyneuropathy had developed. Ghrelin administration did not alter food intake, body weight gain, blood glucose levels, or plasma insulin levels when compared with mice given saline or desacyl-ghrelin administration. Ghrelin administration ameliorated reductions in motor and sensory nerve conduction velocities in diabetic mice and normalized their temperature sensation and plasma concentrations of 8-isoprostaglandin {alpha}, an oxidative stress marker. Desacyl-ghrelin failed to have any effect. Ghrelin administration in a mouse model of diabetes ameliorated polyneuropathy. Thus, ghrelin's effects represent a novel therapeutic paradigm for the treatment of this otherwise intractable disorder.

Kyoraku, Itaru; Shiomi, Kazutaka [Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan)] [Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan); Kangawa, Kenji [Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565 (Japan)] [Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565 (Japan); Nakazato, Masamitsu, E-mail: nakazato@med.miyazaki-u.ac.jp [Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan)] [Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan)

2009-11-20

130

Rapamycin selectively alters serum chemistry in diabetic mice  

PubMed Central

The study was undertaken to explore the effect of rapamycin, an anti-inflammatory agent, on the metabolic profile of type 2 diabetic mice. Seven-month-old diabetic db/db mice and their lean littermate non-diabetic controls (db/m) were randomized to receive control chow or chow mixed with rapamycin (2.24 mg/kg/day) (each group n =20, males and females) for 4 months and sacrificed. Serum samples were analyzed for the measurement of glucose, creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), alanine aminotransferase (ALT), total cholesterol, total triglyceride, and total protein, using the automated dry chemistry analysis. Rapamycin elevated serum glucose in female diabetic mice. Serum creatinine tended to be higher in diabetic mice but was not affected by rapamycin; there was no difference in BUN levels among the groups. Serum ALP was elevated in diabetic mice and rapamycin lowered it only in female diabetic mice; serum ALT levels were increased in female diabetic mice, unaffected by rapamycin. Serum total protein was elevated in diabetic mice of both genders but was not affected by rapamycin. Diabetic mice from both genders had elevated serum cholesterol and triglycerides; rapamycin did not affect serum cholesterol but decreased serum total triglycerides in male diabetic mice. We conclude that rapamycin elicits complex metabolic responses in aging diabetic mice, worsening hyperglycemia in females but improving ALP in female diabetic and total triglycerides in male diabetic mice, respectively. The metabolic effects of rapamycin should be considered while performing studies with rapamycin in mice.

Tabatabai-Mir, Hooman; Sataranatarajan, Kavithalakshmi; Lee, Hak Joo; Bokov, Alex F.; Fernandez, Elizabeth; Diaz, Vivian; Choudhury, Goutam Ghosh; Richardson, Arlan; Kasinath, Balakuntalam S.

2012-01-01

131

Diabetic nephropathy: of mice and men.  

PubMed

Accumulating evidence supports intrinsic genetic susceptibility as an important variable in the progression of diabetic nephropathy in people. Mice provide an experimental platform of unparalleled power for dissecting the genetics of mammalian diseases; however, phenotypic analysis of diabetic mice lags behind that already established for humans. Standardized benchmarks of hyperglycemia, albuminuria, and measurements of renal failure remain to be developed for different inbred strains of mice. The most glaring deficiency has been the lack of a diabetic mouse model that develops progressively worsening renal insufficiency, the sine qua non of diabetic nephropathy in humans. Differences in susceptibility of these inbred strains to complications of diabetes mellitus provide a possible avenue to dissect the genetic basis of diabetic nephropathy; however, the identification of those strains and/or mutants most susceptible to renal injury from diabetes mellitus is lacking. Identification of a mouse model that faithfully mirrors the pathogenesis of DN in humans will undoubtedly facilitate the development of new diagnostic and therapeutic interventions. PMID:15822049

Breyer, Matthew D; Böttinger, Erwin; Brosius, Frank C; Coffman, Thomas M; Fogo, Agnes; Harris, Raymond C; Heilig, Charles W; Sharma, Kumar

2005-04-01

132

Decorin deficiency enhances progressive nephropathy in diabetic mice.  

PubMed

Decorin, a proteoglycan that inhibits active transforming growth factor-beta, is increased in diabetic nephropathy; however, its functional significance is unclear. In this study, we used low-dose streptozotocin to induce type 1 diabetes in wild-type (C57BL/6J Dcn(+/+)), Dcn(-/-), and Dcn(+/-) mice and studied the mice for up to 1 year of diabetes. Decorin gene dose had no effect on severity of diabetes; however, the Dcn(-/-) diabetic mice died significantly earlier than nondiabetic controls (57 versus 7.3% mortality). In contrast to wild-type diabetic mice, which failed to develop significant nephropathy, the Dcn(-/-) diabetic mice developed a significant increase in albuminuria and plasma creatinine and a concurrent decrease in circulating adiponectin levels. Interestingly, adiponectin levels at 6 months of diabetes were predictive of mortality in diabetic mice. Dcn(-/-) diabetic mice exhibited advanced glomerular lesions, including diffuse mesangial matrix accumulation and fibrin cap formation. By immunohistochemistry, Dcn(-/-) diabetic mice exhibited significant increases in glomerular transforming growth factor-beta, type I collagen, macrophage infiltration, and Nox4. We conclude that decorin is a natural protective factor against diabetic nephropathy and that the Dcn(-/-) diabetic mouse is a useful new model of progressive diabetic nephropathy. PMID:17884968

Williams, Kevin Jon; Qiu, Gang; Usui, Hitomi Katoaka; Dunn, Stephen R; McCue, Peter; Bottinger, Erwin; Iozzo, Renato V; Sharma, Kumar

2007-11-01

133

A new tactic to treat postprandial hyperlipidemia in diabetic rats with gastroparesis by improving gastrointestinal transit  

Microsoft Academic Search

Improvement of gastrointestinal transit was thought to be a new tactic to treat postprandial hypertriglyceridemia in diabetic individuals with gastroparesis. Diabetic gastroparesis, lipid load testing, and the effect of domperidone or aqueous extract of rhizomes of Rheum palmatum L. on postprandial hypertriglyceridemia were evaluated in alloxan-induced diabetic rats. Alloxan diabetic animals had a slow gastrointestinal transit, together with delayed and

Weidong Xie; Dongming Xing; Yunan Zhao; Hui Su; Zhen Meng; Yunyun Chen; Lijun Du

2005-01-01

134

Subacute antidiabetic and in vivo antioxidant effects of methanolic extract of Bridelia micrantha (Hochst Baill) leaf on alloxan-induced hyperglycaemic rats.  

PubMed

Abstract The methanolic leaf extract of Bridelia micrantha was tested for subacute antidiabetic and in vivo antioxidant effects in alloxan-induced hyperglycaemic rats. The subacute treatment of the extract (125, 250 and 500 mg/kg) produced 75, 68 and 63% reduction in fasting blood sugar level respectively, on day 14 of treatment. The extract produced time-dependent effect, but did not show a dose-dependent effect. Its optimum antidiabetic activity was noted at the dose of 125 mg/kg and this was comparable to glibenclamide 2 mg/kg (positive control). The extract (125 mg/kg) showed good oral glucose tolerance test (OGTT) effect in both normoglycaemic and hyperglycaemic rats. The OGTT effect of the extract (125 mg/kg) did not differ significantly (p>0.05) from glibenclamide (2 mg/kg). The antioxidant effect of the extract was assayed through the determination of the level of thiobarbituric acid reactive substance (TBARS) and catalase activity. The extract produced a dose-dependent decrease in the serum level of TBARS and gave its optimum catalase activity at the dose of 500 mg/kg. This study suggests that the B. micrantha extract has antihyperglycaemic and antioxidant activities. Therefore, could be a potential source of novel antidiabetic and antioxidant agent for the management of diabetes mellitus. PMID:24760763

Omeh, Yusuf Ndukaku; Onoja, Samuel Okwudili; Ezeja, Maxwell Ikechukwu; Okwor, Peace Obiageli

2014-06-01

135

Therapeutic Impact of Leptin on Diabetes, Diabetic Complications, and Longevity in Insulin-Deficient Diabetic Mice  

PubMed Central

OBJECTIVE The aim of the current study was to evaluate the long-term effects of leptin on glucose metabolism, diabetes complications, and life span in an insulin-dependent diabetes model, the Akita mouse. RESEARCH DESIGN AND METHODS We cross-mated Akita mice with leptin-expressing transgenic (LepTg) mice to produce Akita mice with physiological hyperleptinemia (LepTg:Akita). Metabolic parameters were monitored for 10 months. Pair-fed studies and glucose and insulin tolerance tests were performed. The pancreata and kidneys were analyzed histologically. The plasma levels and pancreatic contents of insulin and glucagon, the plasma levels of lipids and a marker of oxidative stress, and urinary albumin excretion were measured. Survival rates were calculated. RESULTS Akita mice began to exhibit severe hyperglycemia and hyperphagia as early as weaning. LepTg:Akita mice exhibited normoglycemia after an extended fast even at 10 months of age. The 6-h fasting blood glucose levels in LepTg:Akita mice remained about half the level of Akita mice throughout the study. Food intake in LepTg:Akita mice was suppressed to a level comparable to that in WT mice, but pair feeding did not affect blood glucose levels in Akita mice. LepTg:Akita mice maintained insulin hypersensitivity and displayed better glucose tolerance than did Akita mice throughout the follow-up. LepTg:Akita mice had normal levels of plasma glucagon, a marker of oxidative stress, and urinary albumin excretion rates. All of the LepTg:Akita mice survived for >12 months, the median mortality time of Akita mice. CONCLUSIONS These results indicate that leptin is therapeutically useful in the long-term treatment of insulin-deficient diabetes.

Naito, Masaki; Fujikura, Junji; Ebihara, Ken; Miyanaga, Fumiko; Yokoi, Hideki; Kusakabe, Toru; Yamamoto, Yuji; Son, Cheol; Mukoyama, Masashi; Hosoda, Kiminori; Nakao, Kazuwa

2011-01-01

136

WITHDRAWN: Evaluation of antidiabetic effect of embelin from Embelia ribes in alloxan induced diabetes in rats.  

PubMed

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.bionut.2010.08.002. The duplicate article has therefore been withdrawn. PMID:20863647

Mahendran, S; Badami, S; Maithili, V

2010-09-21

137

Antihyperglycemic Activity of Chromium(III) Malate Complex in Alloxan-Induced Diabetic Rats  

Microsoft Academic Search

The synthesis, characterization, anti-hyperglycemic activity, oxidative DNA damage capacity, and acute toxicity of chromium(III)\\u000a malate complex [Cr2(LMA)3] were described. [Cr2(LMA)3] was synthesized in a single-step reaction by chelating chromium(III) with L-malic acid in aqueous solution. Based on elemental\\u000a analysis, thermodynamic analysis, and spectroscopy studies, the molecular formula of [Cr2(LMA)3] was inferred as Cr2(C4H4O5)3·5H2O. Daily treatment with 2.85–17.10 mg\\/kg body mass of

Xiang-Yang Wu; Fang Li; Wei-Dong Xu; Jiang-Li Zhao; Ting Zhao; Ling-Hong Liang; Liu-Qing Yang

138

Neonatal pancreas transplantation and liver enzyme activities in diabetic mice.  

PubMed

The aim of this study was to estimate the influence of transplantation of neonatal pancreas from singenic donors on glucose production and utilisation in alloxan diabetic mice. The alloxan diabetic mice, 20 days after alloxan, received neonatal pancreas from singenic donors under the kidney capsule. Enzymes involved in glycolytic, gluconeogenic, lipogenic and pentose phosphate pathway were examined in liver of experimental mice. The fructose-1, 6-diphosphatase (FDPase) activity in the liver of diabetics increased for about 60%, while the pyruvate inase (PK) and ATP-citrate lyase (CEE) activity decreased for about 40% of the values in the healthy mice. The values of glucose-6-phosphate dehydrogenase (G6P-DH) and 6-phosphogluconate dehydrogenase (6-PGDH) were not statistically different in diabetic liver compared with the liver off healthy animals. After pancreas transplantation some of diabetic animals become normoglycaemic, while the others remained hyperglycaemic. The FDPase activity in hyperglycaemic diabetic recipients was similar to those in diabetic mice that did not received transplant, while in normoglycaemic recipients the FDPase activity returned to the normal values. However, the activities of PK and CCE in hyperglycaemic recipients were similar to those in healthy animals, while in normogglycaemic recipients the enzyme activities were much higher. Results obtained showed that glycolytic, gluconeogenic and lipogenic enzyme activities in the liver of normoglycaemic mice that received pancreas transplant reached approximate the physiological values within 30 days after transplantation. PMID:10664326

Novak Mirceti?, R; Slijepcevi?, M; Cetkovi?-Cvrlje, M; Svetina, A

1999-12-01

139

Enhanced anti-diabetic activity of a combination of chromium(III) malate complex and propolis and its acute oral toxicity evaluation.  

PubMed

In order to obtain the additional benefit of anti-diabetic activity and protective effects of liver injury for diabetes, the anti-diabetic effect and acute oral toxicity of a combination of chromium(III) malate complex (Cr(2)(LMA)(3)) and propolis were assessed. The anti-diabetic activity of the combination of the Cr(2)LMA(3) and propolis was compared with Cr(2)(LMA)(3) and propolis alone in alloxan-induced diabetic mice by daily oral gavage for a period of 2 weeks. Acute oral toxicity of the combination of the Cr(2)LMA(3) and propolis was tested using ICR mice at the dose of 1.0-5.0 g/kg body mass by a single oral gavage and observed for a period of 2 weeks. The results of the anti-diabetic activity of the combination from the aspects of blood glucose level, liver glycogen level, and the activities of aspartate transaminase, alanine transaminase, and alkaline phosphatase indicated that the increased anti-diabetic activity and the protective efficacy of liver injury for diabetes were observed. In acute toxicity study, LD(50) (median lethal dose) value for the combination was greater than 5.0 g/kg body mass. The combination of Cr(2)LMA(3) and propolis might represent the nutritional supplement with potential therapeutic value to control blood glucose and exhibit protective efficacy of liver injury for diabetes and non-toxicity in acute toxicity. PMID:22322882

Wu, Xiang-Yang; Li, Fang; Zhao, Ting; Mao, Guang-Hua; Li, Jing; Qu, Hong-Yuan; Ren, Yue-Na; Yang, Liu-Qing

2012-07-01

140

Decreased thyroidal response to thyrotropin in diabetic mice  

Microsoft Academic Search

The effect of diabetes mellitus on the synthesis and secretion of thyroid hormone ws investigated in mice with streptozotocin-induced diabetes. Thyroid glands were labeled in vivo with 131I for 2 h. In control animals, TSH stimulated the synthesis of PB127I and 131I-labeled iodothyronines and simultaneously decreased the proportion of 131I-. These effects of TSH were not observed in diabetic animals

N. Bagchi; T. R. Brown; B. Shivers; S. Lucas; R. E. Mack

1981-01-01

141

Quercetin vs chrysin: effect on liver histopathology in diabetic mice.  

PubMed

Effects of flavonoids quercetin and chrysin on lipid peroxidation and histopathological changes in liver of diabetic mice were studied and compared with the antioxidant and reducing ability of quercetin and chrysin and their ability to chelate Fe(2+) ions in vitro. Diabetes was induced in Swiss albino mice with a single intravenous injection of alloxan (75 mg kg(-1)). Two days after alloxan injection, flavonoid preparations (50 mg kg(-1) per day) were given intraperitoneally for 7 days in diabetic mice. The lipid peroxidation was evaluated by measuring the malondialdehyde production using the 2-thiobarbituric acid test. Administration of quercetin and chrysin to diabetic mice resulted in a significant decrease in lipid peroxidation level in liver tissue. Treatment of diabetic mice with flavonoids solutions results in decreased number of vacuolated cells and degree of vacuolization of the liver tissue. The protective role of flavonoids against the reactive oxygen species-induced damages in diabetic mice gives a hope that they may exert similar protective action in humans. PMID:23357962

Sirovina, D; Orsoli?, N; Konci?, M Z; Kovacevi?, G; Benkovi?, V; Gregorovi?, G

2013-10-01

142

B lymphocytes not required for progression from insulitis to diabetes in non-obese diabetic mice.  

PubMed

Previous studies have implicated B lymphocytes in the pathogenesis of diabetes in the non-obese diabetic (NOD) mouse. While it is clear that B lymphocytes are necessary, it has not been clear at which stage of disease they play a role; early, late or both. To clarify when B lymphocytes are needed, T lymphocytes were transferred from 5-week-old NOD female mice to age-matched NOD/severe combined immunodeficiency (SCID) recipient mice. NOD/SCID mice, which lack functionally mature T and B lymphocytes, do not normally develop insulitis or insulin-dependent diabetes melitus (IDDM). The NOD/SCID mice that received purified T lymphocytes from 5-week-old NOD mice subsequently developed insulitis and diabetes even though they did not have detectable B lymphocytes. This suggests that while B lymphocytes may be essential for an initial priming event they are not requisite for disease progression in the NOD mouse. PMID:11903619

Charlton, B; Zhang, M D; Slattery, R M

2001-12-01

143

The Islet Estrogen Receptor-? Is Induced by Hyperglycemia and Protects Against Oxidative Stress-Induced Insulin-Deficient Diabetes  

PubMed Central

The female steroid, 17?-estradiol (E2), is important for pancreatic ?-cell function and acts via at least three estrogen receptors (ER), ER?, ER?, and the G-protein coupled ER (GPER). Using a pancreas-specific ER? knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PER?KO?/?), we previously reported that islet ER? suppresses islet glucolipotoxicity and prevents ?-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ER? to prevent ?-cell apoptosis in vivo. However, the contribution of the islet ER? to ?-cell survival in vivo, without the contribution of ER? in other tissues is still unclear. Using the PER?KO?/? mouse, we show that ER? mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ER? elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PER?KO?/? mice exhibited a predisposition to ?-cell destruction and insulin deficient diabetes. In male PER?KO?/? mice, exposure to E2 partially prevented alloxan-induced ?-cell destruction and diabetes. ER? mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ER? mRNA by hyperglycemia was retained in insulin receptor-deficient ?-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ER? expression acts to naturally protect ?-cells against oxidative injury.

Kilic, Gamze; Alvarez-Mercado, Ana I.; Zarrouki, Bader; Opland, Darren; Liew, Chong Wee; Alonso, Laura C.; Myers, Martin G.; Jonas, Jean-Christophe; Poitout, Vincent; Kulkarni, Rohit N.; Mauvais-Jarvis, Franck

2014-01-01

144

The islet estrogen receptor-? is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes.  

PubMed

The female steroid, 17?-estradiol (E2), is important for pancreatic ?-cell function and acts via at least three estrogen receptors (ER), ER?, ER?, and the G-protein coupled ER (GPER). Using a pancreas-specific ER? knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PER?KO ?/?), we previously reported that islet ER? suppresses islet glucolipotoxicity and prevents ?-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ER? to prevent ?-cell apoptosis in vivo. However, the contribution of the islet ER? to ?-cell survival in vivo, without the contribution of ER? in other tissues is still unclear. Using the PER?KO ?/? mouse, we show that ER? mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ER? elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PER?KO ?/? mice exhibited a predisposition to ?-cell destruction and insulin deficient diabetes. In male PER?KO ?/? mice, exposure to E2 partially prevented alloxan-induced ?-cell destruction and diabetes. ER? mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ER? mRNA by hyperglycemia was retained in insulin receptor-deficient ?-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ER? expression acts to naturally protect ?-cells against oxidative injury. PMID:24498408

Kilic, Gamze; Alvarez-Mercado, Ana I; Zarrouki, Bader; Opland, Darren; Liew, Chong Wee; Alonso, Laura C; Myers, Martin G; Jonas, Jean-Christophe; Poitout, Vincent; Kulkarni, Rohit N; Mauvais-Jarvis, Franck

2014-01-01

145

Diabetes Adversely Affects Macrophages During Atherosclerotic Plaque Regression in Mice  

PubMed Central

OBJECTIVE Patients with diabetes have increased cardiovascular risk. Atherosclerosis in these patients is often associated with increased plaque macrophages and dyslipidemia. We hypothesized that diabetic atherosclerosis involves processes that impair favorable effects of lipid reduction on plaque macrophages. RESEARCH DESIGN AND METHODS Reversa mice are LDL receptor–deficient mice that develop atherosclerosis. Their elevated plasma LDL levels are lowered after conditional knockout of the gene encoding microsomal triglyceride transfer protein. We examined the morphologic and molecular changes in atherosclerotic plaques in control and streptozotocin-induced diabetic Reversa mice after LDL lowering. Bone marrow–derived macrophages were also used to study changes mediated by hyperglycemia. RESULTS Reversa mice were fed a western diet for 16 weeks to develop plaques (baseline). Four weeks after lipid normalization, control (nondiabetic) mice had reduced plasma cholesterol (?77%), plaque cholesterol (?53%), and plaque cells positive for macrophage marker CD68+ (?73%), but increased plaque collagen (+116%) compared with baseline mice. Diabetic mice had similarly reduced plasma cholesterol, but collagen content increased by only 34% compared with baseline; compared with control mice, there were lower reductions in plaque cholesterol (?30%) and CD68+ cells (?41%). Diabetic (vs. control) plaque CD68+ cells also exhibited more oxidant stress and inflammatory gene expression and less polarization toward the anti-inflammatory M2 macrophage state. Many of the findings in vivo were recapitulated by hyperglycemia in mouse bone marrow–derived macrophages. CONCLUSIONS Diabetes hindered plaque regression in atherosclerotic mice (based on CD68+ plaque content) and favorable changes in plaque macrophage characteristics after the reduction of elevated plasma LDL.

Parathath, Saj; Grauer, Lisa; Huang, Li-Shin; Sanson, Marie; Distel, Emilie; Goldberg, Ira J.; Fisher, Edward A.

2011-01-01

146

Experimental diabetes in neonatal mice induces early peripheral sensorimotor neuropathy.  

PubMed

Animal models of diabetes do not reach the severity of human diabetic neuropathy but relatively mild neurophysiological deficits and minor morphometric changes. The lack of degenerative neuropathy in diabetic rodent models seems to be a consequence of the shorter length of the axons or the shorter animal life span. Diabetes-induced demyelination needs many weeks or even months before it can be evident by morphometrical analysis. In mice myelination of the peripheral nervous system starts at the prenatal period and it is complete several days after birth. Here we induced experimental diabetes to neonatal mice and we evaluated its effect on the peripheral nerve 4 and 8weeks after diabetes induction. Neurophysiological values showed a decline in sensory nerve conduction velocity at both time-points. Morphometrical analysis of the tibial nerve demonstrated a decrease in the number of myelinated fibers, fiber size and myelin thickness at both time-points studied. Moreover, aldose reductase and poly(ADP-ribose) polymerase activities were increased even if the amount of the enzyme was not affected. Thus, type 1 diabetes in newborn mice induces early peripheral neuropathy and may be a good model to assay pharmacological or gene therapy strategies to treat diabetic neuropathy. PMID:24846610

Ariza, L; Pagès, G; García-Lareu, B; Cobianchi, S; Otaegui, P J; Ruberte, J; Chillón, M; Navarro, X; Bosch, A

2014-08-22

147

GSK3 INHIBITION PREVENTS LEARNING DEFICITS IN DIABETIC MICE  

PubMed Central

There is an increasing awareness that diabetes has an impact on the central nervous system, with reports of impaired learning, memory and mental flexibility being more common in diabetic subjects than in the general population. Insulin-deficient diabetic mice also display learning deficits associated with defective insulin-signaling in the brain and increased activity of GSK3. In the present study, AR-A014418, a GSK3? inhibitor and TX14(A), a neurotrophic factor with GSK3 inhibitory properties, were tested against the development of learning deficits in mice with insulin-deficient diabetes. Treatments were started at onset of diabetes and continued for 10 weeks. Treatment with AR-A014418 or TX14(A) prevented the development of learning deficits, assessed by the Barnes maze, while only AR-A014418 prevented memory deficits, as assessed by the object recognition test. Diabetes-induced increased levels of amyloid beta protein and phosphorylated tau were not significantly affected by the treatments. However the diabetes-induced decrease in synaptophysin, a presynaptic protein marker of hippocampal plasticity, was partially prevented by both treatments. These results suggest a role for GSK3 and/or reduced neurotrophic support in the development of cognitive deficits in diabetic mice that are associated with synaptic damage.

King, Matthew R.; Anderson, Nicholas J.; Guernsey, Lucie S.; Jolivalt, Corinne G.

2012-01-01

148

Anti-diabetic effects of electrolyzed reduced water in streptozotocin-induced and genetic diabetic mice.  

PubMed

Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic beta-cell dysfunction found in diabetes. Both an increase in reactive oxygen free radical species (ROS) and a decrease in the antioxidant defense mechanism lead to the increase in oxidative stress in diabetes. Electrolyzed reduced water (ERW) with ROS scavenging ability may have a potential effect on diabetic animals, a model for high oxidative stress. Therefore, the present study examined the possible anti-diabetic effect of ERW in two different diabetic animal models. The genetically diabetic mouse strain C57BL/6J-db/db (db/db) and streptozotocin (STZ)-induced diabetic mouse were used as insulin deficient type 1 and insulin resistant type 2 animal model, respectively. ERW, provided as a drinking water, significantly reduced the blood glucose concentration and improved glucose tolerance in both animal models. However, ERW fail to affect blood insulin levels in STZ-diabetic mice whereas blood insulin level was markedly increased in genetically diabetic db/db mice. This improved blood glucose control could result from enhanced insulin sensitivity, as well as increased insulin release. The present data suggest that ERW may function as an orally effective anti-diabetic agent and merit further studies on its precise mechanism. PMID:16945392

Kim, Mi-Ja; Kim, Hye Kyung

2006-11-10

149

Suppression of Diabetes in Nonobese Diabetic Mice by Oral Administration of Porcine Insulin  

Microsoft Academic Search

Nonobese diabetic (NOD) mice spontaneously develop an autoimmune form of diabetes associated with insulitis. A number of immunomodulatory therapies have been investigated as a treatment for the disease process. Oral administration of the autoantigens myelin basic protein and collagen type II suppresses experimental models of encephalomyelitis and arthritis. We have now found that oral administration of insulin delays the onset

Z. Jenny Zhang; Laurie Davidson; George Eisenbarth; Howard L. Weiner

1991-01-01

150

Circulatory and Renal Consequences of Pregnancy in Diabetic NOD Mice  

PubMed Central

Objectives Women with diabetes have elevated gestational risks for severe hemodynamic complications, including preeclampsia in mid- to late pregnancy. This study employed continuous, chronic radiotelemetry to compare the hemodynamic patterns in non-obese diabetic (NOD) mice who were overtly diabetic or normoglycemic throughout gestation. We hypothesized that overtly diabetic, pregnant NOD mice would develop gestational hypertension and provide understanding of mechanisms in progression of this pathology. Study Design Telemeter-implanted, age-matched NOD females with and without diabetes were assessed for six hemodynamic parameters (mean, systolic, diastolic, pulse pressures, heart rate and activity) prior to mating, over pregnancy and over a 72 hr post-partum interval. Urinalysis, serum biochemistry and renal histopathology were also conducted. Results Pregnant, normoglycemic NOD mice had a hemodynamic profile similar to other inbred strains, despite insulitis. This pattern was characterized by an interval of pre-implantation stability, post implantation decline in arterial pressure to mid gestation, and then a rebound to pre-pregnancy baseline during later gestation. Overtly diabetic NOD mice had a blood pressure profile that was normal until mid-gestation then become mildly hypotensive (?7mmHg, P<0.05), severely bradycardic (?80bpm, P<0.01) and showed signs of acute kidney injury. Pups born to diabetic dams were viable but growth restricted, despite their mothers’ failing health, which did not rebound post-partum (?10% pre-pregnancy pressure and HR, P<0.05). Conclusions Pregnancy accelerates circulatory and renal pathologies in overtly diabetic NOD mice and is characterized by depressed arterial pressure from mid-gestation and birth of growth 45 restricted offspring.

Burke, S.D.; Barrette, V.F.; David, S.; Khankin, E. V.; Adams, M.A.; Croy, B.A.

2011-01-01

151

Dimethyl sulfoxide modulation of diabetes onset in NOD mice.  

PubMed

Dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, is known as an immunosuppressive agent and can reduce autoantibody levels in experimental autoimmune diseases. Because classic diabetogens damage the DNA and membrane of the beta-cell by the generation of free radicals, the purpose of these investigations was to determine whether the intake of DMSO or its derivatives methylsulfonylmethane (MSM) and dimethylsulfide (DMS) could prevent the expression of autoimmune diabetes in the spontaneously diabetic NOD mouse. DMSO (2.5%), MSM (2.5%), and DMS (0.25%) were added to the drinking water of female NOD mice immediately after weaning. Control animals were maintained on regular drinking water. The presence of overt diabetes was monitored from the age of 2 mo by weekly urinary glucose testing until the animals either became overtly glucosuric or were greater than 240 days of age. In contrast to what we expected, DMSO (2.5%) markedly increased the rate at which the animals expressed overt diabetes (P less than .0004, log-rank test). MSM had no effect, whereas DMS reduced the incidence and rate of diabetes onset. When DMSO (2.5%) was administered to male NOD mice and control strains of mice (BALB/c and ICR), the control group did not develop glucosuria or insipidus, whereas DMSO increased the incidence of diabetes in the male NOD mice from 21 to 79%. In contrast, when DMSO was fed to female NOD mice on a purified AIN-76 diet, diabetes onset was reduced to 36%. We conclude that DMSO accelerates the uptake of dietary diabetogens into the beta-cell of genetically susceptible animals (NOD mice). The protective effect of the purified diet in such animals may be due to a lack of putative diabetogens in purified diet, or alternatively, the diet itself contains factor(s) that protect the beta-cell from autoimmune attack and/or destruction. PMID:2914623

Klandorf, H; Chirra, A R; DeGruccio, A; Girman, D J

1989-02-01

152

RhoB Loss Prevents Streptozotocin-Induced Diabetes and Ameliorates Diabetic Complications in Mice  

PubMed Central

RhoB is an early-response gene whose expression is elevated by multiple cellular stresses; this gene plays an important role in cancer, macrophage motility, and apoptosis. These factors are essential for the onset of type 1 diabetes mellitus and related complications. This study explores the role of RhoB in ?-cell depletion and hyperglycemia-associated complications and tests whether the pleiotropic effect of statins on glycemic control is RhoB dependent. We induced ?-cell depletion in RhoB+/+, RhoB+/?, and RhoB?/? mice with streptozotocin (STZ). Diabetic status was assessed by glucose tolerance and pancreatic islet loss. RhoB?/? mice showed a significant reduction in the severity of STZ-induced diabetes; only 13% of the STZ-treated RhoB-null animals became hyperglycemic, as opposed to 61% of the wild-type controls. Diabetes-related complications, such as wound healing rate and onset of nephropathy, were also assessed. Hyperglycemic RhoB?/? mice had fewer signs of nephropathy and showed faster wound healing than RhoB+/+ animals. After assessing the diabetic status of mice treated simultaneously with STZ and simvastatin, we conclude that the effect of statins in improving glycemic control is RhoB independent. We propose that RhoB is a modifier of diabetes, important for the induction of ?-cell loss. Suppression of RhoB expression may have potential application in the treatment of diabetes and associated complications.

Bravo-Nuevo, Arturo; Sugimoto, Hikaru; Iyer, Seema; Fallon, Zachary; Lucas, Jason M.; Kazerounian, Shiva; Prendergast, George C.; Kalluri, Raghu; Shapiro, Nathan I.; Benjamin, Laura E.

2011-01-01

153

Anti-diabetic effects of CTB-APSL fusion protein in type 2 diabetic mice.  

PubMed

To determine whether cholera toxin B subunit and active peptide from shark liver (CTB-APSL) fusion protein plays a role in treatment of type 2 diabetic mice, the CTB-APSL gene was cloned and expressed in silkworm (Bombyx mori) baculovirus expression vector system (BEVS), then the fusion protein was orally administrated at a dose of 100 mg/kg for five weeks in diabetic mice. The results demonstrated that the oral administration of CTB-APSL fusion protein can effectively reduce the levels of both fasting blood glucose (FBG) and glycosylated hemoglobin (GHb), promote insulin secretion and improve insulin resistance, significantly improve lipid metabolism, reduce triglycerides (TG), total cholesterol (TC) and low density lipoprotein (LDL) levels and increase high density lipoprotein (HDL) levels, as well as effectively improve the inflammatory response of type 2 diabetic mice through the reduction of the levels of inflammatory cytokines tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6). Histopathology shows that the fusion protein can significantly repair damaged pancreatic tissue in type 2 diabetic mice, significantly improve hepatic steatosis and hepatic cell cloudy swelling, reduce the content of lipid droplets in type 2 diabetic mice, effectively inhibit renal interstitial inflammatory cells invasion and improve renal tubular epithelial cell nucleus pyknosis, thus providing an experimental basis for the development of a new type of oral therapy for type 2 diabetes. PMID:24633252

Liu, Yunlong; Gao, Zhangzhao; Guo, Qingtuo; Wang, Tao; Lu, Conger; Chen, Ying; Sheng, Qing; Chen, Jian; Nie, Zuoming; Zhang, Yaozhou; Wu, Wutong; Lv, Zhengbing; Shu, Jianhong

2014-03-01

154

The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice  

PubMed Central

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon ?–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Ansari, Mohammed Javeed I.; Salama, Alan D.; Chitnis, Tanuja; Smith, R. Neal; Yagita, Hideo; Akiba, Hisaya; Yamazaki, Tomohide; Azuma, Miyuki; Iwai, Hideyuki; Khoury, Samia J.; Auchincloss, Hugh; Sayegh, Mohamed H.

2003-01-01

155

Inhibition of diabetes in NOD mice by human pregnancy factor  

Microsoft Academic Search

Clinical symptoms of Th1 mediated autoimmune diseases regress in many patients during pregnancy. A prominent feature of pregnancy is the presence of human chorionic gonadotrophin hormone (hCG) in blood and urine. In this report we tested the effect of clinical grade hCG (c-hCG) on the development of diabetes, a Th1 mediated autoimmune disease, in nonobese diabetic (NOD) mice. We show

Nisar A Khan; Afshan Khan; Huub F. J Savelkoul; Robbert Benner

2001-01-01

156

High density insulin receptor-positive T lymphocytes from nonobese diabetic mice transfer insulitis and diabetes.  

PubMed

In the nonobese diabetic mouse, insulin-dependent diabetes is an autoimmune disease characterized by T cell-mediated invasion and destruction of pancreatic islet beta cells. The importance of insulin receptor (IR) expression in the pathogenesis of diabetes was examined, since it has been shown that the IR is a chemotactic receptor capable of directing cell movement in response to insulin. Using polyclonal antisera to the IR, phenotypic analysis of purified splenic T cells from diabetic mice showed that about 15% of T cells expressed high density IR (IRhigh). In addition, IRhigh T cells were already a dominant phenotype in the insulitis of young prediabetic mice. To determine the ability of IRhigh T cells to transfer diabetes, cells were sorted by flow cytometry before adoptive transfer into young (6- to 8-wk-old) nondiabetic irradiated nonobese mice. Transfer of as few as 3 x 10(6) purified IRhigh T cells alone resulted in rapid onset of insulitis and diabetes, and IRhigh-depleted T cells were essentially unable to passage either insulitis or diabetes. The adoptive transfer of disease was not due to the transfer of activated cells, since removal of IL-2R+ or transferrin R+ cells did not alter diabetes transfer. Therefore, IRhigh T cells are aggressively diabetogenic, suggesting that increased IR expression may provide a mechanism for delivering potentially autoreactive T cells to the islet, regardless of their activation state. PMID:8871675

McInerney, M F; Flynn, J C; Goldblatt, P J; Najjar, S M; Sherwin, R S; Janeway, C A

1996-10-15

157

Skin wound healing in diabetic ss6 integrin deficient mice  

PubMed Central

Integrin ?v?6 is a heterodimeric cell surface receptor which is absent from normal epithelium, but expressed in wound-edge keratinocytes during re-epithelialization. However, the function of the ?v?6 integrin in wound repair remains unclear. Impaired wound healing in patients with diabetes constitutes a major clinical problem worldwide and has been associated with accumulation of advanced glycated endproducts (AGEs) in the tissues. AGEs may account for aberrant interactions between integrin receptors and their extracellular matrix ligands such as fibronectin (FN). In this study, we compared healing of experimental excisional skin wounds in wild-type (WT) and ?6-knockout (?6-/-) mice with streptozotocin (STZ)-induced diabetes. Results showed that diabetic ?6-/- mice had significant delay in early wound closure rate as compared to diabetic WT mice, suggesting that the ?v?6 integrin may serve as a protective role in re-epithelialization of diabetic wounds. To mimic glycosylated wound matrix, we generated a methylglyoxal (MG)-glycated variant of FN. Keratinocytes utilized ?v?6 and ß1 integrins for spreading on both nonglycated and MG-FN, but their spreading was reduced on MG-FN. These findings indicated that glycation of FN and possibly other integrin ligands could hamper keratinocyte interactions with the provisional matrix proteins during re-epithelialization of diabetic wounds.

Jacobsen, Jasper N.; Steffensen, Bj?rn; Hakkinen, Lari; Krogfelt, Karen A.; Larjava, Hannu S.

2010-01-01

158

Protective Effect of Enicostemma littorale Blume on Rat Model of Diabetic Neuropathy  

Microsoft Academic Search

Problem statement: Poor glycemic control and oxidative stress is impl icated as a common pathway in the development of diabetic neuropathy. Approach: In the present study, we investigated the protective effects of Enicostemma littorale Blume (EL) (2.5 g kg -1 ), a hypoglycemic and antioxidant herbal medicine in alloxan-induced diab etic neuropathy in male Charles foster rats. Results: Tail flick

Niraj Mukundray Bhatt; Suparna Barua; Sarita Gupta

2009-01-01

159

Some toxicological studies of Momordica charantia L. on albino rats in normal and alloxan diabetic rats.  

PubMed

Momordica charantia L. (MC) (Cucurbitaceae) commonly known as balsam pear, bitter gourd or karela, used in several purposes in traditional medicine is an important medicinal plant. Two sets of experiments were carried out, the first experiment indicated that the LD(50) for MC juice and alcoholic extracts were 91.9 and 362.34 mg/100g b.wt., respectively, of subcutaneously "s.c." injected mice. The toxic signs were recorded within the first 24 h post-injection. The second experiment was performed to evaluate the effect of MC juice and alcoholic extracts on blood glucose and other biochemical parameters in normal and diabetic rats. Both extracts induced a significant decrease in serum glucose levels in normal and diabetic rats. The two extracts did not show any significant effect in urea, creatinine, ALT, AST and AP in normal rat, while in diabetic rats the two extracts caused a significant decrease in serum urea, creatinine, ALT, AST, AP, cholesterol and triglyceride levels. Also, these results suggested that MC extracts possesses anti-diabetic, hepato-renal protective and hypolipidemic effect in alloxan-induced diabetic rats. Thus, MC is alternative therapy that has primarily been used for lowering blood glucose levels in patients with diabetes mellitus. PMID:16815658

Abd El Sattar El Batran, Seham; El-Gengaihi, Souad E; El Shabrawy, Osama A

2006-11-24

160

Can garlic oil ameliorate diabetes-induced oxidative stress in a rat liver model? A correlated histological and biochemical study.  

PubMed

This study aimed to characterise the structural changes in liver of an alloxan-induced diabetic rat and to explain such changes in terms of the biochemical changes in free radicals and antioxidants. In addition, it aimed to determine the potential ability of garlic oil to alter these changes. The study groups were: control (n=12), alloxan-induced diabetic rats (n=10) and alloxan-induced diabetic rats treated with garlic oil (10 mg/kg body weight (n=10)). Markers of oxidative stress were assessed. Small pieces of the liver were processed for transmission electron microscopic study. Garlic oil caused a significant decrease in levels of LPO in plasma (0.26 vs 0.53), erythrocyte lysate (14.4 vs 24.8) and liver tissue homogenate (1.04 vs 2.08), whereas those of thiols were significantly elevated (1.2 vs 0.46), (24 vs 15) in plasma and erythrocyte lysate respectively. SOD activity and G-S-T activity were significantly elevated in erythrocyte lysate (5.7 vs 3.3) (377 vs 179) and liver homogenate (1.4 vs 0.5) (752 vs 623) respectively after garlic oil administration. Ultrastructural study of the liver confirmed the ability of garlic to retard lipid peroxidation of cellular membranes induced by oxidative stress associated with diabetes. Therefore, garlic could normalise oxidative stress in alloxan-induced diabetic rats. PMID:23856496

Abdultawab, Hanem Saad; Ayuob, Nasra N

2013-09-01

161

Arginase II Deletion Increases Corpora Cavernosa Relaxation in Diabetic Mice  

PubMed Central

Introduction Diabetes-induced erectile dysfunction involves elevated arginase (Arg) activity and expression. Because nitric oxide (NO) synthase and Arg share and compete for their substrate L-arginine, NO production is likely linked to regulation of Arg. Arg is highly expressed and implicated in erectile dysfunction. Aim It was hypothesized that Arg-II isoform deletion enhances relaxation function of corpora cavernosal (CC) smooth muscle in a streptozotocin (STZ) diabetic model. Methods Eight weeks after STZ-induced diabetes, vascular functional studies, Arg activity assay, and protein expression levels of Arg and constitutive NOS (using western blots) were assessed in CC tissues from non-diabetic wild type (WT), diabetic (D) WT (WT+D), Arg-II knockout (KO) and Arg-II KO+D mice (N=8–10 per group). Main Outcome Measures Inhibition or lack of arginase results in facilitation of CC relaxation in diabetic CC. Results Strips of CC from Arg-II KO mice exhibited an enhanced maximum endothelium-dependent relaxation (from 70+3% to 84+4%) and increased nitrergic relaxation (by 55%, 71%, 42%, 42%, and 24% for 1, 2, 4, 8 and 16 Hz, respectively) compared to WT mice. WT+D mice showed a significant reduction of endothelium-dependent maximum relaxation (44+8%), but this impairment of relaxation was significantly prevented in Arg-II KO+D mice (69+4%). Sympathetic-mediated and alpha-adrenergic agent-induced contractile responses also were increased in CC strips from D compared to non-D controls. Contractile responses were significantly lower in Arg-II KO control and D versus the WT groups. WT+D mice increased Arg activity (1.5-fold) and Arg-II protein expression and decreased total and phospho-eNOS at Ser-1177, and nNOS levels. These alterations were not seen in Arg-II KO mice. Additionally, the Arg inhibitor BEC (50 ?M) enhanced nitrergic and endothelium-dependent relaxation in CC of WT+D mice. Conclusion These studies show for the first time that Arg-II deletion improves CC relaxation in type 1 diabetes.

Toque, Haroldo; Tostes, Rita; Yao, Lin; Xu, Zhimin; Webb, Clinton R.; Caldwell, Ruth; Caldwell, Robert

2010-01-01

162

Oral administration of Eucalyptus globulus extract reduces the alloxan-induced oxidative stress in rats.  

PubMed

In light of evidence that some complications of diabetes mellitus may be caused or exacerbated by an oxidative stress, the putative protective effect of Eucalyptus globulus, a medicinal plant, was investigated in alloxan-diabetic rats. E. globulus extract was given in drinking water for 15 days at a daily dose equivalent to 130 mg dry leaves/kg of body weight. Lipids peroxidation level and activities of catalase, superoxide-dismutase and glutathione peroxidase were then measured in liver and kidney. Under our experimental conditions, eucalyptus extract was found to significantly reduce the blood glucose level in diabetic animals but failed to restore the liver glycogen level, whereas insulin lowered blood glucose and restored liver glycogen to high concentration. Our results suggest that the antihyperglycemic action of eucalyptus extract is not exerted via the stimulation of insulin secretion but rather unveil a proper effect of the extract involving the enhancement of peripheral glucose uptake. In addition, eucalyptus extract appears to exert an antioxidative activity demonstrated (1) by the increase of catalase, superoxide-dismutase and gluthatione-peroxidase activities in liver and kidney, and (2) a lowering of lipids peroxidation level in these organs. In conclusion, the present study indicates that extract of E. globulus, administered per os, could be used with some profit in diabetic patients. PMID:19540215

Ahlem, Soussi; Khaled, Hamden; Wafa, Marouane; Sofiane, Bezzine; Mohamed, Damak; Jean-Claude, Murat; Abdelfattah, El Feki

2009-09-14

163

Influence of experimental type 1 diabetes on the pulmonary effects of diesel exhaust particles in mice.  

PubMed

Epidemiologically, exposure to particulate air pollution is associated with increases in morbidity and mortality, and diabetics are especially vulnerable to effects of particles. This study was carried out to determine the respiratory effect of diesel exhaust particles (DEP; 0.4mg/kg) on mice rendered diabetic by the injection of streptozotocin or vehicle (control). Four weeks following induction of diabetes, the animals were intratracheally instilled (i.t.) with DEP (0.4mg/kg) or saline. 24h later, the measurement of airway reactivity to methacholine in vivo by a forced oscillation technique showed a significant and dose-dependent increase in airway resistance in non-diabetic mice exposed to DEP versus non-diabetic mice exposed to saline. Similarly, the airway resistance was significantly increased in diabetic mice exposed to DEP versus diabetic mice exposed to saline. Nevertheless, there was no difference in the airway resistance between diabetic and non-diabetic mice after i.t. administration of DEP. Following DEP administration there were neutrophil polymorphs infiltration of pulmonary interalveolar septae and the alveolar spaces with many macrophages containing DEP in both diabetic and non-diabetic mice. Interestingly, apoptotic cells were only found in the examined lung sections from diabetic mice exposed to DEP. Total proteins and albumin concentrations in bronchoalveolar lavage (BAL) fluid, markers for increase of epithelial permeability, were significantly increased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice. Superoxide dismutase activity and reduced glutathione concentration in BAL were significantly decreased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice. Moreover, tumor necrosis factor ? (TNF?) concentrations were significantly increased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice. We conclude that, at the dose and time point investigated, DEP equally increased airway resistance and caused infiltration of inflammatory cells in the lung of both diabetic and non-diabetic mice. However, the occurrence of oxidative stress, the presence lung apoptotic cells and the increase of total proteins, albumin and TNF? in BAL fluid were only seen in DEP-exposed diabetic mice suggesting an increased respiratory susceptibility to particulate air pollution. PMID:23147376

Nemmar, Abderrahim; Al-Salam, Suhail; Subramaniyan, Deepa; Yasin, Javed; Yuvaraju, Priya; Beegam, Sumaya; Ali, Badreldin H

2013-02-27

164

Effects of oral zinc and magnesium supplementation on serum thyroid hormone and lipid levels in experimentally induced diabetic rats  

Microsoft Academic Search

This study was designed to investigate the effects of oral zinc and magnesium supplementation on serum thyroid hormone and\\u000a lipid levels in alloxan-induced diabetic rats. Thirty-two albino male rats, weighing 234±34 g, were divided into four experimental\\u000a groups (control, diabetic, diabetic+zinc supplemented and diabetic+ magnesium supplemented). The experiment lasted for 60\\u000a d. The first 45 d of the experiment was

Burhanettin Baydas; Suzan Karagoz; Ismail Meral

2002-01-01

165

Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice  

Microsoft Academic Search

The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results

Cédric Louvet; Gregory L. Szot; Jiena Lang; Michael R. Lee; Nicolas Martinier; Gideon Bollag; Shirley Zhu; Arthur Weiss; Jeffrey A. Bluestone

2008-01-01

166

The Role of Macrophages in T Cell-mediated Autoimmune Diabetes in Nonobese Diabetic Mice  

PubMed Central

We have shown previously that the inactivation of macrophages in nonobese diabetic (NOD) mice results in the prevention of diabetes; however, the mechanisms involved remain unknown. In this study, we found that T cells in a macrophage-depleted environment lost their ability to differentiate into ? cell–cytotoxic T cells, resulting in the prevention of autoimmune diabetes, but these T cells regained their ? cell–cytotoxic potential when returned to a macrophage-containing environment. To learn why T cells in a macrophage-depleted environment lose their ability to kill ? cells, we examined the islet antigen–specific immune response and T cell activation in macrophage-depleted NOD mice. There was a shift in the immune balance, a decrease in the T helper cell type 1 (Th1) immune response, and an increase in the Th2 immune response, due to the reduced expression of the macrophage-derived cytokine IL-12. As well, there was a deficit in T cell activation, evidenced by significant decreases in the expression of Fas ligand and perforin. The administration of IL-12 substantially reversed the prevention of diabetes in NOD mice conferred by macrophage depletion. We conclude that macrophages play an essential role in the development and activation of ? cell–cytotoxic T cells that cause ? cell destruction, resulting in autoimmune diabetes in NOD mice.

Jun, Hee-Sook; Yoon, Chang-Soon; Zbytnuik, Lori; van Rooijen, Nico; Yoon, Ji-Won

1999-01-01

167

Mechanism of protection from alloxan diabetes provided by n-butanol.  

PubMed

Pretreatment with n-butanol (10 mmol/kg i.p.) 30 minutes before alloxan (100 mg/kg) protects mice from the permanent hyperglycemic effects (measured at 72 hours) of the diabetogenic agent. This dose of n-butanol caused an elevation of serum glucose at 30 minutes, the time of alloxan administration. Since glucose administration can protect animals from alloxan, the possibility that alcohol-induced hyperglycemia protected mice from alloxan was investigated. Mannoheptulose, an antagonist of glucose action at the pancreatic beta-cell, when given 24 minutes after n-butanol and 6 minutes before alloxan, eliminated the alcohol-induced protection. Fasted mice did not exhibit n-butanol-induced hyperglycemia at 30 minutes and alloxan given at that time produced diabetes. No protection was observed in fed animals when n-butanol was given 5 minutes before alloxan. The high serum levels of butanol and normal serum glucose which were observed at 5 minutes after alcohol administration indicated that the lack of protection was not due to a lack of circulating alcohol but resulted from an absence of hyperglycemia. The results indicate that pretreatment with n-butanol protects mice from alloxan-induced diabetes by the indirect mechanism of producing hyperglycemia at the time of alloxan administration. PMID:323464

Schauberger, C W; Thies, R L; Fischer, L J

1977-05-01

168

Hypoglycaemic action of stevioside and ? barley and brewer's yeast based preparation in the experimental model on mice.  

PubMed

The aim of this study was to investigate influence of the preparation based on barley and brewer's yeast extracts with chromium (BBCr) and stevioside (S) on fasting glycaemia and glycaemia in mice after glucose, adrenalin and alloxan application. The animals were divided into three groups: glucose 500 mgkg(-1) (I); adrenalin 0.2 mgkg(-1)(II) and alloxan 100 mg kg(-1) (III) and into subgroups according to the substance they received: stevioside 20 mg kg(-1) (I-S, II-S, III-S); BBCr 750 mg kg(-1)(I-BBCr, II-BBCr, III-BBCr) and saline 1 ml/100g (III-placebo). Glycaemia was measured before and after 7-day treatment with stevioside or BBCr in the following conditions: fasting, 30 min after glucose load (I) or 45 min after adrenaline load (II). In group III glycaemia was measured before and after 12-day treatment with S, BBCr or placebo and alloxan application (7th, 8th and 10th days of treatment ). BBCr significantly reduced fasting glycaemia in I and II groups and glycaemia values after the glucose load (I-BBCr: 9.20 ± 0.61 vs. 7.42 ± 0.59 mmol/L, p = 0.01). Stevioside significantly reduced glycaemia after the adrenalin load (II-S: 13.45 ± 0.71 vs. 11.65 ± 1.19 mmol/L; p = 0.03). In the III-BBCr glycaemia values did not indicate the development of alloxan-induced diabetes and were significantly lower than in the III-placebo (8.6 ± 3.16 vs. 18.8 ± 5.53 mmol/L; p < 0.05). In conclusion, BBCr caused a significant decrease of fasting glycaemia, significant reduction of glycaemia after glucose load and prevented onset of alloxan-induced diabetes. Stevioside caused the decrease of adrenalin-induced hyperglycaemia. PMID:21342135

Cekic, Vlada; Vasovic, Velibor; Jakovljevic, Vida; Mikov, Momir; Sabo, Ana

2011-02-01

169

Treatment of Type 1 Diabetes Mellitus in Non-Obese Diabetic Mice by Transplantation of Allogeneic Bone Marrow and Pancreatic Tissue  

Microsoft Academic Search

Non-obese diabetic (NOD) mice provide a model for type 1 diabetes mellitus. We previously showed that allogeneic bone marrow transplantation (ABMT) can prevent and treat insulitis and overt diabetes in NOD mice. However, ABMT alone could not be used to treat overt diabetes in NOD mice whose islets had been completely destroyed. To provide insulin-producing cells, pancreatic tissue from newborn

Ryoji Yasumizu; Kikuya Sugiura; Hiroshi Iwai; Muneo Inaba; Susumu Makino; Tatuya Ida; Hiroshi Imura; Yoshihiro Hamashima; Robert A. Good; Susumu Ikehara

1987-01-01

170

Effects of Ballota nigra on glucose and insulin in alloxan-diabetic albino rats.  

PubMed

The hypoglycemic effect of Ballota nigra extract on albino rats was investigated. Alloxan-induced diabetes mellitus was accompanied by several fold increases in plasma glucose. Administration of aqueous extract of B. nigra extract significantly reduced glucose in both healthy and diabetic rats. These results suggest that B. nigra possess hypoglycemic effects in rats and therefore, can be useful for the treatment of diabetes mellitus. PMID:17627273

Nusier, Mohamad K; Bataineh, Hameed N; Bataineh, Ziad M; Daradka, Haytham M

2007-08-01

171

Cardiovascular autonomic dysfunction in non-obese diabetic mice.  

PubMed

It is known that diabetes is associated with autonomic dysfunction; however, data about autonomic function in non-obese diabetic mice (NOD) remain scarce. We evaluated the autonomic profile of NOD mice. Female mice, 24-28 week old, were divided in two groups: NOD (n = 6) and control (n = 6, Swiss mice). NOD mice with glycemia ? 300 mg/dl were used. Heart rate variability (HRV) and arterial pressure variability (APV) in time and frequency domains, symbolic analysis of heart rate (HR) and baroreflex sensitivity were evaluated. HR and arterial pressure (AP) were similar between the groups; however, HRV (total variance of RR interval: NOD=21.07 ± 3.75 vs. C = 42.02 ± 6.54 ms(2)) and the vagal modulation index RMSSD were lower in NOD group (4.01 ± 0.32 vs. 8.28 ± 0.97 ms). Moreover, the absolute and normalized low-frequency (LF) components were also enhanced in NOD (normalized = 61.0 ± 4.0%) as compared to control mice (normalized = 20.0 ± 4.0%). Both the absolute and normalized high-frequency (HF) components were lower in NOD (normalized = 39.0 ± 4.0%) when compared to the control group (normalized = 80.0 ± 4.0). In the symbolic analysis the 0V pattern, an indication of sympathetic activity, was higher in NOD and 2 LV pattern, an indication of parasympathetic activity, was lower in the NOD than in the control group. Both bradycardic and tachycardic responses were decreased in NOD (3.01 ± 0.72 vs. 4.54 ± 0.36 bpm/mmHg and 2.49 ± 0.31 vs. C = 3.43 ± 0.33 bpm/mmHg) when compared to the control group. Correlation analysis showed negative correlations between vagal indexes (RMSSD, %HF and 2LV) and glycemic levels. In conclusion, NOD mice develop severe diabetes correlated with autonomic dysfunction. PMID:23622812

Moraes, Oscar A; Colucci, Juliana A; Souza, Leandro E; Scapini, Kátia B; Moraes-Silva, Ivana C; Mostarda, Cristiano; De Angelis, Kátia; Casarini, Dulce E; Irigoyen, Maria Cláudia

2013-10-01

172

Amelioration of Diabetes and Painful Diabetic Neuropathy by Punica granatum L. Extract and Its Spray Dried Biopolymeric Dispersions  

PubMed Central

Aims. To evaluate the effect of Punica granatum (Pg) rind extract and its spray dried biopolymeric dispersions with casein (F1) or chitosan (F2) against Diabetes mellitus (DM) and diabetic neuropathy (DN). Methods. We measured the acute (6?h) and subacute (8 days) effect of various doses of Pg, F1, and F2 and the active compounds on alloxan-induced DM mouse model. We evaluated DN utilizing latency tests for longer period of time (8 weeks). In addition, the in vivo antioxidant activity was assessed utilizing serum catalase level. Results. The results proved that the highest dose levels of Pg extract, F1, F2 exerted remarkable hypoglycemic activity with 48, 52, and 40% drop in the mice glucose levels after 6 hours, respectively. The tested compounds also improved peripheral nerve function as observed from the latency tests. Bioguided fractionation suggested that gallic acid (GA) was Pg main active ingredient responsible for its actions. Conclusion. Pg extract, F1, F2, and GA could be considered as a new therapeutic potential for the amelioration of diabetic neuropathic pain and the observed in vivo antioxidant potential may be involved in its antinociceptive effect. It is highly significant to pay attention to Pg and GA for amelioration and control of DM and its complications.

Raafat, K.; Samy, W.

2014-01-01

173

Amelioration of Diabetes and Painful Diabetic Neuropathy by Punica granatum L. Extract and Its Spray Dried Biopolymeric Dispersions.  

PubMed

Aims. To evaluate the effect of Punica granatum (Pg) rind extract and its spray dried biopolymeric dispersions with casein (F1) or chitosan (F2) against Diabetes mellitus (DM) and diabetic neuropathy (DN). Methods. We measured the acute (6?h) and subacute (8 days) effect of various doses of Pg, F1, and F2 and the active compounds on alloxan-induced DM mouse model. We evaluated DN utilizing latency tests for longer period of time (8 weeks). In addition, the in vivo antioxidant activity was assessed utilizing serum catalase level. Results. The results proved that the highest dose levels of Pg extract, F1, F2 exerted remarkable hypoglycemic activity with 48, 52, and 40% drop in the mice glucose levels after 6 hours, respectively. The tested compounds also improved peripheral nerve function as observed from the latency tests. Bioguided fractionation suggested that gallic acid (GA) was Pg main active ingredient responsible for its actions. Conclusion. Pg extract, F1, F2, and GA could be considered as a new therapeutic potential for the amelioration of diabetic neuropathic pain and the observed in vivo antioxidant potential may be involved in its antinociceptive effect. It is highly significant to pay attention to Pg and GA for amelioration and control of DM and its complications. PMID:24982685

Raafat, K; Samy, W

2014-01-01

174

Neurobehavioral deficits in db/db diabetic mice  

PubMed Central

Recent clinical studies indicate neurobehavioral disturbances in type-2 diabetics. However, there is paucity of preclinical research to support this concept. The validity of db/db mouse as an animal model to study type-2 diabetes and related complications is known. The present study was designed to investigate comprehensively the db/db mouse behavior as preclinical evidence of type-2 diabetes related major neurobehavioral complications. We tested juvenile (5–6 weeks) and adult (10–11 weeks) db/db mice for behavioral depression in forced swim test (FST), psychosis-like symptoms using pre-pulse inhibition (PPI) test, anxiety behavior employing elevated plus maze (EPM) test, locomotor behavior and thigmotaxis using open field test and working memory deficits in Y-maze test. Both juvenile and adult group db/db mice displayed behavioral despair with increased immobility time in FST. There was an age-dependent progression of psychosis-like symptoms with disrupted PPI in adult db/db mice. In the EPM test, db/db mice were less anxious as observed by increased percent open arms time and entries. They were also hypolocomotive as evident by a decrease in their basic and fine movements. There was no impairment of working memory in the Y-maze test in db/db mice. This is the first report of depression, psychosis-like symptoms and anxiolytic behavior of db/db mouse strain. It is tempting to speculate that this mouse strain can serve as useful preclinical model to study type-2 diabetes related neurobehavioral complications.

Sharma, Ajaykumar N.; Elased, Khalid M.; Garrett, Teresa L.; Lucot, James B.

2011-01-01

175

Requirement of Fas for the Development of Autoimmune Diabetes in Nonobese Diabetic Mice  

PubMed Central

Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell–mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic ? cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate ? cell autoimmunity in NOD mice. Fas–Fas ligand system might be critical for autoimmune ? cell destruction leading to IDDM.

Itoh, Naoto; Imagawa, Akihisa; Hanafusa, Toshiaki; Waguri, Masako; Yamamoto, Koji; Iwahashi, Hiromi; Moriwaki, Makoto; Nakajima, Hiromu; Miyagawa, Junichiro; Namba, Mitsuyoshi; Makino, Susumu; Nagata, Shigekazu; Kono, Norio; Matsuzawa, Yuji

1997-01-01

176

Lipoatrophic diabetes in Irs1?/?/Irs3?/? double knockout mice  

PubMed Central

Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1?/? mice with respect to growth and glucose homeostasis. In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. However, in contrast to other models of lipoatrophic diabetes, there was no accumulation of fat in liver or muscle. Furthermore, plasma leptin levels were markedly decreased, and adenovirus-mediated expression of leptin in liver reversed the hyperglycemia and hyperinsulinemia. The results indicate that IRS-1 and IRS-3 play important complementary roles in adipogenesis and establish the Irs1?/?/Irs3?/? double knockout mouse as a novel model of lipoatrophic diabetes.

Laustsen, Palle G.; Michael, M. Dodson; Crute, Barbara E.; Cohen, Shmuel E.; Ueki, Kohjiro; Kulkarni, Rohit N.; Keller, Susanna R.; Lienhard, Gustav E.; Kahn, C. Ronald

2002-01-01

177

Immune Depletion With Cellular Mobilization Imparts Immunoregulation and Reverses Autoimmune Diabetes in Nonobese Diabetic Mice  

PubMed Central

OBJECTIVE The autoimmune destruction of ?-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony–stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes. RESEARCH DESIGN AND METHODS Effects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or ?-cell area. RESULTS Here, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic ?-cell area, attenuation of pancreatic inflammation) benefits. CONCLUSIONS In addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.

Parker, Matthew J.; Xue, Song; Alexander, John J.; Wasserfall, Clive H.; Campbell-Thompson, Martha L.; Battaglia, Manuela; Gregori, Silvia; Mathews, Clayton E.; Song, Sihong; Troutt, Misty; Eisenbeis, Scott; Williams, John; Schatz, Desmond A.; Haller, Michael J.; Atkinson, Mark A.

2009-01-01

178

Cytopiloyne, a polyacetylenic glucoside, prevents type 1 diabetes in nonobese diabetic mice.  

PubMed

Some polyacetylenes from the plant Bidens pilosa have been reported to treat diabetes. In this study, we report that the cytopiloyne from B. pilosa, which is structurally different from the above-mentioned polyacetylenes and inhibits CD4(+) T cell proliferation, effectively prevents the development of diabetes in nonobese diabetic mice as evidenced by a normal level of blood glucose and insulin and normal pancreatic islet architecture. Cytopiloyne also suppresses the differentiation of type 1 Th cells but promotes that of type 2 Th cells, which is consistent with it enhancing GATA-3 transcription. Also, long-term application of cytopiloyne significantly decreases the level of CD4(+) T cells inside pancreatic lymph nodes and spleens but does not compromise total Ab responses mediated by T cells. Coculture assays imply that this decrease in CD4(+) T cells involves the Fas ligand/Fas pathway. Overall, our results suggest that cytopiloyne prevents type 1 diabetes mainly via T cell regulation. PMID:17513748

Chang, Cicero Lee-Tian; Chang, Shu-Lin; Lee, Yi-Mei; Chiang, Yi-Ming; Chuang, Da-Yung; Kuo, Hui-Kai; Yang, Wen-Chin

2007-06-01

179

BTBR Ob/Ob Mutant Mice Model Progressive Diabetic Nephropathy  

PubMed Central

There remains a need for robust mouse models of diabetic nephropathy (DN) that mimic key features of advanced human DN. The recently developed mouse strain BTBR with the ob/ob leptin-deficiency mutation develops severe type 2 diabetes, hypercholesterolemia, elevated triglycerides, and insulin resistance, but the renal phenotype has not been characterized. Here, we show that these obese, diabetic mice rapidly develop morphologic renal lesions characteristic of both early and advanced human DN. BTBR ob/ob mice developed progressive proteinuria beginning at 4 weeks. Glomerular hypertrophy and accumulation of mesangial matrix, characteristic of early DN, were present by 8 weeks, and glomerular lesions similar to those of advanced human DN were present by 20 weeks. By 22 weeks, we observed an approximately 20% increase in basement membrane thickness and a >50% increase in mesangial matrix. Diffuse mesangial sclerosis (focally approaching nodular glomerulosclerosis), focal arteriolar hyalinosis, mesangiolysis, and focal mild interstitial fibrosis were present. Loss of podocytes was present early and persisted. In summary, BTBR ob/ob mice develop a constellation of abnormalities that closely resemble advanced human DN more rapidly than most other murine models, making this strain particularly attractive for testing therapeutic interventions.

Hudkins, Kelly L.; Pichaiwong, Warangkana; Wietecha, Tomasz; Kowalewska, Jolanta; Banas, Miriam C.; Spencer, Min W.; Muhlfeld, Anja; Koelling, Mariko; Pippin, Jeffrey W.; Shankland, Stuart J.; Askari, Bardia; Rabaglia, Mary E.; Keller, Mark P.; Attie, Alan D.

2010-01-01

180

Insulin-tumour interrelationship in EL4 lymphoma or thymoma-bearing mice. I. Alloxan-diabetic or non-diabetic mice.  

PubMed Central

A study has been carried out in which a comparison was made between EL4 lymphoma (assumed to be an insulin-producing secreting tumour) and thymoma (an insulin-dependent tumour). Tumour development and incidence, 3H-thymidine incorporation and insulin content in tumours, the host's food intake, blood insulin, glucose and cholesterol were determined in non-diabetic and alloxan-diabetic mice. Whereas no significant differences were observed between the diabetic and non-diabetic EL4 tumour-bearing mice, the diabetic, thymoma tumour-bearing mice showed reduced tumour growth and lower tumour incidence as compared with their non-diabetic counterparts. Insulin administration to diabetic tumour bearing mice, enhanced 3H-thymidine incorporation in the thymoma tumour cells only, and the insulin content of the EL4 tumours was found to be higher than that of the thymoma tumours. Rapid diabetes remission was observed in the diabetic, EL4 tumour-bearing mice as compared with the thymoma tumour-bearing mice.

Yam, D.; Zilberstein, A.; Fink, A.; Nir, I.

1990-01-01

181

In situ hybridization study of myelin protein mRNA in rats with an experimental diabetic neuropathy  

Microsoft Academic Search

Distribution of protein zero (P0) and myelin basic protein (MBP) mRNAs in the sciatic nerve from rats with alloxan-induced diabetes was analyzed at two different time points using in situ hybridization. Some animals of each diabetic group were treated with insulin. Densitometric quantitation of silver clusters revealed that 5 weeks after diabetes induction P0 mRNA only is significantly increased, while

Anna Maria Conti; Elio Scarpini; Maria Luisa Malosio; Anna Maria Di Giulio; Pierluigi Baron; Guglielmo Scarlato; Paolo Mantegazza; Alfredo Gorio

1996-01-01

182

Anti-diabetic effects of lactic acid bacteria in normal and type 2 diabetic mice  

PubMed Central

The antidiabetic effects of lactic acid bacteria were investigated using mice. In Experiment 1, normal ICR mice were loaded with sucrose or starch with or without viable Lactobacillus rhamnosus GG cells. GG significantly inhibited postprandial blood glucose levels when administered with sucrose or starch. In Experiment 2, KK-Ay mice, a model of genetic type 2 diabetes, were given a basal diet containing viable GG cells or viable Lactobacillus delbrueckii subsp. bulgaricus cells for 6 weeks. Viable GG cells significantly inhibited fasting blood glucose, postprandial blood glucose in a glucose tolerance test and HbA1c. Such effects were not shown by viable L. bulgaricus cells. In Experiment 3, the KK-Ay mice were given a basal diet containing viable GG cells or heat-treated GG cells for 3 weeks. The viable GG cells significantly suppressed fasting blood glucose and impaired glucose tolerance, but the heat-treated GG showed no effects. These results demonstrated that GG decreased the postprandial blood glucose in ICR mice, and that the antidiabetic activity of lactic acid bacteria on the KK-Ay mice differed depending on the bacterial strain and whether the bacterium is viable when it arrives in the intestine. In the present study, we conclude that the antidiabetic activity may result from continuous inhibition of the postprandial blood glucose through suppression of glucose absorption from the intestine. These findings indicate that specific strains of lactic acid bacterium can be expected to be beneficial for the management of type 2 diabetes.

Honda, Kayoko; Moto, Mihoko; Uchida, Naoko; He, Fang; Hashizume, Naotaka

2012-01-01

183

Antiradical activity of different copper(II) Schiff base complexes and their effect on alloxan-induced diabetes  

Microsoft Academic Search

Considering the important role of antioxidants in biological systems, the group of copper(II) complexes derived from salicylaldehyde and ?- or ?-alanine and its thiourea derivative and copper(II) complexes derived from pyruvic acid and ?-alanine were studied. The antiradical activity of the tested compounds was studied by both in vitro and in vivo methods. The chemical methods based on inhibition of

Ján Van?o; O?ga Švajlenová; Eva Ra?anská; Jan Muselík; Jindra Valentová

2004-01-01

184

Recombinant soluble CD137 prevents type one diabetes in nonobese diabetic mice.  

PubMed

Nonobese diabetic (NOD) mice are genetically programmed to spontaneously develop type one diabetes (T1D). Multiple Insulin dependent diabetes (Idd) genetic loci have been identified but their functional effects are mostly poorly understood. TnfsfR9, expressing the protein product CD137, is a strong candidate gene in the Idd9.3 locus, and NOD.B10 Idd9.3 mice are significantly protected from type one diabetes (T1D). We previously showed that nonobese diabetic (NOD) mice have a deficiency in the numbers of CD137(pos) T regulatory cells, that CD137(pos) Tregs are the source of soluble CD137 (sCD137), and that NOD mice have low serum levels of sCD137. To test the hypothesis that correcting low levels of sCD137 could affect the disease, we constructed a lentiviral vector producing recombinant sCD137; this physiologic sCD137 is glycosylated and exists primarily as a dimer. NOD mice treated with the recombinant sCD137 are protected from developing T1D. Insulitis is significantly decreased, but not eliminated in the sCD137 treated mice, however insulin producing pancreatic beta cells are preserved despite residual insulitis. To begin to understand the protective immune mechanisms of sCD137, we tested sCD137 in vitro. It was previously suggested that sCD137 simply blocked the interaction between CD137 (on T cells) and CD137 ligand (on antigen presenting cells (APCs)). Here however, we use an APC independent assay and demonstrate that sCD137 can actively suppress highly purified CD4 T cells in a CD137L dependent fashion. These results support the hypothesis that sCD137 acts in a negative feedback loop to actively suppress over-zealous immune responses, and that it can be used clinically to suppress autoimmunity. sCD137 is an important Treg derived natural immunosuppressive molecule that regulates effector T cells to avert diabetes in vivo. PMID:24145149

Kachapati, Kritika; Bednar, Kyle J; Adams, David E; Wu, Yuehong; Mittler, Robert S; Jordan, Michael B; Hinerman, Jennifer M; Herr, Andrew B; Ridgway, William M

2013-12-01

185

Diabetes Insipidus in Mice with a Mutation in Aquaporin-2  

PubMed Central

Congenital nephrogenic diabetes insipidus (NDI) is a disease characterized by failure of the kidney to concentrate urine in response to vasopressin. Human kindreds with nephrogenic diabetes insipidus have been found to harbor mutations in the vasopressin receptor 2 (Avpr2) gene or the vasopressin-sensitive water channel aquaporin-2 (Aqp2) gene. Development of a treatment is rendered difficult due to the lack of a viable animal model. Through forward genetic screening of ethylnitrosourea-mutagenized mice, we report the identification and characterization of a mouse model of NDI, with an F204V mutation in the Aqp2 gene. Unlike previously attempted murine models of NDI, our mice survive to adulthood and more exactly recapitulate the human disorder. Previous in vitro experiments using renal cell lines suggest recessive Aqp2 mutations result in improper trafficking of the mutant water pore. Using these animals, we have directly proven this hypothesis of improper AQP2 translocation as the molecular defect in nephrogenic diabetes insipidus in the intact organism. Additionally, using a renal cell line we show that the mutated protein, AQP2-F204V, is retained in the endoplasmic reticulum and that this abnormal localization can be rescued by wild-type protein. This novel mouse model allows for further mechanistic studies as well as testing of pharmacological and gene therapies for NDI.

Lloyd, David J; Hall, Frank Wesley; Tarantino, Lisa M; Gekakis, Nicholas

2005-01-01

186

Mitochondrial redox studies of oxidative stress in kidneys from diabetic mice  

PubMed Central

Chronic hyperglycemia during diabetes leads to increased production of reactive oxygen species (ROS) and increased oxidative stress (OS). Here we investigated whether changes in the metabolic state can be used as a marker of OS progression in kidneys. We examined redox states of kidneys from diabetic mice, Akita/+ and Akita/+;TSP1–/– mice (Akita mice lacking thrombospondin-1, TSP1) with increasing duration of diabetes. OS as measured by mitochondrial redox ratio (NADH/FAD) was detectable shortly after the onset of diabetes and further increased with the duration of diabetes. Thus, cryo fluorescence redox imaging was used as a quantitative marker of OS progression in kidneys from diabetic mice and demonstrated that alterations in the oxidative state of kidneys occur during the early stages of diabetes.

Maleki, Sepideh; Sepehr, Reyhaneh; Staniszewski, Kevin; Sheibani, Nader; Sorenson, Christine M.; Ranji, Mahsa

2012-01-01

187

Maternal obesity exacerbates insulitis and type 1 diabetes in non-obese diabetic mice.  

PubMed

Accompanying the dramatic increase in maternal obesity, the incidence of type 1 diabetes (T1D) in children is also rapidly increasing. The objective of this study was to explore the effects of maternal obesity on the incidence of T1D in offspring using non-obese diabetic (NOD) mice, a common model for TID. Four-week-old female NOD mice were fed either a control diet (10% energy from fat, CON) or a high-fat diet (60% energy from fat) for 8 weeks before mating. Mice were maintained in their respective diets during pregnancy and lactation. All offspring mice were fed the CON to 16 weeks. Female offspring (16-week-old) born to obese dams showed more severe islet lymphocyte infiltration (major manifestation of insulitis) (P<0.01), concomitant with elevated nuclear factor kappa-light-chain-enhancer of activated B cells p65 signaling (P<0.01) and tumor necrosis factor alpha protein level (P<0.05) in the pancreas. In addition, maternal obesity resulted in impaired (P<0.05) glucose tolerance and lower (P<0.05) serum insulin levels in offspring. In conclusion, maternal obesity resulted in exacerbated insulitis and inflammation in the pancreas of NOD offspring mice, providing a possible explanation for the increased incidence of T1D in children. PMID:24692565

Wang, Hui; Xue, Yansong; Wang, Baolin; Zhao, Junxing; Yan, Xu; Huang, Yan; Du, Min; Zhu, Mei-Jun

2014-07-01

188

Petalonia improves glucose homeostasis in streptozotocin-induced diabetic mice  

SciTech Connect

The anti-diabetic potential of Petalonia binghamiae extract (PBE) was evaluated in vivo. Dietary administration of PBE to streptozotocin (STZ)-induced diabetic mice significantly lowered blood glucose levels and improved glucose tolerance. The mode of action by which PBE attenuated diabetes was investigated in vitro using 3T3-L1 cells. PBE treatment stimulated 3T3-L1 adipocyte differentiation as evidenced by increased triglyceride accumulation. At the molecular level, peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and terminal marker protein aP2, as well as the mRNA of GLUT4 were up-regulated by PBE. In mature adipocytes, PBE significantly stimulated the uptake of glucose and the expression of insulin receptor substrate-1 (IRS-1). Furthermore, PBE increased PPAR{gamma} luciferase reporter gene activity in COS-1 cells. Taken together, these results suggest that the in vivo anti-diabetic effect of PBE is mediated by both insulin-like and insulin-sensitizing actions in adipocytes.

Kang, Seong-Il; Jin, Young-Jun [Department of Life Science, Cheju National University, 66 Jejudaehakno, Ara-1 Dong, Jejusi, Jeju 690-756 (Korea, Republic of); Ko, Hee-Chul [Department of Chemistry, Cheju National University, 66 Jejudaehakno, Ara-1 Dong, Jejusi, Jeju 690-756 (Korea, Republic of); Choi, Soo-Youn; Hwang, Joon-Ho [Regional Innovation Center, Cheju National University, 66 Jejudaehakno, Ara-1 Dong, Jejusi, Jeju 690-756 (Korea, Republic of); Whang, Ilson; Kim, Moo-Han; Shin, Hye-Sun; Jeong, Hyung-Bok [Department of Life Science, Cheju National University, 66 Jejudaehakno, Ara-1 Dong, Jejusi, Jeju 690-756 (Korea, Republic of); Kim, Se-Jae [Department of Life Science, Cheju National University, 66 Jejudaehakno, Ara-1 Dong, Jejusi, Jeju 690-756 (Korea, Republic of)], E-mail: sjkim@cheju.ac.kr

2008-08-22

189

Glycaemic effects of traditional European plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice.  

PubMed

Twelve plants used for the traditional treatment of diabetes mellitus in northern Europe were studied using normal and streptozotocin diabetic mice to evaluate effects on glucose homeostasis. The plants were administered in the diet (6.25% by weight) and/or as decoctions or infusions in place of drinking water, to coincide with the traditional method of preparation. Treatment for 28 days with preparations of burdock (Arctium lappa), cashew (Anacardium occidentale), dandelion (Taraxacum officinale), elder (Sambucus nigra), fenugreek (Trigonella foenum-graecum), guayusa (Ilex guayusa), hop (Humulus lupulus), nettle (Urtica dioica), cultivated mushroom (Agaricus bisporus), periwinkle (Catharanthus roseus), sage (Salvia officinale), and wild carrot (Daucus carrota) did not affect the parameters of glucose homeostasis examined in normal mice (basal plasma glucose and insulin, glucose tolerance, insulin-induced hypoglycaemia and glycated haemoglobin). After administration of streptozotocin (200 mg/kg) burdock and nettle aggravated the diabetic condition, while cashew, dandelion, elder, fenugreek, hop, periwinkle, sage and wild carrot did not significantly affect the parameters of glucose homeostasis studied (basal glucose and insulin, insulin-induced hypoglycaemia, glycated haemoglobin and pancreatic insulin concentration). Guayusa and mushroom retarded the development of hyperglycaemia in streptozotocin diabetes and reduced the hyperphagia, polydipsia, body weight loss, and glycated haemoglobin. Mushroom also countered the initial reduction in plasma insulin and the reduction in pancreatic insulin concentration, and improved the hypoglycaemic effect of exogenous insulin. These studies suggest the presence of potentially useful antidiabetic agents in guayusa and mushroom. PMID:2743711

Swanston-Flatt, S K; Day, C; Flatt, P R; Gould, B J; Bailey, C J

1989-02-01

190

Increased inner ear susceptibility to noise injury in mice with streptozotocin-induced diabetes.  

PubMed

We aimed to investigate the pathophysiology of diabetes-associated hearing impairment in type 1 diabetes using mice with streptozotocin-induced diabetes (C57BL/6J; male). Hearing function was evaluated 1, 3, and 5 months after induction of diabetes (five diabetic and five control animals per time point) using auditory-evoked brain stem responses (ABRs). Mice (four diabetic and four control) were exposed to loud noise (105 dB) 5 months after induction of diabetes. ABRs were measured before and after noise exposure. Cochlear blood flows were measured by laser-Doppler flowmeter. Spiral ganglion cells (SGCs) were counted. Vessel endothelial cells were observed by CD31 immunostaining. Chronologic changes in the ABR threshold shift were not significantly different between the diabetic and control groups. However, vessel walls in the modiolus of the cochleae were significantly thicker in the diabetic group than the control group. Additionally, recovery from noise-induced injury was significantly impaired in diabetic mice. Reduced cochlea blood flows and SGC loss were observed in diabetic mice cochleae after noise exposure. Our data suggest that diabetic cochleae are more susceptible than controls to loud noise exposure, and decreased cochlear blood flow due to sclerosis of the vessels and consequent loss of SGCs are possible mechanisms of hearing impairment in diabetic patients. PMID:22851574

Fujita, Takeshi; Yamashita, Daisuke; Katsunuma, Sayaka; Hasegawa, Shingo; Tanimoto, Hitoshi; Nibu, Ken-Ichi

2012-11-01

191

Increased Inner Ear Susceptibility to Noise Injury in Mice With Streptozotocin-Induced Diabetes  

PubMed Central

We aimed to investigate the pathophysiology of diabetes-associated hearing impairment in type 1 diabetes using mice with streptozotocin-induced diabetes (C57BL/6J; male). Hearing function was evaluated 1, 3, and 5 months after induction of diabetes (five diabetic and five control animals per time point) using auditory-evoked brain stem responses (ABRs). Mice (four diabetic and four control) were exposed to loud noise (105 dB) 5 months after induction of diabetes. ABRs were measured before and after noise exposure. Cochlear blood flows were measured by laser-Doppler flowmeter. Spiral ganglion cells (SGCs) were counted. Vessel endothelial cells were observed by CD31 immunostaining. Chronologic changes in the ABR threshold shift were not significantly different between the diabetic and control groups. However, vessel walls in the modiolus of the cochleae were significantly thicker in the diabetic group than the control group. Additionally, recovery from noise-induced injury was significantly impaired in diabetic mice. Reduced cochlea blood flows and SGC loss were observed in diabetic mice cochleae after noise exposure. Our data suggest that diabetic cochleae are more susceptible than controls to loud noise exposure, and decreased cochlear blood flow due to sclerosis of the vessels and consequent loss of SGCs are possible mechanisms of hearing impairment in diabetic patients.

Fujita, Takeshi; Yamashita, Daisuke; Katsunuma, Sayaka; Hasegawa, Shingo; Tanimoto, Hitoshi; Nibu, Ken-ichi

2012-01-01

192

Myocardial Adipose Triglyceride Lipase Overexpression Protects Diabetic Mice From the Development of Lipotoxic Cardiomyopathy  

PubMed Central

Although diabetic cardiomyopathy is associated with enhanced intramyocardial triacylglycerol (TAG) levels, the role of TAG catabolizing enzymes in this process is unclear. Because the TAG hydrolase, adipose triglyceride lipase (ATGL), regulates baseline cardiac metabolism and function, we examined whether alterations in cardiomyocyte ATGL impact cardiac function during uncontrolled type 1 diabetes. In genetic (Akita) and pharmacological (streptozotocin) murine models of type 1 diabetes, cardiac ATGL protein expression and TAG content were significantly increased. To determine whether increased ATGL expression during diabetes is detrimental or beneficial to cardiac function, we studied streptozotocin-diabetic mice with heterozygous ATGL deficiency and cardiomyocyte-specific ATGL overexpression. After diabetes, streptozotocin-diabetic mice with heterozygous ATGL deficiency displayed increased TAG accumulation, lipotoxicity, and diastolic dysfunction comparable to wild-type mice. In contrast, myosin heavy chain promoter (MHC)-ATGL mice were resistant to diabetes-induced increases in intramyocardial TAG levels, lipotoxicity, and cardiac dysfunction. Moreover, hearts from diabetic MHC-ATGL mice exhibited decreased reliance on palmitate oxidation and blunted peroxisome proliferator--activated receptor-? activation. Collectively, this study shows that after diabetes, increased cardiac ATGL expression is an adaptive, albeit insufficient, response to compensate for the accumulation of myocardial TAG, and that overexpression of ATGL is sufficient to ameliorate diabetes-induced cardiomyopathy.

Pulinilkunnil, Thomas; Kienesberger, Petra C.; Nagendran, Jeevan; Waller, Terri J.; Young, Martin E.; Kershaw, Erin E.; Korbutt, Gregory; Haemmerle, Guenter; Zechner, Rudolf; Dyck, Jason R.B.

2013-01-01

193

Co-Therapy Using Lytic Bacteriophage and Linezolid: Effective Treatment in Eliminating Methicillin Resistant Staphylococcus aureus (MRSA) from Diabetic Foot Infections  

PubMed Central

Background Staphylococcus aureus remains the predominant pathogen in diabetic foot infections and prevalence of methicillin resistant S.aureus (MRSA) strains further complicates the situation. The incidence of MRSA in infected foot ulcers is 15–30% and there is an alarming trend for its increase in many countries. Diabetes acts as an immunosuppressive state decreasing the overall immune functioning of body and to worsen the situation, wounds inflicted with drug resistant strains represent a morbid combination in diabetic patients. Foot infections caused by MRSA are associated with an increased risk of amputations, increased hospital stay, increased expenses and higher infection-related mortality. Hence, newer, safer and effective treatment strategies are required for treating MRSA mediated diabetic foot infections. The present study focuses on the use of lytic bacteriophage in combination with linezolid as an effective treatment strategy against foot infection in diabetic population. Methodology Acute hindpaw infection with S.aureus ATCC 43300 was established in alloxan induced diabetic BALB/c mice. Therapeutic efficacy of a well characterized broad host range lytic bacteriophage, MR-10 was evaluated alone as well as in combination with linezolid in resolving the course of hindpaw foot infection in diabetic mice. The process of wound healing was also investigated. Results and Conclusions A single administration of phage exhibited efficacy similar to linezolid in resolving the course of hindpaw infection in diabetic animals. However, combination therapy using both the agents was much more effective in arresting the entire infection process (bacterial load, lesion score, foot myeloperoxidase activity and histopathological analysis). The entire process of tissue healing was also hastened. Use of combined agents has been known to decrease the frequency of emergence of resistant mutants, hence this approach can serve as an effective strategy in treating MRSA mediated foot infections in diabetic individuals who do not respond to conventional antibiotic therapy.

Chhibber, Sanjay; Kaur, Tarsem; Sandeep Kaur

2013-01-01

194

Altered dynamics in the renal lymphatic circulation of type 1 and type 2 diabetic mice.  

PubMed

The dynamics of the renal lymphatic circulation in diabetic nephropathy is not fully elucidated. The present study evaluated the effect of diabetic nephropathy on the renal lymphatic circulation in streptozotocin (STZ)-induced type 1 diabetic mice (ICR-STZ) and in type 2 diabetic KK/Ta mice which were fed a high fat diet (KK/Ta-HF). The diabetic mouse kidneys developed edema because of the nephropathy. In control mice renal lymphatic vessels distributed in the cortex but rarely in the medulla while in ICR-STZ and KK/Ta-HF mice, there were many lymphatic vessels with small lumen in both cortex and medulla. Total numbers and areas of renal blood vessels in the diabetic mice were similar to those in the controls while the total numbers and areas of renal lymphatic vessels were larger in diabetic mice than in the controls. There were statistically significant differences in the numbers of lymphatic vessels with diameters of 50-100 µm between the ICR-STZ and the control ICR mice, and in the numbers of lymphatic capillaries with diameters smaller than 50 µm between the KK/Ta-HF and the control KK/Ta mice. The diabetic nephropathy may induce the lymphangiogenesis or result in at least the renal lymphatic vessel expansion. PMID:23720608

Uchiyama, Takanobu; Takata, Shunsuke; Ishikawa, Hiroyuki; Sawa, Yoshihiko

2013-04-30

195

The effect of gestation and fetal mismatching on the development of autoimmune diabetes in non-obese diabetic mice  

PubMed Central

The impact of gestation and fetal–maternal interactions on pre-existent autoimmune beta cell destruction is widely unknown. The aim of this study was to investigate the influence of gestation per se and fetal mismatching on the onset of autoimmune diabetes in female non-obese diabetic (NOD) mice. We examined cumulative diabetes frequencies of NOD dams mated to syngeneic NOD, haploidentical CByB6F1/J and fully mismatched C57BL/6J male mice. Pregnancy from NOD males neither increased nor accelerated the diabetes onset of NOD dams (71% by age 28 weeks) compared to unmated female NOD mice (81% by age 28 weeks; P = 0·38). In contrast, delayed diabetes onset was observed when NOD dams were mated at 10 weeks of age with major histocompatibility complex (MHC) haploidentical CByB6F1/J male mice (38% at age 28 weeks; P = 0·01). Mating with fully MHC mismatched C57BL/6J male mice (72% diabetes by age 28 weeks; P = 0·22) or mating with the haploidentical males at the later time-point of age 13 weeks (64% versus 91% in unmated litter-matched controls; P = 0·13) did not delay diabetes significantly in NOD females. Because infusion of haploidentical male mouse splenocytes was found previously to prevent diabetes in NOD mice we looked for, but found no evidence of, persistent chimeric lymphocytes from haploidentical paternal origin within the dams' splenocytes. Gestation per se appears to have no aggravating or ameliorating effects on pre-existent autoimmune beta cell destruction, but pregnancy from MHC partially mismatched males delays diabetes onset in female NOD mice.

Adler, K; Krause, S; Fuchs, Y F; Foertsch, K; Ziegler, A-G; Bonifacio, E

2012-01-01

196

Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice.  

PubMed

Signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is crucial for metabolic responses to insulin, and defects in PI3K signaling have been demonstrated in type 2 diabetes. PTEN (MMAC1) is a lipid/protein phosphatase that can negatively regulate the PI3K pathway by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate, but it is unclear whether PTEN is physiologically relevant to insulin signaling in vivo. We employed an antisense oligonucleotide (ASO) strategy in an effort to specifically inhibit the expression of PTEN. Transfection of cells in culture with ASO targeting PTEN reduced PTEN mRNA and protein levels and increased insulin-stimulated Akt phosphorylation in alpha-mouse liver-12 (AML12) cells. Systemic administration of PTEN ASO once a week in mice suppressed PTEN mRNA and protein expression in liver and fat by up to 90 and 75%, respectively, and normalized blood glucose concentrations in db/db and ob/ob mice. Inhibition of PTEN expression also dramatically reduced insulin concentrations in ob/ob mice, improved the performance of db/db mice during insulin tolerance tests, and increased Akt phosphorylation in liver in response to insulin. These results suggest that PTEN plays a significant role in regulating glucose metabolism in vivo by negatively regulating insulin signaling. PMID:11916922

Butler, Madeline; McKay, Robert A; Popoff, Ian J; Gaarde, William A; Witchell, Donna; Murray, Susan F; Dean, Nicholas M; Bhanot, Sanjay; Monia, Brett P

2002-04-01

197

Anti-diabetic effects of lactic acid bacteria in normal and type 2 diabetic mice.  

PubMed

The antidiabetic effects of lactic acid bacteria were investigated using mice. In Experiment 1, normal ICR mice were loaded with sucrose or starch with or without viable Lactobacillus rhamnosus GG cells. GG significantly inhibited postprandial blood glucose levels when administered with sucrose or starch. In Experiment 2, KK-A(y) mice, a model of genetic type 2 diabetes, were given a basal diet containing viable GG cells or viable Lactobacillus delbrueckii subsp. bulgaricus cells for 6 weeks. Viable GG cells significantly inhibited fasting blood glucose, postprandial blood glucose in a glucose tolerance test and HbA1c. Such effects were not shown by viable L. bulgaricus cells. In Experiment 3, the KK-A(y) mice were given a basal diet containing viable GG cells or heat-treated GG cells for 3 weeks. The viable GG cells significantly suppressed fasting blood glucose and impaired glucose tolerance, but the heat-treated GG showed no effects. These results demonstrated that GG decreased the postprandial blood glucose in ICR mice, and that the antidiabetic activity of lactic acid bacteria on the KK-A(y) mice differed depending on the bacterial strain and whether the bacterium is viable when it arrives in the intestine. In the present study, we conclude that the antidiabetic activity may result from continuous inhibition of the postprandial blood glucose through suppression of glucose absorption from the intestine. These findings indicate that specific strains of lactic acid bacterium can be expected to be beneficial for the management of type 2 diabetes. PMID:22962525

Honda, Kayoko; Moto, Mihoko; Uchida, Naoko; He, Fang; Hashizume, Naotaka

2012-09-01

198

Coronary blood flow in chronic insulin-dependent diabetic dogs.  

PubMed

Diabetic patients appear to be at an increased risk for perioperative morbidity and mortality following coronary artery bypass grafting. Many have suggested that microangiopathy is a primary cause. Using radionuclide labelled microspheres, we measured the perfusion of the subendocardium, midmyocardium, subepicardium, and the subendocardium/subepicardium ratio in alloxan-induced diabetic and normal dogs. We found no statistical difference in the myocardial perfusion of dogs made diabetic for five months when compared to normal dogs. By using repeated measures two-factor analysis of variance-regression model, changing blood glucose levels had no effect on coronary blood flow in either the diabetic or normal dogs. PMID:2629449

Small, K W; Stefansson, E; Hatchell, D L

1989-01-01

199

Rotavirus Infection Accelerates Type 1 Diabetes in Mice with Established Insulitis  

Microsoft Academic Search

Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen,

Kate L. Graham; Natalie Sanders; Yan Tan; Janette Allison; Thomas W. H. Kay; Barbara S. Coulson

2008-01-01

200

Improved Cutaneous Healing in Diabetic Mice Exposed to Healthy Peripheral Circulation  

Microsoft Academic Search

Impaired repair of skin defects is a major complication of diabetes; yet, the pathophysiology of diabetic (db) wound healing remains largely opaque. Here, we investigate the role of humoral factors in modulating db wound repair by generating chimeric animals through parabiotic joining of wild-type (wt) and diabetic (db\\/db) mice. This strategy allows wounds on healing-deficient db\\/db mice to be exposed

Giorgio Pietramaggiori; Sandra S Scherer; Michael Alperovich; Bin Chen; Dennis P Orgill; Amy J Wagers

2009-01-01

201

B cells and type 1 diabetes …in mice and men.  

PubMed

Nearly 70% of newly produced B cells express autoreactive antigen receptors and must be silenced to prevent autoimmunity. Failure of silencing mechanisms is apparent in type 1 diabetes (T1D), where islet antigen-specific B cells appear critical for development of disease. Evidence for a B cell role in T1D includes success of B cell targeted anti-CD20 therapy, which delays T1D progression in both NOD mice and new onset patients. Demonstrating the importance of specificity, NOD mice whose B cell repertoire is biased toward insulin reactivity show increased disease development, while bias away from insulin reactivity largely prevents disease. Finally, though not required for illness, high affinity insulin autoantibodies are often the first harbingers of T1D. B cell cytokine production and auto-antigen presentation to self-reactive T cells are likely important in pathogenesis. Here we review B cell function, as described above, in T1D in humans and the non-obese diabetic (NOD) mouse. We will discuss recent broad-based B cell depletion studies and how they may provide the basis for refinement of future treatments for the disorder. PMID:24472603

Hinman, Rochelle M; Smith, Mia J; Cambier, John C

2014-08-01

202

Influences of crude extract of tea leaves, Camellia sinensis, on streptozotocin diabetic male albino mice  

PubMed Central

Natural remedies from medicinal plants are considered to be effective and safe alternative treatment for diabetes mellitus. The aim of the present study was to investigate the hypoglycemic activity of the crude tea leaves extract on streptozotocin (STZ)-induced diabetic mice. The average body weight of animals with diabetes and their percentage changes of body weight gain after 15 and 30 days were significantly lower than that of the normal control mice. In diabetic mice, supplementation with tea leaves extract decreased the loss of body weight. After 15 and 30 days, significant increases in the levels of serum glucose, triglycerides, cholesterol, creatinine, urea, uric acid, glutamic pyruvic acid transaminase (GPT) and glutamic oxaloacetic acid transaminase (GOT) were noted in STZ-diabetic mice fed with normal diet. Also, the values of total protein in this group were statistically declined after 15 and 30 days. The levels of serum glucose and GPT were significantly elevated after 15 and 30 days in diabetic mice supplemented with tea leaves extract. Moreover, the level of serum GOT was notably increased after 30 days. Insignificant alterations were observed in the levels of serum triglycerides, cholesterol, total protein, creatinine, urea and uric acid in diabetic mice supplemented with tea leaves extract. Thus, the present results have shown that tea leaves extract has the antihyperglycemic, antihyperlipidemic, and antihyperproteinemic effects and consequently may alleviate liver and kidney damage associated with STZ-induced diabetes in mice.

Al-Attar, Atef M.; Zari, Talal A.

2010-01-01

203

Influences of crude extract of tea leaves, Camellia sinensis, on streptozotocin diabetic male albino mice.  

PubMed

Natural remedies from medicinal plants are considered to be effective and safe alternative treatment for diabetes mellitus. The aim of the present study was to investigate the hypoglycemic activity of the crude tea leaves extract on streptozotocin (STZ)-induced diabetic mice. The average body weight of animals with diabetes and their percentage changes of body weight gain after 15 and 30 days were significantly lower than that of the normal control mice. In diabetic mice, supplementation with tea leaves extract decreased the loss of body weight. After 15 and 30 days, significant increases in the levels of serum glucose, triglycerides, cholesterol, creatinine, urea, uric acid, glutamic pyruvic acid transaminase (GPT) and glutamic oxaloacetic acid transaminase (GOT) were noted in STZ-diabetic mice fed with normal diet. Also, the values of total protein in this group were statistically declined after 15 and 30 days. The levels of serum glucose and GPT were significantly elevated after 15 and 30 days in diabetic mice supplemented with tea leaves extract. Moreover, the level of serum GOT was notably increased after 30 days. Insignificant alterations were observed in the levels of serum triglycerides, cholesterol, total protein, creatinine, urea and uric acid in diabetic mice supplemented with tea leaves extract. Thus, the present results have shown that tea leaves extract has the antihyperglycemic, antihyperlipidemic, and antihyperproteinemic effects and consequently may alleviate liver and kidney damage associated with STZ-induced diabetes in mice. PMID:23961092

Al-Attar, Atef M; Zari, Talal A

2010-10-01

204

Inhibition of Diabetes in NOD Mice by Idiotypic Induction of SLE  

Microsoft Academic Search

The present study was undertaken to investigate whether active induction of systemic lupus erythematosus (SLE) in non-obese diabetic (NOD) mice could affect their development of insulin-dependent diabetes mellitus (IDDM). NOD mice were immunized with a human IgM mAb carrying the 16\\/6 idiotype (MIV-7) or with control human IgM. The mice were bled monthly and tested for SLE-associated autoantibodies in the

I. Krause; Y. Tomer; D. Elias; M. Blank; B. Gilburd; I. R. Cohen; Y. Shoenfeld

1999-01-01

205

Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice  

PubMed Central

We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and phosphorylation of p38, c-Jun NH2-terminal kinase (JNK), and extracellular signal–regulated kinase (Erk) were assessed in mesenteric arteries of 3- (3M) and 9-month-old (9M) male diabetic and control mice. The expression of p38, JNK, and Erk was comparable in all groups of mice, but the phosphorylation of p38 and JNK was increased in 3M and further increased in 9M diabetic mice, whereas the phosphorylation of Erk was substantially reduced in 9M diabetic mice. NADPH oxidase–dependent superoxide production was significantly increased in vessels of two ages of diabetic mice. Inhibition of either p38 with SB203580 or JNK with SP600125 reduced superoxide production and improved shear stress–induced dilation (SSID) in 3M, but not in 9M, diabetic mice. Treating the vessels of 9M diabetic mice with resveratrol increased Erk phosphorylation and shear stress–induced endothelial nitric oxide synthase (eNOS) phosphorylation and activity, but resveratrol alone did not improve SSID. Administration of resveratrol and SB203580 or resveratrol and SP600125 together significantly improved SSID in vessels of 9M diabetic mice. The improved response was prevented by U0126, an Erk inhibitor. Thus, p38/JNK-dependent increase in oxidative stress diminished nitric oxide–mediated dilation in vessels of 3M diabetic mice. Oxidative stress and impaired Erk-dependent activation of eNOS exacerbates endothelial dysfunction in the advanced stage of diabetes.

Huang, An; Yang, Yang-Ming; Yan, Changdong; Kaley, Gabor; Hintze, Thomas H.; Sun, Dong

2012-01-01

206

Endothelial Arginine Resynthesis Contributes to the Maintenance of Vasomotor Function in Male Diabetic Mice  

PubMed Central

Aim Argininosuccinate synthetase (ASS) is essential for recycling L-citrulline, the by-product of NO synthase (NOS), to the NOS substrate L-arginine. Here, we assessed whether disturbed arginine resynthesis modulates endothelium-dependent vasodilatation in normal and diabetic male mice. Methods and Results Endothelium-selective Ass-deficient mice (Assfl/fl/Tie2Cretg/??=?Ass-KOTie2) were generated by crossing Assfl/fl mice (?=?control) with Tie2Cre mice. Gene ablation in endothelial cells was confirmed by immunohistochemistry. Blood pressure (MAP) was recorded in 34-week-old male mice. Vasomotor responses were studied in isolated saphenous arteries of 12- and 34-week-old Ass-KOTie2 and control animals. At the age of 10 weeks, diabetes was induced in control and Ass-KOTie2 mice by streptozotocin injections. Vasomotor responses of diabetic animals were studied 10 weeks later. MAP was similar in control and Ass-KOTie2 mice. Depletion of circulating L-arginine by arginase 1 infusion or inhibition of NOS activity with L-NAME resulted in an increased MAP (10 and 30 mmHg, respectively) in control and Ass-KOTie2 mice. Optimal arterial diameter, contractile responses to phenylephrine, and relaxing responses to acetylcholine and sodium nitroprusside were similar in healthy control and Ass-KOTie2 mice. However, in diabetic Ass-KOTie2 mice, relaxation responses to acetylcholine and endothelium-derived NO (EDNO) were significantly reduced when compared to diabetic control mice. Conclusions Absence of endothelial citrulline recycling to arginine did not affect blood pressure and systemic arterial vasomotor responses in healthy mice. EDNO-mediated vasodilatation was significantly more impaired in diabetic Ass-KOTie2 than in control mice demonstrating that endothelial arginine recycling becomes a limiting endothelial function in diabetes.

Chennupati, Ramesh; Meens, Merlijn J. P. M. T.; Marion, Vincent; Janssen, Ben J.; Lamers, Wouter H.; De Mey, Jo G. R.; Kohler, S. Eleonore

2014-01-01

207

Prophylactic oral administration of metabolically active insulin entrapped in isobutylcyanoacrylate nanocapsules reduces the incidence of diabetes in nonobese diabetic mice.  

PubMed

Nonobese diabetic (NOD) mice develop an autoimmune disease with a long prodromal period and constitute a model for investigating the prevention of human type 1 diabetes. Since prophylactic insulin injections reduced the incidence of diabetes in NOD mice, we tested a new prophylactic strategy to prevent diabetes in NOD mice consisting of oral administration of insulin, protected in polyalkylcyanoacrylate nanocapsules from degradation in the gastrointestinal tract. In humans, this form of prophylactic insulin administration would be less constraining than insulin injections. Ninety female NOD mice were randomized at weaning and fed once a week (from 60 to 300 days of age) with insulin nanocapsules (100 U/kg) or empty nanocapsules. Within the group fed with insulin nanocapsules, the incidence of diabetes was reduced (38% vs 75%; P < 0.02), the onset of disease was delayed (P < 0.02), and the severity of lymphocytic inflammation of endogenous islets was reduced (P < 0.03). Although the oral treatment was stopped at 300 days of age, the incidence of diabetes at 360 days remained lower in mice previously fed insulin nanocapsules (P < 0.02). Previous feedings with insulin nanocapsules did not protect against cyclophosphamide-induced diabetes, since final incidence of diabetes (sum of the incidence during the initial 360 days and the further CY-induced incidence) reached the final incidence obtained in mice previously fed empty nanocapsules and treated with cyclophosphamide. Intestinal absorption of insulin nanocapsules was evidenced by HPLC separation of human insulin in NOD sera. During cotransfer, T splenocytes from mice fed insulin nanocapsules were able to reduce the capacity of T cells from diabetic donors to adoptively transfer the disease (P < 0.01). Antigens for islet-cell autoantibodies (ICA) in pancreata from both NOD groups were compared by immunofluorescence with the same ICA-positive human sera to ensure that differences were due to quantitative changes in antigen. These antigens, which could serve as an index of a possibly more extended antigen beta-cell rest, were decreased (P < 0.02) and pancreatic insulin content was reduced (P < 0.05) in mice fed with insulin nanocapsules, suggesting a mechanism of 'beta cell rest'. To summarize, early feeding with insulin nanocapsules reduces diabetes and insulitis in the NOD mouse model that mimics human type 1 diabetes. This may be due both to generation of cellular mechanisms that actively suppress disease and a decrease in antigens which makes beta cells less vulnerable to autoimmune aggression. PMID:9115573

Saï, P; Damagé, C; Rivereau, A S; Hoeltzel, A; Gouin, E

1996-12-01

208

Telmisartan treatment ameliorates memory deficits in streptozotocin-induced diabetic mice via attenuating cerebral amyloidosis.  

PubMed

Telmisartan, an angiotensin II type 1-receptor blocker (ARBs), has been reported to exert beneficial effects on the central nervous system (CNS). However, the effect of telmisartan on cognitive impairment associated with type 1 diabetes is not well known. Here, we examined the possibility that telmisartan could improve memory function in a type 1 diabetic mouse model, streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice subjected to the Morris Water Maze (MWM) task exhibited a significant decline of spatial learning and memory. Oral administration of telmisartan at two nonhypotensive doses (0.7 or 0.35 mg/kg) significantly improved memory deficits in STZ-induced diabetic mice. Telmisartan treatment markedly reduced A???, APP, BACE1, RAGE, and NF-?B p65 of the hippocampus and cortex, but did not beneficially affect hyperglycemia and hypoinsulinemia in the STZ-induced diabetic mice compared with untreated diabetic mice. Taken together, our findings suggest that telmisartan ameliorates memory deficits in type 1 diabetic mice, at least partly because of attenuation of amyloidosis in the brain. PMID:24671053

Du, Guan Tao; Hu, Meng; Mei, Zhen Lin; Wang, Chao; Liu, Guang Jun; Hu, Mei; Long, Yan; Miao, Ming Xing; Chang Li, Jia; Hong, Hao

2014-01-01

209

Portulaca oleracea Ameliorates Diabetic Vascular Inflammation and Endothelial Dysfunction in db/db Mice  

PubMed Central

Type 2 diabetes is associated with significantly accelerated rates of micro- and macrovascular complications such as diabetic vascular inflammation and endothelial dysfunction. In the present study, we investigated the protective effect of the aqueous extract of Portulaca oleracea L. (AP), an edible plant used as a folk medicine, on diabetic vascular complications. The db/db mice were treated with AP (300?mg/kg/day, p.o.) for 10 weeks, and AP treatment markedly lowered blood glucose, plasma triglyceride, plasma level of LDL-cholesterol, and systolic blood pressure in diabetic db/db mice. Furthermore, AP significantly increased plasma level of HDL-cholesterol and insulin level. The impairment of ACh- and SNP-induced vascular relaxation of aortic rings were ameliorated by AP treatment in diabetic db/db mice. This study also showed that overexpression of VCAM-1, ICAM-1, E-selectin, MMP-2, and ET-1 were observed in aortic tissues of untreated db/db mice, which were significantly suppressed by treatment with AP. We also found that the insulin immunoreactivity of the pancreatic islets remarkably increased in AP treated db/db mice compared with untreated db/db mice. Taken together, AP suppresses hyperglycemia and diabetic vascular inflammation, and prevents the development of diabetic endothelial dysfunction for the development of diabetes and its vascular complications.

Lee, An Sook; Lee, Yun Jung; Lee, So Min; Yoon, Jung Joo; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

2012-01-01

210

Portulaca oleracea Ameliorates Diabetic Vascular Inflammation and Endothelial Dysfunction in db/db Mice.  

PubMed

Type 2 diabetes is associated with significantly accelerated rates of micro- and macrovascular complications such as diabetic vascular inflammation and endothelial dysfunction. In the present study, we investigated the protective effect of the aqueous extract of Portulaca oleracea L. (AP), an edible plant used as a folk medicine, on diabetic vascular complications. The db/db mice were treated with AP (300?mg/kg/day, p.o.) for 10 weeks, and AP treatment markedly lowered blood glucose, plasma triglyceride, plasma level of LDL-cholesterol, and systolic blood pressure in diabetic db/db mice. Furthermore, AP significantly increased plasma level of HDL-cholesterol and insulin level. The impairment of ACh- and SNP-induced vascular relaxation of aortic rings were ameliorated by AP treatment in diabetic db/db mice. This study also showed that overexpression of VCAM-1, ICAM-1, E-selectin, MMP-2, and ET-1 were observed in aortic tissues of untreated db/db mice, which were significantly suppressed by treatment with AP. We also found that the insulin immunoreactivity of the pancreatic islets remarkably increased in AP treated db/db mice compared with untreated db/db mice. Taken together, AP suppresses hyperglycemia and diabetic vascular inflammation, and prevents the development of diabetic endothelial dysfunction for the development of diabetes and its vascular complications. PMID:22474522

Lee, An Sook; Lee, Yun Jung; Lee, So Min; Yoon, Jung Joo; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

2012-01-01

211

Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice.  

PubMed

Mounting evidence supports a link between diabetes, cognitive dysfunction, and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age-associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence-accelerated prone 8 (SAMP8) and senescence-resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in the development of cognitive deficits in SAMR1 mice similar to those seen in age-matched, nondiabetic SAMP8 mice. No further cognitive deficits were observed when the SAMP8 mice were made diabetic. T1D dramatically increased A? and glial fibrillary acidic protein immunoreactivity in the hippocampus of SAMP8 mice and to a lesser extent in age-matched SAMR1 mice. Further analysis revealed aggregated A? within astrocyte processes surrounding vessels. Western blot analyses from T1D SAMP8 mice showed elevated amyloid precursor protein processing and protein glycation along with increased inflammation. T1D elevated tau phosphorylation in the SAMR1 mice but did not further increase it in the SAMP8 mice where it was already significantly higher. These data suggest that aberrant glucose metabolism potentiates the aging phenotype in old mice and contributes to early stage central nervous system pathology in younger animals. PMID:22938075

Currais, Antonio; Prior, Marguerite; Lo, David; Jolivalt, Corinne; Schubert, David; Maher, Pamela

2012-12-01

212

Apolipoprotein E4 Exaggerates Diabetic Dyslipidemia and Atherosclerosis in Mice Lacking the LDL Receptor  

PubMed Central

OBJECTIVE We investigated the differential roles of apolipoprotein E (apoE) isoforms in modulating diabetic dyslipidemia—a potential cause of the increased cardiovascular disease risk of patients with diabetes. RESEARCH DESIGN AND METHODS Diabetes was induced using streptozotocin (STZ) in human apoE3 (E3) or human apoE4 (E4) mice deficient in the LDL receptor (LDLR?/?). RESULTS Diabetic E3LDLR?/? and E4LDLR?/? mice have indistinguishable levels of plasma glucose and insulin. Despite this, diabetes increased VLDL triglycerides and LDL cholesterol in E4LDLR?/? mice twice as much as in E3LDLR?/? mice. Diabetic E4LDLR?/? mice had similar lipoprotein fractional catabolic rates compared with diabetic E3LDLR?/? mice but had larger hepatic fat stores and increased VLDL secretion. Diabetic E4LDLR?/? mice demonstrated a decreased reliance on lipid as an energy source based on indirect calorimetry. Lower phosphorylated acetyl-CoA carboxylase content and higher gene expression of fatty acid synthase in the liver indicated reduced fatty acid oxidation and increased fatty acid synthesis. E4LDLR?/? primary hepatocytes cultured in high glucose accumulated more intracellular lipid than E3LDLR?/? hepatocytes concomitant with a 60% reduction in fatty acid oxidation. Finally, the exaggerated dyslipidemia in diabetic E4LDLR?/? mice was accompanied by a dramatic increase in atherosclerosis. CONCLUSIONS ApoE4 causes severe dyslipidemia and atherosclerosis independent of its interaction with LDLR in a model of STZ-induced diabetes. ApoE4-expressing livers have reduced fatty acid oxidation, which contributes to the accumulation of tissue and plasma lipids.

Johnson, Lance A.; Arbones-Mainar, Jose M.; Fox, Raymond G.; Pendse, Avani A.; Altenburg, Michael K.; Kim, Hyung-Suk; Maeda, Nobuyo

2011-01-01

213

Nonobese Diabetic (NOD) Mice Congenic for a Targeted Deletion of 12/15-Lipoxygenase Are Protected From Autoimmune Diabetes  

PubMed Central

OBJECTIVE 12/15-lipoxygenase (12/15-LO), one of a family of fatty acid oxidoreductase enzymes, reacts with polyenoic fatty acids to produce proinflammatory lipids. 12/15-LO is expressed in macrophages and pancreatic ?-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of ?-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in ?-cell damage in the streptozotocin model of diabetes. Since the gene encoding 12/15-LO (gene designation Alox15) lies within the Idd4 diabetes susceptibility interval in NOD mice, we hypothesized that 12/15-LO is also a key regulator of diabetes susceptibility in the NOD mouse. RESEARCH DESIGN AND METHODS We developed NOD mice carrying an inactivated 12/15-LO locus (NOD-Alox15null) using a “speed congenic” protocol, and the mice were monitored for development of insulitis and diabetes. RESULTS NOD mice deficient in 12/15-LO develop diabetes at a markedly reduced rate compared with NOD mice (2.5 vs. >60% in females by 30 weeks). Nondiabetic female NOD-Alox15null mice demonstrate improved glucose tolerance, as well as significantly reduced severity of insulitis and improved ?-cell mass, when compared with age-matched nondiabetic NOD females. Disease resistance is associated with decreased numbers of islet-infiltrating activated macrophages at 4 weeks of age in NOD-Alox15null mice, preceding the development of insulitis. Subsequently, islet-associated infiltrates are characterized by decreased numbers of CD4+ T cells and increased Foxp3+ cells. CONCLUSIONS These results suggest an important role for 12/15-LO in conferring susceptibility to autoimmune diabetes in NOD mice through its effects on macrophage recruitment or activation.

McDuffie, Marcia; Maybee, Nelly A.; Keller, Susanna R.; Stevens, Brian K.; Garmey, James C.; Morris, Margaret A.; Kropf, Elizabeth; Rival, Claudia; Ma, Kaiwen; Carter, Jeffrey D.; Tersey, Sarah A.; Nunemaker, Craig S.; Nadler, Jerry L.

2010-01-01

214

Impact of experimental type 1 diabetes mellitus on systemic and coagulation vulnerability in mice acutely exposed to diesel exhaust particles  

PubMed Central

Background Epidemiological evidence indicates that diabetic patients have increased susceptibility to adverse cardiovascular outcomes related to acute increases in exposures to particulate air pollution. However, mechanisms underlying these effects remain unclear. Methods To evaluate the possible mechanisms underlying these actions, we assessed the systemic effects of diesel exhaust particles (DEP) in control mice, and mice with streptozotocin–induced type 1 diabetes. Four weeks following induction of diabetes, the animals were intratracheally instilled (i.t.) with DEP (0.4 mg/kg) or saline, and several cardiovascular endpoints were measured 24 h thereafter. Results DEP caused leukocytosis and a significant increase in plasma C-reactive protein and 8-isoprostane concentrations in diabetic mice compared to diabetic mice exposed to saline or non-diabetic mice exposed to DEP. The arterial PO2 as well as the number of platelets and the thrombotic occlusion time in pial arterioles assessed in vivo were significantly decreased following the i.t. instillation of DEP in diabetic mice compared to diabetic mice exposed to saline or non-diabetic mice exposed to DEP. Both alanine aminotransferase and aspartate transaminase activities, as well as the plasma concentrations of plasminogen activator inhibitor and von Willebrand factor were significantly increased in DEP-exposed diabetic mice compared to diabetic mice exposed to saline or DEP-exposed non-diabetic mice. The in vitro addition of DEP (0.25-1 ?g/ml) to untreated mouse blood significantly and dose-dependently induced in vitro platelet aggregation, and these effects were exacerbated in blood of diabetic mice. Conclusion This study has shown that systemic and coagulation events are aggravated by type 1 diabetes in mice, acutely exposed to DEP and has described the possible mechanisms for these actions that may also be relevant to the exacerbation of cardiovascular morbidity accompanying particulate air pollution in diabetic patients.

2013-01-01

215

Experimental diabetes attenuates calcium mobilization and proliferative response in splenic lymphocytes from mice  

Microsoft Academic Search

The present study was conducted to investigate the effects of the diabetic condition on cytosolic free Ca2+ concentration, [Ca2+]i, and the proliferation of splenic lymphocytes from mice. Diabetes was induced in mice by intraperitoneal injection of alloxan.\\u000a [Ca2+]i and the proliferation ex vivo of splenic lymphocytes isolated from mice were examined using fura-2 and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium\\u000a bromide, respectively. Diabetes caused a

Eiki Satoh; Ryota Iwasaki

2011-01-01

216

Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system.  

PubMed

Diabetes is a persistent metabolic disorder, which often leads to depression as a result of the impaired neurotransmitter function. Insulin is believed to have antidepressant effects in depression associated with diabetes; however, the mechanism underlying the postulated effect is poorly understood. In the present study, it is hypothesized that insulin mediates an antidepressant effect in streptozotocin (STZ) induced diabetes in mice through modulation of the serotonin system in the brain. Therefore, the current study investigated the antidepressant effect of insulin in STZ induced diabetes in mice and insulin mediated modulation in the brain serotonin system. In addition, the possible pathways that lead to altered serotonin levels as a result of insulin administration were examined. Experimentally, Swiss albino mice of either sex were rendered diabetic by a single intraperitoneal (i.p.) injection of STZ. After one week, diabetic mice received a single dose of either insulin or saline or escitalopram for 14days. Thereafter, behavioral studies were conducted to test the behavioral despair effects using forced swim test (FST) and tail suspension test (TST), followed by biochemical estimations of serotonin concentrations and monoamine oxidase (MAO) activity in the whole brain content. The results demonstrated that, STZ treated diabetic mice exhibited an increased duration of immobility in FST and TST as compared to non-diabetic mice, while insulin treatment significantly reversed the effect. Biochemical assays revealed that administration of insulin attenuated STZ treated diabetes induced neurochemical alterations as indicated by elevated serotonin levels and decreased MAO-A and MAO-B activities in the brain. Collectively, the data indicate that insulin exhibits antidepressant effects in depression associated with STZ induced diabetes in mice through the elevation of the brain serotonin levels. PMID:24582678

Gupta, Deepali; Kurhe, Yeshwant; Radhakrishnan, Mahesh

2014-04-22

217

RAGE Deficiency Improves Postinjury Sciatic Nerve Regeneration in Type 1 Diabetic Mice  

PubMed Central

Peripheral neuropathy and insensate limbs and digits cause significant morbidity in diabetic individuals. Previous studies showed that deletion of the receptor for advanced end-glycation products (RAGE) in mice was protective in long-term diabetic neuropathy. Here, we tested the hypothesis that RAGE suppresses effective axonal regeneration in superimposed acute peripheral nerve injury attributable to tissue-damaging inflammatory responses. We report that deletion of RAGE, particularly in diabetic mice, resulted in significantly higher myelinated fiber densities and conduction velocities consequent to acute sciatic nerve crush compared with wild-type control animals. Consistent with key roles for RAGE-dependent inflammation, reconstitution of diabetic wild-type mice with RAGE-null versus wild-type bone marrow resulted in significantly improved axonal regeneration and restoration of function. Diabetic RAGE-null mice displayed higher numbers of invading macrophages in the nerve segments postcrush compared with wild-type animals, and these macrophages in diabetic RAGE-null mice displayed greater M2 polarization. In vitro, treatment of wild-type bone marrow–derived macrophages with advanced glycation end products (AGEs), which accumulate in diabetic nerve tissue, increased M1 and decreased M2 gene expression in a RAGE-dependent manner. Blockade of RAGE may be beneficial in the acute complications of diabetic neuropathy, at least in part, via upregulation of regeneration signals.

Juranek, Judyta K.; Geddis, Matthew S.; Song, Fei; Zhang, Jinghua; Garcia, Jose; Rosario, Rosa; Yan, Shi Fang; Brannagan, Thomas H.; Schmidt, Ann Marie

2013-01-01

218

Impaired sensory nerve function and axon morphology in mice with diabetic neuropathy  

PubMed Central

Diabetes is the most prevalent metabolic disorder in the United States, and between 50% and 70% of diabetic patients suffer from diabetes-induced neuropathy. Yet our current knowledge of the functional changes in sensory nerves and their distal terminals caused by diabetes is limited. Here, we set out to investigate the functional and morphological consequences of diabetes on specific subtypes of cutaneous sensory nerves in mice. Diabetes was induced in C57Bl/6 mice by a single intraperitoneal injection of streptozotocin. After 6–8 wk, mice were characterized for behavioral sensitivity to mechanical and heat stimuli followed by analysis of sensory function using teased nerve fiber recordings and histological assessment of nerve fiber morphology. Diabetes produced severe functional impairment of C-fibers and rapidly adapting A?-fibers, leading to behavioral hyposensitivity to both mechanical and heat stimuli. Electron microscopy images showed that diabetic nerves have axoplasm with more concentrated organelles and frequent axon-myelin separations compared with control nerves. These changes were restricted to the distal nerve segments nearing their innervation territory. Furthermore, the relative proportion of A?-fibers was reduced in diabetic skin-nerve preparations compared with nondiabetic control mice. These data identify significant deficits in sensory nerve terminal function that are associated with distal fiber loss, morphological damage, and behavioral hyposensitivity in diabetic C57Bl/6 mice. These findings suggest that diabetes damages sensory nerves, leading to functional deficits in sensory signaling that underlie the loss of tactile acuity and pain sensation associated with insensate diabetic neuropathy.

Lennertz, Richard C.; Medler, Karen A.; Bain, James L.; Wright, Douglas E.

2011-01-01

219

Fentanyl produces an anti-hyperalgesic effect through the suppression of sodium channels in mice with painful diabetic neuropathy.  

PubMed

Diabetic neuropathy is one of the most frequent complications of diabetes mellitus. Therefore, the present study was designed to investigate the anti-hyperalgesic mechanism of fentanyl in a mouse model of streptozotocin-induced diabetic neuropathy. The antinociceptive response was assessed by recording the latency in a tail-flick test. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. Fentanyl, at doses of 3 and 10?g/kg, s.c., produced a dose-dependent increase in the tail-flick latencies in diabetic mice. While fentanyl (3?g/kg, s.c.) did not produce a significant inhibition of the tail-flick response in non-diabetic mice, it significantly prolonged the tail-flick latency in diabetic mice to the same level as the baseline latency in non-diabetic mice. Although pretreatment with naloxone (3mg/kg, s.c.) completely antagonized fentanyl-induced antinociception in non-diabetic mice, it had no effect on the antinociceptive effect of fentanyl in diabetic mice. Pretreatment with either of the voltage-gated sodium channel openers fenvarelarte and veratridine practically abolished the antinociceptive effects of fentanyl in diabetic mice. However, neither fenvarelate nor veratridine affected the antinociceptive effect of fentanyl in non-diabetic mice. These results suggest that the anti-hyperalgesic effect of fentanyl is mediated through the blockade of sodium channels in diabetic mice, whereas opioid receptors mediate the antinociceptive effect of fentanyl in non-diabetic mice. PMID:24704555

Tanaka, Ken-Ichiro; Nakanishi, Yuki; Sekino, Shyota; Ikegami, Megumi; Ikeda, Hiroko; Kamei, Junzo

2014-06-15

220

Dietary Flavonol Epicatechin Prevents the Onset of Type 1 Diabetes in Non-obese Diabetic (NOD) Mice  

PubMed Central

Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective destruction of pancreatic ?-cells. Although successful islet transplantation provides a promising treatment, high cost, lack of donor organs, immune-mediated destruction of transplanted islets, and side effects from immunosuppressive drugs greatly limit its uses. Therefore, the search for novel and cost-effective agents that can prevent or ameliorate T1D is extremely important to decrease the burden of T1D. In this study, we discovered that epicatechin (EC, 0.5% in drinking water), a flavonol primarily in cocoa, effectively prevented T1D in non-obese diabetic (NOD) mice. At 32 weeks of age, 66.7% control mice had overt diabetes, whereas only 16.6% EC-treated mice became diabetic. Consistently, EC mice had significantly higher plasma insulin levels but lower glycosylated hemoglobin concentrations compared to control mice. EC had no significant effects on food or water intake and body weight gain in NOD mice, suggesting that EC’s effect was not due to alterations in these variables. Treatment with EC elevates circulating anti-inflammatory cytokine interleukin-10 levels, ameliorates pancreatic insulitis, and improved pancreatic islet mass. These findings demonstrate that EC may be a novel, plant-derived compound capable of preventing T1D by modulating immune function and thereby preserving islet mass.

Fu, Zhuo; Yuskavage, Julia; Liu, Dongmin

2013-01-01

221

Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice  

PubMed Central

Accumulating evidence favors a role for proinsulin as a key autoantigen in diabetes. In the mouse, two proinsulin isoforms coexist. Most studies point to proinsulin 2 as the major isoform recognized by T cells in the NOD mouse. We studied mice in which a null proinsulin 2 mutation was transferred from proinsulin 2–deficient 129 mice onto the NOD background along with 16 genetic markers (including I-Ag7 MHC molecule) associated with diabetes. Intercross mice from the fourth backcross generation showed that proinsulin 2–/– mice develop accelerated insulitis and diabetes. The high prevalence of anti-insulin autoantibodies in proinsulin 2–/– mice indicates that diabetes acceleration relates to altered recognition of proinsulin. The prevalence of anti–glutamic acid decarboxylase autoantibodies and of sialitis is not increased in proinsulin 2–/– mice. We give evidence that proinsulin 2 expression leads to silencing of T cells specific for an epitope shared by proinsulin 1 and proinsulin 2. In the human, alleles located in the VNTR region flanking the insulin gene control ? cell response to glucose and proinsulin expression in the thymus and are key determinants of diabetes susceptibility. Proinsulin 2–/– NOD mice provide a model to study the role of thymic expression of insulin in susceptibility to diabetes.

Thebault-Baumont, Karine; Dubois-Laforgue, Danielle; Krief, Patricia; Briand, Jean-Paul; Halbout, Philippe; Vallon-Geoffroy, Karine; Morin, Joelle; Laloux, Veronique; Lehuen, Agnes; Carel, Jean-Claude; Jami, Jacques; Muller, Sylviane; Boitard, Christian

2003-01-01

222

A soybean peptide aglycin regulates glucose homeostasis in type 2 diabetic mice via IR\\/IRS1 pathway  

Microsoft Academic Search

It has been previously reported that aglycin, a natural bioactive peptide isolated from soybean, is stable in digestive enzymes and has an anti-diabetic potential. With a view to explore the pharmacological activity of aglycin in vivo, studies have been conducted to examine its therapeutical effect in diabetic mice, administered intragastrically as an oral agent. Diabetes was induced in BALB\\/c mice

Jingli Lu; Ying Zeng; Wenrui Hou; Shasha Zhang; Lulu Li; Xiang Luo; Wei Xi; Zhengwang Chen; Ming Xiang

223

Decoy receptor 3 protects non-obese diabetic mice from autoimmune diabetes by regulating dendritic cell maturation and function  

Microsoft Academic Search

Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, regulates immune responses through competing with receptors of Fas ligand (FasL), LIGHT and TNF-like molecule 1A (TL1A). We have previously demonstrated that transgenic expression of DcR3 in a ? cell-specific manner significantly protects non-obese diabetic (NOD) mice from autoimmune diabetes. In this study, we further investigated the

Yen-Ling Wang; Feng-Cheng Chou; Hsiang-Hsuan Sung; Pao-Luo Fan; Chao-Wen Hsueh; Wen-Chi Lin; Shyi-Jou Chen; Wan-Wan Lin; Huey-Kang Sytwu

2010-01-01

224

Effects of two pediatric vaccines on autoimmune diabetes in NOD female mice  

Microsoft Academic Search

The induction or exacerbation of autoimmune diseases is a potential adverse effect of immunostimulating drugs. Vaccines have been suspected of such actions. Epidemiological studies, however, have so far failed to demonstrate any causal relationship between vaccination and autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). In this study, autoimmune diabetes-prone non-obese diabetic (NOD) mice were treated with two multivalent diphtheria, tetanus,

Guillaume Ravel; Marielle Christ; Pierre Liberge; Roger Burnett; Jacques Descotes

2003-01-01

225

Hypoglycemic effects of Ganoderma lucidum polysaccharides in type 2 diabetic mice.  

PubMed

Our aims were to investigate the hypoglycemic effects and mechanisms of action of Ganoderma lucidum polysaccharides (GLPs) administered for 7 days in type 2 diabetic mice. The mice were randomly divided into four groups (8 mice/group): normal control group, diabetic control group, low-dose GLP-treated diabetic group (50 mg/kg/d), and high-dose GLP-treated diabetic group (100 mg/kg/d). Diabetes was induced by streptozotocin injection and high-fat dietary feeding. At the end of the study, fasting serum glucose, insulin, body weight (BW) and epididymal white adipose tissue weight were measured. The hepatic mRNA levels of glycogen phosphorylase (GP), fructose-1,6-bisphosphatase (FBPase), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes were determined by real-time polymerase chain reaction. Both doses of GLPs significantly decreased fasting serum glucose, insulin and epididymal fat/BW ratio compared with the diabetic control group (p < 0.05). The hepatic mRNA levels of GP, FBPase, PEPCK and G6Pase were significantly lower in both GLP-treated groups compared with the diabetic control group. Taken together, GLPs significantly decrease fasting serum glucose levels in type 2 diabetic mice in a dose-dependent manner. The decreases in fasting serum glucose levels may be associated with decreased mRNA expression levels of several key enzymes involved in gluconeogenesis and/or glycogenolysis. PMID:23139131

Xiao, Chun; Wu, Qing-Ping; Cai, Wen; Tan, Jian-Bin; Yang, Xiao-Bing; Zhang, Ju-Mei

2012-10-01

226

Heat-killed yeast protects diabetic ketoacidotic-steroid treated mice from pulmonary mucormycosis.  

PubMed

Previous studies have shown that vaccination with heat-killed yeast, Saccharomyces cerevisiae (HKY), protects mice against systemic candidiasis, aspergillosis, cryptococcosis or coccidioidomycosis. Here we sought to define the potential use of HKY as a vaccine to protect mice from mucormycosis. Mice were vaccinated with different regimens of HKY prior to induction of diabetes. Diabetic ketoacidotic (DKA) mice were then treated with steroids prior to intratracheal challenge with Rhizopus oryzae. All regimens of HKY vaccine improved survival of DKA mice and reduced fungal burden in the primary target organ, lungs, as determined by qPCR. Furthermore, compared to mice vaccinated with diluent, vaccination with HKY substantially increased the mouse immune response as determined by detection of increased anti-Rhizopus antibody titers. Our results show that HKY protects steroid-treated DKA mice from pulmonary R. oryzae infection. Considering its demonstrated efficacy against other fungal infections, HKY is a promising candidate for development as a panfungal vaccine. PMID:24814556

Luo, Guanpingsheng; Gebremariam, Teclegiorgis; Clemons, Karl V; Stevens, David A; Ibrahim, Ashraf S

2014-06-17

227

Daintain/AIF-1 (Allograft Inflammatory Factor-1) accelerates type 1 diabetes in NOD mice  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Daintain/AIF-1 is over-expressed in the blood of NOD mice suffering from insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 stimulates white blood cell proliferation in NOD mice. Black-Right-Pointing-Pointer Daintain/AIF-1 increases blood glucose levels and triggers type 1 diabetes. Black-Right-Pointing-Pointer Daintain/AIF-1 accelerates insulitis, while its antibody prevents insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 enhances the levels of nitric oxide in the pancreases of NOD mice. -- Abstract: A large body of experimental evidence suggests that cytokines trigger pancreatic {beta}-cell death in type 1 diabetes mellitus. Daintain/AIF-1 (Allograft Inflammatory Factor-1), a specific marker for activated macrophages, is accumulated in the pancreatic islets of pre-diabetic BB rats. In the present study, we demonstrate that daintain/AIF-1 is released into blood and the levels of daintain/AIF-1 in the blood of type 1 diabetes-prone non-obese diabetic (NOD) mice suffering from insulitis are significantly higher than that in healthy NOD mice. When injected intravenously into NOD mice, daintain/AIF-1 stimulates white blood cell proliferation, increases the concentrations of blood glucose, impairs insulin expression, up-regulates nitric oxide (NO) production in pancreases and accelerates diabetes in NOD mice, while the antibody against daintain/AIF-1 delays or prevents insulitis in NOD mice. These results imply daintain/AIF-1 triggers type 1 diabetes probably via arousing immune cells activation and induction of NO production in pancreas of NOD mice.

Zhao, Yan-Ying, E-mail: biozyy@163.com [College of Life Science and Technology, Southwest University for Nationalities, Chengdu 610041 (China)] [College of Life Science and Technology, Southwest University for Nationalities, Chengdu 610041 (China); Huang, Xin-Yuan [College of Life Science and Technology, Hubei Engineering University, Xiaogan 432000 (China)] [College of Life Science and Technology, Hubei Engineering University, Xiaogan 432000 (China); Chen, Zheng-Wang [Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074 (China)] [Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074 (China)

2012-10-26

228

Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody  

PubMed Central

Inflammatory destruction of insulin-producing ? cells in the pancreatic islets is the hallmark of insulin-dependent diabetes mellitus, a spontaneous autoimmune disease of non-obese diabetic mice resembling human juvenile (type I) diabetes. Histochemical analysis of diabetic pancreata revealed that mononuclear cells infiltrating the islets and causing autoimmune insulitis, as well as local islet cells, express the CD44 receptor; hyaluronic acid, the principal ligand of CD44, is detected in the islet periphery and islet endothelium. Injection of anti-CD44 mAb 1 hr before cell transfer of diabetogenic splenocytes and subsequently on alternate days for 4 weeks induced considerable resistance to diabetes in recipient mice, reflected by reduced insulitis. Contact sensitivity to oxazolone was not influenced by this treatment. A similar antidiabetic effect was observed even when the anti-CD44 mAb administration was initiated at the time of disease onset: i.e., 4–7 weeks after cell transfer. Administration of the enzyme hyaluronidase also induced appreciable resistance to insulin-dependent diabetes mellitus, suggesting that the CD44–hyaluronic acid interaction is involved in the development of the disease. These findings demonstrate that CD44-positive inflammatory cells may be a potential therapeutic target in insulin-dependent diabetes.

Weiss, Lola; Slavin, Shimon; Reich, Shoshana; Cohen, Patrizia; Shuster, Svetlana; Stern, Robert; Kaganovsky, Ella; Okon, Elimelech; Rubinstein, Ariel M.; Naor, David

2000-01-01

229

Cilostazol improves the response to ischemia in diabetic mice by a mechanism dependent on PPAR?.  

PubMed

Cilostazol is effective for the treatment of peripheral ischemia. This compound has several beneficial effects on platelet aggregation, serum lipids and endothelial cells, and we recently found that it enhances collateral blood flow in the ischemic hind limbs of mice. Peroxisome proliferator-activated receptor (PPAR)?, a receptor for thiazolidinediones, plays a role in angiogenesis. The aim of this work was to investigate the underlying molecular mechanisms and effects of cilostazol in a model of peripheral ischemia in diabetic mice. We induced diabetes in mice by streptozotocin (STZ) administration and studied ischemia-induced angiogenesis in the ischemic hind limbs of cilostazol-treated and untreated control mice. We found that perfusion recovery was significantly improved in treated compared with control diabetic mice. Interestingly, we found that the expression of PPAR? is reduced in ischemic tissues of diabetic mice. Furthermore, we discovered that local inhibition of the activity of this nuclear receptor decreased the angiogenic response to cilostazol treatment. Finally, we noted that this phenomenon is dependent on VEGF and modulated by PPAR?. Cilostazol administration enhances collateral blood flow in the ischemic hind limbs of STZ-induced diabetic mice through a PPAR?-dependent mechanism. PMID:23891623

Biscetti, Federico; Pecorini, Giovanni; Arena, Vincenzo; Stigliano, Egidio; Angelini, Flavia; Ghirlanda, Giovanni; Ferraccioli, Gianfranco; Flex, Andrea

2013-12-01

230

Gastric nNOS reduction accompanied by natriuretic peptides signaling pathway upregulation in diabetic mice  

PubMed Central

AIM: To investigate the relationship between neuronal nitric oxide synthase (nNOS) expression and the natriuretic peptide signaling pathway in the gastric fundus of streptozotocin (STZ)-induced diabetic mice. METHODS: Diabetic mice were induced by injection of STZ solution. Immunofluorescence labeling of HuC/D, nNOS and natriuretic peptide receptor-A, B, C (NPRs) in the gastric fundus (GF) was used to observe nNOS expression and whether NPRs exist on enteric neurons. The expression levels of nNOS and NPRs in the diabetic GF were examined by western blotting. An isometric force transducer recorded the electric field stimulation (EFS)-induced relaxation and contraction in the diabetic GF. An intracellular recording method assessed EFS-induced inhibitory junction potentials (IJP) on the GF. GF smooth muscles acquired from normal mice were incubated with different concentrations of the NPRs agonist C-type natriuretic peptide (CNP) for 24 h, after which their nNOS expressions were detected by western blotting. RESULTS: Eight weeks after injection, 43 diabetic mice were obtained from mouse models injected with STZ. Immunofluorescence indicated that the number of NOS neurons was significantly decreased and that nNOS expression was significantly downregulated in the diabetic GF. The results of physiological and electrophysiological assays showed that the EFS-induced relaxation that mainly caused by NO was significantly reduced, while the contraction was enhanced in the diabetic GF. EFS-induced IJP showed that L-NAME sensitive IJP in the diabetic GF was significantly reduced compared with control mice. However, both NPR-A and NPR-B were detected on enteric neurons, and their expression levels were upregulated in the diabetic GF. The nNOS expression level was downregulated dose-dependently in GF smooth muscle tissues exposed to CNP. CONCLUSION: These findings suggested that upregulation of the NPs signaling pathway may be involved in GF neuropathy caused by diabetes by decreasing nNOS expression.

Lu, Hong-Li; Huang, Xu; Wu, Yi-Song; Zhang, Chun-Mei; Meng, Xiang-Min; Liu, Dong-Hai; Kim, Young-chul; Xu, Wen-Xie

2014-01-01

231

Toll-Like Receptor 4 Deficiency Accelerates the Development of Insulin-Deficient Diabetes in Non-Obese Diabetic Mice  

PubMed Central

Background/Objective Toll-like receptors (TLR) mediate the recognition of microbial constituents and stress-induced endogenous ligands by the immune system. They may also be involved in the maintenance or break down of tolerance against autologous antigens. The aim of our investigation was to study the consequence of TLR4 deficiency on the development of insulin-deficient diabetes in the NOD mouse. Methods The TLR4 defect of the C57BL/10ScN mouse was backcrossed onto the NOD background and the effect of TLR4 deficiency on diabetes development was analysed by in vivo and in vitro studies. Results Compared to animals with wildtype TLR4 expression (TLR4+/+), female NOD mice carrying a homozygous TLR4 defect (TLR4?/?), showed significant acceleration of diabetes development, with a younger age at diabetes onset (TLR4+/+ 177±22 d, TLR?/?: 118±21 d; p<0.01). Pancreata of 120 d old TLR4?/? NOD mice revealed increased proportions of islets with advanced stages of immune cell infiltration compared to TLR4+/+ mice (p<0.05). TLR4 deficiency did not affect the susceptibility of islet cells to the beta cell damaging mediators nitric oxide or the inflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta and interferon gamma. The lack of TLR4 further had no effect on the frequency of regulatory T-cells but reduced their capacity to inhibit T-cell proliferation. Conclusions Our findings demonstrate that TLR4 deficiency results in an acceleration of diabetes development and immune cell infiltration of islets in NOD mice. We conclude that TLR4 is involved in the progression of the insulitis process thereby controlling the development of insulin-deficient diabetes in NOD mice.

Gulden, Elke; Ihira, Masaru; Ohashi, Atsushi; Reinbeck, Anna Lena; Freudenberg, Marina A.; Kolb, Hubert; Burkart, Volker

2013-01-01

232

Correction of Hyperglycemia with Phloridzin Restores the Glucagon Response to Glucose in Insulin-Deficient Dogs: Implications for Human Diabetes  

Microsoft Academic Search

In insulin-deprived alloxan-induced diabetic dogs with severe hyperglycemia and marked hyperglucagonemia, glucagon was not suppressed by intravenous infusion of glucose at a progressively increasing rate up to 24 mg\\/kg of body weight per min. However, when the hyperglycemia was corrected by phloridzin, a blocker of renal tubular glucose reabsorption, the hyperglucagonemia was readily suppressed by as little as 2 mg

Achim Starke; Scott Grundy; J. Denis McGarry; Roger H. Unger

1985-01-01

233

Alterations in the formation of cyclic nucleotides and prostaglandins in the lower urinary tract of the diabetic rabbit  

Microsoft Academic Search

Dysfunction of the urinary bladder is a recognised complication of diabetes mellitus (DM) which has been attributed, in part,\\u000a to a direct effect on bladder smooth muscle tissue. The objective of this study was to investigate the effect of alloxan-induced\\u000a DM on endogenous modulators of smooth muscle tone such as cyclic AMP (cAMP), cyclic GMP (cGMP) and prostaglandins. Male New

F. H. Mumtaz; C. S. Thompson; M. A. Khan; D. P. Mikhailidis; R. J. Morgan; G. D. Angelini; J. Y. Jeremy

1999-01-01

234

Induction of Type I Diabetes by Interferon-alpha in Transgenic Mice  

Microsoft Academic Search

Type I diabetes is an autoimmune disease involving an interaction between an epigenetic event (possibly a viral infection), the pancreatic beta cells, and the immune system in a genetically susceptible host. The possibility that the type I interferons could mediate this interaction was tested with transgenic mice in which the insulin-producing beta cells expressed an interferon-alpha. These mice developed a

T. A. Stewart; B. Hultgren; X. Huang; S. Pitts-Meek; J. Hully; N. J. MacLachlan

1993-01-01

235

The influence of the major histocompatibility complex (H-2) on experimental diabetes in mice  

Microsoft Academic Search

Summary  Mice with different histocompatibility loci on an identical background genome (congenic resistant lines of mice) were used to study the possible influence of the histocompatibility complex on experimental diabetes. The major histocompatibility complex (H-2) was not found to influence the diabetogenic effect of encephalomyocarditis (EMC) virus. In contrast the glucose intolerance following heterologous and homologous immunization with pancreatic antigens appeared

H. Kromann; Å. Lernmark; B. F. Vestergaard; J. Egeberg; J. Nerup

1979-01-01

236

Immunological aspect of non-obese diabetic mice: immune islet cell-killing mechanism and cell-mediated immunity  

Microsoft Academic Search

Summary  The non-obese diabetic mouse is thought to be one of the best available animal models for human Type 1 (insulin-dependent) diabetes. By 51Cr release assay we investigated cell-mediated cytotoxicity to the islet cells of Balb\\/C mice, natural killer activity, and antibody-dependent cell-mediated cytotoxicity activity of spleen lymphocytes from pre-diabetic non-obese diabetic mice. The cell-mediated cytotoxicity to islet cells of non-obese

T. Maruyama; I. Takei; M. Taniyama; K. Kataoka; S. Matsuki

1984-01-01

237

Adeno-associated virus vector-mediated IL10 gene delivery prevents type 1 diabetes in NOD mice  

Microsoft Academic Search

The development of spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice provides for their use as a model of human type 1 diabetes. To test the feasibility of muscle-directed gene therapy to prevent type 1 diabetes, we developed recombinant adeno-associated virus (rAAV) vectors containing murine cDNAs for immunomodulatory cytokines IL-4 or IL-10. Skeletal muscle transduction of female NOD mice with

Kevin Goudy; Sihong Song; Clive Wasserfall; Y. Clare Zhang; Matthias Kapturczak; Andrew Muir; Matthew Powers; Marda Scott-Jorgensen; Martha Campbell-Thompson; James M. Crawford; Tamir M. Ellis; Terence R. Flotte; Mark A. Atkinson

2001-01-01

238

Intravital imaging of CTLs killing islet cells in diabetic mice  

PubMed Central

Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing ? cells in the pancreatic islets, which are essentially mini-organs embedded in exocrine tissue. CTLs are considered to have a predominant role in the autoimmune destruction underlying T1D. Visualization of CTL-mediated killing of ? cells would provide new insight into the pathogenesis of T1D, but has been technically challenging to achieve. Here, we report our use of intravital 2-photon imaging in mice to visualize the dynamic behavior of a virally expanded, diabetogenic CTL population in the pancreas at cellular resolution. Following vascular arrest and extravasation, CTLs adopted a random motility pattern throughout the compact exocrine tissue and displayed unimpeded yet nonlinear migration between anatomically nearby islets. Upon antigen encounter within islets, a confined motility pattern was acquired that allowed the CTLs to scan the target cell surface. A minority of infiltrating CTLs subsequently arrested at the ? cell junction, while duration of stable CTL–target cell contact was on the order of hours. Slow-rate killing occurred in the sustained local presence of substantial numbers of effector cells. Collectively, these data portray the kinetics of CTL homing to and between antigenic target sites as a stochastic process at the sub-organ level and argue against a dominant influence of chemotactic gradients.

Coppieters, Ken; Amirian, Natalie; von Herrath, Matthias

2011-01-01

239

Influence of Two Different Fluences on Laser Photobiomodulation of Wound Healing in Diabetic and Nondiabetic Mice  

NASA Astrophysics Data System (ADS)

Background: Laser irradiation of wounds in mice and rats was shown in previous studies to stimulate healing but in almost all the studies the wounds were not covered. Purpose: To compare the healing of covered wounds in diabetic and nondiabetic mice and the effect of laser irradiation 660 nm at two different fluences (energy densities). Method: A single wound 5-mm diameter was made on the left flank of forty-seven diabetic and twenty nondiabetic mice and covered with Tegaderm HP dressing (day 1). Wounds were irradiated 660 nm 20 s using a low power (18 mW) or high power (80 mW) laser starting immediately post-wounding for 7 consecutive days, with non-irradiated wounds as controls. Mice were euthanized on day 8, 10 or 14. Wound specimens were cut and stained with haematoxylin and eosin, and examined by light microscopy. Results: Wound healing was impaired in diabetic mice. Tegaderm HP dressing had retarded contraction in a large proportion of diabetic mice (splinted the wounds) and to a lesser extent in nondiabetic mice. Healing of splinted wounds was delayed compared to unsplinted wounds, but laser irradiation at high power stimulated healing by re-epithelization and granulation tissue formation. The fluence of low power laser was estimated to be about 1 J/cm2, while that of the high power laser was 3.7 to 5.0 J/cm2. Conclusion: Laser irradiation of wounds 660 nm with 1 J/cm2 had little effect on healing of wounds in diabetic and nondiabetic mice, whereas irradiation with 3.7 to 5.0 J/cm2 stimulated healing of wounds in diabetic mice most of which were splinted by the dressing.

Peplow, Philip V.

2011-08-01

240

Pseudomonas aeruginosa biofilms perturb wound resolution and antibiotic tolerance in diabetic mice  

PubMed Central

Diabetic patients are more susceptible to the development of chronic wounds than non-diabetics. The impaired healing properties of these wounds, which often develop debilitating bacterial infections, significantly increase the rate of lower extremity amputation in diabetic patients. We hypothesize that bacterial biofilms, or sessile communities of bacteria that reside in a complex matrix of exopolymeric material, contribute to the severity of diabetic wounds. To test this hypothesis, we developed an in vivo chronic wound, diabetic mouse model to determine the ability of the opportunistic pathogen, Pseudomonas aeruginosa, to cause biofilm-associated infections. Utilizing this model, we observed that diabetic mice with P. aeruginosa-infected chronic wounds displayed impaired bacterial clearing and wound closure in comparison with their non-diabetic littermates. While treating diabetic mice with insulin improved their overall health, it did not restore their ability to resolve P. aeruginosa wound infections or speed healing. In fact, the prevalence of biofilms and the tolerance of P. aeruginosa to gentamicin treatment increased when diabetic mice were treated with insulin. Insulin treatment was observed to directly affect the ability of P. aeruginosa to form biofilms in vitro. These data demonstrate that the chronically wounded diabetic mouse appears to be a useful model to study wound healing and biofilm infection dynamics, and suggest that the diabetic wound environment may promote the formation of biofilms. Further, this model provides for the elucidation of mechanistic factors, such as the ability of insulin to influence antimicrobial effectiveness, which may be relevant to the formation of biofilms in diabetic wounds.

Watters, Chase; DeLeon, Katrina; Trivedi, Urvish; Griswold, John A.; Lyte, Mark; Hampel, Ken J.; Wargo, Matthew J.

2012-01-01

241

Diabetes-prone NOD mice are resistant to Mycobacterium avium and the infection prevents autoimmune disease.  

PubMed Central

It was recently proposed that the diabetes genes of non-obese diabetic (NOD) mice are linked to the Bcg gene that is associated with resistance to infection by mycobacteria; however, it has not been established whether NOD mice are resistant or susceptible to the infection, although there are previous investigations on response of NOD mice to other intracellular parasites (e.g. Kaye et al., Eur. J. Immunol. 22: 357-364). We have investigated here this question, as well as the consequences of mycobacterial infection on the natural history of murine diabetes. Female NOD mice were intraperitoneally infected with 10(8) viable bacilli of Mycobacterium avium at 2 months of age, i.e. before the mice show diabetes; they were studied up to the sixth month of age (when more than half of untreated female NOD mice show glycosuria). To determine whether NOD mice were susceptible or resistant to M. avium infection, we have compared the kinetics of bacterial growths in liver and spleen of the mice with those determined in M. avium-susceptible (BALB/c) and resistant (C3H) strains of mice. NOD mice were able to control the M. avium infection, following a pattern similar to that observed in infected C3H mice. The mycobacterial infection prevented the expression of diabetes in all of the infected NOD mice and it also decreased the incidence of proteinuria in the treated mice. The infected NOD mice showed a marked enhancement in antibodies against the 65,000 mycobacteria antigen (heat-shock protein (hsp) 65) up to the second month of infection and these elevated titres slowly decreased in the following months; anti-hsp 65 antibodies were not detected in age-matched controls. This is the first demonstration that NOD mice are naturally resistant to mycobacterial infection, and we reinforce evidence on the role of immune response triggered by mycobacteria and its hsp 65 antigen in prevention of diabetes in NOD mice. Images Figure 4 Figure 5

Bras, A; Aguas, A P

1996-01-01

242

Perforin-independent ?-cell destruction by diabetogenic CD8+ T lymphocytes in transgenic nonobese diabetic mice  

PubMed Central

Autoimmune diabetes in nonobese diabetic (NOD) mice results from destruction of pancreatic ? cells by T lymphocytes. It is believed that CD8+ cytotoxic T lymphocytes (CTLs) effect the initial ?-cell insult in diabetes, but the mechanisms remain unclear. Studies of NOD.lpr mice have suggested that disease initiation is a Fas-dependent process, yet perforin-deficient NOD mice rarely develop diabetes despite expressing Fas. Here, we have investigated the role of perforin and Fas in the ability of ? cell–reactive CD8+ T cells bearing a T-cell receptor (8.3-TCR) that is representative of TCRs used by CD8+ CTLs propagated from the earliest insulitic lesions of NOD mice, and that targets an immunodominant peptide/H-2Kd complex on ? cells, to effect ?-cell damage in vitro and in vivo. In vitro, 8.3-CTLs killed antigenic peptide–pulsed non–?-cell targets via both perforin and Fas, but they killed NOD ? cells via Fas exclusively. Perforin-deficient 8.3-TCR–transgenic NOD mice expressing an oligoclonal or monoclonal T-cell repertoire developed diabetes even more frequently than their perforin-competent littermates. These results demonstrate that diabetogenic CD8+ CTLs representative of CTLs putatively involved in the initiation of autoimmune diabetes kill ? cells in a Fas-dependent and perforin-independent manner.

Amrani, Abdelaziz; Verdaguer, Joan; Anderson, Brad; Utsugi, Toshihiro; Bou, Sonny; Santamaria, Pere

1999-01-01

243

Brazilin augments cellular immunity in multiple low dose streptozotocin (MLD-STZ) induced type I diabetic mice  

Microsoft Academic Search

Brazilin, an active principle ofCaesalprenia sappan, was examined for its immunopotentiating effects in multiple low dose streptozotocin (MLD-STZ) induced type diabetic mice.\\u000a Brazilin was intraperitoneally administered for 5 consecutive days to MLD-STZ induced type I diabetic mice. Delayed type hypersensitivity,\\u000a Con A-induced proliferation of splenocytes and mixed lymphocyte reaction, which had been decreased in diabetic mice, were\\u000a significantly recovered by

Kyoung-Mee Yang; Sun-Duck Jeon; Dhong-Soo So; Chang-Kiu Moon

2000-01-01

244

Stat4-null non-obese diabetic mice: protection from diabetes and experimental allergic encephalomyelitis, but with concomitant epitope spread  

Microsoft Academic Search

There is much interest in therapeutic manipulation of cytokine responses in autoimmunity, yet studies in mouse models have sometimes produced conflicting findings as to the role of particular mediators in disease. Examples include the contradictory findings regarding susceptibility to experimental allergic encephalomyelitis (EAE) or diabetes in knockout mice for various individual Th 1o r Th2 cytokines or their receptors. An

Rosemary J. Boyton; Selina Davies; Chloe Marden; Cristina Fantino; Catherine Reynolds; Karina Portugal; Hamlata Dewchand; Daniel M. Altmann

2005-01-01

245

Antihyperglycemic Effect of Ganoderma Lucidum Polysaccharides on Streptozotocin-Induced Diabetic Mice  

PubMed Central

The current study evaluated the glucose-lowering effect of ganoderma lucidum polysaccharides (Gl-PS) in streptozotocin (STZ)-induced diabetic mice. The diabetic mice were randomly divided into four groups (8 mice per group): diabetic control group, low-dose Gl-PS treated group (50 mg/kg, Gl-PS), high-dose Gl-PS treated group (150 mg/kg, Gl-PS) and positive drug control treated group (glibenclamide, 4 mg/kg), with normal mice used as the control group. Body weights, fasting blood glucose (FBG), serum insulin and blood lipid levels of mice were measured. After 28 days of treatment with Gl-PS, body weights and serum insulin levels of the Gl-PS treated groups was significantly higher than that of the diabetic control group, whereas FBG levels was significantly lower. Moreover, total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) levels of the Gl-PS treated groups had dropped, whereas the high density lipoprotein cholesterol (HDL-C) levels had increased. In addition, according to acute toxicity studies, Gl-PS did not cause behavioral changes and any death of mice. These data suggest that Gl-PS has an antihyperglycemic effect. Furthermore, considering the Gl-PS effects on lipid profile, it may be a potential hypolipidaemic agent, which will be a great advantage in treating diabetic conditions associated with atherosclerosis or hyperlipidemia.

Li, Fenglin; Zhang, Yiming; Zhong, Zhijian

2011-01-01

246

Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice  

PubMed Central

Objective of the Study Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. Methodology and Principal Findings Streptozotocin (STZ)-induced diabetes in apolipoprotein E?/? mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. Conclusions Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications.

Zetterqvist, Anna V.; Berglund, Lisa M.; Blanco, Fabiana; Garcia-Vaz, Eliana; Wigren, Maria; Duner, Pontus; Andersson, Anna-Maria Dutius; To, Fong; Spegel, Peter; Nilsson, Jan; Bengtsson, Eva; Gomez, Maria F.

2013-01-01

247

Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice  

PubMed Central

Background Amiloride derivatives, commonly used for their diuretic and antihypertensive properties, can also cause a sustained but reversible decrease of intracellular pH (pHi). Using dimethyl amiloride (DMA) on normal rodent pancreatic islets, we previously demonstrated the critical influence of islet pHi on insulin secretion. Nutrient-stimulated insulin secretion (NSIS) requires a specific pHi-range, and is dramatically enhanced by forced intracellular acidification with DMA. Furthermore, DMA can enable certain non-secretagogues to stimulate insulin secretion, and induce time-dependent potentiation (TDP) of insulin release in mouse islets where this function is normally absent. The present study was performed to determine whether pHi-manipulation could correct the secretory defect in islets isolated from mice with type 2 diabetes. Methods Using two mouse models of type 2 diabetes, we compared a) pHi-regulation, and b) NSIS with and without treatment with amiloride derivatives, in islets isolated from diabetic mice and wild type mice. Results A majority of the islets from the diabetic mice showed a slightly elevated basal pHi and/or poor recovery from acid/base load. DMA treatment produced a significant increase of NSIS in islets from the diabetic models. DMA also enabled glucose to induce TDP in the islets from diabetic mice, albeit to a lesser degree than in normal islets. Conclusion Islets from diabetic mice show some mis-regulation of intracellular pH, and their secretory capacity is consistently enhanced by DMA/amiloride. Thus, amiloride derivatives show promise as potential therapeutic agents for type 2 diabetes.

Gunawardana, Subhadra C; Head, W Steven; Piston, David W

2005-01-01

248

Chromium, selenium, and zinc multimineral enriched yeast supplementation ameliorates diabetes symptom in streptozocin-induced mice.  

PubMed

Chromium, selenium, and zinc malnutrition has been implicated in the pathogenesis of diabetic mellitus. This study aims to investigate the effects of novel multiminerals-enriched yeast (MMEY) which are minerals supplementation containing elevated levels of chromium, selenium, and zinc simultaneously in a diabetic animal model. Streptozocin-induced diabetic male Balb/c mice (n?=?80) were randomly divided into diabetes control group and three treatment groups. They were administrated oral gavages with low, medium, or high doses of MMEY, respectively. Meanwhile, healthy male Balb/c mice (n?=?40) of the same body weight were randomly assigned into normal control group and high dose of MMEY control group. After 8 weeks duration of treatment, the animals were sacrificed by cervical dislocation. Serum glucose concentrations, lipid profiles, oxidative/antioxidant, and immunity status were determined. No significant adverse effects were observed in the high-dose MMEY control group. Treatment of the diabetic mice with medium- or high-dose MMEY significantly decreased serum glucose, triglyceride, total cholesterol, and malondialdehyde and increased high-density lipoprotein cholesterol, glutathione, and the activities of superoxide dismutase and glutathione peroxidase. In addition, MMEY ameliorated the pathological damage of the pancreatic islets, elevated the thymus or spleen coefficient, and increased the expressions of interleukin-2 and -4 in spleen lymphocytes compared with unsupplemented diabetic mice. In conclusion, these results indicate that supplemental MMEY inhibits hyperglycemia, abates oxidative stress, modulates disorders of lipid metabolism, and reduces the impairment of immune function in diabetic mice; especially notable are the protective effects of medium doses of MMEY on the islet cells of diabetic mice. PMID:22081404

Liu, Jun; Bao, Wei; Jiang, Man; Zhang, Yan; Zhang, Xiping; Liu, Liegang

2012-05-01

249

Abnormalities in hepatic enzyme activities during development of diabetes in db mice  

Microsoft Academic Search

Summary  Seven hepatic enzymes were assayedin vitro in diabetic and control C57BL\\/Ks mice at 1, 2, and 41\\/2 month. An elevation in phosphoenolpyruvate carboxykinase and glucose-6-phosphatase was observed before the onset of hyperglycemia in db mice at the age of 1 month. At two months, these mice had hyperglycemia, hyperinsulinemia and high levels of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, fructose-1,6-diphosphatase, pyruvate kinase and

A. Y. Chang; D. I. Schneider

1970-01-01

250

Lower faecal egg excretion in chemically-induced diabetic mice infected with Schistosoma mansoni due to impaired egg maturation.  

PubMed

The effect of streptozotocin-induced diabetes mellitus was studied in mice infected with Schistosoma mansoni. Faecal egg excretion was lower in diabetic mice but worm load and total amount of eggs in the intestine tissue were equal to the control group. Evaluation of an oogram showed a great number of immature dead eggs and a low number of mature eggs in diabetic mice. It was therefore concluded that faecal egg excretion was lower in diabetic mice due to impaired egg maturation. PMID:11313651

Hulstijn, M; Oliveira, R M; Moura, E G; Machado-Silva, J R

2001-04-01

251

Metabolic profile changes in the testes of mice with streptozotocin-induced type 1 diabetes mellitus.  

PubMed

Contrary to the traditional view, recent studies suggest that diabetes mellitus has an adverse influence on male reproductive function. Our aim was to determine the effect of diabetes on the testicular environment by identifying and then assessing perturbations in small molecule metabolites. Testes were obtained from control and streptozotocin-induced diabetic C57BL/6 mice, 2, 4 and 8 weeks post-treatment. Diabetic status was confirmed by glycated haemoglobin, non-fasting blood glucose, physiological condition and body weight. A novel extraction procedure was utilized to obtain protein free, low-molecular weight, water soluble extracts which were then assessed using (1)H nuclear magnetic resonance spectroscopy. Principal component analysis of the derived profiles was used to classify any variations, and specific metabolites were identified based on their spectral pattern. Characteristic metabolite profiles were identified for control and type 1 diabetic animals with the most distinctive being from mice with the largest physical deterioration and loss of body weight. Eight streptozotocin-treated animals did not develop diabetes and displayed profiles similar to controls. Diabetic mice had decreases in creatine, choline and carnitine and increases in lactate, alanine and myo-inositol. Betaine levels were found to be increased in the majority of diabetic mice but decreased in a few animals with severe loss of body weight and physical condition. The association between perturbations in a number of small molecule metabolites known to be influential in sperm function, with diabetic status and physiological condition, adds further impetus to the proposal that diabetes influences important spermatogenic pathways and mechanisms in a subtle and previously unrecognized manner. PMID:17971162

Mallidis, C; Green, B D; Rogers, D; Agbaje, I M; Hollis, J; Migaud, M; Amigues, E; McClure, N; Browne, R A

2009-04-01

252

Toward Testing the Hypothesis that Group B Coxsackieviruses (CVB) Trigger Insulin-Dependent Diabetes: Inoculating Nonobese Diabetic Mice with CVB Markedly Lowers Diabetes Incidence  

PubMed Central

Insulin-dependent (type 1) diabetes mellitus (T1D) onset is mediated by individual human genetics as well as undefined environmental influences such as viral infections. The group B coxsackieviruses (CVB) are commonly named as putative T1D-inducing agents. We studied CVB replication in nonobese diabetic (NOD) mice to assess how infection by diverse CVB strains affected T1D incidence in a model of human T1D. Inoculation of 4- or 8-week-old NOD mice with any of nine different CVB strains significantly reduced the incidence of T1D by 2- to 10-fold over a 10-month period relative to T1D incidences in mock-infected control mice. Greater protection was conferred by more-pathogenic CVB strains relative to less-virulent or avirulent strains. Two CVB3 strains were employed to further explore the relationship of CVB virulence phenotypes to T1D onset and incidence: a pathogenic strain (CVB3/M) and a nonvirulent strain (CVB3/GA). CVB3/M replicated to four- to fivefold-higher titers than CVB3/GA in the pancreas and induced widespread pancreatitis, whereas CVB3/GA induced no pancreatitis. Apoptotic nuclei were detected by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay in CVB3/M-infected pancreata but not in CVB3/GA-infected pancreata. In situ hybridization detected CVB3 RNA in acinar tissue but not in pancreatic islets. Although islets demonstrated inflammatory infiltrates in CVB3-protected mice, insulin remained detectable by immunohistochemistry in these islets but not in those from diabetic mice. Enzyme-linked immunosorbent assay-based examination of murine sera for immunoglobulin G1 (IgG1) and IgG2a immunoreactivity against diabetic autoantigens insulin and HSP60 revealed no statistically significant relationship between CVB3-protected mice or diabetic mice and specific autoimmunity. However, when pooled sera from CVB3/M-protected mice were used to probe a Western blot of pancreatic proteins, numerous proteins were detected, whereas only one band was detected by sera from CVB3/GA-protected mice. No proteins were detected by sera from diabetic or normal mice. Cumulatively, these data do not support the hypothesis that CVB are causative agents of T1D. To the contrary, CVB infections provide significant protection from T1D onset in NOD mice. Possible mechanisms by which this virus-induced protection may occur are discussed.

Tracy, S.; Drescher, K. M.; Chapman, N. M.; Kim, K.-S.; Carson, S. D.; Pirruccello, S.; Lane, P. H.; Romero, J. R.; Leser, J. S.

2002-01-01

253

Cardiac-specific overexpression of CYP2J2 attenuates diabetic cardiomyopathy in male streptozotocin-induced diabetic mice.  

PubMed

Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active cis-epoxyeicosatrienoic acids, which have potent vasodilatory, antiinflammatory, antiapoptotic, and antidiabetes properties. Here, we showed the effects of cardiac-specific overexpression of CYP epoxygenase 2J2 (CYP2J2) on diabetic cardiomyopathy and insulin resistance in high-fat (HF) diet fed, low-dose streptozotocin-treated mice. Diabetic cardiomyopathy was induced by HF and streptozotocin in cardiac-specific CYP2J2 transgenic mice. Physiological parameters and systemic metabolic parameters were monitored using ELISA kits. Intraperitoneal injection glucose tolerance test and hyperinsulinemic-euglycemic clamp study were implied to indicate insulin resistance. Cardiac function was assessed by echocardiography and Millar catheter system. Real-time PCR and Western blotting were used in signal pathway detection. ?MHC-CYP2J2 transgenic mice showed significantly lower plasma glucose and insulin levels, improved glucose tolerance, and increased cardiac glucose uptake. Furthermore, ?MHC-CYP2J2 transgenic mice were significantly protected from HF-streptozotocin-induced diabetic cardiomyopathy. Strikingly, CYP2J2 overexpression attenuated myocardial hypertrophy induced by diabetes. We conclude that cardiac-specific overexpression of CYP2J2 significantly protects against diabetic cardiomyopathy, which may be due to improved cardiac insulin resistance, glucose uptake, and reversal of cardiac hypertrophy. Relevant mechanisms may include up-regulation of peroxisome proliferator-activated receptor ?, activation of insulin receptor and AMP-activated protein kinase signaling pathways, and inhibition of nuclear factor of activated T cells c3 signal by enhanced atrial natriuretic peptide production. These results suggest that CYP2J2 epoxygenase metabolites likely play an important role in plasma glucose homeostasis, and enhancement of epoxyeicosatrienoic acids activation may serve as an effective therapeutic strategy to prevent diabetic cardiomyopathy. PMID:23696562

Ma, Ben; Xiong, Xiaojv; Chen, Chen; Li, Huaping; Xu, Xizhen; Li, Xuguang; Li, Rui; Chen, Guangzhi; Dackor, Ryan T; Zeldin, Darryl C; Wang, Dao Wen

2013-08-01

254

Nerve Growth Factor Gene Therapy Using Adeno-Associated Viral Vectors Prevents Cardiomyopathy in Type 1 Diabetic Mice  

PubMed Central

Diabetes is a cause of cardiac dysfunction, reduced myocardial perfusion, and ultimately heart failure. Nerve growth factor (NGF) exerts protective effects on the cardiovascular system. This study investigated whether NGF gene transfer can prevent diabetic cardiomyopathy in mice. We worked with mice with streptozotocin-induced type 1 diabetes and with nondiabetic control mice. After having established that diabetes reduces cardiac NGF mRNA expression, we tested NGF gene therapies with adeno-associated viral vectors (AAVs) for the capacity to protect the diabetic mouse heart. To this aim, after 2 weeks of diabetes, cardiac expression of human NGF or ?-Gal (control) genes was induced by either intramyocardial injection of AAV serotype 2 (AAV2) or systemic delivery of AAV serotype 9 (AAV9). Nondiabetic mice were given AAV2–?-Gal or AAV9–?-Gal. We found that the diabetic mice receiving NGF gene transfer via either AAV2 or AAV9 were spared the progressive deterioration of cardiac function and left ventricular chamber dilatation observed in ?-Gal–injected diabetic mice. Moreover, they were additionally protected from myocardial microvascular rarefaction, hypoperfusion, increased deposition of interstitial fibrosis, and increased apoptosis of endothelial cells and cardiomyocytes, which afflicted the ?-Gal–injected diabetic control mice. Our data suggest therapeutic potential of NGF for the prevention of cardiomyopathy in diabetic subjects.

Meloni, Marco; Descamps, Betty; Caporali, Andrea; Zentilin, Lorena; Floris, Ilaria; Giacca, Mauro; Emanueli, Costanza

2012-01-01

255

Electroacupuncture pretreatment inhibits NADPH oxidase-mediated oxidative stress in diabetic mice with cerebral ischemia.  

PubMed

We investigated the protective effect of electroacupuncture (EA) on cerebral ischemic injury in diabetic mice, and explored the role of NADPH oxidase-mediated oxidative stress. Male C57BL/6 mice were injected streptozotocin to induce diabetes. The mice were pretreated with EA at acupoint "Baihui" for 30min. Two hours after the end of EA pretreatment, focal cerebral ischemia was induced following 24h reperfusion. The neurobehavioral scores and infarction volumes, malondialdehyde (MDA), reactive oxygen species (ROS), and activation of NADPH oxidase were determined in the presence or absence of the NADPH oxidase inhibitor apocynin or activator tetrabromocinnamic acid (TBCA). EA pretreatment reduced infarct size and improved neurological outcomes 24h after reperfusion in the diabetic mice. EA also decreased cerebral MDA and ROS levels compared with the control group, and inhibited the NADPH oxidase activation. The beneficial effects were abolished by TBCA while pretreatment with apocynin mimicked the neuroprotective and anti-oxidative effects of EA. Our results demonstrated that EA attenuated cerebral ischemic injury by inhibiting NAPDH oxidase-mediated oxidative damage in diabetic mice. These results suggest a novel mechanism of EA pretreatment-induced tolerance in diabetic cerebral ischemia. PMID:24854123

Guo, Fan; Song, Wenying; Jiang, Tao; Liu, Lixin; Wang, Feng; Zhong, Haixing; Yin, Hong; Wang, Qiang; Xiong, Lize

2014-07-21

256

Transgenic mice overexpressing insulin-like growth factor-II in ? cells develop type 2 diabetes  

PubMed Central

During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in ? cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in ?-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease.

Devedjian, Jean-Christophe; George, Monica; Casellas, Alba; Pujol, Anna; Visa, Joana; Pelegrin, Mireia; Gros, Laurent; Bosch, Fatima

2000-01-01

257

The relationship between hyperglycaemia and renal immune complex deposition in mice with inherited diabetes.  

PubMed Central

Kidney lesions were studied by light microscopy and immunofluorescence in diabetic (db/db) and obese (ob/ob) mutant mice. The db/db mutation was studied both on the C57Bl/KsJ genetic background (where it produces severe hyperglycaemia) and on the C57Bl/6J background (where hyperglycaemia is only mild). In all cases, more IgG, IgM and C3 were deposited in the renal glomeruli of mutant mice than in the glomeruli of normal (+/?) mice of equivalent age. First signs of immunoglobulin deposition occurred at a slightly younger age than first signs of C3 deposition or histological change (mainly mesangial thickening). Insulin deposits were occasionally seen in the glomeruli of older mutant mice and immunoglobulin eluted from diabetic mouse kidneys had anti-insulin activity. Increased anti-DNA activity was present in the serum of older mutants. In those mutants with severe hyperglycaemia, the macula densa and distal convoluted tubules also contained immunoglobulin deposits, probably derived from the glomerular mesangium. Urine from diabetic mice contained high molecular weight material reacting with antisera to Fab or kappa but not the Fc portion of immunoglobulin. We conclude that diabetic mice have immune complexes in the kidney containing antibodies against insulin and possibly other antigens. We find no evidence that hyperglycaemia itself is the direct cause of glomerular immune complex deposition, although there may be a link between hyperglycaemia and tubular dysfunction. Images Fig. 3 Fig. 5 Fig. 6

Meade, C J; Brandon, D R; Smith, W; Simmonds, R G; Harris, S; Sowter, C

1981-01-01

258

Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice.  

PubMed

Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetic kidney disease. The actions of AGEs are mediated both through a non-receptor-mediated pathway and through specific receptors for AGE (RAGEs). To explore a specific role for RAGE in renal changes in type 2 diabetes, we examined the renal effects of a neutralizing murine RAGE antibody in db/db mice, a model of obese type 2 diabetes. One group of db/db mice was treated for 2 months with the RAGE antibody, and another db/db group was treated for the same period with an irrelevant IgG. Two groups of nondiabetic db/+ mice were treated with either RAGE antibody or isotype-matched IgG for 2 months. Placebo-treated db/db mice showed a pronounced increase in kidney weight, glomerular volume, basement membrane thickness (BMT), total mesangial volume, urinary albumin excretion (UAE), and creatinine clearance compared with nondiabetic controls. In RAGE antibody-treated db/db mice, the increase in kidney weight, glomerular volume, mesangial volume, and UAE was reduced, whereas the increase in creatinine clearance and BMT was fully normalized. Notably, these effects in db/db mice were seen without impact on body weight, blood glucose, insulin levels, or food consumption. In conclusion, RAGE is an important pathogenetic factor in the renal changes in an animal model of type 2 diabetes. PMID:14693711

Flyvbjerg, Allan; Denner, Larry; Schrijvers, Bieke F; Tilton, Ronald G; Mogensen, Trine H; Paludan, Søren R; Rasch, Ruth

2004-01-01

259

Flos Puerariae Extract Prevents Myocardial Apoptosis via Attenuation Oxidative Stress in Streptozotocin-Induced Diabetic Mice  

PubMed Central

Background Diabetic cardiomyopathy (DCM) suggests a direct cellular insult to myocardium. Apoptosis is considered as one of the hallmarks of DCM. Oxidative stress plays a key role in the pathogenesis of DCM. In this study, we explored the prevention of myocardial apoptosis by crude extract from Flos Puerariae (FPE) in experimental diabetic mice. Methods Experimental diabetic model was induced by intraperitoneally injection of streptozotocin (STZ, 50 mg/kg/day) for five consecutive days in C57BL/6J mice. FPE (100, 200 mg/kg) was orally administrated once a day for ten weeks. Cardiac structure changes, apoptosis, superoxide production, NADPH oxidase subunits expression (gp91phox, p47phox, and p67phox), and related regulatory factors were assessed in the heart of mice. Results Diabetic mice were characterized by high blood glucose (?11.1 mmol/L) and reduced body weight. In the end of the experiment, aberrant myofilament structure, as well as TUNEL positive cardiac cells coupled with increased Bax/Bcl-2 ratio and Caspase-3 expression was found in diabetic mice. Moreover, ROS formation, the ratio of NADP+/NADPH and NADPH oxidase subunits expression of gp91phox and p47phox, lipid peroxidation level was significantly increased, while antioxidant enzyme SOD and GSH-Px activity were reduced in the myocardial tissue of diabetic mice. In contrast, treatment with FPE resulted in a normalized glucose and weight profile. FPE administration also preserved myocardial structure and reduced apoptotic cardiac cell death in diabetic mice. The elevated markers of oxidative stress were significantly reversed by FPE supplementation. Further, FPE treatment markedly inhibited the increased Bax/Bcl-2 ratio and Caspase-3 expression, as well as suppressed JNK and P38 MAPK activation in the heart of diabetic mice. Conclusions Our data demonstrate for the first time that FPE may have therapeutic potential for STZ-induced diabetic cardiomyopathy through preventing myocardial apoptosis via attenuation oxidative stress. And this effect is probably mediated by JNK and P38 MAPK signaling pathway.

Guo, Shuang; Cheng, Hongke; Wu, Jiliang; Liu, Chao

2014-01-01

260

Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice.  

PubMed Central

The purpose of this study was to determine the relative importance of the metabolic effects of insulin for diabetes prevention by administering insulin or an inactive insulin analog by daily subcutaneous injections to prediabetic mice. A recombinant monomeric human insulin analog, which does not bind to the insulin receptor as a consequence of an alteration of a single amino acid at position 25 of the B chain, was shown to be equally effective at diabetes prevention as was intact insulin. In contrast to native insulin, the insulin analog did not cause hypoglycemia after subcutaneous injection. The insulin analog, however, protected young adult mice from diabetes, even when it was initiated after the onset of extensive lymphocytic infiltration of the islets. Thus, preventative therapy by daily subcutaneous injections of insulin does not require the hypoglycemic response, or binding to the insulin receptor to prevent the onset of type I diabetes.

Karounos, D G; Bryson, J S; Cohen, D A

1997-01-01

261

Blockade of KCa3.1 ameliorates renal fibrosis through the TGF-?1/Smad pathway in diabetic mice.  

PubMed

The Ca(2+)-activated K(+) channel KCa3.1 mediates cellular signaling processes associated with dysfunction of vasculature. However, the role of KCa3.1 in diabetic nephropathy is unknown. We sought to assess whether KCa3.1 mediates the development of renal fibrosis in two animal models of diabetic nephropathy. Wild-type and KCa3.1(-/-) mice, and secondly eNOS(-/-) mice, had diabetes induced with streptozotocin and then were treated with/without a selective inhibitor of KCa3.1 (TRAM34). Our results show that the albumin-to-creatinine ratio significantly decreased in diabetic KCa3.1(-/-) mice compared with diabetic wild-type mice and in diabetic eNOS(-/-) mice treated with TRAM34 compared with diabetic mice. The expression of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM1), F4/80, plasminogen activator inhibitor type 1 (PAI-1), and type III and IV collagen significantly decreased (P < 0.01) in kidneys of diabetic KCa3.1(-/-) mice compared with diabetic wild-type mice. Similarly, TRAM34 reduced the expression of the inflammatory and fibrotic markers described above in diabetic eNOS(-/-) mice. Furthermore, blocking the KCa3.1 channel in both animal models led to a reduction of transforming growth factor-?1 (TGF-?1) and TGF-?1 type II receptor (T?RII) and phosphorylation of Smad2/3. Our results provide evidence that KCa3.1 mediates renal fibrosis in diabetic nephropathy through the TGF-?1/Smad signaling pathway. Blockade of KCa3.1 may be a novel target for therapeutic intervention in patients with diabetic nephropathy. PMID:23656889

Huang, Chunling; Shen, Sylvie; Ma, Qing; Chen, Jason; Gill, Anthony; Pollock, Carol A; Chen, Xin-Ming

2013-08-01

262

Experimental autoimmune thyroiditis in nonobese diabetic mice lacking interferon regulatory factor-1.  

PubMed

Interferon regulatory factor-1 (IRF-1) is pivotal in the regulation of interferon (IFN)-mediated immune reactions, and studies suggest that IRF-1 is involved in the development of autoimmune diseases. IRF-1+/+, +/-, and -/- nonobese diabetic (NOD) mice were immunized with mouse thyroglobulin (mTg) to determine whether IRF-1 is required in experimental autoimmune thyroiditis (EAT), a murine model for Hashimoto's thyroiditis (HT). IRF-1-deficient mice developed EAT and anti-mTg antibodies comparable to IRF-1+/+ and +/- mice. Whereas both CD4+ and CD8+ T cells were found in thyroids of IRF-1+/+ mice, the latter was not in IRF-1-/- mice. Major histocompatibility complex class II antigen was comparably expressed in thyroids of IRF-1+/+ and -/- mice. Lack of IRF-1 resulted in decreased CD8+ T cell number in the spleen and reduced IFNgamma production by splenocytes. Our results suggest that IRF-1 is not pivotal in EAT in NOD mice. PMID:15451476

Jin, Zhongtian; Mori, Kouki; Fujimori, Keisei; Hoshikawa, Saeko; Tani, Jun-ichi; Satoh, Jo; Ito, Sadayoshi; Satomi, Susumu; Yoshida, Katsumi

2004-11-01

263

Hypoglycemic Effect of Sargassum ringgoldianum Extract in STZ-induced Diabetic Mice  

PubMed Central

This study was designed to investigate whether Sargassum ringgoldianum extract may inhibit ?-glucosidase and ?-amylase activities, and alleviate postprandial hyperglycemia in streptozotocin-induced diabetic mice. The IC50 values of Sargassum ringgoldianum extract against ?-glucosidase and ?-amylase were 0.12 mg/mL and 0.18 mg/mL, respectively, which evidenced higher activities than those of acarbose. The blood glucose levels of the Sargassum ringgoldianum extract administered group were significantly lower compared to the control group in the streptozotocin-induced diabetic mice. Moreover, the area under the two-hour blood glucose response curve was significantly reduced and the absorption of dietary carbohydrates was delayed after administration of Sargassum ringgoldianum extract in the diabetic mice. Therefore, these results indicated that Sargassum ringgoldianum extract may help decrease the postprandial blood glucose level via inhibiting ?-glucosidase.

Lee, Chae-Won; Han, Ji-Sook

2012-01-01

264

Polyopes lancifolia Extract, a Potent ?-Glucosidase Inhibitor, Alleviates Postprandial Hyperglycemia in Diabetic Mice.  

PubMed

This study was designed to investigate the inhibitory effects of Polyopes lancifolia extract (PLE) on ?-glucosidase activity, ?-amylase activitiy, and postprandial hyperglycemia in streptozotocin (STZ)-induced diabetic mice. The results of this study revealed a marked inhibitory effect of PLE on ?-glucosidase and ?-amylase activities. The IC50s of PLE against ?-glucosidase and ?-amylase were 0.20 mg/mL and 0.35 mg/mL, respectively. PLE was a more effective inhibitor of ?-glucosidase and ?-amylase activities than acarbose, the positive control. The postprandial blood glucose levels of STZ-induced diabetic mice were significantly lower in the PLE treated group than in the control group. Moreover, PLE administration was associated with a decreased area under the curve for the glucose response in diabetic mice. These results indicate that PLE may be a potent inhibitor of ?-glucosidase and ?-amylase activities and may suppress postprandial hyperglycemia. PMID:24772403

Min, Seong Won; Han, Ji Sook

2014-01-01

265

Polyopes lancifolia Extract, a Potent ?-Glucosidase Inhibitor, Alleviates Postprandial Hyperglycemia in Diabetic Mice  

PubMed Central

This study was designed to investigate the inhibitory effects of Polyopes lancifolia extract (PLE) on ?-glucosidase activity, ?-amylase activitiy, and postprandial hyperglycemia in streptozotocin (STZ)-induced diabetic mice. The results of this study revealed a marked inhibitory effect of PLE on ?-glucosidase and ?-amylase activities. The IC50s of PLE against ?-glucosidase and ?-amylase were 0.20 mg/mL and 0.35 mg/mL, respectively. PLE was a more effective inhibitor of ?-glucosidase and ?-amylase activities than acarbose, the positive control. The postprandial blood glucose levels of STZ-induced diabetic mice were significantly lower in the PLE treated group than in the control group. Moreover, PLE administration was associated with a decreased area under the curve for the glucose response in diabetic mice. These results indicate that PLE may be a potent inhibitor of ?-glucosidase and ?-amylase activities and may suppress postprandial hyperglycemia.

Min, Seong Won; Han, Ji Sook

2014-01-01

266

Protective effects of total flavonoids from Flos Puerariae on retinal neuronal damage in diabetic mice  

PubMed Central

Purpose To investigate the potential protective effects of total flavonoids from Flos Puerariae (TFF) on retinal neural cells in diabetic mice. Methods C57BL/6J mice were intraperitoneally injected with streptozotocin to generate type I diabetes in a murine model, as indicated by blood glucose levels ?11.1 mmol/l. TFF was administered intragastrically at a dose of 50, 100, or 200 mg/kg/day. After 10 weeks of administration, the mice were euthanized, and the eyes were dissected. Retinal histology was examined, and the thickness of the retina was measured. Ultrastructural changes in the retinal ganglion cells and capillary basement membrane were observed with electron microscopy. Apoptosis of retinal neural cells was determined with the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay. Bax and Bcl-2 expression in the retinal tissues was determined with immunohistochemical staining and western blotting. Results Compared with the diabetic mice, the blood glucose level decreased (p<0.01) and the bodyweight increased (p<0.05) in the 100 and 200 mg/kg TFF-treated groups. The thickness of the retina significantly increased (p<0.01), and the retinal capillary basement membrane (BM) thickness was reduced in the 100 and 200 mg/kg TFF-treated diabetic mice (DM). The 100 and 200 mg/kg TFF treatments also attenuated the diabetes-induced apoptosis of retinal neural cells. Consistent with these effects, TFF treatment decreased the Bax expression level and, concurrently, increased the ratio of Bcl-2 to Bax. Conclusions TFF attenuated diabetes-induced apoptosis in retinal neurons by inhibiting Bax expression and increasing the ratio of Bcl-2 to Bax, which suggests that TFF might prevent retinal neuronal damage in diabetes mellitus.

Li, Dai; Yang, Fang; Cheng, Hongke; Liu, Chao; Sun, Ming; Wu, Kaili

2013-01-01

267

Effects of experimentally-induced diabetes on sperm parameters and chromatin quality in mice.  

PubMed

Background: Diabetes mellitus (DM), primary or idiopathic is a chronic disorder of the carbohydrate, lipid and protein metabolism. DM may impact male reproductive function at several levels. It is shown that DM has detrimental effects on sperm parameters in human and experimental animals. Objective: The aim of this study was to observe the effects of diabetes on sperm parameters (viability, count, morphology and motility) and evaluation of sperm chromatin quality in mice. Materials and Methods: Totally twenty adult male Syrian mice were divided randomly into 2 groups (n=10). The animals of group A were considered as controls while group B mice were diabetic that received a single dose (200 mg/kg) streptozotocin (STZ) intra peritoneally. After 35 days, the cauda epididymis of each diabetic mouse was dissected and placed in culture medium for 30 min. The swim-out spermatozoa were analyzed for count, motility, morphology and viability. The sperm chromatin quality and DNA integrity, was evaluated with Aniline Blue (AB), Toluidine blue (TB), Acridine orange (AO) and Chromomycin A3 (CMA3) staining. Results: In sperm analysis, the diabetic mice had poor parameters in comparison with control animals (p=0.000). Regarding sperm chromatin quality, the results of TB and AO tests showed statically significant differences between two groups, but in AB and CMA3 staining, we didn't see any differences between them. Conclusion: The results showed that STZ-induced diabetes mellitus may influence the male fertility potential via affecting sperm parameters and DNA integrity in mice. However, according to our data, the diabetes doesn't have any detrimental effects on histone-protamines replacement during the testicular phase of sperm chromatin packaging. PMID:24639693

Mangoli, Esmat; Talebi, Ali Reza; Anvari, Morteza; Pourentezari, Majid

2013-01-01

268

Beneficial Effects of Exendin-4 on Experimental Polyneuropathy in Diabetic Mice  

PubMed Central

OBJECTIVE The therapeutic potential of exendin-4, an agonist of the glucagon-like peptide-1 receptor (GLP-1R), on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic mice was investigated. RESEARCH DESIGN AND METHODS The presence of the GLP-1R in lumbar dorsal root ganglion (DRG) was evaluated by immunohistochemical analyses. DRG neurons were dissected from C57BL6/J mice and cultured with or without Schwann cell–conditioned media in the presence or absence of GLP-1 (7–37) or exendin-4. Then neurite outgrowth was determined. In animal-model experiments, mice were made diabetic by STZ administration, and after 12 weeks of diabetes, exendin-4 (10 nmol/kg) was intraperitoneally administered once daily for 4 weeks. Peripheral nerve function was determined by the current perception threshold and motor and sensory nerve conduction velocity (MNCV and SNCV, respectively). Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated. RESULTS The expression of the GLP-1R in DRG neurons was confirmed. GLP-1 (7–37) and exendin-4 significantly promoted neurite outgrowth of DRG neurons. Both GLP-1R agonists accelerated the impaired neurite outgrowth of DRG neurons cultured with Schwann cell–conditioned media that mimicked the diabetic condition. At the doses used, exendin-4 had no effect on blood glucose or HbA1c levels. Hypoalgesia and delayed MNCV and SNCV in diabetic mice were improved by exendin-4 without affecting the reduced SNBF. The decreased IENFDs in sole skins of diabetic mice were ameliorated by exendin-4. CONCLUSIONS Our findings indicate that exendin-4 ameliorates the severity of DPN, which may be achieved by its direct actions on DRG neurons and their axons.

Himeno, Tatsuhito; Kamiya, Hideki; Naruse, Keiko; Harada, Norio; Ozaki, Nobuaki; Seino, Yusuke; Shibata, Taiga; Kondo, Masaki; Kato, Jiro; Okawa, Tetsuji; Fukami, Ayako; Hamada, Yoji; Inagaki, Nobuya; Seino, Yutaka; Drucker, Daniel J.; Oiso, Yutaka; Nakamura, Jiro

2011-01-01

269

Imatinib Mesylate Reduces Endoplasmic Reticulum Stress and Induces Remission of Diabetes in db/db Mice  

PubMed Central

OBJECTIVE—Imatinib has been reported to induce regression of type 2 diabetes in chronic leukemia patients. However, the mechanism of diabetes amelioration by imatinib is unknown, and it is uncertain whether imatinib has effects on type 2 diabetes itself without other confounding diseases like leukemia. We studied the effect of imatinib on diabetes in db/db mice and investigated possible mechanism's underlying improved glycemic control by imatinib. RESEARCH DESIGN AND METHODS—Glucose tolerance and insulin tolerance tests were done after daily intraperitoneal injection of 25 mg/kg imatinib into db/db and C57BL/6 mice for 4 weeks. Insulin signaling and endoplasmic reticulum stress responses were studied by Western blotting. ?-Cell mass and apoptotic ?-cell number were determined by combined terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) staining and insulin immunohistochemistry. The in vitro effect of imatinib was studied using HepG2 cells. RESULTS—Imatinib induced remission of diabetes in db/db mice and amelioration of insulin resistance. Expression of endoplasmic reticulum stress markers in the liver and adipose tissues of db/db mice, such as phospho-PERK, phospho-eIF2?, TRB3, CHOP, and phospho–c-Jun NH2-terminal kinase, was reduced by imatinib. Insulin receptor substrate-1 tyrosine phosphorylation and Akt phosphorylation after insulin administration were improved by imatinib. Serum aminotransferase levels and hepatic triglyceride contents were decreased by imatinib. Pancreatic ?-cell mass was increased by imatinib, accompanied by decreased TUNEL+ ?-cell and increased BrdU+ ?-cell numbers. Imatinib attenuated endoplasmic reticulum stress in hepatoma cells in vitro. CONCLUSIONS—Imatinib ameliorated endoplasmic reticulum stress and induced remission of diabetes in db/db mice. Imatinib or related compounds could be used as therapeutic agents against type 2 diabetes and metabolic syndrome.

Han, Myoung Sook; Chung, Kun Wook; Cheon, Hyae Gyeong; Rhee, Sang Dal; Yoon, Chang-Hwan; Lee, Moon-Kyu; Kim, Kwang-Won; Lee, Myung-Shik

2009-01-01

270

Antigen Based Therapies to Prevent Diabetes in NOD Mice  

Microsoft Academic Search

Interventional approaches that have been successful in delaying insulin-dependent diabetes mellitus (IDDM) using antigen-based immunotherapies include parenteral immunization. It has potential for clinical application provided that effective adjuvants suitable for human use can be found. We have previously shown that immunization with insulin and insulin B chain but not A chain in incomplete Freund's adjuvant (IFA) prevented diabetes by reducing

Vijayakumar K. Ramiya; Xiao-Zhou Shang; Peter G. Pharis; Clive H. Wasserfall; Thomas V. Stabler; Andrew B. Muir; Desmond A. Schatz; Noel K. Maclaren

1996-01-01

271

Genetic analysis of autoimmune type 1 diabetes mellitus in mice  

Microsoft Academic Search

Two genes, ldd-3 and ldd-4, that influence the onset of autoimmune type 1 diabetes in the nonobese diabetic mouse have been located on chromosomes 3 and 11, outside the chromosome 17 major histocompatibility complex. A genetic map of the mouse genome, analysed using the polymerase chain reaction, has been assembled specifically for the study. On the basis of comparative maps

John A. Todd; Timothy J. Aitman; Richard J. Cornall; Soumitra Ghosh; Jennifer R. S. Hall; Catherine M. Hearne; Andrew M. Knight; Jennifer M. Love; Marcia A. McAleer; Jan-Bas Prins; Nanda Rodrigues; Mark Lathrop; Alison Pressey; Nicole H. Delarato; Laurence B. Peterson; Linda S. Wicker

1991-01-01

272

Stable activity of diabetogenic cells with age in NOD mice: dynamics of reconstitution and adoptive diabetes transfer in immunocompromised mice.  

PubMed

The non-obese diabetic (NOD) mouse is a prevalent disease model of type 1 diabetes. Immune aberrations that cause and propagate autoimmune insulitis in these mice are being continually debated, with evidence supporting both dominance of effector cells and insufficiency of suppressor mechanisms. In this study we assessed the behaviour of NOD lymphocytes under extreme expansion conditions using adoptive transfer into immunocompromised NOD.SCID (severe combined immunodeficiency) mice. CD4(+)  CD25(+) T cells do not cause islet inflammation, whereas splenocytes and CD4(+)  CD25(-) T cells induce pancreatic inflammation and hyperglycaemia in 80-100% of the NOD.SCID recipients. Adoptively transferred effector T cells migrate to the lymphoid organs and pancreas, proliferate, are activated in the target organ in situ and initiate inflammatory insulitis. Reconstitution of all components of the CD4(+) subset emphasizes the plastic capacity of different cell types to adopt effector and suppressor phenotypes. Furthermore, similar immune profiles of diabetic and euglycaemic NOD.SCID recipients demonstrate dissociation between fractional expression of CD25 and FoxP3 and the severity of insulitis. There were no evident and consistent differences in diabetogenic activity and immune reconstituting activity of T cells from pre-diabetic (11 weeks) and new onset diabetic NOD females. Similarities in immune phenotypes and variable distribution of effector and suppressor subsets in various stages of inflammation commend caution in interpretation of quantitative and qualitative aberrations as markers of disease severity in adoptive transfer experiments. PMID:24601987

Kaminitz, Ayelet; Mizrahi, Keren; Ash, Shifra; Ben-Nun, Avi; Askenasy, Nadir

2014-07-01

273

Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice.  

PubMed

Tyrosine kinase inhibition is known to reduce diabetes-induced end-organ damage but the mechanisms remain elusive. We hypothesized that inhibition of tyrosine kinase reduces renal inflammation and injury in streptozotocin-induced diabetes. Male C57BL/6 mice were given daily injections of streptozotocin (45 mg/kg/day, i.p. for 5 days); control animals received the vehicle (citrate buffer). Thereafter, streptozotocin-treated mice were treated with genistein (10 mg/kg, i.p three times a week for 10 weeks, n=8-10/group) or the vehicle (5% DMSO). The streptozotocin-treated mice displayed significant elevation in blood glucose level and decrease in plasma insulin level compared to their vehicle-treated controls. Treatment with genistein reduced blood glucose level (~15%; p<0.05) without a significant effect on plasma insulin level; however, blood glucose remained significantly higher than the control group. The development of diabetes was associated with significant increases in total protein, albumin, nephrin and collagen excretions compared to their controls. In addition, the diabetic mice displayed increased urinary MCP-1 excretion in association with increased renal ICAM-1 expression and apoptotic cells. Furthermore, renal gp91 expression levels and urinary Thio-Barbituric Acid Reactive Substances (TBARs) excretion, indices of oxidative stress, were also elevated in diabetic mice. These changes were associated with increased renal phospho-tyrosine expression and renal phospho-ERK/ERK ratio. Importantly, treatment with genistein reduced all these parameters towards control values. Collectively, the results suggest that the reno-protective effect of genistein likely relates to reduced renal inflammation, oxidative stress and apoptosis in diabetic mice. PMID:21807121

Elmarakby, Ahmed A; Ibrahim, Ahmed S; Faulkner, Jessica; Mozaffari, Mahmood S; Liou, Gregory I; Abdelsayed, Rafik

2011-01-01

274

Congenic mice reveal genetic epistasis and overlapping disease loci for autoimmune diabetes and listeriosis.  

PubMed

The nonobese diabetic (NOD) mouse strain serves as a genomic standard for assessing how allelic variation for insulin-dependent diabetes (Idd) loci affects the development of autoimmune diabetes. We previously demonstrated that C57BL/6 (B6) mice harbor a more diabetogenic allele than NOD mice for the Idd14 locus when introduced onto the NOD genetic background. New congenic NOD mouse strains, harboring smaller B6-derived intervals on chromosome 13, now localize Idd14 to an ~18-Mb interval and reveal a new locus, Idd31. Notably, the B6 allele for Idd31 confers protection against diabetes, but only in the absence of the diabetogenic B6 allele for Idd14, indicating genetic epistasis between these two loci. Moreover, congenic mice that are more susceptible to diabetes are more resistant to Listeria monocytogenes infection. This result co-localizes Idd14 and Listr2, a resistance locus for listeriosis, to the same genomic interval and indicates that congenic NOD mice may also be useful for localizing resistance loci for infectious disease. PMID:24906421

Wang, Nancy; Elso, Colleen M; Mackin, Leanne; Mannering, Stuart I; Strugnell, Richard A; Wijburg, Odilia L; Brodnicki, Thomas C

2014-08-01

275

Microencapsulated dog and rat islet xenografts into streptozotocin-diabetic and NOD mice.  

PubMed

Microencapsulation is an appealing method for islet xenografting. However, graft failure has been related to a cellular reaction, particularly intense in spontaneously diabetic, NOD mice. The goal of this study was to characterize this reaction. Poly-l-lysine-alginate microcapsules containing dog or rat islets were xenografted intraperitoneally into streptozotocin (SZN)-diabetic C57BL/6J and spontaneously diabetic NOD mice, with or without recipient treatment with GK 1.5 (anti-CD4 monoclonal antibody). Both dog and rat islets in microcapsules normalized blood glucose (BG) routinely in both SZN and NOD mice within 24 hours. Empty microcapsules and GK 1.5 treatment did not affect BG. NODs destroyed both microencapsulated dog and rat islets more rapidly than did SZN-diabetic mice (P less than 0.01). Graft biopsies showed an intense cellular reaction and no viable islets. GK 1.5 treatment significantly prolonged both dog-to-NOD and rat-to-NOD grafts (P less than 0.01). Biopsies of long-term functioning grafts (on days #70-#95) demonstrated viable islets and no cellular reaction. In prediabetic NODs, encapsulated dog and rat islets elicited a moderate cellular reaction. Empty microcapsules excited no cellular reaction in either diabetic or prediabetic NODs. PMID:2088974

Weber, C J; Zabinsi, S; Koschitzky, T; Rajotte, R; Wicker, L; Peterson, L; D'Agati, V; Reemtsma, K

1990-01-01

276

Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice  

Microsoft Academic Search

Aims\\/hypothesis  We aimed to evaluate the effect of the mutant Wld\\u000a \\u000a S\\u000a (slow Wallerian degeneration; also known as Wld) gene in experimental diabetes on early experimental peripheral diabetic neuropathy and diabetic retinopathy.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The experiments were performed in four groups of mice: wild-type (WT), streptozotocin (STZ)-induced diabetic WT, C57BL\\/Wld\\u000a \\u000a S\\u000a and STZ-induced diabetic C57BL\\/Wld\\u000a \\u000a S\\u000a . In each group, intraperitoneal glucose and

S. S. Zhu; Y. Ren; M. Zhang; J. Q. Cao; Q. Yang; X. Y. Li; H. Bai; L. Jiang; Q. Jiang; Z. G. He; Q. Chen

277

Transgenic Expression of Decoy Receptor 3 Protects Islets from Spontaneous and Chemical-induced Autoimmune Destruction in Nonobese Diabetic Mice  

Microsoft Academic Search

Decoy receptor 3 (DCR3) halts both Fas ligand- and LIGHT-induced cell deaths, which are required for pancreaticcell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 incells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and signifi- cantly reduced

Hsiang-Hsuan Sung; Jyuhn-Huarng Juang; Yu-Chun Lin; Chien-Hung Kuo; Jung-Tung Hung; An Chen; Der-Ming Chang; Sun-Yran Chang; Shie-Liang Hsieh; Huey-Kang Sytwu

2004-01-01

278

Protective effect of methanol-methylene chloride extract of Terminalia glaucescens leaves on streptozotocin-induced diabetes in mice  

Microsoft Academic Search

Purpose : Terminalia glaucescens (Combretaceae) is traditionally used in Cameroon in the treatment of diabetes. The anti-hyperglycemic effect of the methanol-methylene chloride extract of the leaves of this plant was investigated in streptozotocin (STZ)-induced diabetic mice. Methods : Diabetes was induced in mice by a daily dose of STZ (45 mg kg -1 body weight i.p.) for 5 days. From

Guy BSN Njomen; René Kamgang; Petit RN Soua; Jean LE Oyono; Njifutie Njikam

279

Alagebrium Reduces Glomerular Fibrogenesis and Inflammation Beyond Preventing RAGE Activation in Diabetic Apolipoprotein E Knockout Mice  

PubMed Central

Advanced glycation end products (AGEs) are important mediators of diabetic nephropathy that act through the receptor for AGEs (RAGE), as well as other mechanisms, to promote renal inflammation and glomerulosclerosis. The relative contribution of RAGE-dependent and RAGE-independent signaling pathways has not been previously studied in vivo. In this study, diabetic RAGE apoE double-knockout (KO) mice with streptozotocin-induced diabetes were treated with the AGE inhibitor, alagebrium (1 mg/kg/day), or the ACE inhibitor, quinapril (30 mg/kg/day), for 20 weeks, and renal parameters were assessed. RAGE deletion attenuated mesangial expansion, glomerular matrix accumulation, and renal oxidative stress associated with 20 weeks of diabetes. By contrast, inflammation and AGE accumulation associated with diabetes was not prevented. However, treatment with alagebrium in diabetic RAGE apoE KO mice reduced renal AGE levels and further reduced glomerular matrix accumulation. In addition, even in the absence of RAGE expression, alagebrium attenuated cortical inflammation, as denoted by the reduced expression of monocyte chemoattractant protein-1, intracellular adhesion molecule-1, and the macrophage marker cluster of differentiation molecule 11b. These novel findings confirm the presence of important RAGE-independent as well as RAGE-dependent signaling pathways that may be activated in the kidney by AGEs. This has important implications for the design of optimal therapeutic strategies for the prevention of diabetic nephropathy.

Watson, Anna M.D.; Gray, Stephen P.; Jiaze, Li; Soro-Paavonen, Aino; Wong, Benedict; Cooper, Mark E.; Bierhaus, Angelika; Pickering, Raelene; Tikellis, Christos; Tsorotes, Despina; Thomas, Merlin C.; Jandeleit-Dahm, Karin A.M.

2012-01-01

280

Edaravone Protect against Retinal Damage in Streptozotocin-Induced Diabetic Mice  

PubMed Central

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the clinical treatment of retinal injury. In this study, we investigated the protective effects of edaravone against diabetic retinal damage in the mouse. Diabetic retinopathy in the mouse was induced by injection of streptozotocin. Edaravone was given once-daily and was intraperitoneally (i.p.) treated at a dose of 3 mg/kg from streptozotocin injection to 4 weeks after onset of diabetes. Retinal ganglion cells (RGCs) damage was evaluated by recording the pattern electroretinogram (ERG). RGCs damage was also detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of reactive oxygen species (ROS) were determined fluorometrically. The expressions of phosporylated-ERK1/2, BDNF, and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expression of BDNF was significantly decreased in the retinas of diabetic mice, compared to nondiabetic mice. Administration of edaravone significantly attenuated diabetes induced RGCs death, upregulation of ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF. These findings suggest that oxidative stress plays a pivotal role in diabetic retinal damage and that systemic administration of edaravone may slow the progression of retinal neuropathy induced by diabetes.

Liu, Xiaoyi; Chen, Xi; Xie, Ping; Yuan, Songtao; Zhang, Weiwei; Lin, Xiaojun; Liu, Qinghuai

2014-01-01

281

Alteration of the Thymic T Cell Repertoire by Rotavirus Infection Is Associated with Delayed Type 1 Diabetes Development in Non-Obese Diabetic Mice  

PubMed Central

Rotaviruses are implicated as a viral trigger for the acceleration of type 1 diabetes in children. Infection of adult non-obese diabetic (NOD) mice with rotavirus strain RRV accelerates diabetes development, whereas RRV infection in infant NOD mice delays diabetes onset. In this study of infant mice, RRV titers and lymphocyte populations in the intestine, mesenteric lymph nodes (MLN) and thymus of NOD mice were compared with those in diabetes-resistant BALB/c and C57BL/6 mice. Enhanced intestinal RRV infection occurred in NOD mice compared with the other mouse strains. This was associated with increases in the frequency of CD8?? TCR?? intraepithelial lymphocytes, and their PD-L1 expression. Virus spread to the MLN and T cell numbers there also were greatest in NOD mice. Thymic RRV infection is shown here in all mouse strains, often in combination with alterations in T cell ontogeny. Infection lowered thymocyte numbers in infant NOD and C57BL/6 mice, whereas thymocyte production was unaltered overall in infant BALB/c mice. In the NOD mouse thymus, effector CD4+ T cell numbers were reduced by infection, whereas regulatory T cell numbers were maintained. It is proposed that maintenance of thymic regulatory T cell numbers may contribute to the increased suppression of inflammatory T cells in response to a strong stimulus observed in pancreatic lymph nodes of adult mice infected as infants. These findings show that rotavirus replication is enhanced in diabetes-prone mice, and provide evidence that thymic T cell alterations may contribute to the delayed diabetes onset following RRV infection.

Webster, Nicole L.; Zufferey, Christel; Pane, Jessica A.; Coulson, Barbara S.

2013-01-01

282

Acute effects of brain-derived neurotrophic factor on energy expenditure in obese diabetic mice  

Microsoft Academic Search

OBJECTIVE: We recently demonstrated that chronic treatment with brain-derived neurotrophic factor (BDNF) regulates energy expenditure in obese diabetic C57BL\\/KsJ-db\\/db mice. In this study, we investigated the acute effects of BDNF on energy expenditure.DESIGN: After BDNF was singly administered to male db\\/db mice (aged 10–12 weeks), their body temperature and whole body glucose oxidation were measured. Their norepinephrine (NE) turnover and

A Tsuchida; T Nonomura; M Ono-Kishino; T Nakagawa; M Taiji; H Noguchi

2001-01-01

283

In Vivo Detection of Extrapancreatic Insulin Gene Expression in Diabetic Mice by Bioluminescence Imaging  

PubMed Central

Background Extrapancreatic tissues such as liver may serve as potential sources of tissue for generating insulin-producing cells. The dynamics of insulin gene promoter activity in extrapancreatic tissues may be monitored in vivo by bioluminescence-imaging (BLI) of transgenic mice Tg(RIP-luc) expressing the firefly luciferase (luc) under a rat-insulin gene promoter (RIP). Methods The Tg(RIP-luc) mice were made diabetic by a single injection of the pancreatic ?-cell toxin streptozotocin. Control mice were treated with saline. Mice were subject to serum glucose measurement and bioluminescence imaging daily. On day eight of the treatment, mice were sacrificed and tissues harvested for quantitative luciferase activity measurement, luciferase protein cellular localization, and insulin gene expression analysis. Results Streptozotocin-induced diabetic Tg(RIP-luc) mice demonstrated a dramatic decline in the BLI signal intensity in the pancreas and a concomitant progressive increase in the signal intensity in the liver. An average of 5.7 fold increase in the liver signal intensity was detected in the mice that were exposed to hyperglycemia for 8 days. Ex vivo quantitative assays demonstrated a 34-fold induction of the enzyme activity in the liver of streptozotocin-treated mice compared to that of the buffer-treated controls. Luciferase-positive cells with oval-cell-like morphology were detected by immunohistochemistry in the liver samples of diabetic mice, but not in that of non-treated control transgenic mice. Gene expression analyses of liver RNA confirmed an elevated expression of insulin genes in the liver tissue exposed to hyperglycemia. Conclusions BLI is a sensitive method for monitoring insulin gene expression in extrapancreatic tissues in vivo. The BLI system may be used for in vivo screening of biological events or pharmacologic activators that have the potential of stimulating the generation of extrapancreatic insulin-producing cells.

Chen, Xiaojuan; Larson, Courtney S.; West, Jason; Zhang, Xiaomin; Kaufman, Dixon B.

2010-01-01

284

Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice  

PubMed Central

Increased expression of the facilitative glucose transporter, GLUT1, leads to glomerulopathy that resembles diabetic nephropathy, whereas prevention of enhanced GLUT1 expression retards nephropathy. While many of the GLUT1-mediated effects are likely due to mesangial cell effects, we hypothesized that increased GLUT1 expression in podocytes also contributes to the progression of diabetic nephropathy. Therefore, we generated two podocyte-specific GLUT1 transgenic mouse lines (driven by a podocin promoter) on a db/m C57BLKS background. Progeny of the two founders were used to generate diabetic db/db and control db/m littermate mice. Immunoblots of glomerular lysates showed that transgenic mice had a 3.5-fold (line 1) and 2.1-fold (line 2) increase in GLUT1 content compared with wild-type mice. Both lines showed similar increases in fasting blood glucose and body weights at 24 wk of age compared with wild-type mice. Mesangial index (percent PAS-positive material in the mesangial tuft) increased 88% (line 1) and 75% (line 2) in the wild-type diabetic mice but only 48% (line 1) and 39% (line 2) in the diabetic transgenic mice (P < 0.05, transgenic vs. wild-type mice). This reduction in mesangial expansion was accompanied by a reduction in fibronectin accumulation, and vascular endothelial growth factor (VEGF) levels increased only half as much in the transgenic diabetic mice as in wild-type diabetic mice. Levels of nephrin, neph1, CD2AP, podocin, and GLUT4 were not significantly different in transgenic compared with wild-type mice. Taken together, increased podocyte GLUT1 expression in diabetic mice does not contribute to early diabetic nephropathy; surprisingly, it protects against mesangial expansion and fibronectin accumulation possibly by blunting podocyte VEGF increases.

Zhang, Hongyu; Schin, MaryLee; Saha, Jharna; Burke, Kathleen; Holzman, Lawrence B.; Filipiak, Wanda; Saunders, Thomas; Xiang, Minghui; Heilig, Charles W.

2010-01-01

285

Effect of whey protein on plasma amino acids in diabetic mice  

PubMed Central

The aim of this study was to investigate the effect of whey protein on plasma amino acid levels in a mouse model of type II diabetes, using high-performance liquid chromatography (HPLC). The composition and content of amino acids in the whey proteins were analyzed using HPLC. Type I and type II diabetic mouse models were prepared using streptozotocin (STZ) and normal mice were used as a control. The ICR mice in each group were then randomly divided into four subgroups, to which 0, 10, 20 and 40% whey protein, respectively, was administered for four weeks. Changes in the plasma amino acid levels were observed in each group. The proportions of leucine, isoleucine and valine in the whey proteins were 14.40, 5.93 and 5.32% of the total amino acids, respectively, that is, the branched-chain amino acid content was 25.65%. The levels of branched-chain amino acids increased in the plasma of the normal and model mice following the administration of whey proteins by gavage and the amino acid levels increased as the concentration of the administered protein increased. In addition, the branched-chain amino acid levels in the blood of the model mice were higher than those in the normal mice. The levels of plasma amino acids in diabetic mice increased following gavage with whey protein, which is rich in branched-chain amino acids.

HAN, TING; CAI, DONGLIAN; GENG, SHANSHAN; WANG, YING; ZHEN, HUI; WU, PEIYING

2013-01-01

286

Interleukin-1 promotes hyperglycemia and insulitis in mice normally resistant to streptozotocin-induced diabetes.  

PubMed Central

By administering physiological doses of interleukin-1 (IL-1) concurrently with multiple low doses of the beta cell toxin streptozotocin (MSZ), we observed an augmentation of diabetes by IL-1 in four different strains of mice. Augmentation of hyperglycemia by IL-1 was most prominent in the two MSZ-resistant mouse strains Balb/cJ and A/J. Furthermore, concurrent treatment with IL-1 and MSZ rendered these MSZ-resistant mice susceptible to the development of significant insulitis when compared to mice treated with MSZ alone. Development of insulitis was dependent upon the dose of IL-1; it was only observed at an IL-1 dose of 250 ng/kg body weight. Analysis of the leukocytic infiltrate in the islets of mice after treatment with 250 ng/kg IL-1 plus MSZ revealed the presence of L3T4+ and Lyt-2+ T lymphocytes. Administration of MSZ alone or IL-1 alone did not produce diabetes in the MSZ-resistant mice, indicating that neither of these agents was toxic to the beta cells by itself. We conclude that IL-1 synergizes with MSZ to augment diabetes in mice that are normally resistant to the diabetogenic effects of MSZ. Images Figure 3 Figure 4

Zunino, S. J.; Simons, L. F.; Sambrook, J. F.; Gething, M. J.

1994-01-01

287

Exacerbated Brain Damage, Edema and Inflammation in Type-2 Diabetic Mice Subjected to Focal Ischemia  

PubMed Central

One of the limiting factors in stroke therapeutic development is the use of animal models that do not well represent the underlying medical conditions of patients. In humans, diabetes increases the risk of stroke incidence as well as post-stroke mortality. To understand the mechanisms that render diabetics to increased brain damage, we evaluated the effect of transient middle cerebral artery occlusion (MCAO) in adult db/db mice. The db/db mouse is a model of type-2 diabetes with 4 times higher blood sugar than its normoglycemic genetic control (db/+ mouse). Following transient MCAO, the db/db mice showed significantly higher mortality, bigger infarcts, increased cerebral edema, worsened neurological status compared to db/+ mice. The db/db mice also showed significantly higher post-ischemic inflammatory markers (ICAM1+ capillaries, extravasated macrophages/neutrophils and exacerbated proinflammatory gene expression) compared to db/+ mice. In addition, the post-ischemic neuroprotective heat-shock chaperone gene expression was curtailed in the db/db compared to db/+ mice.

Tureyen, Kudret; Bowen, Kellie; Liang, Jin; Dempsey, Robert J; Vemuganti, Raghu

2010-01-01

288

Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice  

PubMed Central

OBJECTIVE Interleukin (IL)-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes via the unique biology of the nonobese diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in type 1 diabetes. RESEARCH DESIGN AND METHODS We generated IL-21R–deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic ?-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in type 1 diabetes. RESULTS Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies, and onset of type 1 diabetes. The lymphoid compartment in IL-21R?/? NOD is normal and does not contain an increased regulatory T-cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T-cells in IL-21R?/? NOD by transfer experiments. Conversely, overexpression of IL-21 in pancreatic ?-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-?, monocyte chemoattractant protein (MCP)-1, MCP-2, and interferon-inducible protein-10 in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of ?-cells and spontaneous type 1 diabetes in the normally diabetes-resistant C57Bl/6 and NOD × C57Bl/6 backgrounds. CONCLUSIONS This work provides demonstration of the essential prodiabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human type 1 diabetes.

Sutherland, Andrew P.R.; Van Belle, Tom; Wurster, Andrea L.; Suto, Akira; Michaud, Monia; Zhang, Dorothy; Grusby, Michael J.; von Herrath, Matthias

2009-01-01

289

Proanthocyanidin Attenuation of Oxidative Stress and NF-?B Protects Apolipoprotein E-Deficient Mice against Diabetic Nephropathy  

PubMed Central

Hyperlipidemia and hyperglycemia result in oxidative stress and play a major role in the development of diabetic nephropathy (DN). We explored the effects of proanthocyanidin (PA) on the induction and progression of DN in apolipoprotein E-deficient mice. Diabetes Mellitus was induced in ten-week-old male apoE?/?mice using streptozotocin (STZ). Mice were fed with a high-fat diet in presence or absence of PA. PA treatment significantly reduced the high cholesterol levels, restored renal functions, and reduced albuminuria in the PA-treated diabetic mice compared with the diabetic untreated mice. In addition, the glomerular mesangial expansion in the diabetic mice was attenuated as a result of PA supplementation. Moreover, PA treatment restored the elevated levels of MDA and CML and the reduced activity of SOD and GSH in the diabetic mice. Furthermore, PA feeding reduced the activation and translocation of NF-?B to the nucleus compared with the diabetic untreated animals. Reduction of NF-?B activation resulted in the attenuation of the expression of IL-6, TGF?, and RAGE which protected PA-treated mice against DN. The renoprotective effects of PA were found to be time independent regardless of whether the dietary feeding with PA was started pre-, co-, or post-STZ injection. In conclusion, part of the beneficial effects of PA includes the disruption of the detrimental AGE-RAGE-NF?B pathways.

Al-Malki, Abdulrahman L.; Sayed, Ahmed Amir Radwan; El Rabey, Haddad A.

2013-01-01

290

Transfer of Type 1 (insulin-dependent) diabetes mellitus associated autoimmunity to mice with severe combined immunodeficiency (SCID)  

Microsoft Academic Search

Summary  Pancreatic beta-cell destruction and development of Type 1 (insulin-dependent) diabetes mellitus are associated with circulating\\u000a islet cell antibodies. Mice with severe combined immunodeficiency (SCID mice) were reconstituted with peripheral blood mononuclear\\u000a cells from Type 1 diabetic patients, one who was antibody positive and one antibody negative, and from healthy individuals.\\u000a Reconstituted mice were subsequently immunized with rat islets in incomplete

J. S. Petersen; M. O. Marshall; S. Bækkeskov; K. R. Hejnæs; M. Høier-Madsen; T. Dyrberg

1993-01-01

291

Folic acid consumption reduces resistin level and restores blunted acetylcholine-induced aortic relaxation in obese\\/diabetic mice  

Microsoft Academic Search

Folic acid supplementation provides beneficial effects on endothelial functions in patients with hyperhomocysteinemia. However, its effects on vascular functions under diabetic conditions are largely unknown. Therefore, the effect(s) of folic acid (5.7 and 71 ?g\\/kg\\/day for 4 weeks) on aortic relaxation was investigated using obese\\/diabetic (+db\\/+db) mice and lean littermate (+db\\/+m) mice. Acetylcholine-induced relaxation in +db\\/+db mice was less than

Sai Wang Seto; Tsz Yan Lam; Penelope Mei Yu; Wayne Yuk Wai Lee; Alice Lai Shan Au; Christina Chui Wa Poon; Rachel Wai Sum Li; Shun Wan Chan; John Hok Keung Yeung; George Pak Heng Leung; Simon Ming Yuen Lee; Sai Ming Ngai; Yiu Wa Kwan

2010-01-01

292

Hyperactivity of ON-Type Retinal Ganglion Cells in Streptozotocin-Induced Diabetic Mice  

PubMed Central

Impairment of visual function has been detected in the early stage of diabetes but the underlying neural mechanisms involved are largely unknown. Morphological and functional alterations of retinal ganglion cells, the final output neurons of the vertebrate retina, are thought to be the major cause of visual defects in diabetes but direct evidence to support this notion is limited. In this study we investigated functional changes of retinal ganglion cells in a type 1-like diabetic mouse model. Our results demonstrated that the spontaneous spiking activity of ON-type retinal ganglion cells was increased in streptozotocin-diabetic mice after 3 to 4 months of diabetes. At this stage of diabetes, no apoptotic signals or cell loss were detected in the ganglion cell layer of the retina, suggesting that the functional alterations in ganglion cells occur prior to massive ganglion cell apoptosis. Furthermore, we found that the increased activity of ON-type ganglion cells was mainly a result of reduced inhibitory signaling to the cells in diabetes. This novel mechanism provides insight into how visual function is impaired in diabetic retinopathy.

Yu, Jun; Wang, Lu; Weng, Shi-Jun; Yang, Xiong-Li; Zhang, Dao-Qi; Zhong, Yong-Mei

2013-01-01

293

Leptin monotherapy rescues spermatogenesis in male akita type 1 diabetic mice.  

PubMed

Type 1 diabetes is associated with subfertility in humans. The current treatment for type 1 diabetes, insulin monotherapy, is suboptimal to fully stabilize glycemia, potentially leading to this subfertility. Recent work has demonstrated that treatment with the energy-regulating hormone leptin, alone or in combination with insulin, can more effectively control glycemia in mouse models of type 1 diabetes. Here, we sought to determine whether the fertility defects in a type 1 diabetic mouse model, the Akita mouse, can be rescued with leptin monotherapy in the absence of any exogenous insulin. Akita homozygous mice treated with leptin alone had a larger total body size, testes, and seminal vesicles than their untreated siblings. Leptin treatment prevented testicular degeneration and rescued sperm motility to wild-type levels. Furthermore, sperm obtained from leptin-treated mice could successfully fertilize ooctyes in vitro. Despite completely rescuing spermatogenesis, the critical reproductive hormones LH and testosterone were only modestly higher than in untreated mice, indicating that a minimum threshold of these hormones must be met to maintain spermatogenesis. Cumulatively, these findings implicate the importance of leptin in maintaining fertility and support the use of leptin therapy in the treatment of type 1 diabetes. PMID:24840347

Schoeller, Erica L; Chi, Maggie; Drury, Andrea; Bertschinger, Ashley; Esakky, Prabagaran; Moley, Kelle H

2014-08-01

294

Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice  

PubMed Central

Background Type-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites. Results Transporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice. Conclusion A severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels.

2012-01-01

295

Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice  

PubMed Central

A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models1,2. It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic (NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones3. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens.

Nakayama, Maki; Abiru, Norio; Moriyama, Hiroaki; Babaya, Naru; Liu, Edwin; Miao, Dongmei; Yu, Liping; Wegmann, Dale R.; Hutton, John C.; Elliott, John F.

2005-01-01

296

The Programmed Death1 (PD1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice  

Microsoft Academic Search

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on acti- vated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoim- mune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in predi- abetic female nonobese diabetic

Mohammed Javeed; I. Ansari; Alan D. Salama; Tanuja Chitnis; R. Neal Smith; Hideo Yagita; Hisaya Akiba; Tomohide Yamazaki; Miyuki Azuma; Hideyuki Iwai; Samia J. Khoury; Hugh Auchincloss; Mohamed H. Sayegh

2003-01-01

297

Comparing anti-hyperglycemic activity and acute oral toxicity of three different trivalent chromium complexes in mice.  

PubMed

Three different ligands (rutin, folate and stachyose) of chromium(III) complexes were compared to examine whether they have similar effect on anti-hyperglycemic activity as well as the acute toxicity status. Anti-hyperglycemic activities of chromium rutin complex (CrRC), chromium folate complex (CrFC) and chromium stachyose complex (CrSC) were examined in alloxan-induced diabetic mice with daily oral gavage for a period of 2 weeks at the dose of 0.5-3.0 mg Cr/kg. Acute toxicities of CrRC and CrFC were tested using ICR mice at the dose of 1.0-5.0 g/kg with a single oral gavage and observed for a period of 2 weeks. Biological activities results indicated that only CrRC and CrFC could decrease blood glucose level, reduce the activities of aspartate transaminase, alanine transaminase, alkaline phosphatase, and increase liver glycogen level. In acute toxicity study, LD(50) values for both CrRC and CrFC were above 5.0 g/kg. The minimum lethal dose for CrFC was above 5.0 g/kg, while that for CrRC was 1.0 g/kg. Anti-diabetic activity of those chromium complexes was not similar and their acute toxicities were also different. CrFC represent an optimal chromium supplement among those chromium complexes with potential therapeutic value to control blood glucose in diabetes and non-toxicity in acute toxicity. PMID:22366098

Li, Fang; Wu, Xiangyang; Zou, Yanmin; Zhao, Ting; Zhang, Min; Feng, Weiwei; Yang, Liuqing

2012-05-01

298

Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice  

PubMed Central

Background and purpose: Hydrogen sulphide (H2S) has been involved in cardiovascular homoeostasis but data about its role in animal models of diabetic pathology are still lacking. Here, we have analysed H2S signalling in a genetic model of diabetes, the non-obese diabetic (NOD) mice. Experimental approach: NOD mice exhibit a progressive endothelial dysfunction characterized by a reduced reactivity of blood vessels as diabetes develops. NOD mice were divided into three groups according to different glycosuria values: NOD I, NOD II and NOD III. Age-matched non-obese resistant (NOR) mice were used as controls. H2S levels in plasma and aortic tissue were measured. Functional studies in aorta were carried out in isolated organ baths using both an exogenous source of H2S (NaHS) and the metabolic precursor (L-cysteine). Real time PCR and western blot analysis were also carried out on aortic tissues. Key results: NOD mice exhibited a progressive reduction of H2S plasma levels, which paralleled disease severity. L-cysteine-induced H2S production by aortic tissues was also progressively reduced. L-cysteine-induced vasorelaxation was significantly reduced in NOD mice while NaHS-induced relaxation was unaffected. ODQ (guanylate cyclase inhibitor), L-NAME (NO synthase inhibitor) or PAG, an inhibitor of cystathionine-?-lyase (CSE) inhibited H2S production induced by L-cysteine. Conclusions and implications: In NOD mice, endogenous H2S production is significantly impaired. Also, the ability of isolated aorta to respond to exogenous H2S is enhanced and endothelium-derived NO appears to be involved in the enzymatic conversion of L-cysteine into H2S.

Brancaleone, V; Roviezzo, F; Vellecco, V; De Gruttola, L; Bucci, M; Cirino, G

2008-01-01

299

Y2 Receptor Deletion Attenuates the Type 2 Diabetic Syndrome of ob\\/ob Mice  

Microsoft Academic Search

Hypothalamic neuropeptide Y (NPY) is implicated in the regulation of a variety of physiological functions, nota- bly energy homeostasis and reproduction. Chronically elevated NPY levels in the hypothalamus, as in geneti- cally obese ob\\/ob mice, are associated with obesity, a syndrome of type 2 diabetes, and infertility. However, it is not known which of the five cloned Y receptors mediate

Amanda Sainsbury; Christoph Schwarzer; Michelle Couzens; Herbert Herzog

2002-01-01

300

HYPOGLYCEMIC EFFECT OR NEEM BARK AND FLOWER ON STREPTOZOTOCIN - INDUCED DIABETES IN MICE  

PubMed Central

Three to six hours after the administration of extracts of neem bark or flower, the blood glucose levels of normal and streptozotocin-induced diabetic mice dropped significantly. However, neem flower possesses stronger hypoglycemic activity than the bark. Hypoglycemic action of these extracts may be due to their metabolic effect on tissue and or due to increase in insulin secretion.

Purohit, Ashok; Dixit, V. P.

1991-01-01

301

INFLUENCE OF TYPE II DIABETES AND OBESITY ON THE DISPOSITION AND ELIMINATION OF TCDD IN MICE  

EPA Science Inventory

INFLUENCE OF TYPE II DIABETES AND OBESITY ON THE DISPOSTION AND ELIMINATION OF TCDD IN MICE. MJ DeVito', JJ Diliberto', DG Ross', C Emond2, VM Richardson', and LS Birnbaum', 'ETD, NHEERL, ORD, US EPA, RTP, NC, 27711, USA, 2National Research Council. One possible explanation fo...

302

Sustained inflammasome activity in macrophages impairs wound healing in type 2 diabetic humans and mice.  

PubMed

The hypothesis of this study was that sustained activity of the Nod-like receptor protein (NLRP)-3 inflammasome in wounds of diabetic humans and mice contributes to the persistent inflammatory response and impaired healing characteristic of these wounds. Macrophages (Mp) isolated from wounds on diabetic humans and db/db mice exhibited sustained inflammasome activity associated with low level of expression of endogenous inflammasome inhibitors. Soluble factors in the biochemical milieu of these wounds are sufficient to activate the inflammasome, as wound-conditioned medium activates caspase-1 and induces release of interleukin (IL)-1? and IL-18 in cultured Mp via a reactive oxygen species-mediated pathway. Importantly, inhibiting inflammasome activity in wounds of db/db mice using topical application of pharmacological inhibitors improved healing of these wounds, induced a switch from proinflammatory to healing-associated Mp phenotypes, and increased levels of prohealing growth factors. Furthermore, data generated from bone marrow-transfer experiments from NLRP-3 or caspase-1 knockout to db/db mice indicated that blocking inflammasome activity in bone marrow cells is sufficient to improve healing. Our findings indicate that sustained inflammasome activity in wound Mp contributes to impaired early healing responses of diabetic wounds and that the inflammasome may represent a new therapeutic target for improving healing in diabetic individuals. PMID:24194505

Mirza, Rita E; Fang, Milie M; Weinheimer-Haus, Eileen M; Ennis, William J; Koh, Timothy J

2014-03-01

303

Marrow-Derived Cells Regulate the Development of Early Diabetic Retinopathy and Tactile Allodynia in Mice  

PubMed Central

The hypothesis that marrow-derived cells, and specifically proinflammatory proteins in those cells, play a critical role in the development of diabetes-induced retinopathy and tactile allodynia was investigated. Abnormalities characteristic of the early stages of retinopathy and allodynia were measured in chimeric mice lacking inducible nitric oxide synthase (iNOS) or poly(ADP-ribosyl) polymerase (PARP1) in only their marrow-derived cells. Diabetes-induced capillary degeneration, proinflammatory changes, and superoxide production in the retina and allodynia were inhibited in diabetic animals in which iNOS or PARP1 was deleted from bone marrow cells only. Of the various marrow cells, neutrophils (and monocytes) play a major role in retinopathy development, because retinal capillary degeneration likewise was significantly inhibited in diabetic mice lacking the receptor for granulocyte colony-stimulating factor in their marrow-derived cells. Immunodepletion of neutrophils or monocytes inhibited the endothelial death otherwise observed when coculturing leukocytes from wild-type diabetic animals with retinal endothelium. iNOS and PARP1 are known to play a role in inflammatory processes, and we conclude that proinflammatory processes within marrow-derived cells play a central role in the development of diabetes complications in the retina and nerve.

Li, Guangyuan; Veenstra, Alexander A.; Talahalli, Ramaprasad R.; Wang, Xiaoqi; Gubitosi-Klug, Rose A.; Sheibani, Nader; Kern, Timothy S.

2012-01-01

304

Left ventricular dysfunction with reduced functional cardiac reserve in diabetic and non-diabetic LDL-receptor deficient apolipoprotein B100-only mice  

PubMed Central

Background Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR-/-ApoB100/100). Methods and results 18-month-old LDLR-/-ApoB100/100 (n = 12), diabetic LDLR-/-ApoB100/100 mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells (IGF-II/LDLR-/-ApoB100/100, n = 14) and age-matched C57Bl/6 mice (n = 15) were studied after three months of high-fat Western diet. Compared to LDLR-/-ApoB100/100 mice, diabetic IGF-II/LDLR-/-ApoB100/100 mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60%) and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80%) despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion. Conclusions LDLR-/-ApoB100/100 mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals.

2011-01-01

305

l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice  

PubMed Central

Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of l-arginine (l-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. l-Citrulline (l-cit) supplementation not only increases l-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of l-arg, in the vasculature. Aims: To investigate whether l-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. Methods: STZ-C57BL6 mice received l-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and l-cit-treated STZ-rats were evaluated. Results: l-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, l-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16?weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. l-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, l-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1? and IL-12(p70) generation in the human proximal tubular cells. Conclusion: l-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.

Romero, Maritza J.; Yao, Lin; Sridhar, Supriya; Bhatta, Anil; Dou, Huijuan; Ramesh, Ganesan; Brands, Michael W.; Pollock, David M.; Caldwell, Ruth B.; Cederbaum, Stephen D.; Head, C. Alvin; Bagi, Zsolt; Lucas, Rudolf; Caldwell, Robert W.

2013-01-01

306

Early window of diabetes determinism in NOD mice, dependent on the complement receptor CRIg, identified by noninvasive imaging  

PubMed Central

All juvenile NOD mice exhibit insulitis, but there is substantial variation in their progression to diabetes. We demonstrate that a patient-validated magnetic-resonance-imaging (MRI) strategy to non-invasively visualize local effects of pancreatic-islet inflammation can predict diabetes onset in NOD mice. MRI signals acquired during a narrow early time-window allowed pre-sorting into disease-progressors and -nonprogressors and an estimate of time-to-diabetes. We exploited this capability to identify novel elements correlated with disease protection, including CRIg (complement receptor of the immunoglobulin superfamily), which marked a subset of macrophages associated with diabetes resistance. Administration of CRIg-Fc depressed MRI signals and diabetes incidence. In addition to identifying regulators of disease progression, this study shows that diabetes is set at an early age in NOD mice.

Fu, Wenxian; Wojtkiewicz, Gregory; Weissleder, Ralph; Benoist, Christophe; Mathis, Diane

2012-01-01

307

Hypoglycemic and Hypolipidemic Effects of Ethanolic Extract of Mirabilis jalapa L. Root on Normal and Diabetic Mice  

PubMed Central

The present study investigated the insulin sensitivity, hypoglycemic, and hypolipidemic activities of ethanolic extract of Mirabilis jalapa L. root (EEM) in normal and diabetic mice. After induction of diabetes with streptozotocin, both normal and diabetic mice were singly or repeatedly for 28 days administrated with EEM at doses of 2, 4, 8?g/kg, respectively. Before induction of diabetes, mice were administrated with EEM at doses of 2, 4, 8?g/kg for 14 days and were injected with streptozotocin and continued on EEM administration for another 28 days. Both after and before induction of diabetes, repeated administration with 4, 8?g/kg EEM continually lowered blood glucose level, decreased serum insulin level and improved insulin sensitivity index, and lowered serum total cholesterol, triglyceride levels and triglyceride content in liver and skeletal muscle, and increased glycogen content in these tissues; but repeated administration had no influence on those indexes of normal mice. Single administration with EEM (4, 8?g/kg) showed hypoglycemic effect in oral glucose tolerance test in normal and diabetic mice. Single administration with EEM had no hypoglycemic and hypolipidemic effects on normal and diabetic mice. These results suggest that EEM possesses both potential insulin sensitivity, hypoglycemic, and hypolipidemic effects on diabetes.

Zhou, Ji-Yin; Zhou, Shi-Wen; Zeng, Sheng-Ya; Zhou, Jian-Yun; Jiang, Ming-Jin; He, Yan

2012-01-01

308

Rapid onset of cardiomyopathy in STZ-induced female diabetic mice involves the downregulation of pro-survival Pim-1  

PubMed Central

Background Diabetic women are five times more likely to develop congestive heart failure compared with two fold for men. The underlying mechanism for this gender difference is not known. Here we investigate the molecular mechanisms responsible for this female disadvantage and attempt safeguarding cardiomyocytes viability and function through restoration of pro-survival Pim-1. Methods and Results Diabetes was induced by injection of streptozotocin in CD1 mice of both genders. Functional and dimensional parameters measurement using echocardiography revealed diastolic dysfunction in female diabetic mice within 8 weeks after STZ-induced diabetes. This was associated with significant downregulation of pro-survival Pim-1 and upregulation of pro-apoptotic Caspase-3, microRNA-1 and microRNA-208a. Male diabetic mice did not show any significant changes at this time point (P?diabetic). Further, the onset of ventricular remodelling was quicker in female diabetic mice showing marked left ventricular dilation, reduced ejection fraction and poor contractility (P?diabetic at 12 and 16 weeks of STZ-induced diabetes). Molecular analysis of samples from human diabetic hearts confirmed the results of pre-clinical studies, showing marked downregulation of Pim-1 in the female diabetic heart (P?diabetic). Finally, in vitro restoration of Pim-1 reversed the female disadvantage in diabetic cardiomyocytes. Conclusions We provide novel insights into the molecular mechanisms behind the rapid onset of cardiomyopathy in female diabetics. These results suggest the requirement for the development of gender-specific treatments for diabetic cardiomyopathy.

2014-01-01

309

Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice  

Microsoft Academic Search

Aims\\/hypothesis  During the pathogenesis of type 2 diabetes insulin resistance causes compensatory proliferation of beta cells. As beta cells have a limited replication potential, this compensatory proliferation might accelerate cellular senescence and lead to diabetes. We examined the cellular senescence of beta cells after proliferation during lipoglucotoxicity.Methods  Senescence-associated markers in beta cells were examined in nutrient-induced diabetic C57BL\\/6J mice that were fed

H. Sone; Y. Kagawa

2005-01-01

310

Proteases in Plasma and Kidney of db/db Mice as Markers of Diabetes-Induced Nephropathy  

PubMed Central

Db/db mice are overweight, dyslipidemic and develop diabetic complications, relevant for similar complications in human type 2 diabetes. We have used db/db and db/+ control mice to investigate alterations in proteinase expression and activity in circulation and kidneys by SDS-PAGE zymography, electron microscopy, immunohistochemistry, Western blotting, and in situ zymography. Plasma from db/db mice contained larger amounts of serine proteinases compared to db/+ mice. Kidneys from the db/db mice had a significantly larger glomerular surface area and somewhat thicker glomerular basement membranes compared to the db/+ mice. Furthermore, kidney extracts from db/+ mice contained metalloproteinases with Mr of approximately 92000, compatible with MMP-9, not observed in db/db mice. These results indicate that higher levels of serine proteinases in plasma may serve as potential markers for kidney changes in db/db mice, whereas a decrease in MMP-9 in the kidney may be related to the glomerular changes.

Hadler-Olsen, E.; Winberg, J.-O.; Reinholt, F. P.; Larsen, T.; Uhlin-Hansen, L.; Jenssen, T.; Berg, E.; Kolset, S. O.

2011-01-01

311

Anti-oxidant effect of gold nanoparticles restrains hyperglycemic conditions in diabetic mice  

PubMed Central

Background Oxidative stress is imperative for its morbidity towards diabetic complications, where abnormal metabolic milieu as a result of hyperglycemia, leads to the onset of several complications. A biological antioxidant capable of inhibiting oxidative stress mediated diabetic progressions; during hyperglycemia is still the need of the era. The current study was performed to study the effect of biologically synthesized gold nanoparticles (AuNPs) to control the hyperglycemic conditions in streptozotocin induced diabetic mice. Results The profound control of AuNPs over the anti oxidant enzymes such as GSH, SOD, Catalase and GPx in diabetic mice to normal, by inhibition of lipid peroxidation and ROS generation during hyperglycemia evidence their anti-oxidant effect during hyperglycemia. The AuNPs exhibited an insistent control over the blood glucose level, lipids and serum biochemical profiles in diabetic mice near to the control mice provokes their effective role in controlling and increasing the organ functions for better utilization of blood glucose. Histopathological and hematological studies revealed the non-toxic and protective effect of the gold nanoparticles over the vital organs when administered at dosage of 2.5 mg/kilogram.body.weight/day. ICP-MS analysis revealed the biodistribution of gold nanoparticles in the vital organs showing accumulation of AuNPs in the spleen comparatively greater than other organs. Conclusion The results obtained disclose the effectual role of AuNPs as an anti-oxidative agent, by inhibiting the formation of ROS, scavenging free radicals; thus increasing the anti-oxidant defense enzymes and creating a sustained control over hyperglycemic conditions which consequently evoke the potential of AuNPs as an economic therapeutic remedy in diabetic treatments and its complications.

2010-01-01

312

Selenium acts as an insulin-like molecule for the down-regulation of diabetic symptoms via endoplasmic reticulum stress and insulin signalling proteins in diabetes-induced non-obese diabetic mice  

Microsoft Academic Search

To investigate whether selenium (Sel) treatment would impact on the onset of diabetes, we examined serum biochemical components\\u000a including glucose and insulin, endoplasmic reticulum (ER) stress and insulin signalling proteins, hepatic C\\/EBP-homologous\\u000a protein (CHOP) expression and DNA fragmentation in diabetic and non-diabetic conditions of non-obese diabetic (NOD) mice.\\u000a We conclude that (i) Sel treatment induced insulin-like effects in lowering serum

Daeyoun Hwang; Sujin Seo; Yongkyu Kim; Chuelkyu Kim; Sunbo Shim; Seungwan Jee; Suhae Lee; Mikyong Jang; Minsun Kim; Suyoun Yim; Sang-Koo Lee; Byeongcheol Kang; Insurk Jang; Jungsik Cho

2007-01-01

313

Integrin ?1/Akita double knockout mice on a Balb/c background develop advanced features of human diabetic nephropathy  

PubMed Central

Animal models that mimic human diabetic nephropathy are useful to identify key factors in pathogenesis of this disease as well as the development of new therapies. Several mouse models of diabetes have features of human diabetic nephropathy, yet none of these completely fulfill the Animal Models of Diabetes Complications Consortium criteria and completely reproduce pathological and functional features of the human disease. The Akita mouse carries a mutation in the insulin 2 gene and, to date, only survive as heterozygotes that develop spontaneous type 1 diabetes. Here we show that Akita mice with mutation of both insulin 2 alleles (Akita knockout (KO)) survive if crossed onto the Balb/c background. These mice develop hyperglycemia, more severe albuminuria and mesangial sclerosis compared to heterozygous mice on the same genetic background. Interestingly, crossing these AkitaKO mice with integrin ?1KO mice, a model of exacerbated glomerulosclerosis after injury and also on the Balb/c background, resulted in a 16-fold increase in albuminuria, significant mesangial matrix expansion, nodular and diffuse glomerulosclerosis, and a 2-fold increase in glomerular basement membrane thickening when compared to non-diabetic mice. Moreover a significant decline in glomerular filtration was evident in the ?1KOAkitaKO mice at 6 months of age. Thus, the integrin ?1KOAkitaKO Balb/c mouse represents a promising model presenting with most features of human diabetic nephropathy.

Yu, Ling; Su, Yan; Paueksakon, Paisit; Cheng, Huifang; Chen, Xiwu; Wang, Hongtao; Harris, Raymond C.; Zent, Roy; Pozzi, Ambra

2012-01-01

314

The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension.  

PubMed

Diabetic nephropathy is the leading cause of end-stage renal disease in humans in the Western world. The recent development of Na(+)-glucose cotransporter 2 (SGLT2) inhibitors offers a new antidiabetic therapy via enhanced glucose excretion. Whether this strategy exerts beneficial effects on the development of type 2 diabetic nephropathy is still largely unclear. We investigated the effects of the specific SGLT2 inhibitor empagliflozin in BTBR.Cg-Lep/WiscJ (BTBR ob/ob) mice, which spontaneously develop type 2 diabetic nephropathy. In the first experiment, BTBR ob/ob mice received either a diet containing 300 ppm empagliflozin or equicaloric placebo chow for 12 wk. In the second experiment, BTBR ob/ob mice received 1 ?g·kg body wt(-1)·day(-1) ANG II to induce arterial hypertension and were separated into the same two diet groups for 6 wk. In both experiments, empagliflozin treatment enhanced glucosuria, thereby lowering blood glucose. Independently of hypertension, empagliflozin reduced albuminuria in diabetic mice. However, empagliflozin treatment affected diabetes-related glomerular hypertrophy, markers of renal inflammation, and mesangial matrix expansion only in BTBR ob/ob mice without hypertension. In summary, empagliflozin demonstrated significant antihyperglycemic effects, differentially ameliorating early features of diabetic nephropathy in BTBR ob/ob mice with and without hypertension. PMID:24944269

Gembardt, Florian; Bartaun, Christoph; Jarzebska, Natalia; Mayoux, Eric; Todorov, Vladimir T; Hohenstein, Bernd; Hugo, Christian

2014-08-01

315

Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice.  

PubMed

The activation of the poly(ADP-ribose) polymerase (PARP) plays an important role in the pathophysiology of various diseases associated with oxidative stress. We found increased amounts of poly(ADP) ribosylated proteins in diabetic kidneys of Lepr(db/db) (BKsJ) mice, suggesting increased PARP activity. Therefore, we examined the effects of two structurally unrelated PARP inhibitors (INO-1001 and PJ-34) on the development of diabetic nephropathy of Lepr(db/db) (BKsJ) mice, an experimental model of type 2 diabetes. INO-1001 and PJ-34 were administered in the drinking water to Lepr(db/db) mice. Both INO-1001 and PJ-34 treatment ameliorated diabetes-induced albumin excretion and mesangial expansion, which are hallmarks of diabetic nephropathy. PARP inhibitors decreased diabetes-induced podocyte depletion in vivo and blocked hyperglycemia-induced podocyte apoptosis in vitro. High glucose treatment of podocytes in vitro led to an early increase of poly(ADP) ribosylated modified protein levels. Reactive oxygen species (ROS) generation appears to be a downstream target of hyperglycemia-induced PARP activation, as PARP inhibitors blocked the hyperglycemia-induced ROS generation in podocytes. INO-1001 and PJ-34 also normalized the hyperglycemia-induced mitochondrial depolarization. PARP blockade by INO-1001 and PJ-34 prevented hyperglycemia-induced nuclear factor-kappaB (NFkappaB) activation of podocytes, and it was made evident by the inhibitor of kappaBalpha phosphorylation and NFkappaB p50 nuclear translocation. Our results indicate that hyperglycemia-induced PARP activation plays an important role in the pathogenesis of glomerulopathy associated with type 2 diabetes and could serve as a novel therapeutic target. PMID:17065336

Szabó, Csaba; Biser, Alisha; Benko, Rita; Böttinger, Erwin; Suszták, Katalin

2006-11-01

316

Prevention of Autoimmune Diabetes and Induction of ?-Cell Proliferation in NOD Mice by Hyperbaric Oxygen Therapy  

PubMed Central

We evaluated the effects of hyperbaric oxygen therapy (HOT) on autoimmune diabetes development in nonobese diabetic (NOD) mice. Animals received no treatment or daily 60-min HOT 100% oxygen (HOT-100%) at 2.0 atmospheres absolute and were monitored for diabetes onset, insulitis, infiltrating cells, immune cell function, and ?-cell apoptosis and proliferation. Cyclophosphamide-induced diabetes onset was reduced from 85.3% in controls to 48% after HOT-100% (P < 0.005) and paralleled by lower insulitis. Spontaneous diabetes incidence reduced from 85% in controls to 65% in HOT-100% (P = 0.01). Prediabetic mice receiving HOT-100% showed lower insulitis scores, reduced T-cell proliferation upon stimulation in vitro (P < 0.03), increased CD62L expression in T cells (P < 0.04), reduced costimulation markers (CD40, DC80, and CD86), and reduced major histocompatibility complex class II expression in dendritic cells (DCs) (P < 0.025), compared with controls. After autoimmunity was established, HOT was less effective. HOT-100% yielded reduced apoptosis (transferase-mediated dUTP nick-end labeling-positive insulin-positive cells; P < 0.01) and increased proliferation (bromodeoxyuridine incorporation; P < 0.001) of insulin-positive cells compared with controls. HOT reduces autoimmune diabetes incidence in NOD mice via increased resting T cells and reduced activation of DCs with preservation of ?-cell mass resulting from decreased apoptosis and increased proliferation. The safety profile and noninvasiveness makes HOT an appealing adjuvant therapy for diabetes prevention and intervention trials.

Faleo, Gaetano; Fotino, Carmen; Bocca, Nicola; Molano, R. Damaris; Zahr-Akrawi, Elsie; Molina, Judith; Villate, Susana; Umland, Oliver; Skyler, Jay S.; Bayer, Allison L.; Ricordi, Camillo; Pileggi, Antonello

2012-01-01

317

Losartan and Ozagrel reverse retinal arteriolar constriction in non-obese diabetic mice  

PubMed Central

Objective Reductions in retinal blood flow are observed early in diabetes. Venules may influence arteriolar constriction and flow; therefore, we hypothesized that diabetes would induce the constriction of arterioles that are in close proximity to venules, with the constriction mediated by thromboxane and angiotensin II. Methods Using non-obese diabetic (NOD) mice, retinal measurements were performed 3 weeks following the age at which glucose levels exceeded 200 mg/dl, with accompanying experiments on age-matched normoglycemic NOD mice. The measurements included retinal arteriolar diameters and red blood cell velocities, and were repeated following an injection of the thromboxane synthase inhibitor Ozagrel. Mice were subdivided into equal groups given drinking water with or without the angiotensin II receptor antagonist Losartan. Results Retinal arterioles were constricted in hyperglycemic mice, with a significant reduction in flow. However, not all arterioles were equally affected; the vasoconstriction was limited to arterioles that were in closer proximity to venules. The arteriolar vasoconstriction (mean arteriolar diameters = 51 ± 1 ?m vs 61 ± 1 ?m in controls; p<0.01) was eliminated by both Ozagrel (61 ± 2 ?m) and Losartan (63 ± 2 ?m). Conclusion Venule-dependent arteriolar vasoconstriction in NOD mice is mediated by thromboxane and/or angiotensin II.

Lee, Seungjun; Harris, Norman R.

2008-01-01

318

Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice  

PubMed Central

Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus.

Zhang, Yanqiao; Lee, Florence Ying; Barrera, Gabriel; Lee, Hans; Vales, Charisse; Gonzalez, Frank J.; Willson, Timothy M.; Edwards, Peter A.

2006-01-01

319

Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice  

NASA Astrophysics Data System (ADS)

Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus. glucose | GW4064 | farnesoid X receptor-VP16 | triglyceride | cholesterol

Zhang, Yanqiao; Lee, Florence Ying; Barrera, Gabriel; Lee, Hans; Vales, Charisse; Gonzalez, Frank J.; Willson, Timothy M.; Edwards, Peter A.

2006-01-01

320

Cytochrome P450 epoxygenase CYP2J2 attenuates nephropathy in streptozotocin-induced diabetic mice.  

PubMed

Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play important and diverse roles in the cardiovascular system. The anti-inflammatory, anti-apoptotic, pro-angiogenic, and anti-hypertensive properties of EETs in the cardiovascular system suggest a beneficial role for EETs in diabetic nephropathy. This study investigated the effects of endothelial specific overexpression of CYP2J2 epoxygenase on diabetic nephropathy in streptozotocin-induced diabetic mice. Endothelial CYP2J2 overexpression attenuated renal damage as measured by urinary microalbumin and glomerulosclerosis. These effects were associated with inhibition of TGF-?/Smad signaling in the kidney. Indeed, overexpression of CYP2J2 prevented TGF-?1-induced renal tubular epithelial-mesenchymal transition in vitro. These findings highlight the beneficial roles of the CYP epoxygenase-EET system in the pathogenesis of diabetic nephropathy. PMID:21742052

Chen, Guangzhi; Wang, Peihua; Zhao, Gang; Xu, Gang; Gruzdev, Artiom; Zeldin, Darryl C; Wang, Dao Wen

2011-11-01

321

Multi-Tissue Computational Modeling Analyzes Pathophysiology of Type 2 Diabetes in MKR Mice  

PubMed Central

Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective.

Kumar, Amit; Harrelson, Thomas; Lewis, Nathan E.; Gallagher, Emily J.; LeRoith, Derek; Shiloach, Joseph; Betenbaugh, Michael J.

2014-01-01

322

Inhibition of Th17 Cells Regulates Autoimmune Diabetes in NOD Mice  

PubMed Central

OBJECTIVE The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti–IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study. RESEARCH DESIGN AND METHODS AND RESULTS Although treatment with either anti–IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti–IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti–IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti–IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell–mediated dominant protective effect against autoimmunity. CONCLUSIONS These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease.

Emamaullee, Juliet A.; Davis, Joy; Merani, Shaheed; Toso, Christian; Elliott, John F.; Thiesen, Aducio; Shapiro, A.M. James

2009-01-01

323

Early changes of LIFR and gp130 in sciatic nerve and muscle of diabetic mice.  

PubMed

Peripheral neuropathy is a common complication of diabetes mediated by alterations of growth factors. Members of the neuropoietic cytokine family, which include IL-6, LIF, and CNTF among others, have been shown to be important regulators of peripheral nerves and the muscles that they innervate. To investigate their potential role in diabetic nerve and muscle, we studied the expression of the shared receptor subunits, LIFR and gp130 in a mouse model of streptozotocin (STZ)-induced diabetes. The results of Western blotting and densitometric analysis showed that both LIFR and gp130 protein expression were increased in diabetic sciatic nerve compared to control mice at early time points following STZ injection. In diabetic gastrocnemius muscle, LIFR and gp130 were increased from 3 days to 24 weeks following STZ injection. In contrast, both LIFR and gp130 protein expression were decreased in diabetic soleus muscle at 3-days post-injection. Our results suggest that hyperglycemia results in changes to nerve and muscle soon after the onset of diabetes and that cytokines may play a role in this process. PMID:21565387

Toledo-Corral, Claudia M; Banner, Lisa R

2012-02-01

324

STIM1 Restores Coronary Endothelial Function in Type 1 Diabetic Mice  

PubMed Central

Rationale The endoplasmic reticulum (ER) is a major intracellular Ca2+ store in endothelial cells (ECs). The Ca2+ concentration in the ER greatly contributes to the generation of Ca2+ signals that regulate endothelial functions. Many proteins, including stromal interaction molecule 1/2 (STIM1/2), Orai1/2/3, and sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase 3 (SERCA3), are involved in the ER Ca2+ refilling after store depletion in ECs. Objective This study is designed to examine the role of Ca2+ in the ER in coronary endothelial dysfunction in diabetes. Methods and Results Mouse coronary ECs (MCECs) isolated from diabetic mice exhibited (1) a significant decrease in the Ca2+ mobilization from the ER when the cells were treated by SERCA inhibitor, and (2) significant downregulation of STIM1 and SERCA3 protein expression in comparison to the controls. Overexpression of STIM1 restored (1) the increase in cytosolic Ca2+ concentration due to Ca2+ leak from the ER in diabetic MCECs, (2) the Ca2+ concentration in the ER, and (3) endothelium-dependent relaxation that was attenuated in diabetic coronary arteries. Conclusions Impaired ER Ca2+ refilling in diabetic MCECs, due to the decrease in STIM1 protein expression, attenuates endothelium-dependent relaxation in diabetic coronary arteries, while STIM1 overexpression has a beneficial and therapeutic effect on coronary endothelial dysfunction in diabetes.

Estrada, Irene A.; Donthamsetty, Reshma; Debski, Patryk; Zhou, Meng-Hua; Zhang, Shenyuan L.; Yuan, Jason X.-J.; Han, Wenlong; Makino, Ayako

2013-01-01

325

Stem Cell Transplantation Increases Antioxidant Effects in Diabetic Mice  

PubMed Central

Intra bone marrow-bone marrow transplantation (IBM- BMT) + thymus transplantation (TT) has been shown to reduce the incidence of graft versus host disease (GVHD) and restore donor-derived T cell function. In addition, an increase in insulin sensitivity occurred in db/db mice after IBM-BMT+TT treatment. Heme oxygenase (HO)-1 is a stress inducible enzyme which exert antioxidant, antiapoptotic, and immune-modulating properties. We examined whether IBM-BMT+TT could modulate the expression of HO-1 in the kidneys of db/db mice. Six-week-old db/db mice with blood glucose levels higher than 250 mg/dl were treated with IBM-BMT+TT. Six weeks later, the db/db mice showed decreased body weight, blood glucose levels and insulin, and increased plasma adiponectin levels. The upregulation of HO-1 was associated with significantly (p<0.05) increased levels of peNOS and pAKT, but decreased levels of iNOS in the kidneys of db/db mice. Plasma creatinine levels also decreased (p<0.05), and the expression of type IV collagen was improved. Thus IBM-BMT+TT unregulated the expression of HO-1, peNOS and pAKT, while decreasing iNOS levels in the kidney of db/db mice. This was associated with an improvement in renal function.

Li, Ming; Vanella, Luca; Zhang, Yuming; Shi, Ming; Takaki, Takashi; Shapiro, Joseph I; Ikehara, Susumu

2012-01-01

326

eNOS Knockout Mice with Advanced Diabetic Nephropathy Have Less Benefit from Renin-Angiotensin Blockade than from Aldosterone Receptor Antagonists  

PubMed Central

While blockade of the renin angiotensin system (RAS) is beneficial in treating many patients with diabetic nephropathy, some patients show a poor response. We hypothesized that the poor response of RAS blockade is attributed to inability to stimulate endothelial nitric oxide. Recently, we reported that diabetic eNOS knockout (KO) mice develop advanced diabetic nephropathy similar to human disease. Here, we tested the hypothesis that blockade of the RAS would be less beneficial in this model than in diabetic wild-type mice. Both enalapril and telmisartan were less effective at reducing renal injury in diabetic eNOSKO mice compared with diabetic wild-type mice. Blood pressure was only transiently reduced by these treatments in diabetic eNOSKO mice and later returned to levels similar to that of untreated diabetic eNOSKO mice. Serum aldosterone tended to be paradoxically higher with enalapril or telmisartan in diabetic eNOSKO mice, whereas these treatments tended to lower aldosterone in diabetic wild-type mice. The pathogenic role of aldosterone was demonstrated by the evidence that spironolactone significantly reduced blood pressure and prevented renal injury. In addition, a higher dose of enalapril also failed to prevent hypertension and renal injury in diabetic eNOSKO mice. In conclusion, an impaired endothelial NO response could lessen the benefit of RAS inhibition in diabetic renal disease. Aldosterone blockade may provide superior protection in this setting.

Kosugi, Tomoki; Heinig, Marcelo; Nakayama, Takahiro; Matsuo, Seiichi; Nakagawa, Takahiko

2010-01-01

327

Effects of ursolic acid on glucose metabolism, the polyol pathway and dyslipidemia in non-obese type 2 diabetic mice.  

PubMed

Ursolic acid (UA) is a pentacyclic triterpenoid compound that naturally occurs in fruits, leaves and flowers of medicinal herbs. This study investigated the dose-response efficacy of UA (0.01 and 0.05%) on glucose metabolism, the polyol pathway and dyslipidemia in streptozotocin/nicotinamide-induced diabetic mice. Supplement with both UA doses reduced fasting blood glucose and plasma triglyceride levels in non-obese type 2 diabetic mice. High-dose UA significantly lowered plasma free fatty acid, total cholesterol and VLDL-cholesterol levels compared with the diabetic control mice, while LDL-cholesterol levels were reduced with both doses. UA supplement effectively decreased hepatic glucose-6-phosphatase activity and increased glucokinase activity, the glucokinase/glucose-6-phosphatase ratio, GLUT2 mRNA levels and glycogen content compared with the diabetic control mice. UA supplement attenuated hyperglycemia-induced renal hypertrophy and histological changes. Renal aldose reductase activity was higher, whereas sorbitol dehydrogenase activity was lower in the diabetic control group than in the non-diabetic group. However, UA supplement reversed the biochemical changes in polyol pathway to normal values. These results demonstrated that low-dose UA had preventive potency for diabetic renal complications, which could be mediated by changes in hepatic glucose metabolism and the renal polyol pathway. High-dose UA was more effective anti-dyslipidemia therapy in non-obese type 2 diabetic mice. PMID:25059036

Lee, Jin; Lee, Hae-In; Seo, Kown-Il; Cho, Hyun Wook; Kim, Myung-Joo; Park, Eun-Mi; Lee, Mi-Kyung

2014-07-01

328

Increased methylmercury toxicity related to obesity in diabetic KK-Ay mice.  

PubMed

We examined the toxic effects of methylmercury (MeHg) in KK-Ay type 2 diabetic mice to clarify how metabolic changes associated with type 2 diabetes mellitus affect MeHg toxicity. MeHg (5 mg Hg kg (-1) day(-1) p.o.) was given to 4-week-old male KK-Ay and C57BL/6J (BL/6) mice three times per week for 6 weeks. Average body weights (BW) of vehicle-treated BL/6 and KK-Ay mice were 16.3 and 16.4 g respectively on the first day, and 24.8 and 42.3 g respectively on the last day of the experiment. MeHg-treated KK-Ay mice began to lose weight about 5 weeks after MeHg administration. Six of seven MeHg-treated KK-Ay mice showed hind-limb clasping in the final stage of the experiment. The mean blood mercury level of MeHg-treated KK-Ay mice reached a maximum of 9.8 µg ml(-1) , whereas that of the MeHg-treated BL/6 mice was 2.8 µg ml(-1) after 10 days of treatment. The average total mercury concentrations in the cerebrum and epididymal fat pad were 7.4 and 0.57 µg g(-1) , respectively, for BL/6 mice and 27 and 1.6 µg g(-1) , respectively, for KK-Ay mice. In MeHg-treated KK-Ay mice with neurological symptoms, CD204-positive macrophages were observed in the brain, kidney and spleen, indicating CD204 could be a marker for injured tissues. BW loss and significant pathological changes were not observed in other groups of mice. These results indicate that body fat gain in type 2 diabetes mellitus and low mercury accumulation in adipose tissue increased MeHg concentrations in organs and enhanced toxicity in KK-Ay mice at the same dose of MeHg per BW. Copyright © 2013 John Wiley & Sons, Ltd. PMID:24243536

Yamamoto, Megumi; Yanagisawa, Rie; Motomura, Eriko; Nakamura, Masaaki; Sakamoto, Mineshi; Takeya, Motohiro; Eto, Komyo

2014-08-01

329

Reduced Alpha-Lipoic Acid Synthase Gene Expression Exacerbates Atherosclerosis in Diabetic Apolipoprotein E-Deficient Mice  

PubMed Central

Objectives To study the effects of reduced lipoic acid gene expression on diabetic atherosclerosis in apolipoprotein E null mice (Apoe?/?). Methods and Results Heterozygous lipoic acid synthase gene knockout mice (Lias+/?) crossed with Apoe?/? mice were used to evaluate the diabetic effect induced by streptozotocin on atherosclerosis in the aortic sinus of the heart. While diabetes markedly increased atherosclerotic plaque size in Apoe?/? mice, a small but significant effect of reduced expression of lipoic acid gene was observed in diabetic Lias+/?Apoe?/? mice. In the aortic lesion area, the Lias+/?Apoe?/? mice exhibited significantly increased macrophage accumulation and cellular apoptosis than diabetic Lias+/+Apoe?/? littermates. Plasma glucose, cholesterol, and interleukin-6 were also higher. These abnormalities were accompanied with increased oxidative stress including a decreased ratio of reduced glutathione/oxidized glutathione in erythrocytes, increased systemic lipid peroxidation, and increased Gpx1 and MCP1 gene expression in the aorta. Conclusions Decreased endogenous lipoic acid gene expression plays a role in development of diabetic atherosclerosis. These findings extend our understanding of the role of antioxidant in diabetic atherosclerosis.

Yi, Xianwen; Xu, Longquan; Hiller, Sylvia; Kim, Hyung-Suk; Maeda, Nobuyo

2012-01-01

330

Immunotherapy with Tolerogenic Dendritic Cells Alone or in Combination with Rapamycin Does Not Reverse Diabetes in NOD Mice  

PubMed Central

Type 1 diabetes is a metabolic disease caused by autoimmunity towards ?-cells. Different strategies have been developed to restore ?-cell function and to reestablish immune tolerance to prevent and cure the disease. Currently, there is no effective treatment strategy to restore endogenous insulin secretion in patients with type 1 diabetes. This study aims to restore insulin secretion in diabetic mice with experimental antigen-specific immunotherapy alone or in combination with rapamycin, a compound well known for its immunomodulatory effect. Nonobese diabetic (NOD) mice develop spontaneous type 1 diabetes after 12 weeks of age. Autologous tolerogenic dendritic cells—consisting in dendritic cells pulsed with islet apoptotic cells—were administered to diabetic NOD mice alone or in combination with rapamycin. The ability of this therapy to revert type 1 diabetes was determined by assessing the insulitis score and by measuring both blood glucose levels and C-peptide concentration. Our findings indicate that tolerogenic dendritic cells alone or in combination with rapamycin do not ameliorate diabetes in NOD mice. These results suggest that alternative strategies may be considered for the cure of type 1 diabetes.

Pujol-Autonell, Irma; Ampudia, Rosa M.; Monge, Pau; Lucas, Anna M.; Carrascal, Jorge; Verdaguer, Joan; Vives-Pi, Marta

2013-01-01

331

Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice.  

PubMed

Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of beta cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a mu-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40 mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10 mg/kg/day subcutaneously) for 24 days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1beta, tumor necrosis factor-alpha and interferon-gamma] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of beta cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of beta cells and insulitis in the MLDS model of type 1 diabetes. PMID:18671992

Amirshahrokhi, K; Dehpour, A R; Hadjati, J; Sotoudeh, M; Ghazi-Khansari, M

2008-10-01

332

Aqueous Extract from Pepino (Solanum muricatum Ait.) Attenuated Hyperlipidemia and Cardiac Oxidative Stress in Diabetic Mice  

PubMed Central

This study examined the lipid-lowering and cardiac protective effects of aqueous extract of pepino (Solanum muricatum Ait.) in type 2 diabetic mice. Pepino at 1, 2, or 5% was supplied for 8 weeks. Results showed that pepino significantly decreased water intake and epididymal fat pad weight in diabetic mice (P < 0.05). Pepino treatments also significantly reduced plasma glucose and insulin levels, HOMA-IR index, and improved oral glucose tolerance (P < 0.05). Plasma and hepatic levels of triglyceride and total cholesterol (TC) were higher in diabetic groups when compared with normal group (P < 0.05), pepino treatments at 2 and 5% decreased triglyceride and TC levels in both plasma and liver (P < 0.05). Diabetes enhanced mRNA expression of resistin and diacylglycerol acyltransferase1 (DGAT1) in epididymal fat pad (P < 0.05); however, pepino intake significantly suppressed mRNA expression of resistin and DGAT1 in epididymal fat pad (P < 0.05). Pepino intake significantly reduced reactive oxygen species level, increased glutathione level, and retained glutathione peroxidase and catalase activities in cardiac tissues (P < 0.05). These findings suggest that pepino could be considered as a functional food for the alleviation of type 2 diabetes.

Wang, Zhi-hong; Hsu, Cheng-chin; Yin, Mei-chin

2012-01-01

333

Aqueous Extract from Pepino (Solanum muricatum Ait.) Attenuated Hyperlipidemia and Cardiac Oxidative Stress in Diabetic Mice.  

PubMed

This study examined the lipid-lowering and cardiac protective effects of aqueous extract of pepino (Solanum muricatum Ait.) in type 2 diabetic mice. Pepino at 1, 2, or 5% was supplied for 8 weeks. Results showed that pepino significantly decreased water intake and epididymal fat pad weight in diabetic mice (P < 0.05). Pepino treatments also significantly reduced plasma glucose and insulin levels, HOMA-IR index, and improved oral glucose tolerance (P < 0.05). Plasma and hepatic levels of triglyceride and total cholesterol (TC) were higher in diabetic groups when compared with normal group (P < 0.05), pepino treatments at 2 and 5% decreased triglyceride and TC levels in both plasma and liver (P < 0.05). Diabetes enhanced mRNA expression of resistin and diacylglycerol acyltransferase1 (DGAT1) in epididymal fat pad (P < 0.05); however, pepino intake significantly suppressed mRNA expression of resistin and DGAT1 in epididymal fat pad (P < 0.05). Pepino intake significantly reduced reactive oxygen species level, increased glutathione level, and retained glutathione peroxidase and catalase activities in cardiac tissues (P < 0.05). These findings suggest that pepino could be considered as a functional food for the alleviation of type 2 diabetes. PMID:24527264

Wang, Zhi-Hong; Hsu, Cheng-Chin; Yin, Mei-Chin

2012-01-01

334

Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice  

SciTech Connect

Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of {beta} cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a {mu}-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1{beta}, tumor necrosis factor-{alpha} and interferon-{gamma}] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of {beta} cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of {beta} cells and insulitis in the MLDS model of type 1 diabetes.

Amirshahrokhi, K.; Dehpour, A.R. [Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Hadjati, J. [Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Sotoudeh, M. [Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Ghazi-Khansari, M. [Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)], E-mail: ghazikha@sina.tums.ac.ir

2008-10-01

335

Spontaneously diabetic Ins2+/Akita:apoE-deficient mice exhibit exaggerated hypercholesterolemia and atherosclerosis  

PubMed Central

Type 1 diabetes (T1D) increases the risk of adverse coronary events. Among risk factors, dyslipidemia due to altered hepatic lipoprotein metabolism plays a central role in diabetic atherosclerosis. Nevertheless, the likely alterations in plasma lipid/lipoprotein profile remain unclear, especially in the context of spontaneously developed T1D and atherosclerosis. To address this question, we generated Ins2+/Akita:apoE?/? mouse by cross-breeding Ins2+/Akita mouse (which has Ins2 gene mutation, causing pancreatic ?-cell apoptosis and insulin deficiency) with apoE?/? mouse. Ins2+/Akita:apoE?/? mice developed T1D spontaneously at 4–5 wk of age. At 25 wk of age and while on a standard chow diet, diabetic Ins2+/Akita:apoE?/? mice exhibited an approximately threefold increase in atherosclerotic plaque in association with an approximatelty twofold increase in plasma non-HDL cholesterol, predominantly in the LDL fraction, compared with nondiabetic controls. To determine factors contributing to the exaggerated hypercholesterolemia, we assessed hepatic VLDL secretion and triglyceride content, expression of hepatic lipoprotein receptors, and plasma apolipoprotein composition. Diabetic Ins2+/Akita:apoE?/? mice exhibited diminished VLDL secretion by ?50%, which was accompanied by blunted Akt phosphorylation in response to insulin infusion and decreased triglyceride content in the liver. Although the expression of hepatic LDL receptor was not affected, there was a significant reduction in the expression of lipolysis-stimulated lipoprotein receptor (LSR) by ?28%. Moreover, there was a marked decrease in plasma apoB-100 with a significant increase in apoB-48 and apoC-III levels. In conclusion, exaggerated hypercholesterolemia and atherosclerosis in spontaneously diabetic Ins2+/Akita:apoE?/? mice may be attributable to impaired lipoprotein clearance in the setting of diminished expression of LSR and altered apolipoprotein composition of lipoproteins.

Ma, Zhexi; Segar, Lakshman

2011-01-01

336

Hypoglycaemic effects of alcoholic root extract of Borassus flabellifer (Linn.) in normal and diabetic rats.  

PubMed

The objective of the study was to investigate the alcoholic (ALEBF) extract of B. flabellifer for their hypoglycaemic effects in normal and diabetic rats. Diabetes was induced in rats by single dose administration of alloxan (120 mg/kg, i.p.) or by injecting dexamethasone (10 mg/kg, i.p.) for 10 days. In normal rats, ALEBF (100, 200 and 400 mg/kg) had significantly decreased the blood glucose level in a dose dependent manner after repeated administration for 7 days. In alloxan induced diabetic rats, extract (ALEBF) had decreased blood sugar level and improved glucose tolerance in alloxan induced diabetic rats at the end of 1st, 2nd , 3rd and 4th week after test extract treatment. However, the insulin levels of extract treated group did not significantly change after 28 days treatment with the extract. It did not alter the insulin levels. In alloxan model, repeated dose administration of ALEBF had showed significant increase in body weight, prevention of elimination of sugar in urine and reduced the mortality rate induced by alloxan. In dexamethasone induced insulin resistance diabetic rats, repeated administration of ALEBF inhibited the increase in blood glucose level, improved glucose tolerance and reduced the insulin levels as compared dexamethasone induced diabetic rats. PMID:23811441

Debnath, Titas; Radhakrishnan, Rajesh; Murugananthan, Gopal; Talwar, Sahil; K, Nandakumar

2013-07-01

337

Beneficial effects of Brazilian propolis on type 2 diabetes in ob/ob mice  

PubMed Central

The anti-diabetic effects of Brazilian propolis were examined using ob/ob mice. Although repeated injection of an ethanol extract of Brazilian propolis (100 mg/kg, ip, twice a week for 12 weeks) did not affect body weight gain and food intake of ob/ob mice, blood glucose and plasma cholesterol levels were significantly attenuated. Moreover, the propolis extract partially restored glucose tolerance and insulin resistance, indicating anti-diabetic properties of the extract. The propolis-treated mice exhibited lower weight gain in mesenteric adipose tissue, while weight gains in inguinal and epididymal adipose tissues were not modulated. Flow cytometric and microscopic analyses suggested that the extract promoted accumulation of eosinophils into mesenteric and epididymal adipose tissues. Alternatively, the ratio of M1-like macrophages to M2-like macrophages in mesenteric adipose tissue was reduced by the propolis injection, coincident with the decrement of the number of interleukin-12A+ cells. Levels of M1 macrophage markers, such as Itgax and Il12b transcripts, were decreased in the vascular stromal fraction of mesenteric adipose tissue, whereas those of pan-macrophage markers Emr1 and Cd68 were not influenced. Microarray and subsequent gene ontology term analyses suggested that propolis attenuated immune activation in mesenteric adipose tissues. Taken together, this indicates that Brazilian propolis improves diabetes in ob/ob mice, presumably through modification of immune cells in mesenteric adipose tissues.

Kitamura, Hiroshi; Naoe, Yoshinori; Kimura, Shunsuke; Miyamoto, Tomomi; Okamoto, Shiki; Toda, Chitoku; Shimamoto, Yoshinori; Iwanaga, Toshihiko; Miyoshi, Ichiro

2013-01-01

338

Experimental Protection of Diabetic Mice against Lethal P. aeruginosa Infection by Bacteriophage  

PubMed Central

The emergence of antibiotic-resistant bacterial strains has become a global crisis and is vulnerable for the exploration of alternative antibacterial therapies. The present study emphasizes the use of bacteriophage for the treatment of multidrug resistant P. aeruginosa. P. aeruginosa was used to induce septicemia in streptozotocin (STZ) induced diabetic and nondiabetic mice by intraperitoneal (i.p.) injection of 3 × 108?CFU, resulting in a fatal bacteremia within 48?hrs. A single i.p. injection of 3 × 109?PFU phage GNCP showed efficient protection in both diabetic (90%) and nondiabetic (100%) bacteremic mice. It was further noted that the protection rate was reduced in diabetic mice when phage GNCP was administered after 4?h and 6?h of lethal bacterial challenge. In contrast, nondiabetic bacteremic mice were rescued even when treatment was delayed up to 20?h after lethal bacterial challenge. Evaluation of results confirmed that a single intraperitoneal injection of the phage dose (3 × 109?PFU/mL) was more effective than the multiple doses of imipenem. These results uphold the efficacy of phage therapy against pernicious P. aeruginosa infections, especially in cases of immunocompromised host.

Shivshetty, Nagaveni; Hosamani, Rajeshwari; Ahmed, Liyakat; Oli, Ajay Kumar; Sannauallah, Syed; Sharanbassappa, Shivshetty; Patil, S. A.; Kelmani, Chandrakanth R.

2014-01-01

339

Effect of FTY720 on Some Physiological Indexes of Non-Obese Diabetic (NOD) Mice  

PubMed Central

The studies were performed to investigate the physiological characteristics of non-obese diabetic (NOD) mice treated with FTY720. At the age of 12 weeks, each mouse was fed with FTY720 or physiological saline once a day for 10 weeks running, and their blood glucose, weight, anti-GAD antibody and organ indexes were determined. No mouse in group FTY720 (NOD mice treated with FTY720) showed diabetic symptoms. The average content of serum anti-GAD antibody in group FTY720 decreased 48.75% (P < 0.01). It was concluded that the spleen, kidney and liver of NOD mice treated with FTY720 shriveled significantly in the progression of diabetes (P < 0.01 or P < 0.05). The body weight of group FTY720 mice was slightly lower than that of the model control (MC) group and these two groups both had less body weight than the normal control (NC) group (P < 0.01). The result of tests of anti-GAD antibody suggested that FTY720 treatment could suppress the anti-GAD response.

Chen, Xiaoqiang; Ye, Sudan; Zhang, Shikang; Li, Jianrong; Zhu, Hongying; Zheng, Gaoli; Lu, Yin; Wan, Haitong

2012-01-01

340

Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice.  

PubMed

1. Uncoupling of nitric oxide synthase (NOS) has been implicated in the pathogenesis of left ventricular (LV) dysfunction in diabetes mellitus. In the present study, we investigated the role of NOS uncoupling in oxidative/nitrosative stress and LV dysfunction in the diabetic mouse heart. 2. Diabetes was induced in wild-type (WT), endothelial (e) NOS knockout (eNOS(-/-)), inducible (i) NOS knockout (iNOS(-/-)) and neuronal (n) NOS knockout (nNOS(-/-)) mice by streptozotocin (STZ) treatment. 3. In the diabetic heart, iNOS, but not eNOS or nNOS, expression was increased. Levels of malondialdehyde (MDA), 4-hydroxy-noneal (HNE) and nitrotyrosine (NT), as markers of oxidative/nitrosative stress, were increased in the diabetic mouse heart, but the increase in oxidative/nitrosative stress was significantly repressed in the iNOS(-/-) diabetic mouse heart. Levels of nitrite and nitrate (NO(x)), as an index of nitric oxide, bioavailability were significantly decreased in the iNOS(-/-) diabetic mouse heart. 4. Oral administration of sepiapterin (10 mg/kg per day), a precursor of tetrahydrobiopterin (BH(4)), significantly increased BH(4) and the BH(4)/BH(2) ratio in diabetic mouse heart. Similarly, sepiapterin inhibited the formation of HNE, MDA and NT in diabetic hearts from all three genotypes, but the increase in NO(x) following sepiapterin treatment was significantly attenuated in the iNOS(-/-) diabetic mouse heart. Percentage fractional shortening (FS), evaluated by echocardiography, decreased significantly in all genotypes of diabetic mice. Sepiapterin significantly increased percentage FS in diabetic mice, except in iNOS(-/-) mice. 5. These results suggest that sepiapterin inhibits uncoupling of NOS and improves LV function presumably by increasing iNOS-derived nitric oxide in the diabetic heart. PMID:21554376

Jo, Hiromi; Otani, Hajime; Jo, Fusakazu; Shimazu, Takayuki; Okazaki, Toru; Yoshioka, Kei; Fujita, Masanori; Kosaki, Atsushi; Iwasaka, Toshiji

2011-08-01

341

Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice.  

PubMed

Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The prorenin-to-active renin ratio significantly increases in diabetes, and prorenin binding to its receptor in diabetic animal kidney induces the nephropathy without its conventional proteolytic activation, suggesting that angiotensin II (AngII) may not be the decisive factor causing the nephropathy. For identification of an AngII-independent mechanism, diabetes was induced in wild-type mice and AngII type 1a receptor gene-deficient mice by streptozotocin treatment, and their development and progression of diabetic nephropathy were assessed. In addition, prolonged inhibition of angiotensin-converting enzyme and prolonged prorenin receptor blockade were compared for their efficacy in preventing the nephropathy that occurred in diabetic AngII type 1a receptor gene-deficient mice. Only the prorenin receptor blockade with a short peptide of prorenin practically abolished the increased mitogen-activated protein kinase (MAPK) activation and nephropathy despite unaltered increase in AngII in diabetic kidney. These results indicate that the MAPK activation signal leads to the diabetic nephropathy but not other renin-angiotensin system-activated mechanisms in the glomeruli. It is not only AngII but also intraglomerular activation of MAPK by the receptor-associated prorenin that plays a pivotal role in diabetic nephropathy. PMID:16738017

Ichihara, Atsuhiro; Suzuki, Fumiaki; Nakagawa, Tsutomu; Kaneshiro, Yuki; Takemitsu, Tomoko; Sakoda, Mariyo; Nabi, A H M Nurun; Nishiyama, Akira; Sugaya, Takeshi; Hayashi, Matsuhiko; Inagami, Tadashi

2006-07-01

342

Long-term bisphenol A exposure accelerates insulitis development in diabetes-prone NOD mice.  

PubMed

Exposure to the endocrine disruptor (ED) bisphenol A (BPA) used in polycarbonate plastic and epoxy resins appears ubiquitous since BPA can be found in over 90% of analyzed urine samples from all age groups. There is a parallel occurrence of increased prevalence in type 1 diabetes mellitus (T1DM) and an increased exposure to EDs the last decades. T1DM is caused by insulin deficiency due to autoimmune destruction of insulin producing pancreatic beta cells and has been suggested to be induced by various environmental factors acting together with a genetic predisposition. The objective of the present study was to investigate the effect of BPA (0, 1 and 100 mg/l BPA in the drinking water) on T1DM development in nonobese diabetic (NOD) mice, spontaneously developing T1DM. Histological evaluation of pancreas from 12-weeks-old female mice revealed significantly increased insulitis in mice exposed to 1 mg/l BPA, while the insulitis was less severe at the higher BPA exposure. Serum glucose levels in the 1 mg/ml BPA group tended to be hyperglycaemic, also indicating an accelerated onset of T1DM. The high BPA exposure seemed to counteract the diabetes development in females and also in male NOD mice for both BPA concentrations. Prior to insulitis, both BPA concentrations resulted in increased apoptosis and reduced numbers of tissue resident macrophages in pancreatic islets. In conclusion, long-term BPA exposure at a dose three times higher than the tolerable daily intake of 50 µg/kg, appeared to accelerate spontaneous insulitis and diabetes development in NOD mice. PMID:23496298

Bodin, Johanna; Bølling, Anette Kocbach; Samuelsen, Mari; Becher, Rune; Løvik, Martinus; Nygaard, Unni Cecilie

2013-06-01

343

Weak Proinsulin Peptide-Major Histocompatibility Complexes Are Targeted in Autoimmune Diabetes in Mice  

PubMed Central

OBJECTIVE—Weak major histocompatibility complex (MHC) binding of self-peptides has been proposed as a mechanism that may contribute to autoimmunity by allowing for escape of autoreactive T-cells from the thymus. We examined the relationship between the MHC-binding characteristics of a ?-cell antigen epitope and T-cell autoreactivity in a model of autoimmune diabetes. RESEARCH DESIGN AND METHODS—The binding of a proinsulin epitope, proinsulin-1(47–64) (PI-1[47–64]), to the MHC class II molecules I-Ag7 and I-Ak was measured using purified class II molecules. T-cell reactivity to the proinsulin epitope was examined in I-Ag7+ and I-Ak+ mice. RESULTS—C-peptide epitopes bound very weakly to I-Ag7 molecules. However, C-peptide–reactive T-cells were induced after immunization in I-Ag7–bearing mice (NOD and B6.g7) but not in I-Ak–bearing mice (B10.BR and NOD.h4). T-cells reactive with the PI-1(47–64) peptide were found spontaneously in the peripancreatic lymph nodes of pre-diabetic NOD mice. These T-cells were activated by freshly isolated ?-cells in the presence of antigen-presenting cells and caused diabetes when transferred into NOD.scid mice. CONCLUSIONS—These data demonstrate an inverse relationship between self-peptide–MHC binding and T-cell autoreactivity for the PI-1(47–64) epitope in autoimmune diabetes.

Levisetti, Matteo G.; Lewis, Danna M.; Suri, Anish; Unanue, Emil R.

2008-01-01

344

Neurotensin-loaded collagen dressings reduce inflammation and improve wound healing in diabetic mice.  

PubMed

Impaired wound healing is an important clinical problem in diabetes mellitus and results in failure to completely heal diabetic foot ulcers (DFUs), which may lead to lower extremity amputations. In the present study, collagen based dressings were prepared to be applied as support for the delivery of neurotensin (NT), a neuropeptide that acts as an inflammatory modulator in wound healing. The performance of NT alone and NT-loaded collagen matrices to treat wounds in streptozotocin (STZ) diabetic induced mice was evaluated. Results showed that the prepared dressings were not-cytotoxic up to 72h after contact with macrophages (Raw 264.7) and human keratinocyte (HaCaT) cell lines. Moreover, those cells were shown to adhere to the collagen matrices without noticeable change in their morphology. NT-loaded collagen dressings induced faster healing (17% wound area reduction) in the early phases of wound healing in diabetic wounded mice. In addition, they also significantly reduced inflammatory cytokine expression namely, TNF-? (p<0.01) and IL-1? (p<0.01) and decreased the inflammatory infiltrate at day 3 post-wounding (inflammatory phase). After complete healing, metalloproteinase 9 (MMP-9) is reduced in diabetic skin (p<0.05) which significantly increased fibroblast migration and collagen (collagen type I, alpha 2 (COL1A2) and collagen type III, alpha 1 (COL3A1)) expression and deposition. These results suggest that collagen-based dressings can be an effective support for NT release into diabetic wound enhancing the healing process. Nevertheless, a more prominent scar is observed in diabetic wounds treated with collagen when compared to the treatment with NT alone. PMID:24161538

Moura, Liane I F; Dias, Ana M A; Suesca, Edward; Casadiegos, Sergio; Leal, Ermelindo C; Fontanilla, Marta R; Carvalho, Lina; de Sousa, Hermínio C; Carvalho, Eugénia

2014-01-01

345

An aqueous extract of Portulaca oleracea ameliorates diabetic nephropathy through suppression of renal fibrosis and inflammation in diabetic db/db mice.  

PubMed

Diabetic nephropathy is one of the most common microvascular complications of diabetes and the leading cause of end-stage renal disease. In the present study, we investigated the renoprotective effect of the aqueous extract of Portulaca oleracea (AP) on diabetic nephropathy accelerated by renal fibrosis and inflammation in type 2 diabetic db/db mice. The mice were treated with AP (300 mg/kg/day, p.o.) for ten weeks to examine the long-term effects on diabetic nephropathy and renal dysfunction. We found that AP treatment markedly lowered blood glucose to 412 ± 11.4 mg/dl and plasma creatinine level to 2.3 ± 0.8 mg/dl compared to db/db mice (p < 0.05, p < 0.01, respectively). This study also showed that treatment with AP significantly decreased water intake and urine volume in diabetic db/db mice (p < 0.05). In immunohistological study, the renal expression of transforming growth factor-?1 (TGF-?1), advanced glycation end products (AGE), and intercellular adhesion molecule (ICAM)-1 markedly increased in the renal cortex of untreated db/db mice (p < 0.01). In contrast, AP treatment significantly reduced these expressions to 50 ± 2.1%, 48 ± 2.8%, 61 ± 1.1%, respectively (p < 0.01). Furthermore, NF-?B p65 activation in renal tissues markedly increased in untreated db/db mice, which was significantly suppressed by AP treatment. Taken together, these findings suggest that AP attenuates diabetic nephropathy through inhibition of renal fibrosis and inflammation in db/db mice. PMID:22745066

Lee, An Sook; Lee, Yun Jung; Lee, So Min; Yoon, Jung Joo; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

2012-01-01

346

5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice.  

PubMed

The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT? receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT? receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT? receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT? receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT? receptor agonists may have clinical utility in treating diabetic neuropathic pain. PMID:22609798

Ulugol, Ahmet; Oltulu, Cagatay; Gunduz, Ozgur; Citak, Cihad; Carrara, Roberto; Shaqaqi, Mohammad Reza; Sanchez, Alicia Mansilla; Dogrul, Ahmet

2012-08-01

347

Differential anti-diabetic effects and mechanism of action of charantin-rich extract of Taiwanese Momordica charantia between type 1 and type 2 diabetic mice.  

PubMed

Momordica charantia Linn. (Cucurbitaceae), also called bitter melon, has traditionally been used as a natural anti-diabetic agent for anti-hyperglycemic activity in several animal models and clinical trials. We investigated the differences in the anti-diabetic properties and mechanism of action of Taiwanese M. charantia (MC) between type 1 diabetic (T1D) and type 2 diabetic (T2D) mice. To clarify the beneficial effects of MC, we measured non-fasting glucose, oral glucose tolerance, and plasma insulin levels in KK/HIJ mice with high-fat diet-induced diabetes (200mg/kg/day of charantin-rich extract of MC [CEMC]) and in ICR mice with STZ-induced diabetes. After 8weeks, all the mice were exsanguinated, and the expression of the insulin-signaling-associated proteins in their tissue was evaluated, in coordination with the protective effects of CEMC against pancreatic ?-cell toxicity (in vitro). Eight weeks of data indicated that CEMC caused a significant decline in non-fasting blood glucose, plasma glucose intolerance, and insulin resistance in the KK/HIJ mice, but not in the ICR mice. Furthermore, CEMC decreased plasma insulin and promoted the sensitivity of insulin by increasing the expression of GLUT4 in the skeletal muscle and of IRS-1 in the liver of KK/HIJ mice; however, CEMC extract had no effect on the insulin sensitivity of ICR mice. In vitro study showed that CEMC prevented pancreatic ? cells from high-glucose-induced cytotoxicity after 24h of incubation, but the protective effect was not detectable after 72h. Collectively, the hypoglycemic effects of CEMC suggest that it has potential for increasing insulin sensitivity in patients with T2D rather than for protecting patients with T1D against ?-cell dysfunction. PMID:24751968

Wang, Hsien-Yi; Kan, Wei-Chih; Cheng, Tain-Junn; Yu, Sung-Hsun; Chang, Liang-Hao; Chuu, Jiunn-Jye

2014-07-01

348

Contribution of neural cell death to depressive phenotypes of streptozotocin-induced diabetic mice.  

PubMed

Major depression disorder (MDD) or depression is highly prevalent in individuals with diabetes, and the depressive symptoms are more severe and less responsive to antidepressant therapies in these patients. The underlying mechanism is little understood. We hypothesized that the pathophysiology of comorbid depression was more complex than that proposed for MDD and that neural cell death played a role in the disease severity. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic mice. These mice had blood glucose levels threefold above controls and exhibited depressive phenotypes as judged by a battery of behavioral tests, thus confirming the comorbidity in mice. Immunohistological studies showed markedly increased TUNEL-positive cells in the frontal cortex and hippocampus of the comorbid mice, indicating apoptosis. This finding was supported by increased caspase-3 and decreased Bcl-2 proteins in these brain regions. In addition, the serum brain-derived neurotrophic factor (BDNF) level of comorbid mice was reduced compared with controls, further supporting the neurodegenerative change. Mechanistic analyses showed an increased expression of mitochondrial fission genes fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1), and a decreased expression of mitochondrial fusion genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optical atrophy 1 (Opa1). Representative assessment of the proteins Drp1 and Mfn2 mirrored the mRNA changes. The data demonstrated that neural cell death was associated with the depressive phenotype of comorbid mice and that a fission-dominant expression of genes and proteins mediating mitochondrial dynamics played a role in the hyperglycemia-induced cell death. The study provides new insight into the disease mechanism and could aid the development of novel therapeutics aimed at providing neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes. PMID:24764190

Chen, Cheng; Wang, Yun; Zhang, Juan; Ma, Lian; Gu, Jiang; Ho, Guyu

2014-06-01

349

Borapetoside C from Tinospora crispa improves insulin sensitivity in diabetic mice.  

PubMed

Diabetes mellitus (DM) often leads to disability from vascular complications and neurological complications. Tinospora crispa has been widely used in Asia and Africa as a remedy for diabetes and other diseases. In this study, we investigated the hypoglycemic actions of borapetoside C isolated from T. crispa, and the mechanisms underlying its actions. Acute treatment with borapetoside C (5mg/kg, i.p.) attenuated the elevated plasma glucose induced by oral glucose in normal and type 2 DM (T2DM) mice. Compared to the effect of injected insulin (0.5 IU/kg), borapetoside C caused a more prominent increase of glycogen content in skeletal muscle of T2DM mice, but a less increase in type 1 DM (T1DM) mice. Combined treatment of a low dose borapetoside C (0.1mg/kg, i.p.) plus insulin enhanced insulin-induced lowering of the plasma glucose level and insulin-induced increase of muscle glycogen content. Continuous treatment with 5mg/kg borapetoside C (twice daily) for 7 days increased phosphorylation of insulin receptor (IR) and protein kinase B (Akt) as well as the expression of glucose transporter-2 (GLUT2) in T1DM mice. Combined treatment of a low dose borapetoside C (0.1mg/kg, twice daily) plus insulin for 7 days enhanced insulin-induced IR and Akt phosphorylation and GLUT2 expression in the liver of T1DM mice. This study proved that borapetoside C can increase glucose utilization, delayed the development of insulin resistance and enhanced insulin sensitivity. The activation of IR-Akt-GLUT2 expression and the enhancement of insulin sensitivity may contribute to the hypoglycemic action of borapetoside C in diabetic mice. PMID:22579212

Ruan, Chi-Tun; Lam, Sio-Hong; Chi, Tzong-Cherng; Lee, Shoei-Sheng; Su, Ming-Jai

2012-06-15

350

Contribution of neural cell death to depressive phenotypes of streptozotocin-induced diabetic mice  

PubMed Central

Major depression disorder (MDD) or depression is highly prevalent in individuals with diabetes, and the depressive symptoms are more severe and less responsive to antidepressant therapies in these patients. The underlying mechanism is little understood. We hypothesized that the pathophysiology of comorbid depression was more complex than that proposed for MDD and that neural cell death played a role in the disease severity. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic mice. These mice had blood glucose levels threefold above controls and exhibited depressive phenotypes as judged by a battery of behavioral tests, thus confirming the comorbidity in mice. Immunohistological studies showed markedly increased TUNEL-positive cells in the frontal cortex and hippocampus of the comorbid mice, indicating apoptosis. This finding was supported by increased caspase-3 and decreased Bcl-2 proteins in these brain regions. In addition, the serum brain-derived neurotrophic factor (BDNF) level of comorbid mice was reduced compared with controls, further supporting the neurodegenerative change. Mechanistic analyses showed an increased expression of mitochondrial fission genes fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1), and a decreased expression of mitochondrial fusion genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optical atrophy 1 (Opa1). Representative assessment of the proteins Drp1 and Mfn2 mirrored the mRNA changes. The data demonstrated that neural cell death was associated with the depressive phenotype of comorbid mice and that a fission-dominant expression of genes and proteins mediating mitochondrial dynamics played a role in the hyperglycemia-induced cell death. The study provides new insight into the disease mechanism and could aid the development of novel therapeutics aimed at providing neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes.

Chen, Cheng; Wang, Yun; Zhang, Juan; Ma, Lian; Gu, Jiang; Ho, Guyu

2014-01-01

351

Genetic susceptibility to diabetes in inbred strains of mice: measurements of proinsulin mRNA and response to dexamethasone  

Microsoft Academic Search

Summary  The insulin resistance produced by the recessive db mutation has led to more severe diabetes in C57BL\\/KsJ mice relative to that in C57BL\\/6J mice, suggesting genetic differences between the two strains affecting insulin production or insulin action. To assess these parameters blood glucose, serum insulin, pancreatic insulin, and proinsulin mRNA were measured in both normal and diabetic (db\\/db) KsJ and

M. J. Orland; M. A. Permutt

1987-01-01

352

Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin-induced type 1 diabetes.  

PubMed

There are contradictory results about the effect of angiotensin-converting enzyme inhibitors (ACEIs) on bone. This study was performed to address the skeletal renin-angiotensin system (RAS) activity and the effects of the ACEI, captopril, on the bone of streptozotocin-induced type 1 diabetic mice. Histochemical assessment on bone paraffin sections was conducted by Safranin O staining and tartrate-resistant acid phosphatase staining. Micro-computed tomography was performed to analyze bone biological parameters. Gene and protein expression were determined by real-time polymerase chain reaction and immunoblotting, respectively. Type 1 diabetic mice displayed osteopenia phenotype and captopril treatment showed no osteoprotective effects in diabetic mice as shown by the reduction of bone mineral density, trabecular thickness and bone volume/total volume. The mRNA expression of ACE and renin receptor, and the protein expression of renin and angiotensin II were markedly up-regulated in the bone of vehicle-treated diabetic mice compared to those of non-diabetic mice, and these molecular changes of skeletal RAS components were effectively inhibited by treatment with captopril. However, treatment with captopril significantly elevated serum tartrate-resistant acid phosphatase 5b levels, reduced the ratio of osteoprotegerin/receptor activator of nuclear factor-?B ligand expression, increased carbonic anhydrase II mRNA expression and the number of matured osteoclasts and decreased transforming growth factor-? and osteocalcin mRNA expression in the tibia compared to those of diabetic mice. The present study demonstrated that the use of the ACEI, captopril, has no beneficial effect on the skeletal biological properties of diabetic mice. However, this could be attributed, at least partially, to its suppression of osteogenesis and stimulation of osteoclastogenesis, even though it could effectively inhibit high activity of local RAS in the bone of diabetic mice. PMID:23934056

Diao, Teng-Yue; Pan, Hai; Gu, Sa-Sa; Chen, Xi; Zhang, Fang-Yi; Wong, Man-Sau; Zhang, Yan

2014-05-01

353

Supplementation with chromium picolinate recovers renal Cr concentration and improves carbohydrate metabolism and renal function in type 2 diabetic mice  

Microsoft Academic Search

To study the preventive effect of supplemented chromium picolinate (CrPic) on the development of diabetic nephropathy in mice,\\u000a we analyzed the effects of CrPic supplementation on renal function and concentrations of serum glucose and tissue chromium\\u000a (Cr). In experiment 1, male KK-Ay obese diabetic mice were fed either a control diet (control) or a diet supplemented with\\u000a 2 mg\\/kg diet

Yukiko Mita; Kengo Ishihara; Yoshiko Fukuchi; Yoko Fukuya; Kyoden Yasumoto

2005-01-01

354

Cellular Action of Vasopressin in Medullary Tubules of Mice with Hereditary Nephrogenic Diabetes Insipidus  

PubMed Central

Our previous studies (1974. J. Clin. Invest.54: 753-762.) suggested that impaired metabolism of cyclic AMP (cAMP) may be involved in the renal unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI). To localize such a defect to specific segments of the nephron, we studied the activities of VP-sensitive adenylate cyclase, cAMP phosphodiesterase (cAMP-PDIE), as well as accumulation of cAMP in medullary collecting tubules (MCT) and in medullary thick ascending limbs of Henle's loop (MAL) microdissected from control mice with normal concentrating ability and from mice with hereditary NDI. Adenylate cyclase activity stimulated by VP or by NaF was only slightly lower (?24%) in MCT from NDI mice, compared with controls. In MAL of NDI mice, basal, VP-sensitive, and NaF-sensitive adenylate cyclase was markedly (> ?60%) lower compared with MAL of controls. The specific activity of cAMP-PDIE was markedly higher in MCT of NDI mice compared with controls, but was not different between MAL of control and NDI mice. Under present in vitro conditions, incubation of intact MCT from control mice with VP caused a striking increase in cAMP levels (>10), but VP failed to elicit a change in cAMP levels in MCT from NDI mice. When the cAMP-PDIE inhibitor 1-methyl-3-isobutyl xanthine (MIX) was added to the above incubation, VP caused a significant increase in cAMP levels in MCT from both NDI mice and control mice. Under all tested conditions, cAMP levels in MCT of NDI mice were lower than corresponding values in control MCT. Under the present experimental setting, VP and other stimulating factors (MIX, cholera toxin) did not change cAMP levels in MAL from either control mice or from NDI mice. The results of the present in vitro experiments suggest that the functional unresponsiveness of NDI mice to VP is perhaps mainly the result of the inability of collecting tubules to increase intracellular cAMP levels in response to VP. In turn, this inability to increase cAMP in response to VP is at least partly the result of abnormally high activity of cAMP-PDIE, a somewhat lower activity of VP-sensitive adenylate cyclase in MCT of NDI mice, and perhaps to a deficiency of some other as yet unidentified factors. The possible contribution of low VP-sensitive adenylate cyclase activity in MAL of NDI mice to the renal resistance to VP remains to be defined.