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1

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

2

Hypoglycemic effects of Potentilla fulgens L. in normal and alloxan-induced diabetic mice  

Microsoft Academic Search

Tap roots of Potentilla fulgens L. traditionally chewed along with betel nut (Areca catechu) and betel leaves (Piper betel), are commonly used by local practitioners for various types of ailments. The crude methanolic extract of the roots was tested for its effects in normoglycemic and alloxan-induced diabetic mice. Hypoglycemic activity was observed to be dose- and time- dependent. The extracts

D Syiem; G Syngai; P. Z Khup; B. S Khongwir; B Kharbuli; H Kayang

2002-01-01

3

Antidiabetic potential of Phyllanthus reticulatus in alloxan-induced diabetic mice  

Microsoft Academic Search

The plant Phyllanthus reticulatus is claimed to have antidiabetic activity in tribal area. To validate the tribal claim, the petroleum ether and ethanolic extracts of leaves of the P. reticulatus were orally tested at 500 and 1000 mg\\/kg for hypoglycemic effect in alloxan induces diabetic mice. It shows antidiabetic activity at the dose of 1000 mg\\/kg. The phytochemical screening of the residues

S. Kumar; D. Kumar; R. R. Deshmukh; P. D. Lokhande; S. N. More; V. D. Rangari

2008-01-01

4

Antidiabetic potential of Phyllanthus reticulatus in alloxan-induced diabetic mice.  

PubMed

The plant Phyllanthus reticulatus is claimed to have antidiabetic activity in tribal area. To validate the tribal claim, the petroleum ether and ethanolic extracts of leaves of the P. reticulatus were orally tested at 500 and 1000 mg/kg for hypoglycemic effect in alloxan induces diabetic mice. It shows antidiabetic activity at the dose of 1000 mg/kg. The phytochemical screening of the residues revealed the presence of terpenoids glycosides, protein, carbohydrates and absence of alkaloids and steroids. PMID:17855019

Kumar, S; Kumar, D; Deshmukh, R R; Lokhande, P D; More, S N; Rangari, V D

2008-01-01

5

Berberine ameliorates hyperglycemia in alloxan-induced diabetic C57BL/6 mice through activation of Akt signaling pathway.  

PubMed

Recently, it is implicated that the abnormality of Akt signaling pathway is involved in the diabetic pathology. Previous studies have demonstrated that berberine could decrease blood glucose by elevating liver glycogen synthesis. However, the underlying mechanism is still unclear. In the present study, we investigated the effects of berberine on fasting blood glucose, liver glycogen, Akt, Glycogen synthase kinase-3, glucokinase and insulin receptor substrate (IRS) in alloxan-induced diabetic mice, exploring its possible hypoglycemic mechanism. We found that in alloxan-induced diabetic mice, the high blood glucose was significantly lowered by berberine treatment. Liver glycogen content, the expression and activity of glucokinase and the phosphorylated Akt and IRS were all significantly reduced in diabetic mice whereas berberine blocked these changes. Berberine also depressed the increasing of phosphorylated GSK-3? in diabetic mice. Collectively, Berberine upregulates the activity of Akt possibly via insulin signaling pathway, eventually lowering high blood glucose in alloxan-induced diabetic mice. PMID:21705841

Xie, Xi; Li, Wenyuan; Lan, Tian; Liu, Weihua; Peng, Jing; Huang, Kaipeng; Huang, Juan; Shen, Xiaoyan; Liu, Peiqing; Huang, Heqing

2011-01-01

6

Decreased glutathione peroxidase activity in sciatic nerve of alloxan-induced diabetic mice and its correlation with blood glucose levels  

Microsoft Academic Search

The effect of alloxan-induced diabetes on glutathione peroxidase (GSH-Px) activity in sciatic nerve of mice has been studied. We have found, 7 days after alloxan treatment, a significant decrease in this enzymatic activity in the cytosol of sciatic nerve of diabetic mice, and moreover, that these changes remained unaltered up to 21 days after alloxan injection. No modification in the

Carlos Hermenegildo; Ángel Raya; Joaquin Romfi; Francisco J. Romero

1993-01-01

7

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. PMID:24826032

Saio, Valrielyn; Syiem, Donkupar; Sharma, Ramesh

2012-01-01

8

Decreased glutathione peroxidase activity in sciatic nerve of alloxan-induced diabetic mice and its correlation with blood glucose levels.  

PubMed

The effect of alloxan-induced diabetes on glutathione peroxidase (GSH-Px) activity in sciatic nerve of mice has been studied. We have found, 7 days after alloxan treatment, a significant decrease in this enzymatic activity in the cytosol of sciatic nerve of diabetic mice, and moreover, that these changes remained unaltered up to 21 days after alloxan injection. No modification in the glutathione content of sciatic nerve of diabetic mice was observed throughout the experiment when compared with controls. The decrease in GSH-Px activity in this tissue shows a good correlation with the increase of blood glucose levels throughout the experiment. It is hypothesized whether a combination of mechanisms could be involved in this decrease of GSH-Px activity and if oxygen radicals might be the common mediators of these processes. PMID:8396737

Hermenegildo, C; Raya, A; Romá, J; Romero, F J

1993-08-01

9

Lectin from Crataeva tapia Bark Improves Tissue Damages and Plasma Hyperglycemia in Alloxan-Induced Diabetic Mice.  

PubMed

Crataeva tapia is a plant popularly used for diabetes treatment, in Brazil. Progressive decline in renal and hepatic functions has been described in patients with diabetes mellitus, and mortality rate is increased in patients with chronic liver and renal disease. This study aimed to evaluate whether Crataeva tapia bark lectin (CrataBL) improves hyperglycemia and renal and hepatic damage in diabetic mice. CrataBL was purified by ion exchange chromatography on CM-cellulose, and intraperitoneal administration of CrataBL to alloxan-induced diabetic mice at dose of 10?mg/Kg/day and 20?mg/Kg/day for 10 days significantly reduced serum glucose levels by 14.9% and 55.9%, respectively. Serum urea, creatinine, aspartate aminotransferase, and alanine aminotransferase were also significantly reduced after treatment with both doses of CrataBL. Furthermore, histological analysis of liver, kidney, and pancreas revealed an improvement in the tissue morphology upon treatment with CrataBL. The results suggest that CrataBL has a beneficial hypoglycemic activity and improves the renal and hepatic complications of diabetes. Therefore, this lectin may be a promising agent for the treatment of diabetes, and this might be the basis for its use in the folk medicine as an alternative treatment to manage diabetes-related complications such as hyperglycemia and tissue damage. PMID:24324521

da Rocha, Amanda Alves; Araújo, Tiago Ferreira da Silva; da Fonseca, Caíque Silveira Martins; da Mota, Diógenes Luís; de Medeiros, Paloma Lys; Paiva, Patrícia Maria Guedes; Coelho, Luana Cassandra Breitenbach Barroso; Correia, Maria Tereza Dos Santos; Lima, Vera Lúcia de Menezes

2013-01-01

10

Antihyperglycemic and antioxidative potential of hydroalcoholic extract of Butea monosperma Lam flowers in alloxan-induced diabetic mice.  

PubMed

Daily treatment of alloxan-induced diabetic animals with 50% ethanolic extract of B. monosperma flowers (BMEE) for 45 days significantly lowered blood glucose level thereby preventing steep onset of hyperglycemia which was observed after alloxan administration and maintained body weight and blood glucose level close to the values observed in normal control and glibenclamide-treated diabetic mice. Moreover, the level of serum total cholesterol, triglyceride, low-density lipoprotein and very low-density lipoprotein cholesterol were also lowered, whereas the level of high-density lipoprotein cholesterol, which was reduced in untreated diabetic animals, was significantly elevated. Oxidative damage in the liver, pancreas and kidneys of diabetic mice as evidenced by a marked increment in the level of thiobarbituric acid reactive substances and also a distinct diminution in glutathione content was nullified by BMEE. Activities of antioxidant enzymes were also assessed in all the experimental groups. These enzymes registered a decline in their activity in diabetic animals thus revealing the damaging effects of free radicals generated due to alloxan exposure but their activities were reverted towards near normal range in BMEE-administered mice thus indicating the antioxidant efficacy of the drug in resisting oxidative damage. PMID:19761041

Sharmna, Nidhi; Garg, Veena

2009-07-01

11

The effects of the king oyster mushroom Pleurotus eryngii (higher Basidiomycetes) on glycemic control in alloxan-induced diabetic mice.  

PubMed

The purpose of this study is to investigate the effects of Pleurotus eryngii on glycemic metabolism. Alloxan-induced hyperglycemic mice were used to study the effects of P. eryngii on blood glucose, glycohemoglobin, insulin secretion, damaged pancreatic ?-cells, total antioxidant status (TAOS), and hepatic glycogen in hyperglycemic mice. Sixty diabetic mice were divided equally into 5 groups: the alloxan (AX)-induced hyperglycemic group, the AX and glibenclamide (GLI)-treated group, the AX and P. eryngii extracts (PEEs) 50-treated group (PEE 50 mg/kg), the AX and PEE100-treated group (PEE 100 mg/kg), and the AX and PEE200-treated group (PEE 200 mg/kg). The other 12 normal mice were injected intravenously with the normal saline and used as the control group. After PEE (100 and 200 mg/kg) was orally administered to the mice over 5 weeks, blood glucose and HbAlc were significantly decreased in AX-induced hyperglycemic mice (P < 0.05 and P < 0.01, respectively), whereas the level of insulin secretion was markedly elevated in (P < 0.05). The pancreatic ?-cells damaged by AX partially and gradually recovered after PPE extract was administered to the hyperglycemic mice for 35 days. In addition, PEE treatment gradually increased the body weight and significantly increased the concentration of hepatic glycogen in hyperglycemic mice (P < 0.05). The results suggest that the action of PPE on glycemic metabolism occurs via increasing glycogen and insulin concentrations as well as recovering injured ?-cells and reducing free radical damage. PPE may become a new potential hypoglycemic food for hyperglycemic people. PMID:24941163

Li, Jian-Ping; Lei, Ya-li; Zhan, Huan

2014-01-01

12

Prevention of Alloxan-Induced Diabetes Mellitus in the Rat by Silymarin  

Microsoft Academic Search

Silymarin is a free-radical scavenger and a membrane stabilizer which prevents lipoperoxidation and its associated cell damage in some experimental models. It has been proposed that lipid peroxidation caused by free radicals may be involved in alloxan-induced diabetes mellitus. Alloxan elicits pancreatic lipid peroxidation which precedes the appearance of hyperglycemia in mice. We studied the effects of silymarin on rat

Claudia P Soto; Blanca L Perez; Liliana P Favari; Jose L Reyes

1998-01-01

13

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

14

Antihyperglycemic and antioxidative potential of hydroalcoholic extract of Butea monosperma Lam flowers in alloxan-induced diabetic mice  

Microsoft Academic Search

for 45 days significantly lowered blood glucose level thereby preventing steep onset of hyperglycemia which was observed after alloxan administration and maintained body weight and blood glucose level close to the values observed in normal control and glibenclamide-treated diabetic mice. Moreover, the level of serum total cholesterol, triglyceride, low-density lipoprotein and very low-density lipoprotein cholesterol were also lowered, whereas the

Nidhi Sharma; Veena Garg

2009-01-01

15

Antidiabetic and antioxidant potential of ethanolic extract of Butea monosperma leaves in alloxan-induced diabetic mice.  

PubMed

The possible protective effect of ethanolic extract of B. monosperma leaves (BMEE) on diabetes and diabetes-induced oxidative stress was evaluated in alloxan (ALXN)-induced diabetic male adult mice. Experimental animals were divided into three groups viz., I, II, and III. Diabetes mellitus (DM) was induced in groups II and III mice by a single intraperitoneal injection of alloxan (150 mg/kg body wt). Group I (control mice) received an equal volume of normal saline. Group III mice were further treated with BMEE (300 mg/kg body wt, p.o.) for a period of 45 days. Body weight and fasting blood glucose (FBG) levels were measured at periodic intervals during the test period. At the end of treatment period, blood was collected by cardiac puncture under mild ether anesthesia and serum was isolated to analyze its lipid profile i.e. serum total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL). The homogenates of hepatic, pancreatic and renal tissues were also analyzed for both enzymatic and non-enzymatic antioxidants, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and total protein (TP). Alloxan injection resulted in a significantly (P < 0.05) increased concentration of FBG level. Besides, the levels of enzymatic and nonenzymatic antioxidants were decreased and TBARS level increased significantly (P < 0.05) in hepatic, pancreatic and renal tissues. Also, serum TC, TG, LDL and VLDL-cholesterol level elevated significantly (P < 0.05), whereas HDL-cholesterol reduced significantly (P < 0.05) in group II (alloxan-treated diabetic control). The FBG level decreased significantly (P < 0.05) after 45 days treatment of BMEE from 172 to 117.143 mg/dl, as compared to normal control (79.286 mg/dl). The activities of antioxidant enzymes (CAT and GSH-Px) and GSH level in hepatic, pancreatic and renal tissues also increased significantly (P < 0.05) in BMEE-treated mice, but the activity of SOD was not improved significantly. BMEE treatment also reduced the TBARS levels and lowered serum lipid profile significantly (P < 0.05). The findings of the present study indicated significant hypoglycemic and anti-oxidant activity in B. monosperma leaves, thus lends credence to its folklore use in the management and/or control of type-2 DM. PMID:19374261

Sharma, Nidhi; Garg, Veena

2009-02-01

16

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. PMID:20927247

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

2010-01-01

17

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

18

Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas  

Microsoft Academic Search

The aim of this study was to analyze the effect of the flavonoid silymarin, a free radical scavenger that prevents lipoperoxidation, on the pancreatic activity of superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase (CAT) in rats with alloxan-induced diabetes mellitus. Alloxan intoxicated rats were treated with silymarin in two manners, simultaneously (four or eight doses) or 20 days after

Claudia Soto; Rosa Recoba; Héctor Barrón; Carlos Alvarez; Liliana Favari

2003-01-01

19

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

20

Antidiabetic effect of Cogent db, a herbal drug in alloxan-induced diabetes mellitus  

Microsoft Academic Search

Cogent db, a compound herbal drug, was investigated for its possible antidiabetic effect in alloxan-induced diabetic rats. Oral administration of 0.15, 0.30 and 0.45 g\\/kg body wt. of the aqueous solution of Cogent db for 40 days exhibited a significant reduction in blood glucose, glycosylated haemoglobin and increased plasma insulin, total haemoglobin along with antihyperlipidemic effects in diabetic rats. The

L Pari; G Saravanan

2002-01-01

21

NTPDase and 5?-nucleotidase activities in rats with alloxan-induced diabetes  

Microsoft Academic Search

Diabetes is associated with a hypercoagulable state. In this study, we investigated the potential effects of alloxan-induced diabetes on the activities of the enzymes NTPDase (E.C. 3.6.1.5, apyrase, ATP diphosphohydrolase, ecto\\/CD39) and 5?-nucleotidase (E.C. 3.1.3.5, CD73) that can control the levels of ADP and adenosine, two substances that regulates platelet aggregation. In the alloxan-treated rats, NTPDase activity was significantly increased

Gilberto I. L Lunkes; Daniele S Lunkes; Vera M Morsch; Cintia M Mazzanti; André L. B Morsch; Vin??cius R Miron; Maria R. C Schetinger

2004-01-01

22

Oral Hypoglycaemic Drugs in Alloxan-Induced Diabetes Mellitus in Dogs  

Microsoft Academic Search

Balogh É., M. Tóth, G. Bölcsházi, Zs. Abonyi-Tóth, E. Kocsis, G. Semjén: Oral Hypoglycaemic Drugs in Alloxan-Induced Diabetes Mellitus in Dogs. Acta Vet. Brno 2008, 77: 363-371. The effect of the alpha-glycosidase inhibitor acarbose, the insulin sensitiser metformin and the insulin secretiser gliclazide on blood glucose level of dogs were examined in experimental diabetes. Dogs were randomly divided into three

É. Balogh; M. Tóth; G. Bölcsházi; Zs. Abonyi-Tóth; E. Kocsis; G. Semjén

2008-01-01

23

Antidiabetic effect of T. arjuna bark extract in alloxan induced diabetic rats  

Microsoft Academic Search

The present study was carried out to evaluate the antidiabetic effect of T. arjuna stembark extract and to study the activities\\u000a of hexokinase, aldolase and phosphoglucoisomerase, and gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-diphosphatase\\u000a in liver and kidney of normal and alloxan induced diabetic rats. Oral administration of ethanolic extract of bark (250 and\\u000a 500mg\\/kg body weight) for 30 days,

B. Ragavan; S. Krishnakumari

2006-01-01

24

Antidiabetic properties of aqueous barks extract of Parinari excelsa in alloxan-induced diabetic rats.  

PubMed

The aqueous extract of the Parinari excelsa barks at doses of 100 and 300 mg/kg/day for 7 days has a significant antihyperglycemic effect on alloxan-induced diabetic rats. At the same dose the acute oral administration of aqueous extract of the P. excelsa barks (100 and 300 mg/kg) induced a significant decrease of blood glucose on glucose-loaded normoglycaemic rats. Our results seem to confirm the rational bases for its use in traditional medicine. PMID:18358635

Ndiaye, M; Diatta, W; Sy, A N; Dièye, A M; Faye, B; Bassène, E

2008-06-01

25

Adrenocortical system response to induction of inflammation with silicon dioxide in rats with alloxan-induced diabetes mellitus.  

PubMed

Alloxan-induced diabetes mellitus in rats was characterized by persistent increase in blood levels of corticosterone, while chronic granulomatous inflammation induced by silicon dioxide and its combination with alloxan-induced diabetes mellitus were associated with transient increase in blood corticosterone level followed by gradual development of hypoadrenocorticism. The content of corticosterone in the adrenal glands of rats with alloxan-induced diabetes mellitus remained unchanged in the dynamics of the disease, but the level of progesterone decreased at the early terms of diabetes and then returned to the initial values. After administration of silicon dioxide to intact rats and to rats with diabetes mellitus, changes in hormone content in the adrenal glands were observed only at the initial stages of inflammation and consisted in elevation of corticosterone concentration against the background of reduced progesterone content. PMID:21165420

Kuznetsova, N V; Palchikova, N A; Selyatitskaya, V G; Shkurupiy, V A

2010-11-01

26

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. PMID:24551816

Pourghasem, Mohsen; Nasiri, Ebrahim; Shafi, Hamid

2014-01-01

27

Antidiabetic effect of Sida cordata in alloxan induced diabetic rats.  

PubMed

Medicinal plants are efficient ameliorator of oxidative stress associated with diabetes mellitus. In this study, ethyl acetate fraction (SCEE) of Sida cordata was investigated for scientific validation of its folk use in diabetes. Antidiabetic effect of SCEE was confirmed by antihyperglycemic activity in normal glucose loaded and diabetic glucose loaded animals as well as normal off feed animals. Confirmation of antidiabetic activity and toxicity ameliorative role of S. cordata was investigated in a chronic multiple dose treatment study of fifteen days. A single dose of alloxan (120?mg/kg) produced a decrease in insulin level, hyperglycemia, elevated total lipids, triglycerides, and cholesterol and decreased the high-density lipoproteins. Concurrent with these changes, there was an increase in the concentration of lipid peroxidation (TBARS), H2O2, and nitrite in pancreas, liver, and testis. This oxidative stress was related to a decrease in glutathione content (GSH) and antioxidant enzymes. Administration of SCEE for 15 days after diabetes induction ameliorated hyperglycemia, restored lipid profile, blunted the increase in TBARS, H2O2, and nitrite content, and stimulated the GSH production in the organs of alloxan-treated rats. We suggested that SCEE could be used as antidiabetic component in case of diabetes mellitus. This may be related to its antioxidative properties. PMID:25114914

Shah, Naseer Ali; Khan, Muhammad Rashid

2014-01-01

28

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. PMID:23905020

Monday, Onakpa Michael; Uzoma, Asuzu Isaac

2013-01-01

29

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. PMID:21808555

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

2010-01-01

30

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. PMID:24991066

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

2013-01-01

31

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. PMID:21814425

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

2010-01-01

32

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. PMID:21455444

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

2010-01-01

33

Antioxidant, Antihyperlipidaemic and Antidiabetic Activity of Eugenia Floccosa Bedd Leaves in Alloxan Induced Diabetic Rats  

PubMed Central

The ethanol extract of Eugenia floccosa Bedd (Family: Myrtaceae) leaf was investigated for its antioxidant, antihyperlipidaemic and antidiabetic effect in Wistar Albino rats. Diabetes was induced in Albino rats by administration of alloxan monohydrate (150mg/kg, i.p). The ethanol extracts of E. floccosa at a dose of 150 and 300mg/kg of body weight were administered at single dose per day to diabetes induced rats for a period of 14 days. The effect of ethanol extract of E. floccosa leaf extract on blood glucose, plasma insulin, creatinine, glycosylated haemoglobin, urea serum lipid profile [total cholesterol (TR), triglycerides (TG), low density lipoprotein – cholesterol (LDL-C), very low density lipoprotein – cholesterol (VLDL-C), high density lipoprotein – cholesterol (HDL-C) and phospholipid (PL)] serum protein, albumin, globulin, serum enzymes [serum glutamate pyruvate transaminases (SGPT) and serum glutamate oxaloacetate transaminases (SGOT), and alkaline phosphatase (ALP)], lipoprotein peroxidation (LPO) antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH) and glutathione peroxidase (GPx) were measured in the diabetic rats. The ethanol extract of Eugenia floccosa leaf elicited significant reductions of blood glucose (P<0.05), lipid parameters except HDL-C, serum enzymes and significantly increased HDL-C and antioxidant enzymes. The extracts also caused significant increase in plasma insulin (P<0.05) in the diabetic rats. From the above results, it is concluded that ethanol extract of Eugenia floccosa possesses significant antidiabetic, antihyperlipidaemic and antioxidant effects in alloxan induced diabetic rats. PMID:24826030

Jelastin, Kala S Mary; Tresina, P.S.; Mohan, V.R.

2011-01-01

34

Assessment of Alloxan-Induced Diabetic Rats as a Periodontal Disease Model Using a Selective Cyclooxygenase (COX)-2 Inhibitor  

PubMed Central

Several recent studies have reported that alloxan-treated rats with long-term hyperglycemia can develop naturally occurring periodontal disease (PD). Our previous studies detected dental caries in the same model. Therefore, these two lesions of different etiologies are expected to occur concurrently. In this study, we evaluated the use of diabetic rats as a PD model by employing a selective COX-2 inhibitor reported to be effective against PD. Six-week-old female F344 rats were divided into 3 groups: intact rats (control), alloxan-induced diabetic rats fed a standard diet (AL) and alloxan-induced diabetic rats fed a diet containing 0.01% etodolac (AL+Et). The animals were euthanized at 26 weeks of age, and their oral tissues were examined histopathologically. Gingivitis, marginal periodontitis and alveolar bone resorption were markedly enhanced along with dental caries in the AL group compared with the control group. However, the COX-2 inhibitor had no effect on periodontal inflammation in the AL+Et group. In addition, in the AL group, periodontitis was notably nonexistent around the normal molars, and gingivitis was scarcely worse than that in the control group. In the diabetic rats, the progression of periodontal inflammation was closely correlated with the severity of adjacent dental caries, and marginal periodontitis was frequently continuous with apical periodontitis. In conclusion, an alloxan-induced diabetic rat is not a model of PD but of dental caries. It is probable that in this model, hyperglycemia may enable crown caries to progress to apical periodontitis, while the associated inflammation may rostrally expand to surrounding periodontal tissue. PMID:25352713

Nakahara, Yutaka; Ozaki, Kiyokazu; Sano, Tomoya; Kodama, Yasushi; Matsuura, Tetsuro

2014-01-01

35

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. PMID:24250556

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

2012-01-01

36

Hepatoprotetive, Cardioprotective and Nephroprotective Actions of Essential Oil Extract of Artemisia sieberi in Alloxan Induced Diabetic Rats  

PubMed Central

The aim of the current study is to evaluate the potential mechanism of antidiabetic action of the essential oil of Artemisia sieberi and its effects on some hematological and biochemical parameters in alloxan induced diabetic rats. Extraction of the essential oil from aerial parts of A. sieberi was preformed by hydrodistillation. Fifty rats were divided into five groups. Groups I and II normal rats given 1 mL/day of dimethyl sulfoxide and 80 mg/kg BW of this oil extract, respectively. Groups III, IV and V diabetic rats given 1 mL/day of dimethyl sulfoxide, oil extract (80 mg/kg BW) and metformin (14.2 mg/kg BW), respectively. Several hematological and biochemical parameters were assessed. Oral administration of the extract resulted in a significant reduction in the mean values of blood glucose, glucagon, cholesterol, triglyceride, LDL-C, ESR, urea, uric acid, creatinine accompanied by an increase in the mean values of the total protein, albumin, insulin, HDL-C, neutrophile count and PCV in diabetic rats. No significant changes in these parameters were found in the control group. The effects produced by this extract were closely similar to a standard antidiabetic drug, metformin. In conclusion, the present study indicates that the essential oil extract of A. sieberi appears to exhibit cardioprotective, nephroprotective and hepatoprotective activities in alloxan induced diabetic rats. PMID:24250557

Irshaid, Fawzi; Mansi, Kamal; Bani-Khaled, Ahmad; Aburjia, Talal

2012-01-01

37

Mitigating effects of antioxidant properties of Artemisia campestris leaf extract on hyperlipidemia, advanced glycation end products and oxidative stress in alloxan-induced diabetic rats  

Microsoft Academic Search

Artemisia campestris is used as antivenom and anti-inflammatory Tunisian folk medicine. Recently, increased oxidative stress was shown to play an important role in the etiology and pathogenesis of diabetes mellitus and its complications. This study was designed to examine the effects of A. campestris leaf aqueous extract (Ac) on alloxan-induced diabetic rats by measuring glycemia, lipid profile, lipid peroxidation (MDA),

Mediha Sefi; Hamadi Fetoui; Mohamed Makni; Najiba Zeghal

2010-01-01

38

Insulin-like antigen of mangrove leaves and its anti-diabetic activity in alloxan-induced diabetic rats.  

PubMed

The objective of this study was to evaluate the anti-diabetic potential of three mangrove plants, Rhizophora mucronata, Rhizophora apiculata and Rhizophora annamalayana, and to detect the presence of their insulin-like protein. The in vivo anti-diabetic experiment was done on male albino Wister rats. Oral administration of 60?mg?kg(-1) leaf powder extract of the three different mangrove plants for 30 days modulated the parameters such as blood glucose, plasma insulin, body weight, total haemoglobin, glycosylated haemoglobin, liver glycogen, plasma and tissue lipids, cholesterol, triglycerides, free fatty acids and phospholipids to normal levels in the alloxan-induced diabetic rats. The anti-diabetic activity of R. apiculata was more pronounced than that of the other mangrove extracts, but it was on a par with the commercial drug glibenclamide. The presence of an insulin-like protein in the mangrove extracts was detected by SDS-PAGE analysis and confirmed through ELISA. Hence, the anti-diabetic activity and the presence of an insulin-like protein in Rhizophora species were proved scientifically. PMID:22017188

Alikunhi, Nabeel M; Kandasamy, Kathiresan; Manoharan, Chinthamani; Subramanian, Manivannan

2012-01-01

39

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. PMID:25183126

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

2014-01-01

40

Effect of Carthamus tinctorius (Safflower) on fasting blood glucose and insulin levels in alloxan induced diabetic rabbits.  

PubMed

Diabetes mellitus is a major threat to present and future generations. The role of herbal medication has emerged as a safe alternative to currently available medication due to its decreased potential to produce side effects, hence effect of Carthamus tinctorius was observed on fasting blood glucose and insulin levels in alloxan induced diabetic rabbits. Thirty five healthy male rabbits were divided into 5 groups with 7 rabbits in each (Normal control, diabetic control, diabetic treated with glibenclamide, diabetic treated with Carthamus tinctorius extract at doses of 200 and 300mg/kg of body weight). Drug and extract were given orally for 30 days and the values for blood glucose levels were observed after 15(th) and 30(th) day of treatment by using standard reagent kits provided by Human Germany. While insulin levels were checked at the end of the study by using Architect i1000 by Abbott Diagnostics USA. Animals were also observed for any gross toxicity during the study. Results revealed that Carthamus tinctorius has significant hypoglycemic effect at 200mg/kg and 300mg/kg doses as compared to diabetic control group. Insulin levels were significantly increased in Glibenclamide treated as well as Carthamus tinctorius treated groups as compared to diabetic control. PMID:24577929

Qazi, Nasreen; Khan, Rafeeq Alam; Rizwani, Ghazala H; Feroz, Zeeshan

2014-03-01

41

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. 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

42

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. PMID:24497735

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

2014-01-01

43

Antihyperglycemic Activity of Petroleum Ether Leaf Extract of Ficus krishnae L. on Alloxan-induced Diabetic Rats  

PubMed Central

The petroleum ether leaf extract of Ficus krishnae has been evaluated for the management of diabetes in alloxan induced diabetic rats. Phytochemical screening of the leaf extract for various chemical compounds has also been carried out. Leaf extract was administered continuously for 21 days orally at a dose of 200 mg/kg. Along with this, the blood glucose level was monitored at regular intervals to understand the activity of the extract. The leaf extract has decreased the blood glucose level of diabetic rats which was comparable to an antidiabetic standard drug, glibenclamide, given at a dose of 2.5 mg/kg. It has been observed that the leaves of Ficus krishnae possess antidiabetic activity and it reduces the blood glucose level significantly. The phytochemical screening of leaf has revealed the presence of carbohydrates, flavonoids, tannins, glycosides, terpenoids, steroids, alkaloids, gums and mucilage, phlobatannins, reducing sugars and phenolic compounds. The Fourier Transform Infrared analysis of glibenclamide and leaf powder has displayed some common absorption spectra. This shows that leaf powder has a molecule which is close to glibenclamide. Wavelength Dispersive X-Ray Fluorescence spectroscopy have shown the presence of cellulose, Ca, Si, K, Cl, Mg, P, S, Al, Fe, Na, Sr, Pd, Zn, Mn, Cr, Mo, Br, Ni, Rb and Zr. It is assumed that these elements alongwith other chemical compounds of the plant species may play a role in the management of diabetes. The Raman Specta of both glibenclamide and leaf powder has also shown some similarities. The results obtained during the present investigation have revealed the antidiabetic activity of Ficus krishnae leaves. The phytochemical screening has indicated the various chemical constituents likely to be responsible for this activity. The Fourier Transform Infrared, Wavelength Dispersive X-Ray Fluorescence and Raman Specta of the leaf powder suggested that there is some glibenclamide like molecule or its derivatives which is imparting antidiabetic activity. PMID:25284930

Sidhu, M. C.; Sharma, Tanu

2014-01-01

44

Antihyperglycemic Activity of Petroleum Ether Leaf Extract of Ficus krishnae L. on Alloxan-induced Diabetic Rats.  

PubMed

The petroleum ether leaf extract of Ficus krishnae has been evaluated for the management of diabetes in alloxan induced diabetic rats. Phytochemical screening of the leaf extract for various chemical compounds has also been carried out. Leaf extract was administered continuously for 21 days orally at a dose of 200 mg/kg. Along with this, the blood glucose level was monitored at regular intervals to understand the activity of the extract. The leaf extract has decreased the blood glucose level of diabetic rats which was comparable to an antidiabetic standard drug, glibenclamide, given at a dose of 2.5 mg/kg. It has been observed that the leaves of Ficus krishnae possess antidiabetic activity and it reduces the blood glucose level significantly. The phytochemical screening of leaf has revealed the presence of carbohydrates, flavonoids, tannins, glycosides, terpenoids, steroids, alkaloids, gums and mucilage, phlobatannins, reducing sugars and phenolic compounds. The Fourier Transform Infrared analysis of glibenclamide and leaf powder has displayed some common absorption spectra. This shows that leaf powder has a molecule which is close to glibenclamide. Wavelength Dispersive X-Ray Fluorescence spectroscopy have shown the presence of cellulose, Ca, Si, K, Cl, Mg, P, S, Al, Fe, Na, Sr, Pd, Zn, Mn, Cr, Mo, Br, Ni, Rb and Zr. It is assumed that these elements alongwith other chemical compounds of the plant species may play a role in the management of diabetes. The Raman Specta of both glibenclamide and leaf powder has also shown some similarities. The results obtained during the present investigation have revealed the antidiabetic activity of Ficus krishnae leaves. The phytochemical screening has indicated the various chemical constituents likely to be responsible for this activity. The Fourier Transform Infrared, Wavelength Dispersive X-Ray Fluorescence and Raman Specta of the leaf powder suggested that there is some glibenclamide like molecule or its derivatives which is imparting antidiabetic activity. PMID:25284930

Sidhu, M C; Sharma, Tanu

2014-07-01

45

Lavender (Lavandula stoechas L.) essential oils attenuate hyperglycemia and protect against oxidative stress in alloxan-induced diabetic rats  

PubMed Central

Background The present study described the phytochemical profile of Lavandula stoechas essential oils, collected in the area of Ain-Draham (North-West of Tunisia), as well as their protective effects against alloxan-induced diabetes and oxidative stress in rat. Methods Essential oils samples were obtained from the aerial parts of the plant by hydrodistillation and analyzed by GC–MS. Rats were divided into four groups: Healthy Control (HC); Diabetic Control (DC); Healthy?+?Essential Oils (H?+?EO) and Diabetic?+?Essential Oils (D?+?EO). Antidiabetic and antioxidant activities were evaluated after subacute intraperitoneally injection of Lavandula stoechas essential oils (50 mg/kg b.w., i.p.) to rats during 15 days. Results The principal compounds detected are: D-Fenchone (29.28%), ?-pinene (23.18%), Camphor (15.97%), Camphene (7.83%), Eucapur (3.29%), Limonene, (2.71%) Linalool, (2.01%) Endobornyl Acetate (1.03%). The essential oils also contained smaller percentages of Tricyclene, Cymene, Delta-Cadinene, Selina-3,7(11)-diene. Furthermore, we found that Lavandula stoechas essential oils significantly protected against the increase of blood glucose as well as the decrease of antioxidant enzyme activities induced by aloxan treatment. Subacute essential oils treatment induced a decrease of lipoperoxidation as well as an increase of antioxidant enzyme activities. Conclusions These findings suggested that lavandula stoechas essential oils protected against diabetes and oxidative stress induced by alloxan treatment. These effects are in partly due to its potent antioxidant properties. PMID:24373672

2013-01-01

46

Increased severity of acute Trypanosoma brucei brucei infection in rats with alloxan-induced diabetes  

E-print Network

-induced diabetes Ikechukwu Onyebuchi Igbokwea Sani Isaa Umma Kalsum Aliyub Hajja Gana Hamzab Tobias Egbe made diabetic by treatment with alloxan monohydrate (10 % solution, 100 mg/kg body weight). Ten diabetic and ten non-diabetic rats were intraperitoneally infected with the same infective doses

Paris-Sud XI, Université de

47

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. PMID:22135555

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

2010-01-01

48

Antidiabetic and antihyperlipidaemic effect of alcoholic Syzigium cumini seeds in alloxan induced diabetic albino rats  

Microsoft Academic Search

Syzigium cumini, commonly known as ‘jamun’, is widely used in different parts of India for the treatment of diabetes mellitus. The present study was designed to evaluate the antidiabetic and antihyperlipidaemic effect of an alcoholic extract of Syzigium cumini seeds (JSEt) in alloxan diabetic rats. Diabetes was induced by single intraperitoneal injection of alloxan (150mgkg?1 body weight). Oral administration of

P. Stanely Mainzen Prince; N. Kamalakkannan; Venugopal P. Menon

2004-01-01

49

Antidiabetic effect of hydroalcoholic extract of Carthamus tinctorius L. in alloxan-induced diabetic rats  

PubMed Central

Background: Carthamus tinctorius L. (Compositae) has been used in Iranian traditional medicine for treatment of diabetes. In this study, anti-diabetic effect of its hydroalcoholic extract was compared with that of glibenclamide. Methods: Male white Wistar rats were randomly allocated into four groups of six each: nondiabetic control; diabetic control; diabetic treated with hydroalcoholic extract of Carthamus tinctorius (200 mg kg-1 BW); diabetic rats treated with glibenclamide (0.6 mg kg-1 BW). Alloxan was administered (120 mg kg-1 BW), intraperitoneally to induce diabetes. Fasting blood samples were collected three times, before injection of alloxan, two weeks and six weeks after injection of alloxan and fasting blood sugar (FBS), Hb A1C, insulin, cholesterol, LDL-C, HDL-C, VLDL-C, triglyceride, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured each time. Results: FBS, triglyceride, cholesterol, LDL-C and VLDL-C had a meaningful decrease in diabetic rats treated with Carthamus tinctorius and diabetic rats treated with glibenclamide as compared with diabetic rats with no treatment. Insulin level increased significantly in diabetic groups received treatment (glibenclamide or Carthamus tinctorius L) in comparison with diabetic group with no treatment. The histological study revealed size of islets of Langerhans enlarged significantly consequentially as compared with diabetic rats with no treatment. The extract appeared non toxic as evidenced by normal levels of AST, ALP and ALT. Effects of administrating glibenclamide or extract of Carthamus tinctorius L on all biochemical parameters discussed above showed no difference and both tend to bring the values to near normal. Conclusion: These results suggested that the hydroalcoholic extract of Carthamus tinctorius possesses beneficial effect on treatment of diabetes. PMID:23267403

Asgary, Sedigheh; Rahimi, Parivash; Mahzouni, Parvin; Madani, Hossein

2012-01-01

50

Histopathological abnormalities of prolonged alloxan-induced diabetes mellitus in rabbits.  

PubMed

The objective of this study was to investigate the prolonged complications of untreated diabetes on histomorphology of rabbits. Diabetes mellitus was experimentally induced in one group of New Zealand white male rabbits by intraperitoneal administration of four doses of alloxan @ 80 mg/kg b.w. at weekly intervals following 12 h fasting. Other group of rabbits served as healthy controls that received isotonic saline in a similar manner. The establishment of diabetes mellitus was confirmed by fasting blood glucose levels. For histomorphological study of different organs, 50% of the animals were killed after 7 weeks and the rest after 26 weeks. Routine haematoxylin and eosin stain and Gomori's modified stain were used. The blood glucose level of diabetic rabbits increased significantly throughout the experimental period. The peak values for blood sugar were on the sixth week of the study. Further, histomorphological alterations were recorded in pancreas, kidneys, lungs, heart and brain in diabetic rabbits. However, mild changes were observed in gastrointestinal tract with proliferation of yeasts in the stomach. With the progress of untreated diabetes, the histoanatomical alterations intensify and extend to almost all organs of the body and appear to increase the susceptibility of gastric mucosa to yeast cell proliferation. PMID:19200253

Mir, Sajad Hussain; Darzi, Mohd Maqbool

2009-02-01

51

Impairment of pituitary and gonadal functions in alloxan-induced diabetic male rats.  

PubMed

The inhibitory effect of treatment with a potent LHRH agonist on testicular gonadotropin-receptor levels was compared in intact and diabetic rats. Basal and LHRH-induced pituitary gonadotropin secretion as well as the testicular steroidogenic response to oLH were assessed. A single injection of alloxan (65 mg/kg) led, after 6 weeks, to a 40% decrease of testicular LH- and prolactin-receptor levels. Treatment for 2 weeks with [D-Ala6,des-Gly-NH 1/2 0] LHRH ethylamide (100 ng every second day) led to a 70% reduction of LH-receptor levels accompanied by decreased testicular weight, a similar inhibition being found in intact and diabetic animals. Seminal vesicle and ventral prostate weight were markedly reduced in diabetic animals, a further decrease being obtained after treatment with the LHRH agonist. The loss of accessory sex-organ weight in alloxan-diabetic rats was accompanied by a reduction in the basal testicular content of pregnenolone, progesterone, 17-OH-progesterone, androstenedione, testosterone and dihydrotestosterone whereas the steroid response to oLH was within normal limits. We next examined the possible changes of LH and FSH secretion which could be responsible for the reduced testicular function in diabetic animals. Basal plasma-LH levels were 30% reduced in rats 6 weeks after treatment with alloxan while basal plasma-FSH levels remained unchanged. When the pituitary gonadotropin response to LHRH was measured in chronically cannulated freely-moving intact and diabetic rats, an approx. 50% inhibition of the LH and FSH responses to LHRH was observed in diabetic animals. PMID:6248397

Cusan, L; Bélanger, A; Séguin, C; Labrie, F

1980-06-01

52

Additive effect of lipid lowering drug (simvastatin) in combination with antidiabetic drug (glibenclamide) on alloxan induced diabetic rats with long term dyslipidemia.  

PubMed

High blood glucose level, elevated level of liver enzyme, necrosis and shrinkage of islets of Langerhans has been implicated in the pathogenesis of type 2 diabetes. High blood glucose cause oxidative stress, production of free radical as well as elevated SGPT and SGOT level. Both glibenclamide and simvastatin in fixed dose used as antihyperglycemic antidyslipidemic and antioxidative agents for type 2 diabetes treatment. This study therefore aimed to evaluate the antihyperglycemic, antidyslipidemic and antioxidative effect of fixed dose combination of glibenclamide (0.6 mg/70 kg body weight) and simvastatin (5 mg/70 kg body weight) on long term alloxan induced diabetic rats with cardiovascular disease using various diagnostic kits as a parameter of phamacotherapeutic and pharmacological effect. The study was carried out using 96 Swiss Albino male rats weighing about 200-220 g. Combination therapy induced a significant decrease in blood glucose level in alloxan induced diabetic rats, from 33.75 ± 1.65 to 5.80 ± 0.07 mmol/l 2 h after last dose administration, after 4 weeks treatment. In case of dyslipidemic effect, combination therapy reduced total cholesterol (45 %), triglyceride (36 %) and low density lipoprotein-cholesterol (32 %) levels significantly and increased high density lipoprotein-cholesterol level (57 %) in comparison with their respective diabetic control groups. Results of this study showed that combination therapy effectively decreased SGPT (ALAT) (55 %) and SGOT (ASAT) (51 %) in comparison with diabetic control group. It was also observed that catalase and superoxide dismutase enzyme activity was increased by 58 and 91 % respectively in comparison with diabetic control group after 4 weeks treatment with combination of both drugs. In conclusion, these findings of combination therapy (glibenclamide and simvastatin) on alloxan induced diabetes in rats are significantly better than monotherapy using single drug. The results of the present study suggest that, combination of the fixed dose of glibenclamide and simvastatin might be efficacious in patients with diabetic dyslipidemia and increased oxidative stress. Furthermore, this combination therapy offer dosage convenience to the patients and by virtue of its dual mode of action might be a useful addition to the therapeutic armamentarium for patients with diabetic dyslipidemia and oxidative stress. PMID:25298626

Begum, Mst Marium; Sultana, Zakia; Ershad Ali, Md; Jami, Md Safkath Ibne; Khondkar, Proma; Khan, Md Masuduzzaman; Haque, Md Mominul

2014-10-01

53

Hypoglycemic and antilipidemic properties of kombucha tea in alloxan-induced diabetic rats  

PubMed Central

Background Diabetes has become a serious health problem and a major risk factor associated with troublesome health complications, such as metabolism disorders and liver-kidney dysfunctions. The inadequacies associated with conventional medicines have led to a determined search for alternative natural therapeutic agents. The present study aimed to investigate and compare the hypoglycemic and antilipidemic effects of kombucha and black tea, two natural drinks commonly consumed around the world, in surviving diabetic rats. Methods Alloxan diabetic rats were orally supplied with kombucha and black tea at a dose of 5 mL/kg body weight per day for 30 days, fasted overnight, and sacrificed on the 31st day of the experiment. Their bloods were collected and submitted to various biochemical measurements, including blood glucose, cholesterol, triglcerides, urea, creatinine, transaminases, transpeptidase, lipase, and amylase activities. Their pancreases were isolated and processed to measure lipase and ?-amylase activities and to perform histological analysis. Results The findings revealed that, compared to black tea, kombucha tea was a better inhibitor of ?-amylase and lipase activities in the plasma and pancreas and a better suppressor of increased blood glucose levels. Interestingly, kombucha was noted to induce a marked delay in the absorption of LDL-cholesterol and triglycerides and a significant increase in HDL-cholesterol. Histological analyses also showed that it exerted an ameliorative action on the pancreases and efficiently protected the liver-kidney functions of diabetic rats, evidenced by significant decreases in aspartate transaminase, alanine transaminase, and gamma-glytamyl transpeptidase activities in the plasma, as well as in the creatinine and urea contents. Conclusions The findings revealed that kombucha tea administration induced attractive curative effects on diabetic rats, particularly in terms of liver-kidney functions. Kombucha tea can, therefore, be considered as a potential strong candidate for future application as a functional supplement for the treatment and prevention of diabetes. PMID:22591682

2012-01-01

54

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. PMID:24944826

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

2014-01-01

55

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

56

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. PMID:25050248

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

2012-01-01

57

Mitigating effects of antioxidant properties of Artemisia campestris leaf extract on hyperlipidemia, advanced glycation end products and oxidative stress in alloxan-induced diabetic rats.  

PubMed

Artemisia campestris is used as antivenom and anti-inflammatory Tunisian folk medicine. Recently, increased oxidative stress was shown to play an important role in the etiology and pathogenesis of diabetes mellitus and its complications. This study was designed to examine the effects of A. campestris leaf aqueous extract (Ac) on alloxan-induced diabetic rats by measuring glycemia, lipid profile, lipid peroxidation (MDA), protein carbonyl content (PCO), advanced oxidation protein products (AOPP), activities of both non-enzymatic and enzymatic antioxidants. Results of our study showed an increase in blood glucose levels, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), a decrease in high-density lipoprotein cholesterol (HDL-c) level and disturbed antioxidant enzyme activities (CAT, SOD, GPx) in the pancreatic tissue of diabetic rats. Furthermore, MDA, PCO and AOPP were elevated in the pancreas of the diabetic rats. The administration of Ac to diabetic rats at a dose of 200mgkg(-1)bw resulted in a significant reduction in glycemia, TC, TG, LDL-c, pancreas LPO, PCO and AOPP levels, CAT and GPx activities associated with an elevation of GSH content and SOD activity in comparison with diabetic group. We conclude that A. campestris aqueous extract may be effective for correcting hyperglycemia and preventing diabetic complications. PMID:20457207

Sefi, Mediha; Fetoui, Hamadi; Makni, Mohamed; Zeghal, Najiba

2010-07-01

58

Investigation of the Protective Effects of Taurine against Alloxan-Induced Diabetic Retinal Changes via Electroretinogram and Retinal Histology with New Zealand White Rabbits  

PubMed Central

The purpose of this study was to investigate the protective role of orally administered taurine against diabetic retinal changes via electroretinogram (ERG) and retinal histology on rabbits. Rabbits were randomly assigned into groups: Group I (vehicle administration only); Group II (diabetes: induced by 100?mg/kg alloxan injection); Group III (diabetes and fed with 200?mg/kg taurine); and Group IV (diabetes and fed with 400?mg/kg taurine). The body weight and blood glucose levels of the rabbits were monitored weekly. The ERG was measured on weeks 5 and 15. Retinal histology was analyzed in the end of the experiment. Results revealed that a taurine supplement significantly ameliorates the alloxan-induced hyperglycemia and protects the retina from electrophysiological changes. Group II showed a significant (P < 0.05) change in the mean scotopic b-wave amplitude when compared to that of Group I, whereas the diabetic rabbits treated with taurine (Group III and IV) were analogous to Group I. Histologically, the amount of Bipolar and Müller cells showed no difference (P > 0.05) between all groups and when compared with those of Group I. Our study provides solid evidences that taurine possesses an antidiabetic activity, reduced loss of body weight, and less electrophysiological changes of the diabetic retina.

Yeh, Shang-Min; Chen, Yi-Chen; Lin, Shiun-Long

2014-01-01

59

Investigation of the Protective Effects of Taurine against Alloxan-Induced Diabetic Retinal Changes via Electroretinogram and Retinal Histology with New Zealand White Rabbits.  

PubMed

The purpose of this study was to investigate the protective role of orally administered taurine against diabetic retinal changes via electroretinogram (ERG) and retinal histology on rabbits. Rabbits were randomly assigned into groups: Group I (vehicle administration only); Group II (diabetes: induced by 100?mg/kg alloxan injection); Group III (diabetes and fed with 200?mg/kg taurine); and Group IV (diabetes and fed with 400?mg/kg taurine). The body weight and blood glucose levels of the rabbits were monitored weekly. The ERG was measured on weeks 5 and 15. Retinal histology was analyzed in the end of the experiment. Results revealed that a taurine supplement significantly ameliorates the alloxan-induced hyperglycemia and protects the retina from electrophysiological changes. Group II showed a significant (P < 0.05) change in the mean scotopic b-wave amplitude when compared to that of Group I, whereas the diabetic rabbits treated with taurine (Group III and IV) were analogous to Group I. Histologically, the amount of Bipolar and Müller cells showed no difference (P > 0.05) between all groups and when compared with those of Group I. Our study provides solid evidences that taurine possesses an antidiabetic activity, reduced loss of body weight, and less electrophysiological changes of the diabetic retina. PMID:25298779

Chiang, Samuel Tung-Hsing; Yeh, Shang-Min; Chen, Yi-Chen; Lin, Shiun-Long; Tseng, Jung-Kai

2014-01-01

60

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

61

Moringa oleifera leaf extract ameliorates alloxan-induced diabetes in rats by regeneration of ? cells and reduction of pyruvate carboxylase expression.  

PubMed

Moringa oleifera Lam. contains many active ingredients with nutritional and medicinal values. It is commonly used in folk medicine as an antidiabetic agent. The present study was designed to investigate how an aqueous extract from the leaves of M. oleifera reveals hypoglycemia in diabetic rats. M. oleifera leaf extract counteracted the alloxan-induced diabetic effects in rats as it normalized the elevated serum levels of glucose, triglycerides, cholesterol, and malondialdehyde, and normalized mRNA expression of the gluconeogenic enzyme pyruvate carboxylase in hepatic tissues. It also increased live body weight gain and normalized the reduced mRNA expression of fatty acid synthase in the liver of diabetic rats. Moreover, it restored the normal histological structure of the liver and pancreas damaged by alloxan in diabetic rats. This study revealed that the aqueous extract of M. oleifera leaves possesses potent hypoglycemic effects through the normalization of elevated hepatic pyruvate carboxylase enzyme and regeneration of damaged hepatocytes and pancreatic ? cells via its antioxidant properties. PMID:25289966

Abd El Latif, Amira; El Bialy, Badr El Said; Mahboub, Hamada Dahi; Abd Eldaim, Mabrouk Attia

2014-10-01

62

Supplementation with apple enriched with L-arginine may improve metabolic control and survival rate in alloxan-induced diabetic rats.  

PubMed

Supplementation with L-arginine or fresh food with high content of this amino acid is associated with favorable effects in the metabolic control of diabetes. We aimed to determine whether supplementation with apples enriched with L-arginine offer additional benefits compared to L-arginine by itself in a preclinical study of diabetes. This study combines food-engineer technologies with in vivo and in vitro analysis. In vitro experiments show that cells derived from non-diabetic animals and exposed to high glucose (25 mM, 12 H) and cells isolated from alloxan-induced diabetic animals exhibited a reduction (?50%) in the L-arginine uptake. This effect was reverted by L-arginine pretreatment (12 H) in both the normal and diabetes-derived cells. In preclinical studies, normoglycemic (n = 25) and diabetic groups (n = 50) were divided into subgroups that received either L-arginine (375 mg/kg per 10 days) or apple enriched with L-arginine or vehicle (control). In a preliminary analysis, supplementation with L-arginine by itself (50%) or apple enriched with L-arginine (100%) improve survival rate in the diabetic group compared to control (0%) at the end of the follow up (17 days). This phenomenon was associated with a partial but sustained high plasma level of L-arginine, as well as plasma concentration of nitrites and insulin in the L-arginine or apple + L-arginine groups after supplementation. Apple + L-arginine supplementation in diabetic animals induced the highest and longest effects in the level of these three markers among the studied groups. Therefore, apple enriched by L-arginine offers more benefits than L-arginine by itself in this preclinical study. PMID:23553786

Escudero, Andrea; Petzold, Guillermo; Moreno, Jorge; Gonzalez, Marcelo; Junod, Julio; Aguayo, Claudio; Acurio, Jesenia; Escudero, Carlos

2013-01-01

63

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. PMID:21687353

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

2011-01-01

64

Insulin-like antigen of mangrove leaves and its anti-diabetic activity in alloxan-induced diabetic rats  

Microsoft Academic Search

The objective of this study was to evaluate the anti-diabetic potential of three mangrove plants, Rhizophora mucronata, Rhizophora apiculata and Rhizophora annamalayana, and to detect the presence of their insulin-like protein. The in vivo anti-diabetic experiment was done on male albino Wister rats. Oral administration of 60?mg?kg leaf powder extract of the three different mangrove plants for 30 days modulated the

Nabeel M. Alikunhi; Kathiresan Kandasamy; Chinthamani Manoharan; Manivannan Subramanian

2012-01-01

65

Insulin-like antigen of mangrove leaves and its anti-diabetic activity in alloxan-induced diabetic rats  

Microsoft Academic Search

The objective of this study was to evaluate the anti-diabetic potential of three mangrove plants, Rhizophora mucronata, Rhizophora apiculata and Rhizophora annamalayana, and to detect the presence of their insulin-like protein. The in vivo anti-diabetic experiment was done on male albino Wister rats. Oral administration of 60?mg?kg leaf powder extract of the three different mangrove plants for 30 days modulated the

Nabeel M. Alikunhi; Kathiresan Kandasamy; Chinthamani Manoharan; Manivannan Subramanian

2011-01-01

66

Anti-diabetic activities of the methanol leaf extracts of Hymenocardia acida (tul.) in alloxan-induced diabetic rats.  

PubMed

The effect of methanolic extract of Hymenocardia acida leaves on diabetes and associated lipidemia were investigated on experimentally-induced diabetic rats. The extract did not demonstrate any acutely toxic effect in rats within the dose range (250 mg/kg - 2000 mg/kg) employed in the study; hence it was well tolerated by the rats. In all experiments, the anti-diabetic effects were dose-dependent and comparable to that of glibenclamide (2 mg/kg) standard. At a dose of 500 mg/kg, lipid profile markers such as the serum total cholesterol (TC) levels, LDL-C, triglycerides and HDL-C were significantly lower (p <0.05) than those of both the treated and untreated controls. PMID:23983336

Ezeigbo, Ihechiluru I; Asuzu, Isaac U

2012-01-01

67

The chronic effects of neonatal alloxan-induced diabetes mellitus on ventricular myocyte shortening and cytosolic Ca 2+  

Microsoft Academic Search

Diabetes mellitus is a serious global health problem, and cardiovascular complications are the major cause of morbidity and\\u000a mortality in diabetic patients. The chronic effects of neonatal alloxan- (ALX) induced diabetes mellitus on ventricular myocyte\\u000a contraction and intracellular Ca2+ transport have been investigated. Ventricular myocyte shortening was measured with a video edge detection system and intracellular\\u000a Ca2+ was measured in

Frank Christopher Howarth; Zahra Hassan; Muhammad Anwar Qureshi

2011-01-01

68

Comparative evaluation of the anti-diabetic activity of Pterocarpus marsupium Roxb. heartwood in alloxan induced diabetic rats using extracts obtained by optimized conventional and non conventional extraction methods.  

PubMed

The aim of the present study was to assess the anti-diabetic activity of Pterocarpus marsupium Roxb. heartwood in alloxan induced diabetic rats using extracts obtained by optimized conventional and non conventional extraction methods. Aqueous and ethanol extracts of Pterocarpus marsupium heartwood were prepared by conventional methods (infusion, decoction, maceration and percolation) and non conventional methods, such as ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE). The crude aqueous extracts were administered orally to both normal and alloxan induced male albino rats (Sprague-Dawley strain). The experimental set up consisted of 48 male albino rats divided into 6 groups: Normal control, diabetic control (sterile normal saline, 1 ml/100 g body weight), standard (gliclazide, 25 mg/1000g of body weight), groups 4-6 (crude aqueous percolation, optimized UAE and MAE extract, 250 mg/1000g of body weight). In acute treatment, the reduction of blood glucose level was statistically significant with the oral administration of UAE and percolation aqueous extracts to the hyperglycemic rats. In sub-acute treatment, the UAE aqueous extract led to consistent and statistically significant (p<0.001) reduction in the blood glucose levels. There was no abnormal change in body weight of the hyperglycemic animals after 10 days of administration of plant extracts and gliclazide. This study justifies the traditional claim and provides a rationale for the use of Pterocarpus marsupium to treat diabetes mellitus. The antidiabetic activity of Pterocarpus marsupium can be enhanced by extracting the heartwood by non conventional method of UAE. PMID:24035955

Devgan, Manish; Nanda, Arun; Ansari, Shahid Husain

2013-09-01

69

The chronic effects of neonatal alloxan-induced diabetes mellitus on ventricular myocyte shortening and cytosolic Ca2+.  

PubMed

Diabetes mellitus is a serious global health problem, and cardiovascular complications are the major cause of morbidity and mortality in diabetic patients. The chronic effects of neonatal alloxan- (ALX) induced diabetes mellitus on ventricular myocyte contraction and intracellular Ca(2+) transport have been investigated. Ventricular myocyte shortening was measured with a video edge detection system and intracellular Ca(2+) was measured in fura-2 loaded cells by fluorescence photometry. Diabetes was induced in 5-day old male Wistar rats by a single intraperitoneal injection of ALX (200 mg/kg body weight). Experiments were performed 12 months after ALX treatment. Fasting blood glucose was elevated and blood glucose at 60, 120 and 180 min after a glucose challenge (2 g/kg body weight, intraperitoneal) was elevated in diabetic rats compared to age-matched controls. Amplitude of shortening was significantly (P < 0.05) reduced in electrically stimulated myocytes from diabetic hearts (5.70 ± 0.24%) compared to controls (6.48 ± 0.28%). Amplitude of electrically evoked Ca(2+) transients was also significantly (P < 0.05) reduced in myocytes from diabetic hearts (0.11 ± 0.01 fura-2 ratio units) compared to controls (0.15 ± 0.01 fura-2 ratio units). Fractional sarcoplasmic reticulum Ca(2+) release was not significantly (P > 0.05) altered in myocytes from diabetic heart (0.70 ± 0.03 fura-2 ratio units) compared to controls (0.72 ± 0.03 fura-2 ratio units). Amplitude of caffeine-stimulated Ca(2+) transients was significantly (P < 0.05) reduced in myocytes from diabetic hearts (0.43 ± 0.02 fura-2 ratio units) compared to controls (0.51 ± 0.03 fura-2 ratio units). Area under the caffeine-evoked Ca(2+) transient was significantly (P < 0.05) reduced in myocytes from diabetic heart (0.77 ± 0.06 Vsec) compared to controls (1.14 ± 0.12 Vsec). Intracellular Ca(2+) refilling rate during electrical stimulation following application of caffeine was significantly (P < 0.05) slower in myocytes from diabetic heart (0.013 ± 0.001 V/sec) compared to controls (0.031 ± 0.007 V/sec). Depressed shortening may be partly attributed to depressed sarcoplasmic reticulum Ca(2+) transport in myocytes from neonatal ALX-induced diabetic rat heart. PMID:20941530

Howarth, Frank Christopher; Hassan, Zahra; Qureshi, Muhammad Anwar

2011-01-01

70

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. PMID:22529479

Das, Swarnamoni; Barman, Sarajita

2012-01-01

71

Effect of Kombucha, a fermented black tea in attenuating oxidative stress mediated tissue damage in alloxan induced diabetic rats.  

PubMed

Diabetic complications associated with increased oxidative stress can be suppressed by antioxidants. In the present study we investigated the antidiabetic and antioxidant effects of Kombucha (KT), a fermented black tea, in comparison to that of unfermented black tea (BT), in ALX-induced diabetic rats. ALX exposure lowered the body weight and plasma insulin by about 28.12% and 61.34% respectively and elevated blood glucose level and glycated Hb by about 3.79 and 3.73 folds respectively. The oxidative stress related parameters like lipid peroxidation end products (increased by 3.38, 1.7, 1.65, 1.94 folds respectively), protein carbonyl content (increased by 2.5, 2.35, 1.8, 3.26 folds respectively), glutathione content (decreased by 59.8%, 47.27%, 53.69%, 74.03% respectively), antioxidant enzyme activities were also altered in the pancreatic, hepatic, renal and cardiac tissues of diabetic animals. Results showed significant antidiabetic potential of the fermented beverage (150 mg lyophilized extract/kg bw for 14 days) as it effectively restored ALX-induced pathophysiological changes. Moreover, it could ameliorate DNA fragmentation and caspase-3 activation in the pancreatic tissue of diabetic rats. Although unfermented black tea is effective in the above pathophysiology, KT was found to be more efficient. This might be due to the formation of some antioxidant molecules during fermentation period. PMID:23907022

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

2013-10-01

72

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. PMID:23320026

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

2012-01-01

73

Comparison of the antidiabetic activity of Berberis lyceum root extract and berberine in alloxan-induced diabetic rats.  

PubMed

Berberine has been shown to have hypoglycaemic activity in several in vitro and in vivo models, although the mechanism of action is not fully known. Berberis lyceum Royle root produces high concentrations of berberine, and in traditional medicine, the whole extract of this plant is used widely to treat diabetes. The antidiabetic activity of the ethanol root extract of Berberis lyceum was compared with pure berberine in normal and alloxan-diabetic rats using similar doses of each. The concentration of berberine in the extract was determined to be 80% dry weight with only trace amounts of other alkaloids present. The purpose of the study was to investigate the effects of berberine and a whole extract of Berberis lyceum on blood glucose and other parameters associated with diabetes, to compare the effects of the crude extract with those of pure berberine and thus validate its use as a therapeutic agent, and finally to identify any contribution of the other components of the extract to these effects. Oral administration of 50 mg/kg of Berberis extract and berberine to normal and experimental diabetic rats produced a significant (p < 0.05) reduction in blood glucose levels from days 3-7 days of treatment. Significant effects were also observed on the glucose tolerance, glycosylated haemoglobin, serum lipid profiles and body weight of experimental animals. Berberis extract and berberine demonstrated similar effects on all parameters measured, and although the extract was comparable in efficacy to berberine, it did not produce any effects additional to those shown by pure berberine. The results support the use of the extract in traditional medicine, and demonstrate that apart from being a highly cost-effective means of treating with berberine, the total extract does not appear to confer any additional benefits or disadvantages compared with the pure compound. PMID:18729256

Gulfraz, M; Mehmood, S; Ahmad, A; Fatima, N; Praveen, Z; Williamson, E M

2008-09-01

74

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. PMID:22734822

2012-01-01

75

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. PMID:21808578

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

2010-01-01

76

Modulatory effects of gymnema montanum leaf extract on alloxan-induced oxidative stress in wistar rats  

Microsoft Academic Search

ObjectivesIn light of evidence that some complications of diabetes mellitus may be caused or exacerbated by oxidative damage, we investigated the effect of Gymnema montanum leaf extract (GLEt) on tissue antioxidant defense systems in alloxan-induced diabetes in rats.

R Ananthan; M Latha; K. M Ramkumar; L Pari; C Baskar; V Narmatha Bai

2004-01-01

77

Efficacy of Composite Extract from Leaves and Fruits of Medicinal Plants Used in Traditional Diabetic Therapy against Oxidative Stress in Alloxan-Induced Diabetic Rats  

PubMed Central

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 composite extract (CE) and making small dose of naturally occurring antidiabetic plants leaf and fruits. The aim of the present study was to evaluate the beneficial role of CE against alloxan- (ALX-) induced diabetes of Wistar strain rats. A dose-dependent study for CE (25, 50, and 100?mg/kg body weight) was carried out to find the effective dose of the composite compound in ALX-induced diabetic rats. ALX exposure elevated the blood glucose, plasma advanced oxidation product (AOPP), sialic acid demonstrating disturbed antioxidant status.CE at a dose of 100?mg/kg body weight restored/minimised these alterations towards normal values. In conclusion, small dose of CE possesses the capability of ameliorating the oxidative stress in ALX-induced diabetes and thus could be a promising approach in lessening diabetic complications. PMID:24729889

Kumar, Dileep; Abidi, A. B.

2014-01-01

78

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

79

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

80

Comparative effects of oral administration of Citrullus colocynthis and insulin injection on serum biochemical parameters of alloxan-induced diabetic dogs  

Microsoft Academic Search

Citrullus colocynthis seeds are traditionally used as antidiabetic medication in Mediterranean countries. An experiment was designed to evaluate\\u000a the comparative effects of oral administration of C. colocynthis and insulin injection on the serum biochemical parameters of diabetic dogs. Twelve apparently healthy mixed breed dogs were\\u000a selected and randomly allocated into three groups, two diabetic groups and one control group (n?=?4).

Ameneh Khoshvaghti; Ahmad Reza Hamidi

81

Inhibition of carbohydrate and lipid digestive enzymes activities by Zygophyllum album extracts: effect on blood and pancreas inflammatory biomarkers in alloxan-induced diabetic rats.  

PubMed

Zygophyllum album has been used as herbal medicine in Southern Tunisia to treat several diseases such as diabetes mellitus. This study is aimed to reveal the mechanisms underlying the antihyperglycemic potential, the anti-inflammatory and the protective hematological proprieties of this plant in diabetic rats. The inhibition of the ?-amylase activity by different solvent-extract fractions of Z. album was tested in vitro. The fraction endowed with the powerful inhibitory activity against ?-amylase was administered to surviving diabetic rats for 30 days. Data from in vitro indicated that each extract from the medicinal plant showed moderate inhibition of ?-amylase enzyme except the ethyl acetate extract which was ineffective. The powerful inhibition was achieved by ethanol extract of Z. album (EZA) with an IC50 of 43.48 ?g/ml as compared to acarbose (Acar) with an IC50 of 14.88 ?g/ml. In vivo, the results showed that EZA decreased the ?-amylase levels in serum, pancreas and intestine of diabetic rats by 40 %, 45 % and 46 %, respectively, associated with considerably reduction in blood glucose rate by 61 %. Moreover, the EZA helped to protect the structure and function of the ?-cells. Interestingly, EZA had a potent anti-inflammatory effect which is manifested by decreases in CRP and TNF-? levels. Overall, a notable reduction in lipase activity both in serum and small intestine of treated diabetic rats resulted in the improvement of serum and liver lipids profile. Z. album showed a prominent antidiabetic effect via inhibition of carbohydrate and lipid digestive enzymes and ameliorated the inflammation and the disturbance of hematological biomarkers in diabetes. PMID:23996134

Mnafgui, Kais; Kchaou, Mouna; Hamden, Khaled; Derbali, Fatma; Slama, Sadok; Nasri, Mbarek; Salah, Hichem Ben; Allouche, Noureddine; Elfeki, Abdelfattah

2014-03-01

82

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. PMID:24224091

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

2013-01-01

83

Berberine ameliorates renal injury in diabetic C57BL/6 mice: Involvement of suppression of SphK-S1P signaling pathway.  

PubMed

Berberine (BBR) was previously found to have beneficial effects on renal injury in experimental diabetic rats. However, the mechanisms underlying the effects are not fully understood. Sphingosine kinase-Sphingosine 1-phosphate (SphK-S1P) signaling pathway has been implicated in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the effects of BBR on renal injury and the activation of SphK-S1P signaling pathway in alloxan-induced diabetic mice with nephropathy. Alloxan-induced diabetic mice were treated orally with BBR (300 mg/kg/day) or vehicle for 12 weeks. BBR inhibited the increases in fasting blood glucose, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. It also prevented renal hypertrophy, TGF-beta1 synthesis, FN and Col IV accumulation. Moreover, BBR down-regulated the elevated staining, activity and levels of mRNA and protein of SphK1, and S1P production as well. These findings suggest that the inhibitory effect of BBR on the activation of SphK-S1P signaling pathway in diabetic mouse kidney is a novel mechanism by which BBR partly exerts renoprotective effects on DN. PMID:20646989

Lan, Tian; Shen, Xiaoyan; Liu, Peiqing; Liu, Weihua; Xu, Suowen; Xie, Xi; Jiang, Qin; Li, Wenyuan; Huang, Heqing

2010-10-15

84

Antihyperlipidemic and antiperoxidative effect of Diasulin, a polyherbal formulation in alloxan induced hyperglycemic rats  

PubMed Central

Background This study was undertaken to investigation the effect of Diasulin, a poly herbal drug composed of ethanolic extract of ten medicinal plants on blood glucose, plasma insulin, tissue lipid profile, and lipidperoxidation in alloxan induced diabetes. Methods Ethanolic extract of Diasulin a, poly herbal drug was administered orally (200 mg/kg body weight) for 30 days. The different doses of Diasulin on blood glucose and plasma insulin in diabetic rats were studied and the levels of lipid peroxides [TBARS, and Hydroperoxide] and tissue lipids [cholesterol, triglyceride, phospholipides and free fatty acids] were also estimated in alloxan induced diabetic rats. The effects were compared with glibenclamide. Result Treatment with Diasulin and glibenclamide resulted in a significant reduction of blood glucose and increase in plasma insulin. Diasulin also resulted in a significant decrease in tissue lipids and lipid peroxide formation. The effect produced by Diasulin was comparable with that of glibenclamide. Conclusion The decreased lipid peroxides and tissue lipids clearly showed the antihyperlipidemic and antiperoxidative effect of Diasulin apart from its antidiabetic effect. PMID:15969768

Saravanan, Ramalingam; Pari, Leelavinothan

2005-01-01

85

[Electron microscopical observations on the curative effect of ursodesoxycholic acid in alloxan-induced pancreatic islet cell injury (author's transl)].  

PubMed

The preventive effect of ursodesoxycholic acid on pancreatic injury by alloxan (alloxan diabetes) has been reported by Watari, et al. (1976). In the following experiment, to pursue the findings further, ursodesoxycholic acid was used curatively for alloxan diabetes. A first group of animals (5 mice) were injected with alloxan (4 mg) twice at the fifth and tenth day. The second group (5 mice) was injected with ursodesoxycholic acid (0.2 mg each) for 14 days during the experiment in addition to the same alloxan dosage/frequency as the first group. A third group of animals (5 mice) served as the control. The animals were sacrificed on the 15th day and the blood sugar levels were examined, using commercial test paper. The pancreatic tissues were fixed in a mixture of 2.5% glutaraldehyde and 2% osmid acid solution, which was adjusted at pH 7.4 with a veronal acetate buffer; the osmotic pressure was also regulated by adding sucrose of 0.045 g/ml. Following dehydration using a series of alcohol concentrations, the tissues were embedded in Epon 812. Thin sections were cut with a Porter-Blum MT-2B ultramicrotome, stained with both uranyl acetate and a lead mixture, and then observed by electron microscopy. The results were as follows: The pancreatic islet cells, especially of B-cells in the first group of animals injected with alloxan only, were seriously damaged and contained myelinated mitochondria. Golgi apparatus, and an increasing number of autophagic vacuoles. Some B-cells revealed hydropic degeneration. Some B-granules changed into vacuoles after diacrine secretion. Pancreatic A-cells were increased in number and showed no cell injuries. On the other hand, the pancreatic B-cells of mice treated with both alloxan and ursodesoxycholic acid maintained almost normal fine structures. In summary, ursodesoxycholic acid has a curative effect on alloxan-induced pancreatic B-cell injury. PMID:338378

Watari, N; Mabuchi, Y; Hotta, Y

1977-10-20

86

Assessment of DNA damage and lipid peroxidation in diabetic mice: effects of propolis and epigallocatechin gallate (EGCG).  

PubMed

There is growing recognition that polyphenolic compounds present in many plants and natural products may have beneficial effects on human health. Propolis - a substance produced by honeybees - and catechins in tea, in particular (-)-epigallocatechin gallate (EGCG), are strong antioxidants that appear to have anti-obesity and anti-diabetic effects. The present study was designed to elucidate the anti-diabetic effect of the water-soluble derivative of propolis (WSDP), which contains phenolic acids as the main compounds, and EGCG in alloxan-induced (75mg/kg, iv) diabetes in mice. Intraperitoneal administration of EGCG or propolis at doses of 50mg/kg body weight (bw) to diabetic mice for a period of 7 days resulted in a significant increase in body weight and in haematological/immunological blood parameters, as well as in 100% survival of the mice. A significant decrease in lipid peroxidation in liver, kidney and brain tissue was also observed in diabetic mice treated with these two agents. Additionally, EGCG and propolis clearly reduced DNA damage in peripheral lymphocytes of diabetic mice. Our studies demonstrate the anti-oxidative and anti-inflammatory potential of WSDP and EGCG, which could exert beneficial effects against diabetes and the associated consequences of free-radical formation in kidney, liver, spleen and brain tissue. The results suggest that dietary supplementation with WSDP or EGCG could potentially contribute to nutritional strategies for the prevention and treatment of diabetes mellitus. PMID:23859956

Oršoli?, Nada; Sirovina, Damir; Gajski, Goran; Garaj-Vrhovac, Vera; Jazvinš?ak Jembrek, Maja; Kosalec, Ivan

2013-09-18

87

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. PMID:23112412

Renjith, Raveendran S.; Rajamohan, Thankappan

2012-01-01

88

Antihyperglycemic and antioxidant effect of hydroethanolic extract of Butea monosperma bark in diabetic mice.  

PubMed

The antihyperglycemic, antihyperlipidemic and antioxidative properties of hydroethanolic extract of Butea monosperma bark were investigated in alloxan-induced diabetic mice. Alloxan administration resulted in higher blood glucose level and reduced hepatic glycogen content as compared to normal animals. Besides, serum lipid profile parameters such as total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol were also found to be significantly elevated, whereas the level of high density lipoprotein (HDL) cholesterol was markedly reduced in diabetic animals. Oxidative damage in the tissues of diabetic mice was evidenced by a marked increase in the level of thiobarbituric acid reactive substances (TBARS), distinct decrease in reduced glutathione (GSH) content and declined activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). The daily treatment of diabetic animals with crude extract of B. monosperma bark (300 mg kg(-1)) for 45 days significantly lowered blood glucose level and elevated hepatic glycogen content, bringing the values close to those observed in normal control and glibenclamide-treated diabetic mice. Furthermore, the level of various lipid profile parameters was also reversed towards normal. TBARS and GSH also restored towards normal and the declined activity of antioxidant enzymes in diabetic animals was also normalized in crude extract administered mice, thus indicating the antioxidant efficacy of the drug in diabetes-induced oxidative damage. Significant antihyperglycemic and antioxidant potential of the crude extract of B. monosperma bark indicated that it may find use in the management of diabetes and resultant oxidative stress. PMID:22435145

Sharma, Nidhi; Garg, Veena

2012-02-01

89

Hypoglycaemic and Tissue-Protective Effects of the Aqueous Extract of Persea Americana Seeds on Alloxan-Induced Albino Rats  

PubMed Central

Background: The tissue-protective potential of Persea americana necessitated a look into the histopathological effects of the plant extract on the pancreas, liver, and kidneys. This study was conceived and designed based on the gaps in the research that has been performed and what is known about the plant. The hypoglycaemic and tissue-protective effects of hot aqueous Persea americana (avocado pear) seed extracts on alloxan-induced albino rats were investigated. Methods: Persea americana seeds were extracted using hot water, and different concentrations of the extract were prepared. The effects of different concentrations (20, 30, 40 g/L) of the hot aqueous P. americana seed extract on alloxan-induced Wistar albino rats were compared with those of a reference drug, glibenclamide. The glucose level of the rats was measured daily, and the weight of the animal was monitored on a weekly basis for 21 days. The oral glucose tolerance test (OGTT) was performed at 0, 30, 60, 90 and 120 minutes, and the histopathologies of the liver, kidneys, and pancreas were investigated. Phytochemical analysis of P. americana seed extracts indicated the presence of glycosides, tannins, saponins, carbohydrates, flavonoids, and alkaloids. Results: The results showed that the extract possessed a significant hypoglycaemic (P < 0.05) effect and reversed the histopathological damage that occurred in alloxan-induced diabetic rats, comparable to the effects glibenclamide. The seeds of P. americana also had anti-diabetic and protective effects on some rat tissues such as the pancreas, kidneys, and liver. Conclusion: In conclusion, the present study provides a pharmacological basis for the folkloric use of the hot-water extract of P. americana seeds in the management of diabetes mellitus. PMID:24643349

EZEJIOFOR, Anthonet Ndidi; OKORIE, Abednego; ORISAKWE, Orish Ebere

2013-01-01

90

Inhibition of protein kinase C restores Na+,K(+)-ATPase activity in sciatic nerve of diabetic mice.  

PubMed

We have tested if inhibition of protein kinase C is able to prevent and/or to restore the decrease of Na+,K(+)-ATPase activity in the sciatic nerve of alloxan-induced diabetic mice. Mice were made diabetic by subcutaneous injection of 200 mg of alloxan/kg of body weight. The activity of Na+,K(+)-ATPase decreased rapidly (43% after 3 days) and slightly thereafter (58% at 11 days). We show that intraperitoneal injection of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), an inhibitor of protein kinase C, prevents completely the loss of Na+,K(+)-ATPase activity produced by alloxan. Also, H7 injected into diabetic mice, 4-9 days after the injection of alloxan, restores the activity of the enzyme. The amount of activity recovered depends on the dose of H7 administered; complete recovery was reached with injection of 15 mg of H7/kg of body weight. The effect of H7 is transient, with a half-life of approximately 1 h. PMID:1312572

Hermenegildo, C; Felipo, V; Miñana, M D; Grisolía, S

1992-04-01

91

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

92

Evaluation of antidiabetic effect of Momordica cymbalaria fruit in alloxan-diabetic rats  

Microsoft Academic Search

The oral treatment with the aqueous extract of Momordica cymbalaria fruit (MC) (0.5 g\\/kg) for 6 weeks showed a significant antihyperglycemic as well as antihyperlipidemic effects in the alloxan-induced diabetic rats.

B Kameswararao; M. M Kesavulu; C Apparao

2003-01-01

93

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

94

Decorin Deficiency Enhances Progressive Nephropathy in Diabetic Mice  

PubMed Central

Decorin, a proteoglycan that inhibits active transforming growth factor-?, 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-?, 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

2007-01-01

95

Flax and Pumpkin seeds mixture ameliorates diabetic nephropathy in rats  

Microsoft Academic Search

This study investigated the hypoglycemic and antioxidant effects of Flax and Pumpkin seeds mixture on the kidney of alloxan-induced diabetic rats. Animals were allocated into three groups of six rats each: a control group (CD), a diabetic group (DD) and diabetic rats fed with Flax and Pumpkin seeds mixture (DMS) group. The DD rats showed a significant increase of glycemia

Mohamed Makni; Mediha Sefi; Hamadi Fetoui; El Mouldi Garoui; Nabil K. Gargouri; Tahia Boudawara; Najiba Zeghal

2010-01-01

96

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

PubMed

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

97

Type I diabetes mellitus decreases in vivo macrophage-to-feces reverse cholesterol transport despite increased biliary sterol secretion in mice  

PubMed Central

Type I diabetes mellitus (T1DM) increases atherosclerotic cardiovascular disease; however, the underlying pathophysiology is still incompletely understood. We investigated whether experimental T1DM impacts HDL-mediated reverse cholesterol transport (RCT). C57BL/6J mice with alloxan-induced T1DM had higher plasma cholesterol levels (P < 0.05), particularly within HDL, and increased hepatic cholesterol content (P < 0.001). T1DM resulted in increased bile flow (2.1-fold; P < 0.05) and biliary secretion of bile acids (BA, 10.5-fold; P < 0.001), phospholipids (4.5-fold; P < 0.001), and cholesterol (5.5-fold; P < 0.05). Hepatic cholesterol synthesis was unaltered, whereas BA synthesis was increased in T1DM (P < 0.001). Mass fecal BA output was significantly higher in T1DM mice (1.5-fold; P < 0.05), fecal neutral sterol excretion did not change due to increased intestinal cholesterol absorption (2.1-fold; P < 0.05). Overall in vivo macrophage-to-feces RCT, using [3H]cholesterol-loaded primary mouse macrophage foam cells, was 20% lower in T1DM (P < 0.05), mainly due to reduced tracer excretion within BA (P < 0.05). In vitro experiments revealed unchanged cholesterol efflux toward T1DM HDL, whereas scavenger receptor class BI-mediated selective uptake from T1DM HDL was lower in vitro and in vivo (HDL kinetic experiments) (P < 0.05), conceivably due to increased glycation of HDL-associated proteins (+65%, P < 0.01). In summary, despite higher mass biliary sterol secretion T1DM impairs macrophage-to-feces RCT, mainly by decreasing hepatic selective uptake, a mechanism conceivably contributing to increased cardiovascular disease in T1DM. PMID:22180634

Freark de Boer, Jan; Annema, Wijtske; Schreurs, Marijke; van der Veen, Jelske N.; van der Giet, Markus; Nijstad, Niels; Kuipers, Folkert; Tietge, Uwe J. F.

2012-01-01

98

Chronic rapamycin treatment causes diabetes in male mice.  

PubMed

Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17?-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2 against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2 plays a protective role against the development of rapamycin-induced diabetes. PMID:24965794

Schindler, Christine E; Partap, Uttara; Patchen, Bonnie K; Swoap, Steven J

2014-08-15

99

Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice  

Microsoft Academic Search

The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet ? cell–reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell–deficient

Siri Atma W. Greeley; Makoto Katsumata; Liping Yu; George S. Eisenbarth; Daniel J. Moore; Heidi Goodarzi; Clyde F. Barker; Hooman Noorchashm; Ali Naji

2002-01-01

100

Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers  

Microsoft Academic Search

Background: Diabetic patients are refractory to allergic inflammatory diseases. In this study, the influence of alloxan-induced diabetes on allergic skin inflammation was investigated. Methods: Diabetes was induced by intravenous injection of alloxan into male Wistar rats, and the analyses were performed 21 days later. Animals were actively sensitized with a mixture of aluminium hydroxide plus ovalbumin and challenged intradermally with

Vinicius de F. Carvalho; Leandro V. Campos; Francisco A. Farias-Filho; Luisa T. Florim; Emiliano O. Barreto; Claude Pirmez; Wilson Savino; Marco A. Martins; Patrícia M. R. e Silva

2008-01-01

101

Petalonia improves glucose homeostasis in streptozotocin-induced diabetic mice  

Microsoft Academic Search

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

Seong-Il Kang; Young-Jun Jin; Hee-Chul Ko; Soo-Youn Choi; Joon-Ho Hwang; Ilson Whang; Moo-Han Kim; Hye-Sun Shin; Hyung-Bok Jeong; Se-Jae Kim

2008-01-01

102

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1  

PubMed Central

Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1+/?) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1+/? mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickning and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-?B p65 were significantly exacerbated in the diabetic VASH1+/? mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of I?B?, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31+ endothelial area was also increased in the diabetic VASH1+/? mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-?1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1+/? mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy. PMID:25255225

Hinamoto, Norikazu; Maeshima, Yohei; Yamasaki, Hiroko; Nasu, Tatsuyo; Saito, Daisuke; Watatani, Hiroyuki; Ujike, Haruyo; Tanabe, Katsuyuki; Masuda, Kana; Arata, Yuka; Sugiyama, Hitoshi; Sato, Yasufumi; Makino, Hirofumi

2014-01-01

103

PPAR? activation protects endothelial function in diabetic mice.  

PubMed

Recent evidence highlights the therapeutic potential of peroxisome proliferator-activated receptor-? (PPAR?) agonists to increase insulin sensitivity in diabetes. However, the role of PPAR? in regulating vascular function is incompletely characterized. We investigate whether PPAR? activation improves endothelial function in diabetic and obese mice. PPAR? knockout (KO) and wild-type (WT) mice fed with high-fat diet and db/db mice were used as diabetic mouse models, compared with PPAR? KO and WT mice on normal diet and db/m(+) mice. Endothelium-dependent relaxation (EDR) was measured by wire myograph. Flow-mediated vasodilatation (FMD) was measured by pressure myograph. Nitric oxide (NO) production was examined in primary endothelial cells from mouse aortae. PPAR? agonist GW1516 restored EDRs in mouse aortae under high-glucose conditions or in db/db mouse aortae ex vivo. After oral treatment with GW1516, EDRs in aortae and FMDs in mesenteric resistance arteries were improved in obese mice in a PPAR?-specific manner. The effects of GW1516 on endothelial function were mediated through phosphatidylinositol 3-kinase (PI3K) and Akt with a subsequent increase of endothelial nitric oxide synthase (eNOS) activity and NO production. The current study demonstrates an endothelial-protective effect of PPAR? agonists in diabetic mice through PI3K/Akt/eNOS signaling, suggesting the therapeutic potential of PPAR? agonists for diabetic vasculopathy. PMID:22933110

Tian, Xiao Yu; Wong, Wing Tak; Wang, Nanping; Lu, Ye; Cheang, Wai San; Liu, Jian; Liu, Limei; Liu, Yahan; Lee, Susanna Sau-Tuen; Chen, Zhen Yu; Cooke, John P; Yao, Xiaoqiang; Huang, Yu

2012-12-01

104

PPAR? Activation Protects Endothelial Function in Diabetic Mice  

PubMed Central

Recent evidence highlights the therapeutic potential of peroxisome proliferator–activated receptor-? (PPAR?) agonists to increase insulin sensitivity in diabetes. However, the role of PPAR? in regulating vascular function is incompletely characterized. We investigate whether PPAR? activation improves endothelial function in diabetic and obese mice. PPAR? knockout (KO) and wild-type (WT) mice fed with high-fat diet and db/db mice were used as diabetic mouse models, compared with PPAR? KO and WT mice on normal diet and db/m+ mice. Endothelium-dependent relaxation (EDR) was measured by wire myograph. Flow-mediated vasodilatation (FMD) was measured by pressure myograph. Nitric oxide (NO) production was examined in primary endothelial cells from mouse aortae. PPAR? agonist GW1516 restored EDRs in mouse aortae under high-glucose conditions or in db/db mouse aortae ex vivo. After oral treatment with GW1516, EDRs in aortae and FMDs in mesenteric resistance arteries were improved in obese mice in a PPAR?-specific manner. The effects of GW1516 on endothelial function were mediated through phosphatidylinositol 3-kinase (PI3K) and Akt with a subsequent increase of endothelial nitric oxide synthase (eNOS) activity and NO production. The current study demonstrates an endothelial-protective effect of PPAR? agonists in diabetic mice through PI3K/Akt/eNOS signaling, suggesting the therapeutic potential of PPAR? agonists for diabetic vasculopathy. PMID:22933110

Tian, Xiao Yu; Wong, Wing Tak; Wang, Nanping; Lu, Ye; Cheang, Wai San; Liu, Jian; Liu, Limei; Liu, Yahan; Lee, Susanna Sau-Tuen; Chen, Zhen Yu; Cooke, John P.; Yao, Xiaoqiang; Huang, Yu

2012-01-01

105

Increased Inflammation in Atherosclerotic Lesions of Diabetic Akita-LDLr?/? Mice Compared to Nondiabetic LDLr?/? Mice  

PubMed Central

Background. Diabetes is associated with increased cardiovascular disease, but the underlying cellular and molecular mechanisms are poorly understood. One proposed mechanism is that diabetes aggravates atherosclerosis by enhancing plaque inflammation. The Akita mouse has recently been adopted as a relevant model for microvascular complications of diabetes. Here we investigate the development of atherosclerosis and inflammation in vessels of Akita mice on LDLr?/? background. Methods and Results. Akita-LDLr?/? and LDLr?/? mice were fed high-fat diet from 6 to 24 weeks of age. Blood glucose levels were higher in both male and female Akita-LDLr?/? mice (137% and 70%, resp.). Male Akita-LDLr?/? mice had markedly increased plasma cholesterol and triglyceride levels, a three-fold increase in atherosclerosis, and enhanced accumulation of macrophages and T-cells in plaques. In contrast, female Akita-LDLr?/? mice demonstrated a modest 29% increase in plasma cholesterol and no significant increase in triglycerides, atherosclerosis, or inflammatory cells in lesions. Male Akita-LDLr?/? mice had increased levels of plasma IL-1? compared to nondiabetic mice, whereas no such difference was seen between female diabetic and nondiabetic mice. Conclusion. Akita-LDLr?/? mice display considerable gender differences in the development of diabetic atherosclerosis. In addition, the increased atherosclerosis in male Akita-LDLr?/? mice is associated with an increase in inflammatory cells in lesions. PMID:23243415

Engelbertsen, Daniel; To, Fong; Duner, Pontus; Kotova, Olga; Soderberg, Ingrid; Alm, Ragnar; Gomez, Maria F.; Nilsson, Jan; Bengtsson, Eva

2012-01-01

106

Docosahexaenoic acid has an anti-diabetic effect in streptozotocin-induced diabetic mice  

PubMed Central

Consumption of fish oil-rich foods containing docosahexaenoic acid (DHA) can result in a low incidence of diabetes. The underlying mechanisms of these anti-hyperglycemic effects are ambiguous. This study aims to investigate the role of DHA in the prevention and treatment of type 1 diabetes in a murine model. Forty streptozotocin-induced diabetic mice were divided into control with diabetes, diabetes prevention (500 ?g/kg DHA orally for 5 days) or diabetes treatment groups (DHA solvent in DMSO into the colon for 5 days). The groups were observed for 25 days after administration of DHA. Mice in the prevention and treatment group had shinier fur, increased body weight, significantly lower food and water intake and were more active compared with the control group with diabetes. Elevated insulin and liver SOD and T-AOC levels were also observed. Furthermore, islet cell apoptosis was reduced and islet cell GLP-1R expression increased. PMID:25356177

Li, Ping; Zhang, Li; Tian, Xin; Xing, Jie

2014-01-01

107

Antidiabetic and hypolipidemic effects of Momordica cymbalaria Hook. fruit powder in alloxan-diabetic rats  

Microsoft Academic Search

This study was undertaken to investigate the effect of Momordica cymbalaria fruit powder on blood glucose and other biochemical parameters in alloxan-induced diabetic rats. The treatment was given for 15 days. After the treatment, a significant reduction was observed in fasting blood glucose levels in the treated diabetic rats, but no hypoglycaemic activity in the treated normal rats. M. cymbalaria

B Kameswara Rao; M. M Kesavulu; R Giri; Ch Appa Rao

1999-01-01

108

IFN-{gamma} gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice  

SciTech Connect

Insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice results from selective destruction of pancreatic islet {beta}-cells following islet filtration by mononuclear leukocytes. Cytokines produced by islet-infiltrating mononuclear cells may be involved in {beta}-cell destruction. Therefore, we analyzed cytokine mRNA expression, by reverse-transcriptase PCR (RT-PCR) assay, in mononuclear leukocytes isolated from pancreatic islets of four groups of mice: diabetes-prone female NOD mice; female NOD mice protected from diabetes by injection of CFA at an early age; male NOD mice with a low diabetes incidence; and female BALB/c mice that do not develop diabetes. We found that mRNA levels of IL-1{beta}, IL-2, IL-4, IL-10, and IFN-{gamma} in mononuclear cells from islets of diabetes-prone female NOD mice increased progressively as these cells infiltrated the islets from age 5 wk to diabetes onset (>13 wk). However, only IFN-{gamma} mRNA levels were significantly higher in islet mononuclear cells from 12-wk-old diabetes-prone female NOD mice than from less diabetes-prone NOD mice (CFA-treated females, and males) and normal mice (BALB/c). In contrast, IL-4 mRNA levels were lower in islet mononuclear cells from diabetes-prone female NOD mice than from NOD mice with low diabetes incidence (CFA-treated females and males). Splenic cell mRNA levels of IFN-{gamma} and IL-4 were not different in the four groups of mice. These results suggest that islet {beta}-cell destruction and diabetes in female NOD mice are dependent upon intra-islet IFN-{gamma} production by mononuclear cells, and that CFA-treated female NOD mice and male NOD mice may be protected from diabetes development by down-regulation of IFN-{gamma} production in the islets. 56 refs., 4 figs., 3 tabs.

Rabinovitch, A.; Suarez-Pinzon, W.L.; Sorensen, O. [Univ. of Alberta, Edmonton (Canada)] [and others

1995-05-01

109

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

110

Modeling Type 1 Diabetes in NOD Mice  

E-print Network

concentration · cells in pancreas respond - Insulin released · Cells increase glucose uptake - Insulin in pancreas · Other autoimmune diseases are similar Diabetes Oct 2006 ­ p. 10/3 #12;Model Scheme for Diabetes-MHC Apoptotic cell PANCREAS LYMPH NODE Dendritic cell peptide p Cell injury Diabetes Oct 2006 ­ p. 11/3 #12

Mahaffy, Joseph M.

111

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. 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

112

Evaluation of traditional plant treatments for diabetes: Studies in streptozotocin diabetic mice  

Microsoft Academic Search

Summary  Seven plants and a herbal mixture used for traditional treatment of diabetes were studied in streptozotocin diabetic mice.\\u000a The treatments were supplied as 6.25% by weight of the diet for 9 days. Consumption of diets containing bearberry (Arctostaphylos uva-ursi), golden seal (Hydrastis canadensis), mistletoe (Viscum album) and tarragon (Artemisia dracunculus) significantly reduced the hyperphagia and polydipsia associated with streptozotocin diabetes,

Sara K. Swanston-Flatt; Caroline Day; Clifford J. Bailey; Peter R. Flatt

1989-01-01

113

Prevention of diabetes in nonobese diabetic mice by dendritic cell transfer.  

PubMed Central

The purpose of this study was to determine the effect of dendritic cell (DC) transfers on the incidence of diabetes in female nonobese diabetic (NOD) mice. Groups of 4-wk-old NOD female mice were given a single foot pad of DCs (70-90% purity) isolated from the draining lymph nodes (LN) of the pancreas (PLN), the cervical LNs, or the axillary/inguinal LNs. In addition, other groups of NOD mice received purified spleen DCs, purified PLN T cells (the major contaminating population in DC preparations), or the injection vehicle PBS. All groups were monitored for diabetes for one year. Significant protection from diabetes was observed in NOD mice receiving greater than 1 x 10(4) PLN DCs in comparison to mice receiving other DCs populations, PLN T cells, or PBS (P less than 0.05). The pancreata of NOD mice that received PLN DCs demonstrated significantly lower levels of lymphocytic infiltration in the islets that age-sex matched nondiabetic female NOD control mice (P less than 0.05). LN cells from nondiabetic NOD mice that received PLN DC protected irradiated female recipients from the adoptive transfer of diabetes to a greater degree than LN cells from age and sex matched nondiabetic female NOD mice that did not receive PLN DC transfers at 36 d (P = 0.014) and at 1 yr (P = 0.0015) after transfer. These data suggest that the PLN DC transfers are able to modulate autoimmunity and limit diabetes expression in the NOD mouse. PLN DCs transfers may regulate autoimmunity by the induction of regulatory cells. Images PMID:1522229

Clare-Salzler, M J; Brooks, J; Chai, A; Van Herle, K; Anderson, C

1992-01-01

114

Leptin Administration Enhances Islet Transplant Performance in Diabetic Mice  

PubMed Central

Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose-response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ-induced diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose-response study revealed that leptin reverses STZ-induced diabetes in a dose-dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 µg/day leptin only modestly reduced blood glucose but maintained efficacy throughout the study duration. We then administered 1 µg/day leptin to diabetic mice that underwent transplantation of 50 or 125 islets. Although these islet doses were insufficient to ameliorate hyperglycemia alone, coadministration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-induced diabetic mice. PMID:23656888

Denroche, Heather C.; Quong, Whitney L.; Bruin, Jennifer E.; Tuduri, Eva; Asadi, Ali; Glavas, Maria M.; Fox, Jessica K.; Kieffer, Timothy J.

2013-01-01

115

The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.  

PubMed

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 gamma-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. PMID:12847137

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

2003-07-01

116

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. PMID:12847137

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

117

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. PMID:21224061

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

118

Role of intracellular calcium in thermal allodynia and hyperalgesia in diabetic mice  

Microsoft Academic Search

We examined the involvement of cytosolic calcium on thermal hyperalgesia and allodynia seen in diabetic mice. Tail-flick latencies at source voltages of a 50-W projection bulb to 35 and 50 V in diabetic mice were significantly shorter than those in non-diabetic mice. Tail-flick latencies at 35 and 50 V in diabetic mice were increased by pretreatment with ryanodine, which blocks

Masahiro Ohsawa; Junzo Kamei

1999-01-01

119

Role of vanilloid VR1 receptor in thermal allodynia and hyperalgesia in diabetic mice  

Microsoft Academic Search

We examined the role of the vanilloid VR1 receptor in the thermal hyperalgesia and allodynia seen in diabetic mice. Tail-flick latencies at source voltages of 35 and 50 V for a 50-W projection bulb in diabetic mice were significantly shorter than those in non-diabetic mice. Tail-flick latencies at 35 and 50 V in diabetic mice were increased by pretreatment with

Junzo Kamei; Ko Zushida; Kayo Morita; Mitsumasa Sasaki; Shun-ichi Tanaka

2001-01-01

120

DBA/2J Mice Are Susceptible to Diabetic Nephropathy and Diabetic Exacerbation of IOP Elevation  

PubMed Central

Some pathological manifestations of diabetes in the eye include retinopathy, cataracts and elevated intraocular pressure (IOP). Loss of retinal ganglion cells (RGCs) in non-proliferative stages of diabetic retinopathy and small increases in IOP in diabetic patients has raised the possibility that diabetes affects the development and progression of ocular hypertension and glaucoma. The Ins2Akita mutation is known to cause diabetes and retinopathy on a C57BL/6J (B6) background by as early as 3 months of age. Here, the impact of the Akita mutation on glaucoma was assessed using DBA/2J (D2) mice, a widely used mouse model of ocular hypertension induced glaucoma. In D2.Ins2Akita/+ mice, the contribution of diabetes to vascular permeability, IOP elevation, RGC loss, and glaucoma development was assessed. D2.Ins2Akita/+ mice developed a severe diabetic nephropathy and early mortality between 6–8 months of age. This agrees with previous reports showing that the D2 background is more susceptible to diabetes than the B6 background. In addition, D2.Ins2Akita/+ mice had vascular leakage, astrocyte reactivity and a significant increase in IOP. However no RGC loss and no anterograde axonal transport dysfunction were found at 8.5 months of age. Therefore, our data show that despite severe diabetes and an increased IOP compared to controls, RGCs do not lose axon transport or degenerate. This may be due to a DBA/2J-specific genetic modifier(s) that could provide novel and important avenues for developing new therapies for diabetic retinopathy and possibly glaucoma. PMID:25207540

Soto, Ileana; Howell, Gareth R.; John, Cai W.; Kief, Joseph L.; Libby, Richard T.; John, Simon W. M.

2014-01-01

121

The optimal extraction parameters and anti-diabetic activity of flavonoids from Ipomoea batatas leaf.  

PubMed

Extraction parameters of flavonoids from Ipomoea batatas leaf (FIBL) and anti-diabetic activity of FIBL on alloxan induced diabetic mice were studied. The optimal extraction parameters of FIBL were obtained by single factor test and orthogonal test, as follows: ethanol concentration 60 %, ratio of solvent to raw material 30, extraction temperature 75 degrees and extraction time 1.5 h, while extraction yield of FIBL was 5.94 %. FIBL treatment (50, 100, and 150 mg/ kg body weight) for 28 days resulted in a significant decrease in the concentration of fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) in diabetes mellitus mice. Furthermore, FIBL significantly increased body weight (bw) and serum high-density lipoprotein cholesterol (HDL-c) level. The data demonstrated FIBL at the dose of 100 mg/kg bw exhibited the optimal effect. The above results suggest that FIBL can control blood glucose and modulate the metabolism of blood lipid in diabetes mellitus mice. PMID:20209012

Li, Fenglin; Li, Qingwang; Gao, Dawei; Peng, Yong

2009-01-01

122

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

123

Nrf2 induces fibroblast growth factor 21 in diabetic mice.  

PubMed

Transcription factor Nrf2 (nuclear factor E2-related factor 2) is a master regulator of cellular defense system against oxidative and electrophilic stresses and is negatively regulated by an adaptor protein Keap1 (Kelch-like ECH-associated protein 1). Nrf2 also plays a pivotal role in metabolic homeostasis, such as lipid metabolism and energy expenditure as well as redox homeostasis. FGF21 (fibroblast growth factor 21) is known as a key mediator of glucose and lipid metabolism. Here, we found that Nrf2 is involved in FGF21 regulation in diabetic model mice. Nrf2 induction by genetic knockdown of Keap1 increased plasma FGF21 level and hepatic Fgf21 expression in diabetic db/db mice and high-calorie-diet-induced obesity model mice. Administration of CDDO-Im (oleanolic triterpenoid 1-[2-cyano-3,12-dioxooleane-1, 9(11)-dien-28-oyl] imidazole), a potent Nrf2 inducer, up-regulated plasma FGF21 level and hepatic Fgf21 expression in db/db mice, whereas CDDO-Im did not induce FGF21 in db/db mice with Nrf2 knockout background. Furthermore, in Keap1-knockdown db/db mice, Nrf2 enhanced expression of glucose- and lipid-metabolism-related genes in adipose tissues, which improved plasma lipid profiles. These results show that Nrf2 positively regulates FGF21 expression in diabetic mice. We propose that FGF21 is a potential efficacy biomarker that mediates metabolic regulation by the Keap1-Nrf2 system. PMID:25270507

Furusawa, Yuki; Uruno, Akira; Yagishita, Yoko; Higashi, Chika; Yamamoto, Masayuki

2014-12-01

124

Vitamin E and diabetic nephropathy in mice model and humans  

PubMed Central

Diabetes mellitus (DM) is associated with increased oxidative stress due to elevated glucose levels in the plasma. Glucose promotes glycosylation of both plasma and cellular proteins with increased risk for vascular events. Diabetic patients suffer from a higher incidence of cardiovascular complications such as diabetic nephropathy. Haptoglobin (Hp) is an antioxidant plasma protein which binds free hemoglobin, thus preventing heme-iron mediated oxidation. Two alleles exist at the Hp gene locus (1 and 2) encoding three possible Hp genotypes that differ in their antioxidant ability, and may respond differently to vitamin E treatment. Several clinical studies to have shown that Hp 1-1 genotype is a superior antioxidant to the Hp 2-2 genotype and Hp 2-2 genotype is associated with a higher incidence of cardiovascular disease. Vitamin E was found to have beneficial effect in patient and mice with Hp 2-2 genotype. In this review we have summarized the results of our studies in patients with diabetic nephropathy treated with vitamin E and in diabetic mice with different haptoglobin genotypes. PMID:24255894

Farid, Nakhoul; Inbal, Dahan; Nakhoul, Nakhoul; Evgeny, Farber; Miller-Lotan, Rachel; Levy, Andrew P; Rabea, Asleh

2013-01-01

125

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

126

Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice.  

PubMed

Although age remains the main risk factor to suffer Alzheimer's disease (AD) and vascular dementia (VD), type 2 diabetes (T2D) has turned up as a relevant risk factor for dementia. However, the ultimate underlying mechanisms for this association remain unclear. In the present study we analyzed central nervous system (CNS) morphological and functional consequences of long-term insulin resistance and T2D in db/db mice (leptin receptor KO mice). We also included C57Bl6 mice fed with high fat diet (HFD) and a third group of C57Bl6 streptozotocin (STZ) treated mice. Db/db mice exhibited pathological characteristics that mimic both AD and VD, including age dependent cognitive deterioration, brain atrophy, increased spontaneous hemorrhages and tau phosphorylation, affecting the cortex preferentially. A similar profile was observed in STZ-induced diabetic mice. Moreover metabolic parameters, such as body weight, glucose and insulin levels are good predictors of many of these alterations in db/db mice. In addition, in HFD-induced hyperinsulinemia in C57Bl6 mice, we only observed mild CNS alterations, suggesting that central nervous system dysfunction is associated with well established T2D. Altogether our results suggest that T2D may promote many of the pathological and behavioral alterations observed in dementia, supporting that interventions devoted to control glucose homeostasis could improve dementia progress and prognosis. PMID:23790682

Ramos-Rodriguez, Juan Jose; Ortiz, Oscar; Jimenez-Palomares, Margarita; Kay, Kevin R; Berrocoso, Esther; Murillo-Carretero, Maria Isabel; Perdomo, German; Spires-Jones, Tara; Cozar-Castellano, Irene; Lechuga-Sancho, Alfonso Maria; Garcia-Alloza, Monica

2013-11-01

127

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. PMID:20637218

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

2011-01-01

128

-Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice  

E-print Network

-Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice Mary E of insulin by islets from diabetes-susceptible mice. Am J Physiol Endocrinol Metab 289: E218­E224, 2005 type 2 diabetes are hyperinsulinemic. Hy- perinsulinemia may be a response to insulin resistance

Attie, Alan D.

129

Diabetes Provides an Unfavorable Environment for Muscle Mass and Function after Muscle Injury in Mice  

Microsoft Academic Search

It is of common knowledge that diabetes decreases skeletal muscle contractility and induces atrophy. However, how hyperglycemia and insulin deficiency modify muscle mass and neuromuscular recovery after muscle injury is not well known. We have analyzed two models of diabetes: streptozotocin (STZ)-treated Swiss mice and Akita mice that spontaneously develop diabetes. A fast muscle, the tibialis anterior, was injured following

A. Vignaud; F. Ramond; C. Hourdé; A. Keller; G. Butler-Browne; A. Ferry

2007-01-01

130

Gene Expression Profiles of Nondiabetic and Diabetic Obese Mice Suggest a Role of Hepatic Lipogenic  

E-print Network

for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes from a failure of the pancreatic -cells to compensate for insulin resistance. Obesity, which leads

Attie, Alan D.

131

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

132

Berberine Improves Kidney Function in Diabetic Mice via AMPK Activation  

PubMed Central

Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Effective therapies to prevent the development of this disease are required. Berberine (BBR) has several preventive effects on diabetes and its complications. However, the molecular mechanism of BBR on kidney function in diabetes is not well defined. Here, we reported that activation of AMP-activated protein kinase (AMPK) is required for BBR-induced improvement of kidney function in vivo. AMPK phosphorylation and activity, productions of reactive oxygen species (ROS), kidney function including serum blood urea nitrogen (BUN), creatinine clearance (Ccr), and urinary protein excretion, morphology of glomerulus were determined in vitro or in vivo. Exposure of cultured human glomerulus mesangial cells (HGMCs) to BBR time- or dose-dependently activates AMPK by increasing the thr172 phosphorylation and its activities. Inhibition of LKB1 by siRNA or mutant abolished BBR-induced AMPK activation. Incubation of cells with high glucose (HG, 30 mM) markedly induced the oxidative stress of HGMCs, which were abolished by 5-aminoimidazole-4-carboxamide ribonucleoside, AMPK gene overexpression or BBR. Importantly, the effects induced by BBR were bypassed by AMPK siRNA transfection in HG-treated HGMCs. In animal studies, streptozotocin-induced hyperglycemia dramatically promoted glomerulosclerosis and impaired kidney function by increasing serum BUN, urinary protein excretion, and decreasing Ccr, as well as increased oxidative stress. Administration of BBR remarkably improved kidney function in wildtype mice but not in AMPK?2-deficient mice. We conclude that AMPK activation is required for BBR to improve kidney function in diabetic mice. PMID:25409232

Zhao, Long; Sun, Li-Na; Nie, Hui-Bin; Wang, Xue-Ling; Guan, Guang-Ju

2014-01-01

133

A novel quantitative method for diabetic cardiac autonomic neuropathy assessment in type 1 diabetic mice.  

PubMed

In this work, we used a sensitive and noninvasive computational method to assess diabetic cardiovascular autonomic neuropathy (DCAN) from pulse oximeter (photoplethysmographic; PPG) recordings from mice. The method, which could be easily applied to humans, is based on principal dynamic mode (PDM) analysis of heart rate variability (HRV). Unlike the power spectral density, PDM has been shown to be able to separately identify the activities of the parasympathetic and sympathetic nervous systems without pharmacological intervention. HRV parameters were measured by processing PPG signals from conscious 1.5- to 5-month-old C57/BL6 control mice and in Akita mice, a model of insulin-dependent type 1 diabetes, and compared with the gold-standard Western blot and immunohistochemical analyses. The PDM results indicate significant cardiac autonomic impairment in the diabetic mice in comparison to the controls. When tail-cuff PPG recordings were collected and analyzed starting from 1.5 months of age in both C57/Bl6 controls and Akita mice, onset of DCAN was seen at 3 months in the Akita mice, which persisted up to the termination of the recording at 5 months. Western blot and immunohistochemical analyses also showed a reduction in nerve density in Akita mice at 3 and 4 months as compared to the control mice, thus, corroborating our PDM data analysis of HRV records. Western blot analysis of autonomic nerve proteins corroborated the PPG-based HRV analysis via the PDM approach. In contrast, traditional HRV analysis (based on either the power spectral density or time-domain measures) failed to detect the nerve rarefaction. PMID:25097056

Chon, Ki H; Yang, Bufan; Posada-Quintero, Hugo F; Siu, Kin L; Rolle, Marsha; Brink, Peter; Birzgalis, Aija; Moore, Leon C

2014-11-01

134

The hypoglycaemic and antihyperglycaemic effect of Citrullus colocynthis fruit aqueous extract in normal and alloxan diabetic rabbits  

Microsoft Academic Search

Effects of the aqueous, glycosidic, alkaloidal and saponin extracts of the rind of Citrullus colocynthis on the plasma glucose levels were investigated in normal rabbits, while the effects of saponin extract on the fasting plasma glucose levels were studied in alloxan induced diabetic rabbits. In normal rabbits, oral administration of aqueous extract (300 mg\\/kg) produced significant reduction in plasma glucose

Issa Abed Abdel-Hassan; Jamal Ahmed Abdel-Barry; Sarah Tariq Mohammeda

2000-01-01

135

Combined vitamins (C and E) and insulin improve oxidative stress and pancreatic and hepatic injury in alloxan diabetic rats  

Microsoft Academic Search

The aim of the present study is to determine if a combination of vitamins (C and E) has any advantage over insulin therapy on lipid peroxidation, antioxidant activity, liver dysfunction parameters, and histological changes in the alloxan-induced diabetic rats. The enzymatic activities of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) and the lipid peroxidation product, thiobarbituric acid-reacting substances

Khaled Hamden; Mohamed Ali Boujbiha; Hatem Masmoudi; Fatma Makni Ayadi; Kamel Jamoussi; Abdelfattah Elfeki

2009-01-01

136

Evaluation of traditional plant treatments for diabetes: studies in streptozotocin diabetic mice.  

PubMed

Seven plants and a herbal mixture used for traditional treatment of diabetes were studied in streptozotocin diabetic mice. The treatments were supplied as 6.25% by weight of the diet for 9 days. Consumption of diets containing bearberry (Arctostaphylos uva-ursi), golden seal (Hydrastis canadensis), mistletoe (Viscum album) and tarragon (Artemisia dracunculus) significantly reduced the hyperphagia and polydipsia associated with streptozotocin diabetes, but bayberry (Cinnamomum tamala), meadowsweet (Filipendula ulmaria), senna (Cassia occidentalis) and the herbal mixture did not alter these parameters. Bearberry, mistletoe and tarragon retarded the body weight loss but none of the eight treatments significantly altered plasma glucose or insulin concentrations. These studies suggest that bearberry, golden seal, mistletoe and tarragon may counter some of the symptoms of streptozotocin diabetes without, however, affecting glycemic control. PMID:2750445

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

1989-01-01

137

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

138

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. PMID:22962525

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

2012-01-01

139

HoxD3 accelerates wound healing in diabetic mice  

SciTech Connect

Poorly healing diabetic wounds are characterized by diminished collagen production and impaired angiogenesis. HoxD3, a homeobox transcription factor that promotes angiogenesis and collagen synthesis, is up-regulated during normal wound repair whereas its expression is diminished in poorly healing wounds of the genetically diabetic (db/db) mouse. To determine whether restoring expression of HoxD3 would accelerate diabetic wound healing, we devised a novel method of gene transfer, which incorporates HoxD3 plasmid DNA into a methylcellulose film that is placed on wounds created on db/db mice. The HoxD3 transgene was expressed in endothelial cells, fibroblasts, and keratinocytes of the wounds for up to 10 days. More importantly, a single application of HoxD3 to db/db mice resulted in a statistically significant acceleration of wound closure compared to control-treated wounds. Furthermore, we also observed that the HoxD3-mediated improvement in diabetic wound repair was accompanied by increases in mRNA expression of the HoxD3 target genes, Col1A1 and beta 3-integrin leading to enhanced angiogenesis and collagen deposition in the wounds. Although HoxD3-treated wounds also show improved re-epithelialization as compared to control db/db wounds, this effect was not due to direct stimulation of keratinocyte migration by HoxD3. Finally, we show that despite the dramatic increase in collagen synthesis and deposition in HoxD3-treated wounds, these wounds showed normal remodeling and we found no evidence of abnormal wound healing. These results indicate that HoxD3 may provide a means to directly improve collagen deposition, angiogenesis and closure in poorly healing diabetic wounds.

Hansen, Scott L.; Myers, Connie A.; Charboneau, Aubri; Young, David M.; and Boudreau, Nancy

2003-12-01

140

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

141

Effect of acute hyperglycaemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischaemic late preconditioning in the rabbit heart in vivo  

Microsoft Academic Search

Diabetes mellitus (DM) and the resulting hyperglycaemia may interfere with the cardioprotective effect of ischaemic late preconditioning (LPC). Therefore, we investigated the effect of acute hyperglycaemia (part 1) and the effect of alloxan-induced DM with or without short-term insulin treatment (part 2) on LPC. Rabbits, chronically instrumented with a coronary artery occluder, were subjected to 30 min coronary artery occlusion

Dirk Ebel; Jost Müllenheim; Jan Fräßdorf; Andre Heinen; Ragnar Huhn; Thomas Bohlen; Jan Ferrari; Hendrik Südkamp; Benedikt Preckel; Wolfgang Schlack; Volker Thämer

2003-01-01

142

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

143

The antidiabetic effects of cysteinyl metformin, a newly synthesized agent, in alloxan- and streptozocin-induced diabetic rats  

Microsoft Academic Search

In this paper, the antidiabetic effects of cysteinyl metformin (CM), a newly synthesized agent, were investigated to evaluate the hypoglycemic\\/hypolipidemic effects by measuring blood glucose, triglyceride and insulin levels in CM- and metformin-treated diabetic rats. Two diabetic models were used: (1) an alloxan-induced model in which diabetes was produced by alloxan (200mg\\/kg, i.p.), then rats were treated with CM (300,

Zheng Liu; Jianchun Li; Zhaojun Zeng; Ming Liu; Minwei Wang

2008-01-01

144

Amelioration in Wound healing in Diabetic Toll-like Receptor-4 Knockout mice  

PubMed Central

Toll-like receptor-4 (TLR4) is a sentinel pathogen recognition receptor with a pivotal role in inflammation, tissue injury, diabetes and its complications. The aim of the study was to examine the contribution of TLR4 expression and activation to the prolonged inflammation observed in diabetic wounds. Diabetes was induced in male C57BL/6J and TLR4 knockout (KO) mice using streptozotocin (STZ) with matching non-diabetic mice as control. After 2 weeks of persistent hyperglycemia in the mice, full-thickness excision wounds were made on the backs aseptically. Total RNA and protein were subjected to real-time PCR and western blot analyses. Wound sizes were measured using digital planimetry. TLR4 mRNA and protein expression increased significantly in wounds of diabetic mice compared with non-diabetic mice (P<0.05). IL-6, TNF-? concentration and nuclear factor-?B (NF-?B) activation were increased in diabetic wounds compared to non-diabetic wounds and knockout of TLR4 alleviates wound healing and decreases inflammation in diabetic TLR4 KO mice. Collectively, our findings show that increased TLR4 mRNA and protein expression and activation contribute to the prolonged inflammation in the diabetic wounds and that absence of TLR4 may result in decreased inflammation and improved wound healing. PMID:23773694

Dasu, Mohan R.; Jialal, Ishwarlal

2013-01-01

145

The Dual Role of Scavenger Receptor Class A in Development of Diabetes in Autoimmune NOD Mice  

PubMed Central

Human type 1 diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic ? cells by T cells. Antigen presenting cells including dendritic cells and macrophages are required to activate and suppress antigen-specific T cells. It has been suggested that antigen uptake from live cells by dendritic cells via scavenger receptor class A (SR-A) may be important. However, the role of SR-A in autoimmune disease is unknown. In this study, SR-A?/? nonobese diabetic (NOD) mice showed significant attenuation of insulitis, lower levels of insulin autoantibodies, and suppression of diabetes development compared with NOD mice. We also found that diabetes progression in SR-A?/? NOD mice treated with low-dose polyinosinic-polycytidylic acid (poly(I?C)) was significantly accelerated compared with that in disease-resistant NOD mice treated with low-dose poly(I?C). In addition, injection of high-dose poly(I?C) to mimic an acute RNA virus infection significantly accelerated diabetes development in young SR-A?/? NOD mice compared with untreated SR-A?/? NOD mice. Pathogenic cells including CD4+CD25+ activated T cells were increased more in SR-A?/? NOD mice treated with poly(I?C) than in untreated SR-A?/? NOD mice. These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects. In conclusion, our studies demonstrated that diabetes progression was suppressed in SR-A?/? NOD mice and that acceleration of diabetes development could be induced in young mice by poly(I?C) treatment even in SR-A?/? NOD mice. These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection. Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes. PMID:25343451

Shimizu, Mami; Yasuda, Hisafumi; Hara, Kenta; Takahashi, Kazuma; Nagata, Masao; Yokono, Koichi

2014-01-01

146

The role of mast cells in cutaneous wound healing in streptozotocin-induced diabetic mice.  

PubMed

Mast cells (MCs) reside in cutaneous tissue, and an increment of MCs is suggested to induce vascular regression in the process of wound healing. To clarify participation of MCs in diabetic cutaneous wound healing, we created an excisional wound on diabetic mice 4 weeks after streptozotocin injections and subsequently investigated the healing processes for 49 days, comparing them with control mice. The rate of wound closure was not markedly different between the diabetic and control mice. In the proliferative phase at days 7 and 14, neovascularization in the wound was weaker in diabetic mice than in control mice. In the remodeling phase at day 21 and afterward, rapid vascular regression occurred in control mice; however, neovascularization was still observed in diabetic mice where the number of vessels in granulation tissues was relatively higher than in control mice. In the remodeling phase of the control mice, MCs within the wound began to increase rapidly and resulted in considerable accumulation, whereas the increment of MCs was delayed in diabetic mice. In addition, the number of fibroblast growth factor (FGF)- or vascular endothelial growth factor (VEGF)-immunopositive hypertrophic fibroblast-like spindle cells and c-Kit-positive/VEGFR2-positive/Fc?RI?-negative endothelial progenitor cells (EPCs) were higher in diabetic wounds. In conclusion, neovascularization in the proliferative phase and vascular regression in the remodeling phase were impaired in diabetic mice. The delayed increment of MCs and sustained angiogenic stimuli by fibroblast-like spindle cells and EPCs may inhibit vascular regression in the remodeling phase and impair the wound-healing process in diabetic mice. PMID:25218083

Nishikori, Yoriko; Shiota, Naotaka; Okunishi, Hideki

2014-11-01

147

Oxidative stress and susceptibility to mitochondrial permeability transition precedes the onset of diabetes in autoimmune non-obese diabetic mice.  

PubMed

Abstract Beta cell destruction in type 1 diabetes (TID) is associated with cellular oxidative stress and mitochondrial pathway of cell death. The aim of this study was to determine whether oxidative stress and mitochondrial dysfunction are present in T1D model (non-obese diabetic mouse, NOD) and if they are related to the stages of disease development. NOD mice were studied at three stages: non-diabetic, pre-diabetic, and diabetic and compared with age-matched Balb/c mice. Mitochondria respiration rates measured at phosphorylating and resting states in liver and soleus biopsies and in isolated liver mitochondria were similar in NOD and Balb/c mice at the three disease stages. However, NOD liver mitochondria were more susceptible to calcium-induced mitochondrial permeability transition as determined by cyclosporine-A-sensitive swelling and by decreased calcium retention capacity in all three stages of diabetes development. Mitochondria H2O2 production rate was higher in non-diabetic, but unaltered in pre-diabetic and diabetic NOD mice. The global cell reactive oxygen species (ROS), but not specific mitochondria ROS production, was significantly increased in NOD lymphomononuclear and stem cells in all disease stages. In addition, marked elevated rates of 2',7'-dichlorodihydrofluorescein (H2DCF) oxidation were observed in pancreatic islets from non-diabetic NOD mice. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) and lipidomic approach, we identified oxidized lipid markers in NOD liver mitochondria for each disease stage, most of them being derivatives of diacylglycerols and phospholipids. These results suggest that the cellular oxidative stress precedes the establishment of diabetes and may be the cause of mitochondrial dysfunction that is involved in beta cell death. PMID:25236567

Malaguti, C; La Guardia, P G; Leite, A C R; Oliveira, D N; de Lima Zollner, R L; Catharino, R R; Vercesi, A E; Oliveira, H C F

2014-12-01

148

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

Microsoft Academic Search

Summary Contrary to the traditional view, recent studies suggest that diabetes mellitus has an adverse influence on male reproductive function. Our aim was to deter- mine 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

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

2009-01-01

149

Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice  

Microsoft Academic Search

Beginning at the time of insulitis (7 wk of age), CD4+ and CD8+ mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. This unresponsiveness does not result from either insulitis or thymic involution and is long lasting, i.e., persists until diabetes onset (24 wk of age). We previously proposed that

M. J. Rapoport; A Jaramillo; D Zipris; A H Lazarus; D V Serreze; E H Leiter; P Cyopick; J S Danska; T L Delovitch

1993-01-01

150

Effects of xenoestrogens on streptozotocin-induced diabetic mice.  

PubMed

In diabetic mellitus, apoptotic or necrotic deaths of pancreatic ?-cells lead to insulin deficiency because plasma insulin is synthesized and released from pancreatic ?-cells and involved with blood glucose homeostasis. Since estrogen receptors have been related with glucose metabolis, estrogen-like chemicals (xenoestrogens) including bisphenol A (BPA) and octylphenol (OP) alter the endocrine system, and cause adverse health consequences such as obesity and diabetes. In the current study, levels of plasma glucose were evaluated after administration of BPA and OP using biochemical analysis, and were investigated in insulin and insulin synthesis-related genes in the pancreas and liver of streptozotocin (STZ)-induced insulin-deficient mice. Although the STZ-induced insulin-deficient groups showed an increase in blood glucose compared with control groups, the induced blood glucose level dropped to that of baseline after administration of xenoestrogens. When insulin level and mRNA expression of insulin transcriptional regulators (Pdx1, Mafa, and Neurod1) in pancreatic ?-cells were decreased in STZ-induced insulin-deficient groups, they were significantly restored by administration of xenoestrogens. The latter observation is also related to NF-?B activation for anti-apoptosis effects in pancreatic ?-cells. In addition, we observed a complementary convergence in regulation of gluconeogenesis for determination of blood glucose levels. Therefore, the current study may be particularly important for assessment of xenoestrogens under condition of diabetic mellitus or metabolic disorder. PMID:24781736

Kang, H S; Yang, H; Ahn, C; Kang, H Y; Hong, E J; Jaung, E B

2014-04-01

151

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. PMID:23961092

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

2010-01-01

152

Partial deficiency of HIF-1? stimulates pathological cardiac changes in streptozotocin-induced diabetic mice  

PubMed Central

Background Diabetic cardiomyopathy is associated with a number of functional and structural pathological changes such as left ventricular dysfunction, cardiac remodeling, and apoptosis. The primary cause of diabetic cardiomyopathy is hyperglycemia, the metabolic hallmark of diabetes. Recent studies have shown that a diabetic environment suppresses hypoxia-inducible factor (HIF)-1? protein stability and function. The aim of this study was to analyze the functional role of HIF-1? in the development of diabetic cardiomyopathy. We have hypothesized that the partial deficiency of HIF-1? may compromise cardiac responses under diabetic conditions and increase susceptibility to diabetic cardiomyopathy. Methods Diabetes was induced by streptozotocin in wild type (Wt) and heterozygous Hif1a knock-out (Hif1a +/- ) mice. Echocardiographic evaluations of left ventricular functional parameters, expression analyses by qPCR and Western blot, and cardiac histopathology assessments were performed in age-matched groups, diabetic, and non-diabetic Wt and Hif1a +/- mice. Results Five weeks after diabetes was established, a significant decrease in left ventricle fractional shortening was detected in diabetic Hif1a +/- but not in diabetic Wt mice. The combination effects of the partial deficiency of Hif1a and diabetes affected the gene expression profile of the heart, including reduced vascular endothelial growth factor A (Vegfa) expression. Adverse cardiac remodeling in the diabetic Hif1a +/- heart was shown by molecular changes in the expression of structural molecules and components of the extracellular matrix. Conclusions We have shown a correlation between heterozygosity for Hif1? and adverse functional, molecular, and cellular changes associated with diabetic cardiomyopathy. Our results provide evidence that HIF-1? regulates early cardiac responses to diabetes, and that HIF-1? deregulation may influence the increased risk for diabetic cardiomyopathy. PMID:24502509

2014-01-01

153

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. PMID:25033204

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

154

Treatment with a melanocortin agonist improves abnormal lipid metabolism in streptozotocin-induced diabetic mice  

Microsoft Academic Search

Impairments in leptin–melanocortin signaling are associated with insulin-deficient diabetes and leptin treatment has been shown to be effective in reversing hyperglycemia in animal models of type 1 diabetes. Therefore, we hypothesized that enhanced central melanocortin signaling reverses the metabolic impairments associated with type 1 diabetes. To address this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with daily intracerebroventricular injection of

Arnold Leckstrom; Pei San Lew; Nicole J. Poritsanos; Tooru M. Mizuno

2011-01-01

155

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

156

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. 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

157

Treatment with a melanocortin agonist improves abnormal lipid metabolism in streptozotocin-induced diabetic mice.  

PubMed

Impairments in leptin-melanocortin signaling are associated with insulin-deficient diabetes and leptin treatment has been shown to be effective in reversing hyperglycemia in animal models of type 1 diabetes. Therefore, we hypothesized that enhanced central melanocortin signaling reverses the metabolic impairments associated with type 1 diabetes. To address this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with daily intracerebroventricular injection of MTII, a melanocortin agonist, for 11days. STZ-induced hyperglycemia and glucose intolerance were not improved by MTII treatment. MTII treatment did not alter expression levels of genes encoding gluconeogenic enzymes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the liver of diabetic mice. Skeletal muscle and white adipose tissue glucose transporter 4 (GLUT4) mRNA levels were not altered by MTII treatment in diabetic mice. In contrast, serum nonesterified fatty acid (NEFA) levels were significantly increased in STZ-induced diabetic mice compared to non-diabetic control mice and MTII treatment significantly reduced serum NEFA levels in diabetic mice. MTII treatment also significantly reduced expression levels of hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) mRNA in white adipose tissue of diabetic mice without a significant change in serum insulin levels. Expression levels of lipoprotein lipase (LPL) and fatty acid translocase (FAT/CD36) mRNA in white adipose tissue and skeletal muscle were not changed by MTII treatment. These data suggest that central melanocortin signaling regulates lipid metabolism and that enhancing central melanocortin signaling is effective in reversing abnormal lipid metabolism, but not carbohydrate metabolism, at least partly by reducing lipolysis in type 1 diabetes. PMID:21216462

Leckstrom, Arnold; Lew, Pei San; Poritsanos, Nicole J; Mizuno, Tooru M

2011-04-01

158

Islet Remodeling in Female Mice with Spontaneous Autoimmune and Streptozotocin-Induced Diabetes  

PubMed Central

Islet alpha- and delta-cells are spared autoimmune destruction directed at beta-cells in type 1 diabetes resulting in an apparent increase of non-beta endocrine cells in the islet core. We determined how islet remodeling in autoimmune diabetes compares to streptozotocin (STZ)-induced diabetes. Islet cell mass, proliferation, and immune cell infiltration in pancreas sections from diabetic NOD mice and mice with STZ-induced diabetes was assessed using quantitative image analysis. Serial sections were stained for various beta-cell markers and Ngn3, typically restricted to embryonic tissue, was only upregulated in diabetic NOD mouse islets. Serum levels of insulin, glucagon and GLP-1 were measured to compare hormone levels with respect to disease state. Total pancreatic alpha-cell mass did not change as autoimmune diabetes developed in NOD mice despite the proportion of islet area comprised of alpha- and delta-cells increased. By contrast, alpha- and delta-cell mass was increased in mice with STZ-induced diabetes. Serum levels of glucagon reflected these changes in alpha-cell mass: glucagon levels remained constant in NOD mice over time but increased significantly in STZ-induced diabetes. Increased serum GLP-1 levels were found in both models of diabetes, likely due to alpha-cell expression of prohormone convertase 1/3. Alpha- or delta-cell mass in STZ-diabetic mice did not normalize by replacement of insulin via osmotic mini-pumps or islet transplantation. Hence, the inflammatory milieu in NOD mouse islets may restrict alpha-cell expansion highlighting important differences between these two diabetes models and raising the possibility that increased alpha-cell mass might contribute to the hyperglycemia observed in the STZ model. PMID:25101835

Plesner, Annette; ten Holder, Joris T.; Verchere, C. Bruce

2014-01-01

159

Evaluation of the Effects of Novel Nafimidone Derivatives on Thermal Hypoalgesia in Mice with Diabetic Neuropathy  

PubMed Central

Objective: Diabetic neuropathy (DN) is a common complication in Diabetes Mellitus. The streptozotocin-induced diabetic rodent is the most commonly used animal model of diabetes and increased sodium channel expression and activity were revealed in this model. At this study, we evaluated the effect of three different nafimidone derivatives which have possible anticonvulsant activity on disorders of thermal pain sensation in diabetic mice. Study Design: Randomized animal experiment. Material and Methods: Mice were divided randomly into five groups (5 mice per group): Control, Diabetes, Dibetes+C1, Diabetes+C2, Diabetes+C3. We used hot and cold plate, and tail-immersion tests for assessment of thermal nociceptive responses. Results: Compared with the control group, the hot-plate response time and the number of paw liftings on cold plate as important indicators of loss of sensation increased, but no significant difference (p>0.05) was found in tail-immersion response time test in diabetes group. C3 compound moved it back to control group levels in the all of three tests. C1 and C2 compounds were effective only in cold-plate test. Conclusion: Nafimidone derivatives may be effective in the cases where epilepsy and diabetes occur together since it has shown efficacy against “loss of sensation” which evolves in diabetic neuropathy over time as well as its antiepileptic effect.

Kam?sl?, Suat; Karakurt, Arzu; Uyumlu, Ayse B.; Sat?lm?s, Basri; Alagoz, Abdullah; Genc, Metin F.; Batc?oglu, Kadir

2013-01-01

160

The Gut Microbiota Modulates Glycaemic Control and Serum Metabolite Profiles in Non-Obese Diabetic Mice  

PubMed Central

Islet autoimmunity in children who later progress to type 1 diabetes is preceded by dysregulated serum metabolite profiles, but the origin of these metabolic changes is unknown. The gut microbiota affects host metabolism and changes in its composition contribute to several immune-mediated diseases; however, it is not known whether the gut microbiota is involved in the early metabolic disturbances in progression to type 1 diabetes. We rederived non-obese diabetic (NOD) mice as germ free to explore the potential role of the gut microbiota in the development of diabetic autoimmunity and to directly investigate whether the metabolic profiles associated with the development of type 1 diabetes can be modulated by the gut microbiota. The absence of a gut microbiota in NOD mice did not affect the overall diabetes incidence but resulted in increased insulitis and levels of interferon gamma and interleukin 12; these changes were counterbalanced by improved peripheral glucose metabolism. Furthermore, we observed a markedly increased variation in blood glucose levels in the absence of a microbiota in NOD mice that did not progress to diabetes. Additionally, germ-free NOD mice had a metabolite profile similar to that of pre-diabetic children. Our data suggest that germ-free NOD mice have reduced glycaemic control and dysregulated immunologic and metabolic responses. PMID:25390735

Greiner, Thomas U.; Hyötyläinen, Tuulia; Knip, Mikael; Bäckhed, Fredrik; Oreši?, Matej

2014-01-01

161

The gut microbiota modulates glycaemic control and serum metabolite profiles in non-obese diabetic mice.  

PubMed

Islet autoimmunity in children who later progress to type 1 diabetes is preceded by dysregulated serum metabolite profiles, but the origin of these metabolic changes is unknown. The gut microbiota affects host metabolism and changes in its composition contribute to several immune-mediated diseases; however, it is not known whether the gut microbiota is involved in the early metabolic disturbances in progression to type 1 diabetes. We rederived non-obese diabetic (NOD) mice as germ free to explore the potential role of the gut microbiota in the development of diabetic autoimmunity and to directly investigate whether the metabolic profiles associated with the development of type 1 diabetes can be modulated by the gut microbiota. The absence of a gut microbiota in NOD mice did not affect the overall diabetes incidence but resulted in increased insulitis and levels of interferon gamma and interleukin 12; these changes were counterbalanced by improved peripheral glucose metabolism. Furthermore, we observed a markedly increased variation in blood glucose levels in the absence of a microbiota in NOD mice that did not progress to diabetes. Additionally, germ-free NOD mice had a metabolite profile similar to that of pre-diabetic children. Our data suggest that germ-free NOD mice have reduced glycaemic control and dysregulated immunologic and metabolic responses. PMID:25390735

Greiner, Thomas U; Hyötyläinen, Tuulia; Knip, Mikael; Bäckhed, Fredrik; Oreši?, Matej

2014-01-01

162

Ciliary Neurotrophic Factor Protects Mice Against Streptozotocin-induced Type 1 Diabetes through SOCS3  

PubMed Central

Type 1 diabetes is characterized by a loss of islet ?-cells. Ciliary neurotrophic factor (CNTF) protects pancreatic islets against cytokine-induced apoptosis. For this reason, we assessed whether CNTF protects mice against streptozotocin-induced diabetes (a model of type 1 diabetes) and the mechanism for this protection. WT and SOCS3 knockdown C57BL6 mice were treated for 5 days with citrate buffer or 0.1 mg/kg CNTF before receiving 80 mg/kg streptozotocin. Glycemia in non-fasted mice was measured weekly from days 0–28 after streptozotocin administration. Diabetes was defined as a blood glucose > 11.2 mmol/liter. Wild-type (WT) and SOCS3 knockdown MIN6 cells were cultured with CNTF, IL1?, or both. CNTF reduced diabetes incidence and islet apoptosis in WT but not in SOCS3kd mice. Likewise, CNTF inhibited apoptosis in WT but not in SOCS3kd MIN6 cells. CNTF increased STAT3 phosphorylation in WT and SOCS3kd mice and MIN6 cells but reduced STAT1 phosphorylation only in WT mice, in contrast to streptozotocin and IL1?. Moreover, CNTF reduced NF?B activation and required down-regulation of inducible NO synthase expression to exert its protective effects. In conclusion, CNTF protects mice against streptozotocin-induced diabetes by increasing pancreatic islet survival, and this protection depends on SOCS3. In addition, SOCS3 expression and ?-cell fate are dependent on STAT1/STAT3 ratio. PMID:23038263

Rezende, Luiz F.; Santos, Gustavo J.; Carneiro, Everardo M.; Boschero, Antonio C.

2012-01-01

163

Optical cryo-imaging of kidney mitochondrial redox state in diabetic mice models  

NASA Astrophysics Data System (ADS)

Oxidative stress (OS), which increases during diabetes, exacerbates the development and progression of diabetes complications including renal vascular and proximal tubule cell dysfunction. The objective of this study was to investigate the changes in the metabolic state of the tissue in diabetic mice kidneys using fluorescence imaging. Mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide), and FADH-2 (Flavin Adenine Dinucleotide) are autofluorescent and can be monitored without exogenous labels by optical techniques. The ratio of the fluorescence intensity of these fluorophores, (NADH/FAD), called the NADH redox ratio (RR), is a marker of metabolic state of a tissue. We examined mitochondrial redox states of kidneys from diabetic mice, Akita/+ and its control wild type (WT) for a group of 8- and 12-week-old mice. Average intensity and histogram of maximum projected images of FAD, NADH, and NADH RR were calculated for each kidney. Our results indicated a 17% decrease in the mean NADH RR of the kidney from 8-week-old mice compared with WT mice and, a 30% decrease in the mean NADH RR of kidney from12-week-old mice compared with WT mice. These results indicated an increase in OS in diabetic animals and its progression over time. Thus, NADH RR can be used as a hallmark of OS in diabetic kidney allowing temporal identification of oxidative state.

Maleki, S.; Sepehr, R.; Staniszewski, K.; Sheibani, N.; Sorenson, C. M.; Ranji, M.

2012-03-01

164

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

165

Divergent effects of oxytocin treatment of obese diabetic mice on adiposity and diabetes.  

PubMed

Oxytocin has been suggested as a novel therapeutic against obesity, because it induces weight loss and improves glucose tolerance in diet-induced obese rodents. A recent clinical pilot study confirmed the oxytocin-induced weight-reducing effect in obese nondiabetic subjects. Nevertheless, the mechanisms involved and the impact on the main comorbidity associated with obesity, type 2 diabetes, are unknown. Lean and ob/ob mice (model of obesity, hyperinsulinemia, and diabetes) were treated for 2 weeks with different doses of oxytocin, analogues with longer half-life (carbetocin) or higher oxytocin receptor specificity ([Thr4,Gly7]-oxytocin). Food and water intake, body weight, and glycemia were measured daily. Glucose, insulin, and pyruvate tolerance, body composition, several hormones, metabolites, gene expression, as well as enzyme activities were determined. Although no effect of oxytocin on the main parameters was observed in lean mice, the treatment dose-dependently reduced food intake and body weight gain in ob/ob animals. Carbetocin behaved similarly to oxytocin, whereas [Thr4,Gly7]-oxytocin (TGOT) and a low oxytocin dose decreased body weight gain without affecting food intake. The body weight gain-reducing effect was limited to the fat mass only, with decreased lipid uptake, lipogenesis, and inflammation, combined with increased futile cycling in abdominal adipose tissue. Surprisingly, oxytocin treatment of ob/ob mice was accompanied by a worsening of basal glycemia and glucose tolerance, likely due to increased corticosterone levels and stimulation of hepatic gluconeogenesis. These results impose careful selection of the conditions in which oxytocin treatment should be beneficial for obesity and its comorbidities, and their relevance for human pathology needs to be determined. PMID:25157455

Altirriba, Jordi; Poher, Anne-Laure; Caillon, Aurélie; Arsenijevic, Denis; Veyrat-Durebex, Christelle; Lyautey, Jacqueline; Dulloo, Abdul; Rohner-Jeanrenaud, Françoise

2014-11-01

166

Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice  

PubMed Central

Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic ?-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic ?-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes. PMID:25367288

Liu, Su; Guo, Xuechao; Wu, Bing; Yu, Haiyan; Zhang, Xuxiang; Li, Mei

2014-01-01

167

Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice.  

PubMed

Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic ?-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic ?-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes. PMID:25367288

Liu, Su; Guo, Xuechao; Wu, Bing; Yu, Haiyan; Zhang, Xuxiang; Li, Mei

2014-01-01

168

Dendritic Cells Transduced to Express Interleukin 4 Reduce Diabetes Onset in Both Normoglycemic and Prediabetic Nonobese Diabetic Mice  

PubMed Central

Background We and others have previously demonstrated that treatment with bone marrow derived DC genetically modified to express IL-4 reduce disease pathology in mouse models of collagen-induced arthritis and delayed-type hypersensitivity. Moreover, treatment of normoglycemic NOD mice with bone marrow derived DC, genetically modified to express interleukin 4 (IL-4), reduces the onset of hyperglycemia in a significant number of animals. However, the mechanism(s) through which DC expressing IL-4 function to prevent autoimmune diabetes and whether this treatment can reverse disease in pre-diabetic NOD mice are unknown. Methodology/Principal Findings DC were generated from the bone marrow of NOD mice and transduced with adenoviral vectors encoding soluble murine IL-4 (DC/sIL-4), a membrane-bound IL-4 construct, or empty vector control. Female NOD mice were segregated into normoglycemic (<150mg/dL) and prediabetic groups (between 150 and 250 mg/dL) on the basis of blood glucose measurements, and randomized for adoptive transfer of 106 DC via a single i.v. injection. A single injection of DC/sIL-4, when administered to normoglycemic 12-week old NOD mice, significantly reduced the number of mice that developed diabetes. Furthermore, DC/sIL-4, but not control DC, decreased the number of mice progressing to diabetes when given to prediabetic NOD mice 12–16 weeks of age. DC/sIL-4 treatment also significantly reduced islet mononuclear infiltration and increased the expression of FoxP3 in the pancreatic lymph nodes of a subset of treated animals. Furthermore, DC/sIL-4 treatment altered the antigen-specific Th2:Th1 cytokine profiles as determined by ELISPOT of splenocytes in treated animals. Conclusions Adoptive transfer of DC transduced to express IL-4 into both normoglycemic and prediabetic NOD mice is an effective treatment for T1D. PMID:20686610

Ruffner, Melanie A.; Robbins, Paul D.

2010-01-01

169

Activating Fc Receptors Participate in the Development of Autoimmune Diabetes in NOD Mice1  

Microsoft Academic Search

Type 1 diabetes mellitus (T1D) in humans is an organ-specific autoimmune disease in which pancreatic islet cells are ruptured by autoreactive T cells. NOD mice, the most commonly used animal model of T1D, show early infiltration of leukocytes in the islets (insulitis), resulting in islet destruction and diabetes later. NOD mice produce various islet cell-specific autoantibodies, although it remains a

Yoshihiro Inoue; Tomonori Kaifu; Akiko Sugahara-Tobinai; Akira Nakamura; Jun-Ichi Miyazaki; Toshiyuki Takai

170

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

171

Genetic Control of T and B Lymphocyte Activation in Nonobese Diabetic Mice1  

Microsoft Academic Search

Type 1 diabetes in nonobese diabetic (NOD) mice is characterized by the infiltration of T and B cells into pancreatic islets. T cells bearing the TCR V3 chain are disproportionately represented in the earliest stages of islet infiltration (insulitis) despite clonal deletion of most V3 immature thymocytes by the mammary tumor virus-3 (Mtv-3) superantigen (SAg). In this report we showed

Priscilla P. L. Chiu; Anthony M. Jevnikar; Jayne S. Danska

2001-01-01

172

?-Glucosidase inhibitors prevent diet-induced increases in intestinal sugar transport in diabetic mice  

Microsoft Academic Search

The recommended diet for diabetes mellitus is rich in complex carbohydrates. We have previously shown that high carbohydrate levels in the intestinal lumen induce adaptive increases in sugar absorption which in turn exacerbate postprandial hyperglycemia in diabetic mice. ?-Glucosidase inhibitors (AGIs) hinder digestion of complex carbohydrates and therefore alleviate postprandial glycemic excursions. In this study, we tested the hypothesis that

Donatella M. Casirola; Ronaldo P. Ferraris

2006-01-01

173

[Alveolar surfactant and experimental diabetes (protective action of citicoline)].  

PubMed

Above normal or normal S.R. values (0,70-0,90) (S.R. = 0,81 +/- 0,11), were noted in 13 alloxaneinduced diabetic rabbits treated with CDP-choline, and decreased values (S.R. = 0,57 +/- 0,06) in 9 diabetic rabbits not so treated. This difference was statistically significant (P less than 0,001). The results show that CDP-choline can protect surfactant from damage caused by alloxane-induced diabetes. The most likely explanation is increased synthesis of dipalmitoyllecithin, by intervention of CDP-choline, as cofactor, on lipid metabolism in the lung. PMID:581158

Iozzo, A; Cardellino, G; Dalmasso, F; Garbagni, R

1978-01-01

174

Dexamethasone induction of hypertension and diabetes is PPAR-? dependent in LDL receptor–null mice  

Microsoft Academic Search

Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator–activated receptor-? (PPAR-?) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr?\\/?), with (Ppara+\\/+) or without (Ppara?\\/?) PPAR-?, were treated chronically with dexamethasone. Ppara+\\/+, but not Ppara?\\/?, mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using

Carlos Bernal-Mizrachi; Sherry Weng; Chu Feng; Brian N Finck; Russell H Knutsen; Teresa C Leone; Trey Coleman; Robert P Mecham; Daniel P Kelly; Clay F Semenkovich

2003-01-01

175

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. PMID:22016649

Li, Fenglin; Zhang, Yiming; Zhong, Zhijian

2011-01-01

176

T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice.  

PubMed

Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants. PMID:9221759

Pakala, S V; Kurrer, M O; Katz, J D

1997-07-21

177

Exercise Increases Insulin Content and Basal Secretion in Pancreatic Islets in Type 1 Diabetic Mice  

PubMed Central

Exercise appears to improve glycemic control for people with type 1 diabetes (T1D). However, the mechanism responsible for this improvement is unknown. We hypothesized that exercise has a direct effect on the insulin-producing islets. Eight-week-old mice were divided into four groups: sedentary diabetic, exercised diabetic, sedentary control, and exercised control. The exercised groups participated in voluntary wheel running for 6 weeks. When compared to the control groups, the islet density, islet diameter, and ?-cell proportion per islet were significantly lower in both sedentary and exercised diabetic groups and these alterations were not improved with exercise. The total insulin content and insulin secretion were significantly lower in sedentary diabetics compared to controls. Exercise significantly improved insulin content and insulin secretion in islets in basal conditions. Thus, some improvements in exercise-induced glycemic control in T1D mice may be due to enhancement of insulin content and secretion in islets. PMID:21912535

Huang, Han-Hung; Farmer, Kevin; Windscheffel, Jill; Yost, Katie; Power, Mary; Wright, Douglas E.; Stehno-Bittel, Lisa

2011-01-01

178

Cellular requirements for diabetes induction in DO11.10xRIPmOVA mice.  

PubMed

Type 1 diabetes (T1D) results from the immune-mediated destruction of the insulin-producing ?-islet cells in the pancreas. The genetic and environmental mechanisms promoting the development of this disease remain poorly understood. We have explored the cellular requirements for T1D development in DO11.10xRIPmOVA (DORmO) mice, which carry a TCR transgene specific for an MHC class II-restricted epitope from OVA and express membrane-bound OVA in the pancreas under the control of the rat insulin promoter. We found that DORmO.RAG2(-/-) mice do not develop insulitis and are completely protected from diabetes, demonstrating that endogenous lymphocyte receptor rearrangement is required for disease development. Diabetes in DORmO mice is preceded by the development of OVA-specific autoantibodies and is delayed in B cell-deficient DORmO.JhD(-/-) mice, demonstrating that B cells contribute to disease progression. In addition, transfer of CD8(+) T cells from diabetic animals into DORmO.RAG2(-/-) mice promoted insulitis by OVA-specific CD4(+) T cells. Finally, although diabetes develops in DORmO mice in the presence of a significant population of Foxp3(+) OVA-specific regulatory T cells, boosting regulatory T cell numbers by injecting IL-2 immune complexes dampens autoantibody production and prevents development of insulitis and overt diabetes. These results help define the events leading to diabetes in DORmO mice and provide new insights into the cellular interactions required for disease development in an Ag-specific model of T1D. PMID:20855871

Wesley, Johnna D; Sather, Blythe D; Perdue, Nikole R; Ziegler, Steven F; Campbell, Daniel J

2010-10-15

179

Cellular requirements for diabetes induction in DO11.10xRIPmOVA mice1  

PubMed Central

Type 1 Diabetes (T1D3) results from the immune-mediated destruction of the insulin producing ?-islet cells in the pancreas. The genetic and environmental mechanisms promoting the development of this disease remain poorly understood. We have explored the cellular requirements for T1D development in DO11.10xRIP-OVA (DORmO) mice, which carry a T cell receptor transgene specific for an MHC class II-restricted epitope from ovalbumin (OVA) and express membrane-bound OVA in the pancreas under the control of the rat insulin promoter. We found that DORmO.RAG2?/? mice do not develop insulitis and are completely protected from diabetes, demonstrating that endogenous lymphocyte receptor rearrangement is required for disease development. Diabetes in DORmO mice is preceded by the development of OVA-specific autoantibodies, and is delayed in B cell-deficient DORmO.JHD?/? mice, demonstrating that B cells contribute to disease progression. In addition, transfer of CD8+ T cells from diabetic animals into DORmO.RAG2?/? mice promoted insulitis by OVA-specific CD4+ T cells. Finally, although diabetes develops in DORmO mice in the presence of a significant population of Foxp3+ OVA-specific regulatory T cells, boosting regulatory T cell numbers by injecting IL-2 immune complexes dampens autoantibody production and prevents development of insulitis and overt diabetes. These results help define the events leading to diabetes in DORmO mice, and provide new insights into the cellular interactions required for disease development in an antigen-specific model of T1D. PMID:20855871

Wesley, Johnna D.; Sather, Blythe D.; Perdue, Nikole; Ziegler, Steven; Campbell, Daniel J.

2011-01-01

180

Anti-diabetic activity of cassava cross-linked octenyl succinic maltodextrin in STZ-induced diabetic mice.  

PubMed

The effect of cassava cross-linked octenyl succinic maltodextrin (CCOMD) on diabetic mice was investigated in this study. For CCOMD-L (low dose) and CCOMD-H (high dose) groups, the body weights were recovered by 14.9% and 18.5%, respectively, which were significantly higher than that of model control group. It was also found that the blood glucose and insulin levels were ameliorated in the diabetic mice by the CCOMD diet. Moreover, the CCOMD diet decreased the plasma total cholesterol level (8.1-9.1%) and LDL cholesterol level (28.9-39.4%), and improved the plasma HDL cholesterol level (13.8-15.3%) and intestine short chain fatty acid content. The results indicated that CCOMD administration may be helpful for treating and preventing hyperlipidemia and hyperglycemia in diabetes. PMID:24296405

Wang, Li; Zheng, Maoqiang; Wang, Yingyao; Zhang, Ying; Qian, Haifeng; Zhang, Hui; Qi, Xiguang

2014-03-01

181

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

182

Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes  

PubMed Central

Mice deficient in programmed cell death 1 (PD-1, Pdcd1), an immunoinhibitory receptor belonging to the CD28/cytotoxic T lymphocyte-associated antigen-4 family, spontaneously develop lupus-like autoimmune disease and autoimmune dilated cardiomyopathy on C57BL/6 and BALB/c backgrounds, respectively. However, how PD-1 deficiency induces different forms of autoimmune diseases on these two strains was unknown. Here, we report that PD-1 deficiency specifically accelerates the onset and frequency of type I diabetes in NOD (nonobese diabetic) mice, with strong T helper 1 polarization of T cells infiltrating into islets. These results suggest that PD-1 deficiency accelerates autoimmune predisposition of the background strain, leading to the induction of different forms of autoimmune diseases depending on the genetic background of the strain. Using NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes, we screened diabetes-susceptible loci by genetic linkage analysis. The diabetic incidence of NOD-Pdcd1-/- mice was controlled by five genetic loci, including three known recessive loci [Idd (insulin-dependent diabetes) 1, Idd17, and Idd20] and two previously unidentified dominant loci [Iddp (Idd under PD-1 deficiency) 1 and Iddp2]. PMID:16087865

Wang, Jian; Yoshida, Taku; Nakaki, Fumio; Hiai, Hiroshi; Okazaki, Taku; Honjo, Tasuku

2005-01-01

183

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. PMID:22187379

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

2012-01-01

184

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 30 min. 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

185

Protective effect of berberine on serum glucose levels in non-obese diabetic mice.  

PubMed

Among the active components in traditional anti-diabetic herbal plants, berberine which is an isoquinoline alkaloid exhibits promising potential for its potent anti-inflammatory and hypoglycemic effects. However, the berberine effect on serum glucose levels in type 1 diabetes (T1D) subjects still remains unknown. This study investigated berberine's effects on serum glucose levels using non-obese diabetic (NOD) mice that spontaneously develop T1D. The NOD mice were randomly divided into four groups, administered water with 50, 150, and 500 mg berberine/kg bw, respectively, through 14 weeks. ICR mice were also selected as a species control group to compare with the NOD mice. Changes in body weight, oral glucose challenge, and serum glucose levels were determined to identify the protective effect of berberine on T1D. After the 14-week oral supplementation, berberine decreased fasting serum glucose levels in NOD mice close to the levels in normal ICR mice in a dose dependent manner. Serum berberine levels showed a significantly (P<0.05) negative and non-linear correlation with fasting glucose levels in berberine-administered NOD mice. Our results suggested that berberine supplemented at appropriate doses for 14 weeks did not cause toxic side effects, but improved hyperglycemia in NOD mice. PMID:22266065

Chueh, Wei-Han; Lin, Jin-Yuarn

2012-03-01

186

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. PMID:10727441

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

2000-01-01

187

TRAIL Deficiency Contributes to Diabetic Nephropathy in Fat-Fed ApoE-/- Mice  

PubMed Central

Background We recently demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is protective of diet-induced diabetes in mice. While TRAIL has been implicated in chronic kidney disease, its role in vivo in diabetic nephropathy is not clear. The present study investigated the role of TRAIL in the pathogenesis of diabetic nephropathy using TRAIL-/-ApoE-/- mice. Methods TRAIL-/-ApoE-/- and ApoE-/- mice were fed a high fat diet for 20 w. Plasma glucose and insulin levels were assessed over 0, 5, 8 and 20 w. At 20 w, markers of kidney function including creatinine, phosphate, calcium and cystatin C were measured. Changes in mRNA expression of MMPs, TIMP-1, IL-1? and IL-18 were assessed in the kidney. Functional and histological changes in kidneys were examined. Glucose and insulin tolerance tests were performed. Results TRAIL-/-ApoE-/- mice had significantly increased urine protein, urine protein:creatinine ratio, plasma phosphorous, and plasma cystatin C, with accelerated nephropathy. Histologically, increased extracellular matrix, mesangial expansion and mesangial cell proliferation in the glomeruli were observed. Moreover, TRAIL-/-ApoE-/- kidneys displayed loss of the brush border and disorganisation of tubular epithelium, with increased fibrosis. TRAIL-deficient kidneys also had increased expression of MMPs, TIMP-1, PAI-1, IL-1? and IL-18, markers of renal injury and inflammation. Compared with ApoE-/- mice, TRAIL-/-ApoE-/- mice displayed insulin resistance and type-2 diabetic features with reduced renal insulin-receptor expression. Conclusions Here, we show that TRAIL-deficiency in ApoE-/- mice exacerbates nephropathy and insulin resistance. Understanding TRAIL signalling in kidney disease and diabetes, may therefore lead to novel strategies for the treatment of diabetic nephropathy. PMID:24667560

Cartland, Sian P.; Erlich, Jonathan H.; Kavurma, Mary M.

2014-01-01

188

Plasminogen Activator Inhibitor-1 Is Involved in Impaired Bone Repair Associated with Diabetes in Female Mice  

PubMed Central

Previous studies suggest that fracture healing is impaired in diabetes; however, the underlying mechanism remains unclear. Here, we investigated the roles of plasminogen activator inhibitor-1 (PAI-1) in the impaired bone repair process by using streptozotocin (STZ)-induced diabetic female wild-type (PAI-1+/+) and PAI-1-deficient (PAI-1?/?) mice. Bone repair and the number of alkaline phosphatase (ALP)-positive cells at the site of a femoral bone damage were comparable in PAI-1+/+ and PAI-1?/? mice without STZ treatment. Although the bone repair process was delayed by STZ treatment in PAI-1+/+ mice, this delayed bone repair was blunted in PAI-1?/? mice. The reduction in the number of ALP-positive cells at the site of bone damage induced by STZ treatment was attenuated in PAI-1?/? mice compared to PAI-1+/+ mice. On the other hand, PAI-1 deficiency increased the levels of ALP and type I collagen mRNA in female mice with or without STZ treatment, and the levels of Osterix and osteocalcin mRNA, suppressed by diabetic state in PAI-1+/+ mice, were partially protected in PAI-1?/? mice. PAI-1 deficiency did not affect formation of the cartilage matrix and the levels of types II and X collagen and aggrecan mRNA suppressed by STZ treatment, although PAI-1 deficiency increased the expression of chondrogenic markers in mice without STZ treatment. The present study indicates that PAI-1 is involved in the impaired bone repair process induced by the diabetic state in part through a decrease in the number of ALP-positive cells. PMID:24651693

Mao, Li; Kawao, Naoyuki; Tamura, Yukinori; Okumoto, Katsumi; Okada, Kiyotaka; Yano, Masato; Matsuo, Osamu; Kaji, Hiroshi

2014-01-01

189

Neurobehavioral deficits in db\\/db diabetic mice  

Microsoft Academic Search

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.

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

2010-01-01

190

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. PMID:24865768

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

2014-01-01

191

Hyperglycaemia, stress oxidant, liver dysfunction and histological changes in diabetic male rat pancreas and liver: Protective effect of 17?-estradiol  

Microsoft Academic Search

Oxidative stress is thought to play a crucial role in the pathogenesis of chronic diabetic complications. We investigated the protective effects of 17?-estradiol (E2) on alloxan-induced stress oxidant, hepatic dysfunction and histological changes in male rats liver and pancreas. Our results showed that17?-estradiol could attenuate the increase of blood glucose in plasma and normalise the hepatic glycogen level. In addition,

Khaled Hamden; Serge Carreau; Mohamed Ali Boujbiha; Samiha Lajmi; Dorra Aloulou; Dalanda Kchaou; Abdelfattah Elfeki

2008-01-01

192

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. PMID:24471057

Lee, Chae-Won; Han, Ji-Sook

2012-01-01

193

Involvement of delta1-opioid receptors in the spatial learning impairment in streptozotocin-induced diabetic mice.  

PubMed

It is well accepted that diabetes leads to learning and memory impairment in humans and rodents. Because central delta-opioid receptors have important roles in learning processes, we investigated the involvement of delta-opioid receptors in the spatial learning impairment in streptozotocin (STZ)-induced diabetic mice by the Morris water maze test. The escape latencies to the platform were significantly increased in diabetic mice without changes in the ability to swim. The delta1/delta2-opioid receptor antagonist naltrindole (1 mg/kg/day, s.c.) slightly, but not significantly, reduced the escape latencies in diabetic mice. The selective delta1-opioid receptor antagonist 7-benzylidenenaltrexone (0.3 and 1 mg/kg/day, s.c.), but not the selective delta2-opioid receptor antagonist naltriben (0.3 and 1 mg/kg/day, s.c.), significantly reduced the escape latencies in diabetic mice. These antagonists had no effect on the escape latencies in non-diabetic mice. The selective delta1-opioid receptor agonist [D-Pen2, D-Pen5]-enkephalin (10 nmol/mouse/day, i.c.v.) significantly increased the escape latencies in both non-diabetic and diabetic mice. Based on these results, we suggest that the enhanced response to central delta1-opioid receptors in diabetic mice is involved, at least in part, in the spatial learning impairment in the Morris water maze test. PMID:16313098

Kamei, Junzo; Miyata, Shigeo; Takahashi, Masashi; Saitoh, Akiyoshi

2005-10-01

194

Pivotal role of oxidative stress in tumor metastasis under diabetic conditions in mice.  

PubMed

Diabetic patients are reported to have a high incidence and mortality of cancer, but little is known about the linkage. In this study, we investigated whether high oxidative stress is involved in the acceleration of tumor metastasis in diabetic mice. Murine melanoma B16-BL6 cells stably labeled with firefly luciferase (B16-BL6/Luc) were inoculated into the tail vein of streptozotocin (STZ)-treated or untreated mice. A luciferase assay demonstrated that tumor cells were present largely in the lung of untreated mice, whereas large numbers of tumor cells were detected in both the lung and liver of STZ-treated mice. Repeated injections of polyethylene glycol-conjugated catalase (PEG-catalase), a long-circulating derivative, reduced the elevated fasting blood glucose levels and plasma lipoperoxide levels of STZ-treated mice, but had no significant effects on these parameters in untreated mice. In addition, the injections significantly reduced the number of tumor cells in the lung and liver in both untreated and STZ-treated mice. Culture of B16-BL6/Luc cells in medium containing over 45 mg/dl glucose hardly affected the proliferation of the cells, whereas the addition of plasma of STZ-treated mice to the medium significantly increased the number of cells. Plasma samples of STZ-treated mice receiving PEG-catalase exhibited no such effect on proliferation. These findings indicate that a hyperglycemia-induced increase in oxidative stress is involved in the acceleration of tumor metastasis, and the removal of systemic hydrogen peroxide by PEG-catalase can inhibit the progression of diabetic conditions and tumor metastasis in diabetes. PMID:23735571

Ikemura, Mai; Nishikawa, Makiya; Kusamori, Kosuke; Fukuoka, Miho; Yamashita, Fumiyoshi; Hashida, Mitsuru

2013-09-10

195

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. PMID:24146535

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

2013-01-01

196

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

197

Possible involvement of spinal protein kinase C in thermal allodynia and hyperalgesia in diabetic mice  

Microsoft Academic Search

We examined the tail-flick response to various heat intensities in diabetic and non-diabetic mice. Heat intensities were set to one of five values by adjusting the source voltage of a 50-W projection bulb to 25, 35, 50, 65 and 80 V. These heat intensities produced surface skin heating rates of 0.1, 0.4, 0.9, 3.0 and 7.3°C\\/s, respectively. Tail-flick latencies at

Masahiro Ohsawa; Junzo Kamei

1999-01-01

198

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

199

Global Renal Gene Expression Profiling Analysis in B2-Kinin Receptor Null Mice: Impact of Diabetes  

PubMed Central

Diabetic nephropathy (DN), the leading cause of end-stage renal failure, is clinically manifested by albuminuria and a progressive decline in glomerular filtration rate. The risk factors and mechanisms that contribute to the development and progression of DN are still incompletely defined. To address the involvement of bradykinin B2-receptors (B2R) in DN, we used a genome wide approach to study the effects of diabetes on differential renal gene expression profile in wild type and B2R knockout (B2R?/?) mice. Diabetes was induced with streptozotocin and plasma glucose levels and albumin excretion rate (AER) were measured at predetermined times throughout the 23 week study period. Longitudinal analysis of AER indicated that diabetic B2R?/?D null mice had a significantly decreased AER levels compared to wild type B2R+/+D mice (P?=?0.0005). Results from the global microarray study comparing gene expression profiles among four groups of mice respectively: (B2R+/+C, B2R+/+D, B2R?/?C and B2R?/?D) highlighted the role of several altered pathological pathways in response to disruption of B2R and to the diabetic state that included: endothelial injury, oxidative stress, insulin and lipid metabolism and inflammatory process with a marked alteration in the pro-apoptotic genes. The findings of the present study provide a global genomics view of biomarkers that highlight the mechanisms and putative pathways involved in DN. PMID:23028588

Jaffa, Miran A.; Kobeissy, Firas; Al Hariri, Moustafa; Chalhoub, Hussein; Eid, Assaad; Ziyadeh, Fuad N.; Jaffa, Ayad A.

2012-01-01

200

Accelerated type 1 diabetes induction in mice by adoptive transfer of diabetogenic CD4+ T cells.  

PubMed

The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes after 12 weeks of age and is the most extensively studied animal model of human Type 1 diabetes (T1D). Cell transfer studies in irradiated recipient mice have established that T cells are pivotal in T1D pathogenesis in this model. We describe herein a simple method to rapidly induce T1D by adoptive transfer of purified, primary CD4+ T cells from pre-diabetic NOD mice transgenic for the islet-specific T cell receptor (TCR) BDC2.5 into NOD.SCID recipient mice. The major advantages of this technique are that isolation and adoptive transfer of diabetogenic T cells can be completed within the same day, irradiation of the recipients is not required, and a high incidence of T1D is elicited within 2 weeks after T cell transfer. Thus, studies of pathogenesis and therapeutic interventions in T1D can proceed at a faster rate than with methods that rely on heterogenous T cell populations or clones derived from diabetic NOD mice. PMID:23685789

Berry, Gregory; Waldner, Hanspeter

2013-01-01

201

Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease  

PubMed Central

IGF-1 has been associated with the pathogenesis of diabetic retinopathy, although its role is not fully understood. Here we show that normoglycemic/normoinsulinemic transgenic mice overexpressing IGF-1 in the retina developed most alterations seen in human diabetic eye disease. A paracrine effect of IGF-1 in the retina initiated vascular alterations that progressed from nonproliferative to proliferative retinopathy and retinal detachment. Eyes from 2-month-old transgenic mice showed loss of pericytes and thickening of basement membrane of retinal capillaries. In mice 6 months and older, venule dilatation, intraretinal microvascular abnormalities, and neovascularization of the retina and vitreous cavity were observed. Neovascularization was consistent with increased IGF-1 induction of VEGF expression in retinal glial cells. In addition, IGF-1 accumulated in aqueous humor, which may have caused rubeosis iridis and subsequently adhesions between the cornea and iris that hampered aqueous humor drainage and led to neovascular glaucoma. Furthermore, all transgenic mice developed cataracts. These findings suggest a role of IGF-1 in the development of ocular complications in long-term diabetes. Thus, these transgenic mice may be used to study the mechanisms that lead to diabetes eye disease and constitute an appropriate model in which to assay new therapies. PMID:15085194

Ruberte, Jesus; Ayuso, Eduard; Navarro, Marc; Carretero, Ana; Nacher, Victor; Haurigot, Virginia; George, Monica; Llombart, Cristina; Casellas, Alba; Costa, Cristina; Bosch, Assumpcio; Bosch, Fatima

2004-01-01

202

TLR9 deficiency promotes CD73 expression in T cells and diabetes protection in NOD mice  

PubMed Central

TLR9-/-NOD mice develop a significantly reduced incidence of diabetes. This study was to investigate the molecular mechanisms of the protective role of TLR9 deficiency. Through gene screening and confirmation by both mRNA and protein expression, we found a significant increase in CD73-expressing immune cells from peripheral lymphoid tissues in TLR9-/-NOD mice. The elevated frequency of CD73-expressing immune cells seemed to be specific for TLR9 deficiency and was MyD88-independent. Moreover, the increased frequency of CD73 expression was limited to the NOD background. Increased frequency of CD73 expression was also associated with lower levels of pro-inflammatory cytokines and more anti-inflammatory cytokine production in CD4+ T cells in TLR9-/-NOD mice. Purified CD73+CD4+ T cells showed stronger immunosuppressive function in vitro and delayed diabetes development in vivo. The immunosuppression appeared to be mediated by TGF?. In addition, elevated frequency of CD73 expressing cells was associated with improved ? cell function. Our observations were further confirmed by protection from diabetes with similar alterations in CD73 in the NY8.3 T cell receptor (TCR) NOD mouse model crossed with TLR9 deficient mice and by the use of a TLR9 inhibitor in NOD mice. Our novel findings suggest an important immune regulatory role of CD73 in regulation of diabetes development and may offer a new therapeutic strategy for specific intervention to prevent T1D. PMID:23956420

Tai, Ningwen; Wong, F. Susan; Wen, Li

2013-01-01

203

CHARACTERIZATION & TREATMENT OF LARGE SENSORY FIBER PERIPHERAL NEUROPATHY IN DIABETIC MICE  

E-print Network

M (~288 mg/dl), and STZ-injected mice with blood glucose levels below the standard were not included in this study. Weight and tail vein blood glucose levels were measured using glucose diagnostic reagents (Sigma) throughout the protocol and analyzed... to alterations in muscle spindle innervation. Behavioral assessments were carried out in streptozotocin (STZ)-injected C57BL/6 mice to quantitate diabetes-induced deficits in balance and gait. Nerve conduction velocities were measured to better understand...

Muller, Karra

2008-11-17

204

Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob\\/ ob mice  

Microsoft Academic Search

Nobiletin is a polymethoxylated flavone found in certain citrus fruits that exhibits various pharmacological effects including anti-inflammatory, antitumor and neuroprotective properties. The present study investigated the effects of nobiletin on insulin sensitivity in obese diabetic ob\\/ob mice, and the possible mechanisms involved. The ob\\/ob mice were treated with nobiletin (200mg\\/kg) for 5 weeks. Nobiletin significantly improved the plasma glucose levels,

Young-Sil Lee; Byung-Yoon Cha; Kiyoto Saito; Hiroshi Yamakawa; Sun-Sil Choi; Kohji Yamaguchi; Takayuki Yonezawa; Toshiaki Teruya; Kazuo Nagai; Je-Tae Woo

2010-01-01

205

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. PMID:24897298

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

2014-01-01

206

Vasopeptidase Inhibitor Ilepatril (AVE7688) Prevents Obesity- and Diabetes-induced Neuropathy in C57Bl/6J Mice  

PubMed Central

Previously we demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, and angiotensin converting enzyme (ACE) with a vasopeptidase inhibitor improves vascular and neural function in diabetic rat models. The purpose of this study was to determine whether inhibition of NEP and ACE or deletion of NEP provides protection from nerve impairment caused by diabetes or diet induced obesity (DIO). To determine the role of NEP and ACE inhibition in neuropathy related to insulin-deficient diabetes or DIO we used C57Bl/6J mice treated with AVE7688, a vasopeptidase inhibitor, or NEP deficient (?/?) mice. Mice at 12 weeks of age were fed a high fat diet for 12 weeks or were diabetic for duration of 12 weeks following a single injection of high dose streptozotocin. Both a prevention and intervention protocol was used for AVE7688 treatment. Glucose utilization was impaired in DIO C57Bl/6J and NEP ?/? mice. However, treating DIO C57Bl/6J or NEP ?/? mice with AVE7688 improved glucose tolerance. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and DIO C57Bl/6J mice but not in AVE7688 treated C57Bl/6J mice or NEP ?/? mice exposed to either streptozotocin-induced diabetes or a high fat diet. Intraepidermal nerve fiber (IENF) profiles were decreased in the hindpaw of C57Bl/6J diabetic or DIO mice and this improved when the mice were treated with AVE7688. IENF profiles were not decreased in diabetic or DIO NEP (?/?) mice. These studies suggest that NEP plays a role in regulating nerve function in insulin-deficient diabetes and DIO. PMID:20849865

Coppey, Lawrence; Davidson, Eric; Lu, Bao; Gerard, Craig; Yorek, Mark

2010-01-01

207

Vasopeptidase inhibitor ilepatril (AVE7688) prevents obesity- and diabetes-induced neuropathy in C57Bl/6J mice.  

PubMed

Previously we demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, and angiotensin converting enzyme (ACE) with a vasopeptidase inhibitor improves vascular and neural function in diabetic rat models. The purpose of this study was to determine whether inhibition of NEP and ACE or deletion of NEP provides protection from nerve impairment caused by diabetes or diet induced obesity (DIO). To determine the role of NEP and ACE inhibition in neuropathy related to insulin-deficient diabetes or DIO we used C57Bl/6J mice treated with AVE7688, a vasopeptidase inhibitor, or NEP deficient (-/-) mice. Mice at 12 weeks of age were fed a high fat diet for 12 weeks or were diabetic for duration of 12 weeks following a single injection of high dose streptozotocin. Both a prevention and intervention protocol was used for AVE7688 treatment. Glucose utilization was impaired in DIO C57Bl/6J and NEP -/- mice. However, treating DIO C57Bl/6J or NEP -/- mice with AVE7688 improved glucose tolerance. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and DIO C57Bl/6J mice but not in AVE7688 treated C57Bl/6J mice or NEP -/- mice exposed to either streptozotocin-induced diabetes or a high fat diet. Intraepidermal nerve fiber (IENF) profiles were decreased in the hindpaw of C57Bl/6J diabetic or DIO mice and this improved when the mice were treated with AVE7688. IENF profiles were not decreased in diabetic or DIO NEP (-/-) mice. These studies suggest that NEP plays a role in regulating nerve function in insulin-deficient diabetes and DIO. PMID:20849865

Coppey, Lawrence; Davidson, Eric; Lu, Bao; Gerard, Craig; Yorek, Mark

2011-01-01

208

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. PMID:24255674

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

2013-01-01

209

Mesenchymal stem cells facilitate mixed hematopoietic chimerism induction and prevent onset of diabetes in NOD mice  

PubMed Central

Objectives Allogeneic mesenchymal stem cells (MSCs) and bone marrow cells (BMCs) were co-transplanted in NOD mice following none myeloablative preconditioning and the development of chimerism, insulitis, diabetes, and graft versus host disease (GVHD) were monitored. Methods Eight-weeks-old female NOD mice were injected intravenously with 2×107 BMCs and 5×105 MSCs from C57BL/6 mice following treatment with 2 intraperitoneal injections of anti-CD3 antibody (days ?7 and ?4), and 3Gy total body irradiation (day ?1). Thereafter, blood glucose and chimerism were monitored on peripheral blood samples. Results Stable mixed chimerism (3->90% of donor phenotype) was induced in 63.2% of BMCs-MSCs-(n=19) and 45.0% of BMCs alone recipients (n=20, p=0.256). Insulitis was prevented and euglycemia persisted for >18 weeks in 89.5% of BMCs-MSCs recipients including those with <3% chimerism and 55% of BM alone recipients (p<0.05). In controls, 9.1% of mice receiving preconditioning treatment alone (n=11) and 16.7% of preconditioned mice receiving only MSCs (n=12) were non-diabetic. GVHD was not detected in all mice. Conclusion Co-injection of MSCs and BMCs increased the success rate in inducing chimerism and preventing insulitis and overt diabetes with no incidence of GVHD. Results also indicated that even micro-chimerism with <3% donor cells is sufficient for blocking autoimmunity. PMID:21562444

Asari, Sadaki; Itakura, Shin; Rawson, Jeffrey; Ito, Taihei; Todorov, Ivan; Nair, Indu; Shintaku, Jonathan; Liu, Chih-Pin; Kandeel, Fouad; Mullen, Yoko

2011-01-01

210

Hypoglycemic effect of extracts from Lagerstroemia speciosa L. leaves in genetically diabetic KK-AY mice.  

PubMed

The hypoglycemic effects of Lagerstroemia speciosa L., known by the Tagalog name of banaba in the Phillipines, were studied using hereditary diabetic mice (Type II, KK-AY/Ta Jcl). The mice were fed a test diet containing 5% of the hot-water extract (HWE) from banaba leaves, 3% of the water eluent of the partial fraction unadsorbed onto HP-20 resin of HWE (HPWE), and 2% of the methanol eluent of the partial fraction adsorbed onto HP-20 resin of it (HPME) for a feeding period of 5 weeks. The elevation of blood plasma glucose level in non-insulin dependent diabetic mice fed the cellulose as control (CEL) diet were almost entirely suppressed by addition of either HWE or HPME in place of cellulose in the CEL diet. Water intakes were inclined to increase gradually in the group fed either CEL or HPWE, but lower in the mice fed either HWE or HPME than in the animals given either CEL or HPME. The level of serum insulin and the amount of urinary excreted glucose were also lowered in mice fed HWE. Plasma total cholesterol level was also lowered in mice fed the either HWE or HPME. It is suggested that HWE, especially HPME, obtained from banaba leaves have beneficial effects on control of the level of plasma glucose in non-insulin dependent diabetes mellitus. PMID:9063966

Kakuda, T; Sakane, I; Takihara, T; Ozaki, Y; Takeuchi, H; Kuroyanagi, M

1996-02-01

211

Ursolic Acid Protects Diabetic Mice Against Monocyte Dysfunction and Accelerated Atherosclerosis  

PubMed Central

Aims Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis. Methods and Results Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1high monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively-stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3 – 10 ?M) for 15 h resulted in the dose-dependent inhibition of H2O2-accelerated chemotaxis in response to MCP-1, but with an IC50 of 0.4 ?M, UA was 2.7-fold more potent than RES. Conclusion Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid. PMID:21752377

Ullevig, Sarah L.; Zhao, Qingwei; Zamora, Debora; Asmis, Reto

2011-01-01

212

Reduced volume-regulated outwardly rectifying anion channel activity in ventricular myocyte of type 1 diabetic mice  

Microsoft Academic Search

The currents through the volume-regulated outwardly rectifying anion channel (VRAC) were measured in single ventricular myocytes\\u000a obtained from streptozotocin (STZ)-induced diabetic mice, using whole-cell voltage-clamp method. In myocytes from STZ-diabetic\\u000a mice, the density of VRAC current induced by hypotonic perfusion was markedly reduced, compared with that in the cells form\\u000a normal control mice. Video-image analysis showed that the regulatory volume

Shintaro Yamamoto; Kunihiko Ichishima; Tsuguhisa Ehara

2009-01-01

213

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. PMID:24023581

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

2013-01-01

214

Abnormal splicing of the leptin receptor in diabetic mice  

Microsoft Academic Search

MUTATIONS in the mouse diabetes(db) gene result in obesity and diabetes in a syndrome resembling morbid human obesity1. Previous data suggest that the db gene encodes the receptor for the obese(ob) gene product, leptin2-7. A leptin receptor was recently cloned from choroid plexus and shown to map to the same 6-cM interval on mouse chromosome 4 as db8. This receptor

Gwo-Hwa Lee; R. Proenca; J. M. Montez; K. M. Carroll; J. G. Darvishzadeh; J. I. Lee; J. M. Friedman

1996-01-01

215

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. PMID:19208913

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

216

Hypertension and disrupted blood pressure circadian rhythm in type 2 diabetic db/db mice.  

PubMed

Human Type 2 diabetes is associated with increased incidence of hypertension and disrupted blood pressure (BP) circadian rhythm. Db/db mice have been used extensively as a model of Type 2 diabetes, but their BP is not well characterized. In this study, we used radiotelemetry to define BP and the circadian rhythm in db/db mice. We found that the systolic, diastolic, and mean arterial pressures were each significantly increased by 11, 8, and 9 mmHg in db/db mice compared with controls. In contrast, no difference was observed in pulse pressure or heart rate. Interestingly, both the length of time db/db mice were active (locomotor) and the intensity of locomotor activity were significantly decreased in db/db mice. In contrast to controls, the 12-h light period average BP in db/db mice did not dip significantly from the 12-h dark period. A partial Fourier analysis of the continuous 72-h BP data revealed that the power and the amplitude of the 24-h period length rhythm were significantly decreased in db/db mice compared with the controls. The acrophase was centered at 0141 in control mice, but became scattered from 1805 to 0236 in db/db mice. In addition to BP, the circadian rhythms of heart rate and locomotor activity were also disrupted in db/db mice. The mean arterial pressure during the light period correlates with plasma glucose, insulin, and body weight. Moreover, the oscillations of the clock genes DBP and Bmal1 but not Per1 were significantly dampened in db/db mouse aorta compared with controls. In summary, our data show that db/db mice are hypertensive with a disrupted BP, heart rate, and locomotor circadian rhythm. Such changes are associated with dampened oscillations of clock genes DBP and Bmal1 in vasculature. PMID:18708447

Su, Wen; Guo, Zhenheng; Randall, David C; Cassis, Lisa; Brown, David R; Gong, Ming C

2008-10-01

217

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...

218

The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice  

PubMed Central

The spontaneous destruction of insulin producing pancreatic beta cells in non-obese diabetic (NOD) mice provides a valuable model of type 1 diabetes. As in humans, disease susceptibility is controlled by the classical MHC class II genes that guide CD4+ T cell responses to self and foreign antigens. It has long been suspected that the dedicated class II chaperone designated HLA-DM in humans or H-2M in mice also makes an important contribution, but due to tight linkage within the MHC, a possible role played by DM peptide editing has not been previously tested by conventional genetic approaches. Here we exploited newly established germ-line competent NOD ES cells to engineer a loss of function allele. DM deficient NOD mice display defective class II peptide occupancy and surface expression, and are completely protected against type 1 diabetes. Interestingly the mutation results in increased proportional representation of CD4+Foxp3+ regulatory T cells and the absence of pathogenic CD4+ T effectors. Overall, this striking phenotype establishes that DM-mediated peptide selection plays an essential role in the development of autoimmune diabetes in NOD mice. PMID:23418596

Morgan, Marc A. J.; Muller, Pari S. S.; Mould, Arne; Newland, Stephen A.; Nichols, Jennifer; Robertson, Elizabeth J.; Cooke, Anne; Bikoff, Elizabeth K.

2013-01-01

219

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. PMID:24069457

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

2013-01-01

220

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. PMID:24400007

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

221

Proteome wide reduction in AGE modification in streptozotocin induced diabetic mice by hydralazine mediated transglycation  

PubMed Central

The non-enzymatic reaction between glucose and protein can be chemically reversed by transglycation. Here we report the transglycation activity of hydralazine using a newly developed MALDI-TOF-MS based assay. Hydralazine mediated transglycation of HbA1c, plasma proteins and kidney proteins was demonstrated in streptozotocin (STZ) induced diabetic mice, as evidenced by decrease in protein glycation, as well as presence of hydralazine-glucose conjugate in urine of diabetic mice treated with hydralazine. Hydralazine down regulated the expression of Receptor for Advanced Glycation End products (RAGE), NADPH oxidase (NOX), and super oxide dismutase (SOD). These findings will provide a new dimension for developing intervention strategies for the treatment of glycation associated diseases such as diabetes complications, atherosclerosis, and aging. PMID:24126953

Kesavan, Suresh K.; Bhat, Shweta; Golegaonkar, Sandeep B.; Jagadeeshaprasad, Mashanipalya G.; Deshmukh, Arati B.; Patil, Harshal S.; Bhosale, Santosh D.; Shaikh, Mahemud L.; Thulasiram, Hirekodathakallu V.; Boppana, Ramanamurthy; Kulkarni, Mahesh J.

2013-01-01

222

Ingested interferon ? suppresses Type I diabetes in non-obese diabetic mice  

Microsoft Academic Search

Summary   Type I diabetes mellitus is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic\\u000a beta cell. The non- obese diabetic mouse is a model of the human autoimmune disease Type I diabetes [1–3]. We have previously\\u000a shown that ingested type 1 interferon inhibits chronic relapsing experimental autoimmune encephalomyelitis and the adoptive\\u000a transfer of experimental autoimmune encephalomyelites

S. A. Brod; M. Malone; S. Darcan; M. Papolla; L. Nelson

1998-01-01

223

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. PMID:22474494

Zhou, Ji-Yin; Zhou, Shi-Wen; Zeng, Sheng-Ya; Zhou, Jian-Yun; Jiang, Ming-Jin; He, Yan

2012-01-01

224

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. PMID:20630072

2010-01-01

225

Rapamycin promotes podocyte autophagy and ameliorates renal injury in diabetic mice.  

PubMed

The aim was to explore the effects of rapamycin on autophagy and injury of podocytes in streptozocin (STZ)-induced type 1 diabetic mice, and its role in delaying progression of diabetic nephropathy. In this study, male Balb/c mice were divided into three groups: control (n = 12), STZ-induced diabetic (n = 12), and rapamycin-treated diabetic (DM + Rapa) (n = 12), which received intraperitoneal injection of rapamycin (2 mg/kg/48 h) after induction of DM. Levels of urinary albumin (UA), blood urea nitrogen, serum creatinine, and kidney weight/body weight were measured at week 12. Renal pathologic changes, number of podocytes autophagy, and organelles injury were investigated by PAS staining, transmission electron microscopy, and immunofluorescence staining, respectively. Western blot was performed to determine the expression of LC3 (a podocyte autophagy marker), phosphorylated mammalian target of rapamycin, p-p70S6K, bax, and caspase-3 protein. Podocytes count was evaluated by immunofluorescence staining and Wilms tumor 1 immunohistochemistry, and Western blot of nephrin and podocin. The results indicated that rapamycin could reduce the kidney weight/body weight and UA secretion. It could alleviate podocyte foot process fusion, glomerular basement membrane thickening, and matrix accumulation, and increase the number of autophagosomes, and LC3-expressing podocytes. Down-regulation of bax and caspase-3 protein, and up-regulation of nephrin and podocin protein were observed in the glomeruli of diabetic mice after administration of rapamycin. In conclusion, rapamycin can ameliorate renal injury in diabetic mice by increasing the autophagy activity and inhibition of apoptosis of podocytes. PMID:24850187

Xiao, Tangli; Guan, Xu; Nie, Ling; Wang, Song; Sun, Lei; He, Ting; Huang, Yunjian; Zhang, Jingbo; Yang, Ke; Wang, Junping; Zhao, Jinghong

2014-09-01

226

Adoptive Transfer of Syngeneic Bone Marrow-Derived Cells in Mice with Obesity-Induced Diabetes  

PubMed Central

There are conflicting data regarding the effects of transplantation of bone marrow-derived cells (BMDCs) on the severity of diabetes. We therefore inquired whether the competence of BMDCs is preserved on adoptive transfer into diabetic (db/db) mice and how the adoptive transfer of BMDCs affects vascular and metabolic abnormalities in these mice. Recipient db/db mice received infusions of BMDCs prepared from either db/db or non-diabetic heterozygout mice (db/m) mice and effects on endothelium-dependent relaxation, insulin sensitivity, and renal function were evaluated. Recipients of BMDCs from db/m, but not db/db donors showed better glucose control, exhibited striking improvement in endothelium-dependent relaxation in response to acetylcholine, and had partially restored renal function. Improved glucose control was due to enhanced insulin sensitivity, most likely secondary to improved vascular function. Enhanced apoptosis of endothelial progenitor cells under oxidative stress, as well as decreased endothelial progenitor cell numbers were responsible for the apparent functional incompetence of BMDCs from db/db donors. Treatment of db/db mice with Ebselen restored the resistance of both BMDCs and endothelial progenitor cells to oxidative stress, improved acetylcholine-induced vasorelaxation, and reduced proteinuria in db/db recipients of BMDC transplantation. In conclusion, infusion of BMDCs obtained from db/m donors to db/db recipient mice benefited macrovascular function, insulin sensitivity, and nephropathy. BMDCs obtained from db/db mice were functionally incompetent secondary to the increased proportion of apoptotic cells on oxidative stress challenge; their competence was restored by Ebselen therapy. PMID:19147816

Chen, Jun; Li, Houwei; Addabbo, Francesco; Zhang, Fung; Pelger, Edward; Patschan, Daniel; Park, Hyeong-Cheon; Kuo, Mei-Chuan; Ni, Jei; Gobe, Glenda; Chander, Praveen N.; Nasjletti, Alberto; Goligorsky, Michael S.

2009-01-01

227

RNase L contributes to experimentally induced type 1 diabetes onset in mice.  

PubMed

The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon ? (IFN?) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFN? contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFN?-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8(+)T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying ?-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L. PMID:25287058

Zeng, Chun; Yi, Xin; Zipris, Danny; Liu, Hongli; Zhang, Lin; Zheng, Qiaoyun; Malathi, Krishnamurthy; Jin, Ge; Zhou, Aimin

2014-12-01

228

Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice.  

PubMed

Liraglutide, a long-lasting glucagon?like peptide?1 analogue, has been used for the treatment of patients with type 2 diabetes mellitus since 2009. In this study, we investigated the anti-diabetic effects and mechanisms of action of liraglutide in a spontaneous diabetic animal model, using KK/Upj-Ay/J (KKAy) mice. The KKAy mice were divided into 2 groups, the liraglutide group (mice were treated with 250 µg/kg/day liraglutide) and the model group (treated with an equivalent amount of normal saline). C57BL/6J mice were used as the controls (treated with an equivalent amount of normal saline). The treatment period lasted 6 weeks. During this treatment period, fasting blood glucose (FBG) levels and the body weight of the mice were measured on a weekly basis. Our results revealed that liraglutide significantly decreased FBG levels, the area under the curve following a oral glucose tolerance test and insulin tolerance test, increased serum insulin levels, reduced homeostasis model assessment of insulin resistance and increased the insulin sensitivity index. Furthermore, liraglutide ameliorated glycometabolism dysfunction by increasing glycolysis via hexokinase and glycogenesis via pyruvate kinase activation. An ultrastructural examination of the pancreas revealed that liraglutide improved the damaged state of islet ? cells and increased the number of insulin secretory granules. The real-time PCR results revealed that the gene expression of glucose transporter 4 (GLUT4) increased following treatment with liraglutide. Liraglutide also upregulated the protein expression of GLUT4 in liver tissue and skeletal muscle. Our results suggest that liraglutide ameliorates glycometabolism and insulin resistance in diabetic KKAy mice by stimulating insulin secretion, increasing glycogenesis and glycolysis and upregulating the expression of GLUT4. PMID:23877319

Chen, Li-Na; Lyu, Juan; Yang, Xue-Fei; Ji, Wen-Jun; Yuan, Bing-Xiang; Chen, Ming-Xia; Ma, Xin; Wang, Bing

2013-10-01

229

Role of Endothelial Nitric Oxide Synthase in Diabetic Nephropathy: Lessons from Diabetic eNOS Knockout Mice  

PubMed Central

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in many countries. The animal models that recapitulate human DN undoubtedly facilitate our understanding of this disease and promote the development of new diagnostic markers and therapeutic interventions. Based on the clinical evidence showing the association of eNOS dysfunction with advanced DN, we and others have created diabetic mice that lack eNOS expression and shown that eNOS-deficient diabetic mice exhibit advanced nephropathic changes with distinct features of progressive DN, including pronounced albuminuria, nodular glomerulosclerosis, mesangiolysis, and arteriolar hyalinosis. These studies clearly defined a critical role of eNOS in DN and developed a robust animal model of this disease, which enables us to study the pathogenic mechanisms of progressive DN. Further, recent studies with this animal model have explored the novel mechanisms by which eNOS deficiency causes advanced DN and provided many new insights into the pathogenesis of DN. Therefore, here we summarize the findings obtained with this animal model and discuss the roles of eNOS in DN, unresolved issues, and future investigations of this animal model study. PMID:25371905

Harris, Raymond C.

2014-01-01

230

Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice  

PubMed Central

The leading cause of death in diabetic patients is cardiovascular disease; diabetic cardiomyopathy is typified by alterations in cardiac morphology and function, independent of hypertension or coronary disease. However, the molecular mechanism that links diabetes to cardiomyopathy is incompletely understood. Insulin resistance is a hallmark feature of diabetes, and the FoxO family of transcription factors, which regulate cell size, viability, and metabolism, are established targets of insulin and growth factor signaling. Here, we set out to evaluate a possible role of FoxO proteins in diabetic cardiomyopathy. We found that FoxO proteins were persistently activated in cardiac tissue in mice with diabetes induced either genetically or by high-fat diet (HFD). FoxO activity was critically linked with development of cardiomyopathy: cardiomyocyte-specific deletion of FoxO1 rescued HFD-induced declines in cardiac function and preserved cardiomyocyte insulin responsiveness. FoxO1-depleted cells displayed a shift in their metabolic substrate usage, from free fatty acids to glucose, associated with decreased accumulation of lipids in the heart. Furthermore, we found that FoxO1-dependent downregulation of IRS1 resulted in blunted Akt signaling and insulin resistance. Together, these data suggest that activation of FoxO1 is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease. PMID:22326951

Battiprolu, Pavan K.; Hojayev, Berdymammet; Jiang, Nan; Wang, Zhao V.; Luo, Xiang; Iglewski, Myriam; Shelton, John M.; Gerard, Robert D.; Rothermel, Beverly A.; Gillette, Thomas G.; Lavandero, Sergio; Hill, Joseph A.

2012-01-01

231

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. PMID:22896585

Estrada, Irene A.; Donthamsetty, Reshma; Debski, Patryk; Zhou, Meng-Hua; Zhang, Shenyuan L.; Yuan, Jason X.-J.; Han, Wenlong; Makino, Ayako

2013-01-01

232

Effect of corosolic acid on dietary hypercholesterolemia and hepatic steatosis in KK-Ay diabetic mice.  

PubMed

Corosolic acid (CA), contained in the leaves of the banaba plant (Lagerstroemia speciosa L.), is a pentacyclic triterpene, and has hypoglycemic effects. The effects of CA on dietary hypercholesterolemia and hepatic steatosis were assessed in KK-Ay mice, an animal model of type 2 diabetes. Two kinds of high cholesterol diet with or without 0.023% CA, were prepared for the study. KK-Ay mice were fed a normal diet (controls), the high cholesterol diet with CA (CA-mice) or that without CA (HC-mice) for 10 weeks. CA inhibited the mean blood cholesterol level by 32% (P<0.05) and the liver cholesterol content by 46% (P<0.05) compared with those of HC-mice 10 weeks after the start of dietary intake. Acutely, CA inhibited the mean blood cholesterol level 4 h after the administration of a high-cholesterol cocktail in an oral cholesterol-loading test, compared with that of control mice (P<0.05). These results suggest that CA has some direct effects on the cholesterol absorption process in the small intestine. CA may inhibit the activity of cholesterol acyltransferase, which acts in the re-esterification of cholesterol in the small intestine, in type 2 diabetes. PMID:20834178

Takagi, Satoshi; Miura, Toshihiro; Ishihara, Eriko; Ishida, Torao; Chinzei, Yasuo

2010-08-01

233

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

234

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. PMID:24527264

Wang, Zhi-hong; Hsu, Cheng-chin; Yin, Mei-chin

2012-01-01

235

Tissue-Specific Remodeling of the Mitochondrial Proteome in Type 1 Diabetic Akita Mice  

PubMed Central

OBJECTIVE To elucidate the molecular basis for mitochondrial dysfunction, which has been implicated in the pathogenesis of diabetes complications. RESEARCH DESIGN AND METHODS Mitochondrial matrix and membrane fractions were generated from liver, brain, heart, and kidney of wild-type and type 1 diabetic Akita mice. Comparative proteomics was performed using label-free proteome expression analysis. Mitochondrial state 3 respirations and ATP synthesis were measured, and mitochondrial morphology was evaluated by electron microscopy. Expression of genes that regulate mitochondrial biogenesis, substrate utilization, and oxidative phosphorylation (OXPHOS) were determined. RESULTS In diabetic mice, fatty acid oxidation (FAO) proteins were less abundant in liver mitochondria, whereas FAO protein content was induced in mitochondria from all other tissues. Kidney mitochondria showed coordinate induction of tricarboxylic acid (TCA) cycle enzymes, whereas TCA cycle proteins were repressed in cardiac mitochondria. Levels of OXPHOS subunits were coordinately increased in liver mitochondria, whereas mitochondria of other tissues were unaffected. Mitochondrial respiration, ATP synthesis, and morphology were unaffected in liver and kidney mitochondria. In contrast, state 3 respirations, ATP synthesis, and mitochondrial cristae density were decreased in cardiac mitochondria and were accompanied by coordinate repression of OXPHOS and peroxisome proliferator–activated receptor (PPAR)-? coactivator (PGC)-1? transcripts. CONCLUSIONS Type 1 diabetes causes tissue-specific remodeling of the mitochondrial proteome. Preservation of mitochondrial function in kidney, brain, and liver, versus mitochondrial dysfunction in the heart, supports a central role for mitochondrial dysfunction in diabetic cardiomyopathy. PMID:19542201

Bugger, Heiko; Chen, Dong; Riehle, Christian; Soto, Jamie; Theobald, Heather A.; Hu, Xiao X.; Ganesan, Balasubramanian; Weimer, Bart C.; Abel, E. Dale

2009-01-01

236

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. PMID:24052898

Kitamura, Hiroshi; Naoe, Yoshinori; Kimura, Shunsuke; Miyamoto, Tomomi; Okamoto, Shiki; Toda, Chitoku; Shimamoto, Yoshinori; Iwanaga, Toshihiko; Miyoshi, Ichiro

2013-01-01

237

Impaired Musculoskeletal Response to Age and Exercise in PPAR?(-/-) Diabetic Mice.  

PubMed

Fragility fractures are recognized complication of diabetes, but yet the underlying mechanisms remain poorly understood. This is particularly pronounced in type 2 diabetes in which the propensity to fall is increased but bone mass is not necessarily low. Thus, whether factors implicated in the development of insulin resistance and diabetes directly impact on the musculoskeletal system remains to be investigated. PPAR?(-/-) mice have reduced metabolic activity and are glucose intolerant. We examined changes in bone and muscle in PPAR?(-/-) mice and investigated both the mechanism behind those changes with age as well as their response to exercise. Compared with their wild type, PPAR?(-/-) mice had an accelerated and parallel decline in both muscle and bone strength with age. These changes were accompanied by increased myostatin expression, low bone formation, and increased resorption. In addition, mesenchymal cells from PPAR?(-/-) had a reduced proliferation capacity and appeared to differentiate into more of an adipogenic phenotype. Concomitantly we observed an increased expression of PPAR?, characteristic of adipocytes. The anabolic responses of muscle and bone to exercise were also diminished in PPAR?(-/-) mice. The periosteal bone formation response to direct bone compression was, however, maintained, indicating that PPAR? controls periosteal bone formation through muscle contraction and/or metabolism. Taken together, these data indicate that PPAR? deficiency leads to glucose intolerance, decreased muscle function, and reduced bone strength. On a molecular level, PPAR? appears to regulate myostatin and PPAR? expression in muscle and bone, thereby providing potential new targets to reverse bone fragility in patients with metabolic disturbances. PMID:25279796

Fu, He; Desvergne, Beatrice; Ferrari, Serge; Bonnet, Nicolas

2014-12-01

238

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. PMID:24999476

Shivshetty, Nagaveni; Hosamani, Rajeshwari; Ahmed, Liyakat; Oli, Ajay Kumar; Sannauallah, Syed; Sharanbassappa, Shivshetty; Patil, S. A.; Kelmani, Chandrakanth R.

2014-01-01

239

Hydrangea dulcis folium preserves beta-cell mass in diabetic db/db mice.  

PubMed

The anti-diabetic efficacy of Hydrangea dulcis folium (HDF) was studied in db/db mice and their littermates (db/-). Supplementation of HDF (1% and 3%) decreased glucose level significantly by 2- and 4-fold and increased significantly insulin level by 3- and 4.5-fold compared to db/db mice (P<0.05). Administration of HDF (1% and 3%) ameliorates hyperglycemia and improves glucose homeostasis in db/db mice in a dose-dependent manner by preventing loss of beta-cell mass resulting in increase of insulin secretion. In addition, 3% HDF treatment significantly reduced the food intake, weight gain, and blood lipids in db/db mice. PMID:19394398

Kim, Mi-Ja; Leem, Kang-Hyun; Kim, Hye Kyung

2009-07-01

240

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

241

Artemisia campestris leaf extract alleviates early diabetic nephropathy in rats by inhibiting protein oxidation and nitric oxide end products.  

PubMed

Chronic hyperglycemia in diabetes leads to free radicals overproduction, which contributes to the development of diabetic nephropathy. The present study investigated the effects of Artemisia campestris (Ac), a plant of the Asteraceae family, on renal impairment and oxidative stress in alloxan-induced diabetic rats. Diabetes was induced by a single subcutaneous injection of alloxan (120 mg kg(-1)) in rats. Ac (200 mg kg(-1)) was administered to diabetic rats for 3 weeks. Diabetic renal injury was associated with hyperglycemia, increased serum creatinine, urea and uric acid levels. This nephropathophysiology was associated with a surproduction of nitric oxide (NO), malondialdehyde (MDA) and advanced oxidation protein products (AOPP) levels and a decrease in glutathione (GSH) levels. In addition, hyperglycemia increased the activities of antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), in the kidney of diabetic rats. Treatment with Ac effectively ameliorated diabetic renal dysfunction by reducing oxidative and nitrosative stress. Histological studies also supported the experimental findings. The results suggested that Ac might act as a beneficial agent against renal dysfunctions developed in alloxan-induced diabetes. PMID:22361035

Sefi, Mediha; Fetoui, Hamadi; Soudani, Nejla; Chtourou, Yassine; Makni, Mohamed; Zeghal, Najiba

2012-03-15

242

Evaluation of Anticonvulsive Effect of Magnesium Oxide Nanoparticles in Comparison with Conventional MgO in Diabetic and Non-diabetic Male Mice  

PubMed Central

Introduction Some studies showed that magnesium has anticonvulsive effect in some animal models. Despite of the availability of well-studied anticonvulsant drugs, this evaluation was not carried on new kind of magnesium supplement, magnesium oxide nanoparticles (nMgO). According to the association between magnesium and convulsion and high prevalence of seizure and epilepsy in diabetics, this study was designed to evaluate the effect of nMgO compared to conventional MgO (cMgO) on strychnine-induced convulsion model in diabetic and non-diabetic mice. Methods Healthy male albino mice were divided into 10 groups. Diabetes mellitus was induced by streptozotocin in 5 groups. Conventional and nanoparticle MgO (5 and 10mg/kg) were administered to diabetic and non-diabetic mice, then strychnine were injected and onset of convulsions and time of death measured after strychnine administration. Results There were no significant differences between normal and diabetic groups in onset of convulsions and time of death. Pretreatment of cMgO did not have anticonvulsant effect in strychnine-induced convulsion in normal and diabetic mice. But nMgO significantly changed convulsion onset and death time after strychnine administration in normal and diabetic status (p < 0.05). Discussion According to our results, it seems that acute administration of nMgO may be important in prevention of convulsion and is more effective than its conventional form in showing anticonvulsive effect that probably is related to the physicochemical properties of nMgO, especially in diabetic subjects, a point that need further investigations. PMID:25337374

Jahangiri, Leila; Kesmati, Mahnaz; Najafzadeh, H.

2014-01-01

243

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 (200 mg/kg/day of charantin-rich extract of MC [CEMC]) and in ICR mice with STZ-induced diabetes. After 8 weeks, 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 24 h of incubation, but the protective effect was not detectable after 72 h. 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

244

QUANTITATIVE PHOSPHOPROTEOMIC ANALYSIS OF T CELL RECEPTOR SIGNALING IN DIABETES PRONE AND RESISTANT MICE  

PubMed Central

Type 1 diabetes, in human patients and NOD mice, results from immune attack on insulin-producing beta-cells of the pancreas by autoreactive T lymphocytes. In NOD mice, genetically-controlled perturbations in the signaling pathways downstream of the antigen-specific T cell receptor (TCR) may be instrumental in the altered responses of T cells, manifest as inefficient induction of apoptosis after recognition of self-antigens in the thymus, or as perturbed reactivity of mature T cells in peripheral organs. To map this signaling difference(s), we have used mass spectrometry-based quantitative phosphoproteomics to compare the activation of primary CD4+ T cells of diabetes-prone NOD and -resistant B6.H2g7 mice. Immunoprecipitation and IMAC purification of tyrosine-phosphorylated peptides, combined with a stable-isotope iTRAQ labeling, enabled us to identify and quantify over 77 phosphorylation events in 54 different proteins downstream of TCR stimulation of primary CD4+ T cells. This analysis showed a generally higher level of phosphotyrosine in activated NOD cells, as well as several phosphorylation sites that appeared to be differentially regulated in these two strains (involving TXK, CD5, PAG1, and ZAP-70). These data highlight the differences in signaling between CD4+ T cell compartments of NOD and B6g7 mice, and may underlie the dysregulation of T cells in NOD mice. PMID:20438120

Iwai, Leo K.; Benoist, Christophe; Mathis, Diane; White, Forest M

2012-01-01

245

Renal Function and Glucose Transport in Male and Female Mice with Diet-Induced Type II Diabetes Mellitus  

Microsoft Academic Search

The aim of this study was to measure cardiovascular and renal function, including the renal transport capacity for glucose, in male and female C57BL\\/6J mice with diet-induced Type II diabetes mellitus. Typical of Type II diabetes, mice fed a high-fat, high-simple carbohydrate diet for 3 months were obese (45-65 g), hypergly- cemic (138-259 mg%), and hyperinsulinemic (1.8-15.06 ng\\/ml); significant gender

W. T. Noonan; R. O. Banks

2000-01-01

246

Islet-Specific T-Cell Clones from Nonobese Diabetic Mice Express Heterogeneous T-Cell Receptors  

Microsoft Academic Search

Nonobese diabetic (NOD) mice spontaneously develop a T-cell-mediated autoimmune disease that is similar in many respects to insulin-dependent diabetes mellitus in humans. T-cell clones that specifically recognize pancreatic islet cell antigens can be derived from NOD mice, and most of these have been diabetogenic upon transfer to healthy recipients. We report herein the sequences of the T-cell receptor alpha and

Serge Candeias; Jonathan Katz; Christophe Benoist; Diane Mathis; Kathryn Haskins

1991-01-01

247

Prevention and Reversal of Diabetes by All-Trans Retinoid Acid and Exendin-4 in NOD Mice  

PubMed Central

It has been shown that all-trans retinoid acid (ATRA) hinders the development of autoimmune diabetes by inducing immune tolerance status. Meanwhile, exendin-4 increases beta-cell function and mass. Thus, we hypothesized that ATRA and exendin-4 combination therapy would prevent and reverse autoimmune diabetes. NOD/scid mice were intravenously transferred with splenocytes isolated from 12-week-old female NOD mice. After adoptive transfer, mice were treated with vehicle, ATRA (0.5?mg/mouse intraperitoneally every other day), exendin-4 (3??g/kg subcutaneously twice daily), or combination for 6 weeks. Compared with vehicle, ATRA (P = 0.022) and ATRA plus exendin-4 (P = 0.013) treatment delayed the onset of diabetes. The pancreatic insulin content in mice treated with ATRA (P = 0.013) and exendin-4 (P < 0.02) was significantly higher than that of control mice. All but one spontaneous diabetic NOD mouse treated with ATRA and/or exendin-4 remained persistent hyperglycemic. ATRA and/or exendin-4 treatment did not alter their blood glucose levels and survival. Our results indicate that, before the onset of autoimmune diabetes, ATRA and exendin-4 treatment alone preserves pancreatic beta cells; ATRA and ATRA plus exendin-4 treatment delays the onset of autoimmune diabetes. However, after the onset of autoimmune diabetes, ATRA and/or exendin-4 treatment is unable to reverse hyperglycemia or improve survival. PMID:24995016

Van, Yang-Hau; Kuo, Chien-Hung; Lin, Mei-Yin; Liu, Ying-Hsiu; Chang, Han-Ying

2014-01-01

248

Hypoglycemic, hypolipidemic and antioxidant effects of Sarcandra glabra polysaccharide in type 2 diabetic mice.  

PubMed

Sarcandra glabra (Thunb.) Nakai is a traditional Chinese herbal medicine and dietary supplement used for treating several diseases. The anti-diabetic activity of S. glabra polysaccharides is reported for the first time. The in vitro ?-glucosidase inhibition assay indicated that the acidic S. glabra polysaccharide (SGP-2) has an IC50 of 87.06 ± 11.76 ?g mL(-1), which was much lower than acarbose at 338.90 ± 46.86 ?g mL(-1). Moreover, high fat diet (HFD) with streptozotocin (STZ) induced diabetic mice were administered SGP-2 (150, 300, or 600 mg kg(-1) per day, respectively) for 3 weeks. Postprandial blood glucose levels (PBGL), total cholesterol, triglyceride and free fatty acid levels in diabetic mice treated with SGP-2 were significantly decreased (p < 0.05) compared to those of the model group. The results of the oral glucose tolerance test (OGTT) and the homeostasis model assessment-insulin resistance (HOMA-IR) index indicated that SGP-2 could significantly improve (p < 0.05) the insulin resistance and glucose tolerance in diabetic mice. Furthermore, the activities of antioxidant enzymes, hexokinase and pyruvate kinase were significantly increased (p < 0.05) in SGP-2 treated groups. Thus we proposed that SGP-2 exerted hypoglycemic activity by relieving insulin resistance, reducing postprandial blood glucose levels and ameliorating lipid metabolism, as well as alleviating oxidative stress. These data suggested that SGP-2 with anti-hyperglycemic activity could be used in medicinal preparations for diabetes mellitus and its complications. PMID:25254968

Liu, Wei; Zheng, Ying; Zhang, Zhenzhen; Yao, Wenbing; Gao, Xiangdong

2014-10-22

249

Bis(quercetinato)oxovanadium IV Reverses Metabolic Changes in Streptozotocin-Induced Diabetic Mice  

PubMed Central

Organic vanadium compounds offer several advantages in the treatment of diabetes, yet they are impractical to use because of known side effects. In order to ameliorate the side effects of vanadium, we conjugated it with quercetin to form bis(quercetinato)oxovanadium IV (BQOV). This study evaluates the effect of BQOV treatment on carbohydrate metabolism and overall oxidative stress in streptozotocin-induced (STZ) diabetic mice. Administration of BQOV orally to diabetic mice for 3 weeks led to a reduction of blood glucose levels and the animals exhibited normal glucose tolerance at the end of the study period. The increase in glucose uptake by skeletal muscle and liver as well as the normalization of mRNA levels of G-6-Pase and glucokinase in the liver after BQOV treatment pointed to improvements in carbohydrate metabolism. The analysis of the antioxidant status of serum, liver and pancreas revealed reduced oxidative stress in BQOV-treated animals compared to untreated diabetic controls. Serum analyses for kidney and liver function showed that BQOV treatment provoked total protection of the kidney and partial protection of the liver from diabetogenic insults. The number of insulin-positive cells and the amount of pancreatic insulin in treated mice (1.2038 ± 0.34 ng/mg tissue) did not account for pancreatic regeneration but suggested an insulin-mimetic action on the part of BQOV. Moreover, administration of BQOV for 3 weeks did not show any visible side-effects. This data indicate that BQOV is a safe and potent agent for diabetes treatment, because it is able to improve carbohydrate metabolism and to reduce overall oxidative stress. PMID:17565414

Shukla, Ruchi; Padhye, Subhash; Modak, Manisha; Ghaskadbi, Saroj S.; Bhonde, Ramesh R.

2007-01-01

250

Transgenic and Knockout Mice in Diabetes Research: Novel Insights into Pathophysiology, Limitations, and Perspectives  

NSDL National Science Digital Library

Insulin resistance and type 2 diabetes are serious public health threats. Although enormous research efforts have been focused on the pathogenesis of these diseases, the underlying mechanisms remain only partly understood. Here we review mouse phenotypes resulting from inactivation of molecules responsible for the control of glucose metabolism that have led to novel insights into insulin action and the development of insulin resistance. In addition, more sophisticated strategies to manipulate genes in mice in the future are presented.

L. Plum (University of Cologne Department of Mouse Genetics and Metabolism, Institute for Genetics); F. T. Wunderlich (University of Cologne Center for Molecular Medicine Cologne); S. Baudler (University of Cologne Center for Molecular Medicine Cologne); W. Krone (University of Cologne Department of Internal Medicine II); J. C. Brüning (University of Cologne Center for Molecular Medicine Cologne)

2005-06-01

251

The Protective Effects of CD39 Overexpression in Multiple Low-Dose Streptozotocin-Induced Diabetes in Mice  

PubMed Central

Islet allograft survival limits the long-term success of islet transplantation as a potential curative therapy for type 1 diabetes. A number of factors compromise islet survival, including recurrent diabetes. We investigated whether CD39, an ectonucleotidase that promotes the generation of extracellular adenosine, would mitigate diabetes in the T cell–mediated multiple low-dose streptozotocin (MLDS) model. Mice null for CD39 (CD39KO), wild-type mice (WT), and mice overexpressing CD39 (CD39TG) were subjected to MLDS. Adoptive transfer experiments were performed to delineate the efficacy of tissue-restricted overexpression of CD39. The role of adenosine signaling was examined using mutant mice and pharmacological inhibition. The susceptibility to MLDS-induced diabetes was influenced by the level of expression of CD39. CD39KO mice developed diabetes more rapidly and with higher frequency than WT mice. In contrast, CD39TG mice were protected. CD39 overexpression conferred protection through the activation of adenosine 2A receptor and adenosine 2B receptor. Adoptive transfer experiments indicated that tissue-restricted overexpression of CD39 conferred robust protection, suggesting that this may be a useful strategy to protect islet grafts from T cell–mediated injury. PMID:23364452

Chia, Joanne S.J.; McRae, Jennifer L.; Thomas, Helen E.; Fynch, Stacey; Elkerbout, Lorraine; Hill, Prue; Murray-Segal, Lisa; Robson, Simon C.; Chen, Jiang-Fan; d'Apice, Anthony J.F.; Cowan, Peter J.; Dwyer, Karen M.

2013-01-01

252

Selenium-enriched exopolysaccharides improve skeletal muscle glucose uptake of diabetic KKAy mice via AMPK pathway.  

PubMed

Selenium-enriched exopolysaccharides (EPS) produced by Enterobacter cloacae Z0206 have been proven to possess effect on reducing blood glucose level in diabetic mice. To investigate the specific mechanism, we studied the effects of oral supply with EPS on skeletal muscle glucose transportation and consumption in high-fat-diet-induced diabetic KKAy mice. We found that EPS supplementation increased expressions of glucose transporter 4 (Glut4), hexokinase 2 (hk2), phosphorylation of AMP-activated kinase subunit ?2 (pAMPK?2), and peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?), and increased expression of characteristic protein of oxidative fibers such as troponin I and cytochrome c (Cytc). Furthermore, we found that EPS increased glucose uptake and expressions of pAMPK?2 and PGC-1? in palmitic acid (PA)-induced C2C12 cells. However, while EPS inhibited AMPK?2 with interference RNA (iRNA), effects of EPS on the improvement of glucose uptake diminished. These results indicated that EPS may improve skeletal muscle glucose uptake of diabetic KKAy mice through AMPK?2-PGC-1? pathway. PMID:24729044

Zhou, Xihong; Chen, Jingqing; Wang, Fengqin; Yang, Hangxian; Yang, Ren; Wang, Xinxia; Wang, Yizhen

2014-06-01

253

Effect of Resveratrol on Behavioral Performance of Streptozotocin-induced Diabetic Mice inAnxiety Tests  

PubMed Central

The aim of this study was to evaluate with anxiety tests the effect of resveratrol (RSV) on streptozotocin (STZ)-induced diabetic mouse behavioral performance at the second and fourth week of treatment. Confirmed diabetic mice (>250 mg/dl of glucose in blood after STZ injection) were treated with RSV (RDM, n=12) or control treated (DM, n=12) for 4 weeks. DM and RDM were tested in the Open Field Test (OFT) and Elevated Plus Maze (EPM). In the second week of RSV treatment, a higher grooming frequency (P<0.05) and a lower defecation and rearing frequency (P<0.05) were detected in the OFT in the RDM group compared with the DM. There was a higher grooming frequency (P<0.05) and higher percentage of entries in open arms (P<0.05) in the RDM group than in the DM group in the EPM. However, in the fourth week of RSV treatment, the only effect observed was a higher grooming frequency in the RDM group than in the DM group (P<0.05) in the EPM. In conclusion, RSV treatment in diabetic mice provoked anxiolytic-like effects in both tests (OFT and EPM), and these effects were observed in a short time window (2 weeks). It is suggested that RSV may help diabetic animals to adapt to new stressing and anxiety situations and thus to improve their welfare. PMID:25077757

Damian, Juan P.; Acosta, Victoria; Da Cuna, Maira; Ramirez, Isara; Oddone, Natalia; Zambrana, Ana; Bervejillo, Veronica; Benech, Juan C.

2014-01-01

254

Transplantation of insulin-secreting multicellular spheroids for the treatment of type 1 diabetes in mice.  

PubMed

The efficacy of cell-based therapy depends on the function and survival of transplanted cells, which have been suggested to be enhanced by spheroid formation. However, few attempts at spheroid generation from insulin-secreting cells, which may be used to treat type 1 diabetes, have been reported. We therefore developed spheroids from the mouse insulinoma cell line NIT-1 by using polydimethylsiloxane (PDMS)-based microwells with a coating of poly(N-isopropylacrylamide) (PNIPAAm). The prepared NIT-1 spheroids or dissociated NIT-1 cells were transplanted into the subrenal capsule in streptozotocin-induced diabetic mice. NIT-1 spheroids prepared using the PNIPAAm-coated PDMS-based microwells had a uniformly sized spherical structure with a diameter of 200-300?m. The PNIPAAm coating increased cell survival in the spheroids and the recovery of the spheroids from the microwells. In diabetic mice, the transplanted NIT-1 spheroids reduced blood glucose levels to normal values faster than dissociated NIT-1 cells did. Additionally, survival was higher among NIT-1 cells in spheroids than among dissociated NIT-1 cells 24h after transplantation. These results indicate that insulin-secreting NIT-1 spheroids prepared using PNIPAAm-coated PDMS-based microwells are more effective for the treatment of type 1 diabetes than dissociated cells in suspension. PMID:24184345

Kusamori, Kosuke; Nishikawa, Makiya; Mizuno, Narumi; Nishikawa, Tomoko; Masuzawa, Akira; Shimizu, Kazunori; Konishi, Satoshi; Takahashi, Yuki; Takakura, Yoshinobu

2014-01-10

255

Manganese Supplementation Protects Against Diet-Induced Diabetes in Wild Type Mice by Enhancing Insulin Secretion  

PubMed Central

Mitochondrial dysfunction is both a contributing mechanism and complication of diabetes, and oxidative stress contributes to that dysfunction. Mitochondrial manganese-superoxide dismutase (MnSOD) is a metalloenzyme that provides antioxidant protection. We have previously shown in a mouse model of hereditary iron overload that cytosolic iron levels affected mitochondrial manganese availability, MnSOD activity, and insulin secretion. We therefore sought to determine the metallation status of MnSOD in wild-type mice and whether altering that status affected ?-cell function. 129/SvEVTac mice given supplemental manganese exhibited a 73% increase in hepatic MnSOD activity and increased metallation of MnSOD. To determine whether manganese supplementation offered glucose homeostasis under a situation of ?-cell stress, we challenged C57BL/6J mice, which are more susceptible to diet-induced diabetes, with a high-fat diet for 12 weeks. Manganese was supplemented or not for the final 8 weeks on that diet, after which we examined glucose tolerance and the function of isolated islets. Liver mitochondria from manganese-injected C57BL/6J mice had similar increases in MnSOD activity (81%) and metallation as were seen in 129/SvEVTac mice. The manganese-treated group fed high fat had improved glucose tolerance (24% decrease in fasting glucose and 41% decrease in area under the glucose curve), comparable with mice on normal chow and increased serum insulin levels. Isolated islets from the manganese-treated group exhibited improved insulin secretion, decreased lipid peroxidation, and improved mitochondrial function. In conclusion, MnSOD metallation and activity can be augmented with manganese supplementation in normal mice on normal chow, and manganese treatment can increase insulin secretion to improve glucose tolerance under conditions of dietary stress. PMID:23372018

Lee, Soh-Hyun; Jouihan, Hani A.; Cooksey, Robert C.; Jones, Deborah; Kim, Hyung J.; Winge, Dennis R.

2013-01-01

256

Protective Effects of Astragaloside IV on db/db Mice with Diabetic Retinopathy  

PubMed Central

Objectives Diabetic retinopathy (DR) is a common diabetic eye disease which is well-known as the result of microvascular retinal changes. Although the potential biological functions of astragaloside IV (AS IV) have long been described in traditional system of medicine, its protective effect on DR remains unclear. This study aims to investigate the function and mechanism of AS IV on type 2 diabetic db/db mice. Methods Db/db mice were treated with AS IV (4.5 mg/kg or 9 mg/kg) or physiological saline by oral gavage for 20 weeks along with db/m mice. In each group, retinal ganglion cell (RGC) function was measured by pattern electroretinogram (ERG) and apoptosis was determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Blood and retina aldose reductase (AR) activity were quantified by chemiluminescence analysis. The expressions of phosporylated-ERK1/2, NF-?B were determined by Western blot analysis. Furthermore, the expression of related downstream proteins were quantified by Label-based Mouse Antibody Array. Results Administration of AS IV significantly improved the amplitude in pattern ERG and reduced the apoptosis of RGCs.in db/db mice. Furthermore, downregulation of AR activity, ERK1/2 phosphorylation, NF-?B and related cytokine were observed in AS IV treatment group. Conclusions Our study indicated that AS IV, as an inhibitor of AR, could prevent the activation of ERK1/2 phosporylation and NF-kB and further relieve the RGCs disfunction in db/db mice with DR. It has provided a basis for investigating the clinical efficacy of AR inhibitors in preventing DR. PMID:25411784

Mao, Pingan; Zhao, Chen; Huang, Qiong; Zhang, Rihua; Fang, Yuan; Song, Qinglu; Yuan, Dongqing; Xie, Ping; Liu, Yun; Liu, Qinghuai

2014-01-01

257

Flexibility of TCR Repertoire and Permissiveness of HLA-DR3 Molecules in Experimental Autoimmune Thyroiditis in Nonobese Diabetic Mice  

Microsoft Academic Search

Experimental autoimmune thyroiditis (EAT) is inducible in genetially susceptible mice by immunization with mouse thyroglobulin (mTg). With susceptibility linked to MHC class II, EAT is useful in studying human leukocyte antigen (HLA) associations with Hashimoto's thyroiditis. In non-obese diabetic (NOD) mice, ?10% thyroiditis incidence occurs with aging. This potential was exploited to examine the T cell repertoire and HLA association

Jeffrey C Flynn; Brian E Fuller; Alvaro A Giraldo; John C Panos; Chella S David; Yi-Chi M Kong

2001-01-01

258

Maternal obesity induces gut inflammation and impairs gut epithelial barrier function in nonobese diabetic mice.  

PubMed

Impairment of gut epithelial barrier function is a key predisposing factor for inflammatory bowel disease, type 1 diabetes (T1D) and related autoimmune diseases. We hypothesized that maternal obesity induces gut inflammation and impairs epithelial barrier function in the offspring of nonobese diabetic (NOD) mice. Four-week-old female NOD/ShiLtJ mice were fed with a control diet (CON; 10% energy from fat) or a high-fat diet (HFD; 60% energy from fat) for 8 weeks to induce obesity and then mated. During pregnancy and lactation, mice were maintained in their respective diets. After weaning, all offspring were fed the CON diet. At 16 weeks of age, female offspring were subjected to in vivo intestinal permeability test, and then ileum was sampled for biochemical analyses. Inflammasome mediators, activated caspase-1 and mature forms of interleukin (IL)-1? and IL-18 were enhanced in offspring of obese mothers, which was associated with elevated serum tumor necrosis factor ? level and inflammatory mediators. Consistently, abundance of oxidative stress markers including catalase, peroxiredoxin-4 and superoxide dismutase 1 was heightened in offspring ileum (P<.05). Furthermore, offspring from obese mothers had a higher intestinal permeability. Morphologically, maternal obesity reduced villi/crypt ratio in the ileum of offspring gut. In conclusion, maternal obesity induced inflammation and impaired gut barrier function in offspring of NOD mice. The enhanced gut permeability in HFD offspring might predispose them to the development of T1D and other gut permeability-associated diseases. PMID:24775094

Xue, Yansong; Wang, Hui; Du, Min; Zhu, Mei-Jun

2014-07-01

259

Experimental Induction of Type 2 Diabetes in Aging-Accelerated Mice Triggered Alzheimer-Like Pathology and Memory Deficits  

PubMed Central

Alzheimer’s disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-?, dysregulated tau-phosphorylating glycogen synthase kinase 3?, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. PMID:24121970

Mehla, Jogender; Chauhan, Balwantsinh C.; Chauhan, Neelima B.

2014-01-01

260

Expression of gluconeogenic enzymes and 11?-hydroxysteroid dehydrogenase type 1 in liver of diabetic mice after acute exercise  

PubMed Central

During acute exercise, normoglycemia is maintained by a precise match between hepatic glucose production and its peripheral utilization. This is met by a complex interplay of hepatic responses and glucose uptake by muscle. However, the effect of a single bout of exercise on hepatic gluconeogenesis, corticosterone (CORT) secretion, and glucose homeostasis in the db/db mouse model of type 2 diabetes is poorly understood. Diabetic db/db and lean control littermates were subjected to a 30 minute session of treadmill running and sacrificed either immediately after exercise or 8 hours later. Plasma glucose levels were markedly increased in db/db mice after exercise, whereas no change in glucose was observed in lean mice. Post-exercise measurements revealed that plasma CORT levels were also significantly increased in db/db mice compared to lean mice. Plasma hypothalamic corticotropin releasing hormone and pituitary adrenocorticotropic hormone levels were reciprocally decreased in both db/db and lean mice after exercise, indicating intact feedback mechanisms. Protein expression, determined by Western blot analysis, of the glucocorticoid receptor in liver was significantly increased in db/db mice subjected to prior exercise. In liver of db/db mice, a significant increase in the expression of phosphoenolpyruvate carboxykinase was noted compared to lean mice after exercise. However, no change in the expression of glucose-6-phosphatase (G6Pase) ? or ? was observed in db/db mice. Expression of 11?-hydroxysteroid dehydrogenase type 1 was increased significantly in db/db mice compared to lean mice after exercise. Our results show differences in plasma glucose and protein expression of gluconeogenic enzymes after acute exercise between lean and diabetic db/db mice. The db/db diabetic mouse is hyperglycemic after acute exercise. This hyperglycemic state may be explained, in part, by enhanced endogenous CORT secretion and regulated hepatic phosphoenolpyruvate carboxykinase and 11?-hydroxysteroid dehydrogenase type 1 protein expression. PMID:25364268

Brust, Korie B; Corbell, Kathryn A; Al-Nakkash, Layla; Babu, Jeganathan Ramesh; Broderick, Tom L

2014-01-01

261

Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells  

PubMed Central

Lately, TNF alpha has been the focus of studies of autoimmunity; its role in the progression of autoimmune diabetes is, however, still unclear. To analyze the effects of TNF alpha in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNF alpha under the control of the rat insulin II promoter (RIP). In transgenic mice, TNF alpha expression on the islets resulted in massive insulitis, composed of CD4+ T cells, CD8+ T cells, and B cells. Despite infiltration of considerable number of lymphoid cells in islets, expression of TNF alpha protected NOD mice from IDDM. To determine the mechanism of TNF alpha action, splenic cells from control NOD and RIP-TNF alpha mice were adoptively transferred to NOD-SCID recipients. In contrast to the induction of diabetes by splenic cells from control NOD mice, splenic cells from RIP- TNF alpha transgenic mice did not induce diabetes in NOD-SCID recipients. Diabetes was induced however, in the RIP-TNF alpha transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNF alpha in islets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNF alpha action and provide evidence that local expression of TNF alpha protects NOD mice from autoimmune diabetes by preventing the development of autoreactive islet-specific T cells. PMID:8920883

1996-01-01

262

Anti-Diabetic Effect of Balanced Deep-Sea Water and Its Mode of Action in High-Fat Diet Induced Diabetic Mice  

PubMed Central

In this study, we investigated the effects of balanced deep-sea water (BDSW) on hyperglycemia and glucose intolerance in high-fat diet (HFD)-induced diabetic C57BL/6J mice. BDSW was prepared by mixing deep-sea water (DSW) mineral extracts and desalinated water to give a final hardness of 500–2000. Mice given an HFD with BDSW showed lowered fasting plasma glucose levels compared to HFD-fed mice. Oral and intraperitoneal glucose tolerance tests showed that BDSW improves impaired glucose tolerance in HFD-fed mice. Histopathological evaluation of the pancreas showed that BDSW recovers the size of the pancreatic islets of Langerhans, and increases the secretion of insulin and glucagon in HFD-fed mice. Quantitative reverse transcription polymerase chain reaction results revealed that the expression of hepatic genes involved in glucogenesis, glycogenolysis and glucose oxidation were suppressed, while those in glucose uptake, ?-oxidation, and glucose oxidation in muscle were increased in mice fed HFD with BDSW. BDSW increased AMP-dependent kinase (AMPK) phosphorylation in 3T3-L1 pre- and mature adipocytes and improved impaired AMPK phosphorylation in the muscles and livers of HFD-induced diabetic mice. BDSW stimulated phosphoinositol-3-kinase and AMPK pathway-mediated glucose uptake in 3T3-L1 adipocytes. Taken together, these results suggest that BDSW has potential as an anti-diabetic agent, given its ability to suppress hyperglycemia and improve glucose intolerance by increasing glucose uptake. PMID:24172214

Ha, Byung Geun; Shin, Eun Ji; Park, Jung-Eun; Shon, Yun Hee

2013-01-01

263

Anti-diabetic effect of balanced deep-sea water and its mode of action in high-fat diet induced diabetic mice.  

PubMed

In this study, we investigated the effects of balanced deep-sea water (BDSW) on hyperglycemia and glucose intolerance in high-fat diet (HFD)-induced diabetic C57BL/6J mice. BDSW was prepared by mixing deep-sea water (DSW) mineral extracts and desalinated water to give a final hardness of 500-2000. Mice given an HFD with BDSW showed lowered fasting plasma glucose levels compared to HFD-fed mice. Oral and intraperitoneal glucose tolerance tests showed that BDSW improves impaired glucose tolerance in HFD-fed mice. Histopathological evaluation of the pancreas showed that BDSW recovers the size of the pancreatic islets of Langerhans, and increases the secretion of insulin and glucagon in HFD-fed mice. Quantitative reverse transcription polymerase chain reaction results revealed that the expression of hepatic genes involved in glucogenesis, glycogenolysis and glucose oxidation were suppressed, while those in glucose uptake, ?-oxidation, and glucose oxidation in muscle were increased in mice fed HFD with BDSW. BDSW increased AMP-dependent kinase (AMPK) phosphorylation in 3T3-L1 pre- and mature adipocytes and improved impaired AMPK phosphorylation in the muscles and livers of HFD-induced diabetic mice. BDSW stimulated phosphoinositol-3-kinase and AMPK pathway-mediated glucose uptake in 3T3-L1 adipocytes. Taken together, these results suggest that BDSW has potential as an anti-diabetic agent, given its ability to suppress hyperglycemia and improve glucose intolerance by increasing glucose uptake. PMID:24172214

Ha, Byung Geun; Shin, Eun Ji; Park, Jung-Eun; Shon, Yun Hee

2013-01-01

264

Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice  

PubMed Central

Diabetic mice are characterized by a disrupted expression pattern of VEGF (vascular endothelial growth factor), and impaired vasculogenesis during healing. Experimental evidence suggests that RLX (relaxin) can improve several parameters associated with wound healing. Therefore we investigated the effects of porcine-derived RLX in diabetes-related wound-healing defects in genetically diabetic mice. An incisional wound model was produced on the back of female diabetic C57BL/KsJ-m+/+Leptdb (db+/db+) mice and their normal littermates (db+/+m). Animals were treated daily with porcine RLX (25 ?g/mouse per day, subcutaneously) or its vehicle. Mice were killed on 3, 6 and 12 days after skin injury for measurements of VEGF mRNA and protein synthesis, SDF-1? (stromal cell-derived factor-1?) mRNA and eNOS (endothelial NO synthase) expression. Furthermore, we evaluated wound-breaking strength, histological changes, angiogenesis and vasculogenesis at day 12. Diabetic animals showed a reduced expression of VEGF, eNOS and SDF-1? compared with non-diabetic animals. At day 6, RLX administration resulted in an increase in VEGF mRNA expression and protein wound content, in eNOS expression and in SDF-1? mRNA. Furthermore, the histological evaluation indicated that RLX improved the impaired wound healing, enhanced the staining of MMP-11 (matrix metalloproteinase-11) and increased wound-breaking strength at day 12 in diabetic mice. Immunohistochemistry showed that RLX in diabetic animals augmented new vessel formation by stimulating both angiogenesis and vasculogenesis. RLX significantly reduced the time to complete skin normalization and this effect was abrogated by a concomitant treatment with antibodies against VEGF and CXCR4 (CXC chemokine receptor 4), the SDF-1? receptor. These data strongly suggest that RLX may have a potential application in diabetes-related wound disorders. PMID:23742173

Bitto, Alessandra; Irrera, Natasha; Minutoli, Letteria; Calò, Margherita; Lo Cascio, Patrizia; Caccia, Paolo; Pizzino, Gabriele; Pallio, Giovanni; Micali, Antonio; Vaccaro, Mario; Saitta, Antonino; Squadrito, Francesco; Altavilla, Domenica

2013-01-01

265

Transplantation of insulin-secreting cells differentiated from human adipose tissue-derived stem cells into type 2 diabetes mice.  

PubMed

Currently, there are limited ways to preserve or recover insulin secretory capacity in human pancreas. We evaluated the efficacy of cell therapy using insulin-secreting cells differentiated from human eyelid adipose tissue-derived stem cells (hEAs) into type 2 diabetes mice. After differentiating hEAs into insulin-secreting cells (hEA-ISCs) in vitro, cells were transplanted into a type 2 diabetes mouse model. Serum levels of glucose, insulin and c-peptide were measured, and changes of metabolism and inflammation were assessed in mice that received undifferentiated hEAs (UDC group), differentiated hEA-ISCs (DC group), or sham operation (sham group). Human gene expression and immunohistochemical analysis were done. DC group mice showed improved glucose level, and survival up to 60 days compared to those of UDC and sham group. Significantly increased levels of human insulin and c-peptide were detected in sera of DC mice. RT-PCR and immunohistochemical analysis showed human gene expression and the presence of human cells in kidneys of DC mice. When compared to sham mice, DC mice exhibited lower levels of IL-6, triglyceride and free fatty acids as the control mice. Transplantation of hEA-ISCs lowered blood glucose level in type 2 diabetes mice by increasing circulating insulin level, and ameliorating metabolic parameters including IL-6. PMID:24148246

Nam, Ji Sun; Kang, Hyun Mi; Kim, Jiyoung; Park, Seah; Kim, Haekwon; Ahn, Chul Woo; Park, Jin Oh; Kim, Kyung Rae

2014-01-10

266

High-molecular weight hyaluronan reduced renal PKC activation in genetically diabetic mice.  

PubMed

The cluster determinant (CD44) seems to play a key role in tissues injured by diabetes type 2. CD44 stimulation activates the protein kinase C (PKC) family which in turn activates the transcriptional nuclear factor kappa B (NF-?B) responsible for the expression of the inflammation mediators such as tumor necrosis factor alpha (TNF-?), interleukin-6 (IL-6), interleukin-18 (IL-18), inducible nitric oxide synthase (iNOS), and matrix metalloproteinases (MMPs). Regulation of CD44 interaction with its ligands depends greatly upon PKC. We investigated the effect of the treatment with high-molecular weight hyaluronan (HA) on diabetic nephropathy in genetically diabetic mice. BKS.Cg-m+/+Lepr(db) mice had elevated plasma insulin from 15 days of age and high blood sugar levels at 4 weeks. The severe nephropathy that developed was characterized by a marked increased in CD44 receptors, protein kinase C betaI, betaII, and epsilon (PKC(?I), PKC(?II), and PKC?) mRNA expression and the related protein products in kidney tissue. High levels of mRNA and related protein levels were also detected in the damaged kidney for NF-?B, TNF-?, IL-6, IL-18, MMP-7, and iNOS. Chronic daily administration of high-molecular mass HA for 2 weeks significantly reduced CD44, PKC(?I), PKC(?II), and PKC? gene expression and the related protein production in kidney tissue and TNF-?, IL-6, IL-18, MMP-7, and iNOS expression and levels also decreased. Histological analysis confirmed the biochemical data. However, blood parameters of diabetes were unchanged. These results suggest that the CD44 and PKC play an important role in diabetes and interaction of high-molecular weight HA with these proteins may reduce inflammation and secondary pathologies due to this disease. PMID:20713153

Campo, Giuseppe M; Avenoso, Angela; Micali, Antonio; Nastasi, Giancarlo; Squadrito, Francesco; Altavilla, Domenica; Bitto, Alessandra; Polito, Francesca; Rinaldi, Maria Grazia; Calatroni, Alberto; D'Ascola, Angela; Campo, Salvatore

2010-11-01

267

Type 1 diabetes in mice and men: gene expression profiling to investigate disease pathogenesis.  

PubMed

Type 1 diabetes (T1D) is a complex polygenic disease that is triggered by various environmental factors in genetically susceptible individuals. The emphasis placed on genome-wide association studies to explain the genetics of T1D has failed to advance our understanding of T1D pathogenesis or identify biomarkers of disease progression or therapeutic targets. Using the nonobese diabetic (NOD) mouse model of T1D and the non-disease prone congenic NOD.B10 mice, our laboratory demonstrated striking tissue-specific and age-dependent changes in gene expression during disease progression. We established a "roadmap" of differential gene expression and used this to identify candidate genes in mice (and human orthologs) that play a role in disease pathology. Here, we describe two genes, Deformed epidermal autoregulatory factor 1 (Deaf1) and Adenosine A1 receptor (Adora1), that are differentially expressed and alternatively spliced in the pancreatic lymph nodes or islets of NOD mice and T1D patients to form dominant-negative non-functional isoforms. Loss of Deaf1 function leads to reduced peripheral tissue antigen expression in lymph node stromal cells and may contribute to a breakdown in peripheral tolerance, while reduced Adora1 function results in an early intrinsic alpha cell defect that may explain the hyperglucagonemia and resulting beta cell stress observed prior to the onset of diabetes. Remarkably, both genes were also alternatively spliced in the same tissues of auto-antibody positive prediabetic patients, and these splicing events resulted in similar downstream effects as those seen in NOD mice. These findings demonstrate the value of gene expression profiling in studying disease pathogenesis in T1D. PMID:24682832

Yip, Linda; Fathman, C Garrison

2014-05-01

268

Anti-diabetic properties of a non-conventional radical scavenger, as compared to pioglitazone and exendin-4, in streptozotocin-nicotinamide diabetic mice.  

PubMed

We previously showed that the innovative radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) improves metabolic dysfunctions in a diabetic mouse model. Here, we compared the in vivo effects of IAC with those of the anti-diabetic drugs pioglitazone (PIO) and exendin-4 (EX-4). Diabetes was induced in C57Bl/6J mice by streptozotocin and nicotinamide administration. Paralleled by healthy controls, diabetic animals (D) were randomly assigned to four groups and treated daily for 7 consecutive weeks: D+saline, ip; D+IAC 30mg/kgb.w., ip; D+PIO 10mg/kgb.w. per os; and D+EX-4, 50?g/kgb.w., ip. Our results show that IAC reduced basal hyperglycemia and improved glucose tolerance better than PIO or EX-4. Interestingly, in the heart of diabetic mice, IAC treatment normalized the increased levels of GSSG/GSH ratio and thiobarbituric acid reactive substances, indexes of oxidative stress and damage, while PIO and EX-4 were less effective. As supported by immunohistochemical data, IAC markedly prevented diabetic islet ?-cell reduced density, differently from PIO and EX-4 that had only a moderate effect. Interestingly, in diabetic animals, IAC treatment enhanced the activity of pancreatic-duodenal homeobox 1 (PDX-1), an oxidative stress-sensitive transcription factor essential for maintenance of ?-cell function, as evaluated by quantification of its nuclear immunostaining, whereas PIO or EX-4 treatments did not. Altogether, these observations support the improvement of the general redox balance and ?-cell function induced by IAC treatment in streptozotocin-nicotinamide diabetic mice. Furthermore, in this model, the correction of diabetic alterations was better obtained by treatment with the radical scavenger IAC than with pioglitazone or exendin-4. PMID:24530416

Novelli, Michela; Canistro, Donatella; Martano, Manuela; Funel, Niccola; Sapone, Andrea; Melega, Simone; Masini, Matilde; De Tata, Vincenzo; Pippa, Anna; Vecoli, Cecilia; Campani, Daniela; De Siena, Rocco; Soleti, Antonio; Paolini, Moreno; Masiello, Pellegrino

2014-04-15

269

Assessment of Gastric Emptying in Non-obese Diabetic Mice Using a [13C]-octanoic Acid Breath Test  

PubMed Central

Gastric emptying studies in mice have been limited by the inability to follow gastric emptying changes in the same animal since the most commonly used techniques require killing of the animals and postmortem recovery of the meal1,2. This approach prevents longitudinal studies to determine changes in gastric emptying with age and progression of disease. The commonly used [13C]-octanoic acid breath test for humans3 has been modified for use in mice4-6 and rats7 and we previously showed that this test is reliable and responsive to changes in gastric emptying in response to drugs and during diabetic disease progression8. In this video presentation the principle and practical implementation of this modified test is explained. As in the previous study, NOD LtJ mice are used, a model of type 1 diabetes9. A proportion of these mice develop the symptoms of gastroparesis, a complication of diabetes characterized by delayed gastric emptying without mechanical obstruction of the stomach10. This paper demonstrates how to train the mice for testing, how to prepare the test meal and obtain 4 hr gastric emptying data and how to analyze the obtained data. The carbon isotope analyzer used in the present study is suitable for the automatic sampling of the air samples from up to 12 mice at the same time. This technique allows the longitudinal follow-up of gastric emptying from larger groups of mice with diabetes or other long-standing diseases. PMID:23542813

Creedon, Christopher T.; Verhulst, Pieter-Jan; Choi, Kyoung M.; Mason, Jessica E.; Linden, David R.; Szurszewski, Joseph H.; Gibbons, Simon J.; Farrugia, Gianrico

2013-01-01

270

Changes in mitochondrial Ca2+ homeostasis in primary sensory neurons of diabetic mice.  

PubMed

Changes in neuronal Ca2+ homeostasis were studied on freshly isolated dorsal root ganglion neurons of adult control mice and mice with streptozotocin (STZ)-induced diabetes. The cytoplasmic free Ca2+ concentration ([Ca2+]in) was measured using indo-1 based microfluorimetry. The participation of mitochondria in [Ca2+]in homeostasis was determined by investigation of changes which occurred after addition of mitochondrial protonophore (CCCP) to the extracellular solution. In control cells 10 microM CCCP applied before membrane depolarization induced an increase of the amplitude of depolarization-induced [Ca2+]in transients and disappearance of their delayed recovery, indicating the participation of mitochondria in fast uptake of Ca2+ ions from the cytosol during the peak of the transient and subsequent slow release them back during its decay. In diabetic animals the increase of the peak transient amplitude under the action of CCCP became diminished in small (nociceptive) neurons and the delayed elevation of [Ca2+]in disappeared in both large and small neurons. It is concluded that in diabetic conditions substantial changes occur in the Ca2+ homeostatic functions of mitochondria, manifested by decreased Ca2+ uptake in small neurons and depressed Ca2+ release into the cytosol in all types of neurons. PMID:9601679

Svichar, N; Shishkin, V; Kostyuk, E; Voitenko, N

1998-04-20

271

SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2(Akita) diabetic mice.  

PubMed

Superoxide dismutase (SOD) is a major defender against excessive superoxide generated under hyperglycemia. We have recently reported that renal SOD1 (cytosolic CuZn-SOD) and SOD3 (extracellular CuZn-SOD) isoenzymes are remarkably down-regulated in KK/Ta-Ins2(Akita) diabetic mice, which exhibit progressive diabetic nephropathy (DN), but not in DN-resistant C57BL/6- Ins2(Akita) (C57BL/6-Akita) diabetic mice. To determine the role of SOD1 and SOD3 in DN, we generated C57BL/6-Akita diabetic mice with deficiency of SOD1 and/or SOD3 and investigated their renal phenotype at the age of 20 weeks. Increased glomerular superoxide levels were observed in SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice but not in SOD1(+/+)SOD3(-/-) C57BL/6-Akita mice. The SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice exhibited higher glomerular filtration rate, increased urinary albumin levels, and advanced mesangial expansion as compared with SOD1(+/+)SOD3(+/+) C57BL/6-Akita mice, yet the severity of DN did not differ between the SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita groups. Increased renal mRNA expression of transforming growth factor-?1 (TGF-?1) and connective tissue growth factor (CTGF), reduced glomerular nitric oxide (NO), and increased renal prostaglandin E2 (PGE2) production were noted in the SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice. This finding indicates that such renal changes in fibrogenic cytokines, NO, and PGE2, possibly caused by superoxide excess, would contribute to the development of overt albuminuria by promoting mesangial expansion, endothelial dysfunction, and glomerular hyperfiltration. The present results demonstrate that deficiency of SOD1, but not SOD3, increases renal superoxide in the setting of diabetes and causes overt renal injury in nephropathy-resistant diabetic mice, and that SOD3 deficiency does not provide additive effects on the severity of DN in SOD1-deficient C57BL/6-Akita mice. PMID:22632894

Fujita, Hiroki; Fujishima, Hiromi; Takahashi, Keiko; Sato, Takehiro; Shimizu, Tatsunori; Morii, Tsukasa; Shimizu, Takahiko; Shirasawa, Takuji; Qi, Zhonghua; Breyer, Matthew D; Harris, Raymond C; Yamada, Yuichiro; Takahashi, Takamune

2012-12-01

272

The anti-diabetic effects and pharmacokinetic profiles of berberine in mice treated with Jiao-Tai-Wan and its compatibility.  

PubMed

Jiao-Tai-Wan (JTW), a classical Chinese prescription, has been clinically employed to treat diabetes mellitus in recent years. To investigate the comparative evaluations on anti-diabetic effects and pharmacokinetics of the active ingredient berberine in mice treated with JTW in various combinations of its constituent herbs. In our study, the anti-diabetic study was carried out in diabetic mice induced by intraperitoneal injection of streptozotocin. The diabetic mice were randomly assigned to three therapy groups and orally administered with different prescription proportions of Rhizoma Coptidis and Cinnamomum cassia respectively. The level of plasma glucose, lipid profile and parameters related to oxidative stress were determined. The concentrations of berberine in non-diabetic mice plasma were determined using HPLC, and main pharmacokinetic parameters were investigated. The results indicated that the compatibility effects of ingredients present in Cinnamomum cassia could affect the anti-diabetic ability and pharmacokinetics of berberine in JTW. PMID:23582408

Chen, Guang; Lu, Fuer; Xu, Lijun; Dong, Hui; Yi, Ping; Wang, Fang; Huang, Zhaoyi; Zou, Xin

2013-07-15

273

Hypoglycemic activity of Eriobotrya japonica seeds in type 2 diabetic rats and mice.  

PubMed

The hypoglycemic effects of Eriobotrya japonica seeds were investigated in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and KK-A(y) mice. The rats and mice were fed on a diet containing 10% powdered Eriobotrya japonica seeds with the coat intact for 4 months. Although the blood glucose concentration in the OLETF rats fed on the control diet without Eriobotrya japonica seeds was increased with time, the concentration in the OLETF rats fed on the diet with Eriobotrya japonica seeds was consistently low throughout the experimental period and was comparable to the level in Long-Evans Tokushima Otsuka (LETO) rats which are normal non-diabetic rats. Serum insulin was significantly lower in the OLETF rats fed on the Eriobotrya japonica seed diet than in those fed on the control diet at the termination of the experimental period. Eriobotrya japonica seeds suppressed the increment of blood glucose for 4 months and also effectively improved the glucose tolerance in the KK-A(y) mice, these actions being mainly exerted by the ethanol extract of the seeds. These results suggest that Eriobotrya japonica seeds had a hypoglycemic property and the effect is attributable to the components extracted by ethanol. PMID:18323632

Tanaka, Kazunari; Nishizono, Shoko; Makino, Nozomi; Tamaru, Shizuka; Terai, Osamu; Ikeda, Ikuo

2008-03-01

274

Transplantation of bone marrow derived cells promotes pancreatic islet repair in diabetic mice  

SciTech Connect

The transplantation of bone marrow (BM) derived cells to initiate pancreatic regeneration is an attractive but as-yet unrealized strategy. Presently, BM derived cells from green fluorescent protein transgenic mice were transplanted into diabetic mice. Repair of diabetic islets was evidenced by reduction of hyperglycemia, increase in number of islets, and altered pancreatic histology. Cells in the pancreata of recipient mice co-expressed BrdU and insulin. Double staining revealed {beta} cells were in the process of proliferation. BrdU{sup +} insulin{sup -} PDX-1{sup +} cells, Ngn3{sup +} cells and insulin{sup +} glucagon{sup +} cells, which showed stem cells, were also found during {beta}-cell regeneration. The majority of transplanted cells were mobilized to the islet and ductal regions. In recipient pancreas, transplanted cells simultaneously expressed CD34 but did not express insulin, PDX-1, Ngn3, Nkx2.2, Nkx6.1, Pax4, Pax6, and CD45. It is concluded that BM derived cells especially CD34{sup +} cells can promote repair of pancreatic islets. Moreover, both proliferation of {beta} cells and differentiation of pancreatic stem cells contribute to the regeneration of {beta} cells.

Gao Xiaodong; Song Lujun; Shen Kuntang; Wang Hongshan [Department of General Surgery, Center Laboratory of Surgery, Zhongshan Hospital, Shanghai Medical School, Fudan University, 180, Fenglin Road, Shanghai 200032 (China); Niu Weixin [Department of General Surgery, Center Laboratory of Surgery, Zhongshan Hospital, Shanghai Medical School, Fudan University, 180, Fenglin Road, Shanghai 200032 (China)], E-mail: niu.weixin@zs-hospital.sh.cn; Qin Xinyu [Department of General Surgery, Center Laboratory of Surgery, Zhongshan Hospital, Shanghai Medical School, Fudan University, 180, Fenglin Road, Shanghai 200032 (China)], E-mail: qin.xinyu@zs-hospital.sh.cn

2008-06-20

275

B6.g7 mice reconstituted with BDC2?5 non-obese diabetic (BDC2?5NOD) stem cells do not develop autoimmune diabetes  

PubMed Central

In BDC2·5 non-obese diabetic (BDC2·5NOD) mice, a spontaneous model of type 1 diabetes, CD4+ T cells express a transgene-encoded T cell receptor (TCR) with reactivity against a pancreatic antigen, chromogranin. This leads to massive infiltration and destruction of the pancreatic islets and subsequent diabetes. When we reconstituted lethally irradiated, lymphocyte-deficient B6.g7 (I-Ag7+) Rag–/– mice with BDC2·5NOD haematopoietic stem and progenitor cells (HSPC; ckit+Lin–Sca-1hi), the recipients exhibited hyperglycaemia and succumbed to diabetes. Surprisingly, lymphocyte-sufficient B6.g7 mice reconstituted with BDC2·5NOD HSPCs were protected from diabetes. In this study, we investigated the factors responsible for attenuation of diabetes in the B6.g7 recipients. Analysis of chimerism in the B6.g7 recipients showed that, although B cells and myeloid cells were 98% donor-derived, the CD4+ T cell compartment contained ?50% host-derived cells. These host-derived CD4+ T cells were enriched for conventional regulatory T cells (Tregs) (CD25+forkhead box protein 3 (FoxP3)+] and also for host- derived CD4+CD25–FoxP3– T cells that express markers of suppressive function, CD73, FR4 and CD39. Although negative selection did not eliminate donor-derived CD4+ T cells in the B6.g7 recipients, these cells were functionally suppressed. Thus, host-derived CD4+ T cells that emerge in mice following myeloablation exhibit a regulatory phenoytpe and probably attenuate autoimmune diabetes. These cells may provide new therapeutic strategies to suppress autoimmunity. PMID:23795893

Rajasekaran, N; Wang, N; Hang, Y; Macaubas, C; Rinderknecht, C; Beilhack, G F; Shizuru, J A; Mellins, E D

2013-01-01

276

B6.g7 mice reconstituted with BDC2·5 non-obese diabetic (BDC2·5NOD) stem cells do not develop autoimmune diabetes.  

PubMed

In BDC2·5 non-obese diabetic (BDC2·5NOD) mice, a spontaneous model of type 1 diabetes, CD4(+) T cells express a transgene-encoded T cell receptor (TCR) with reactivity against a pancreatic antigen, chromogranin. This leads to massive infiltration and destruction of the pancreatic islets and subsequent diabetes. When we reconstituted lethally irradiated, lymphocyte-deficient B6.g7 (I-A(g7+)) Rag(-/-) mice with BDC2·5NOD haematopoietic stem and progenitor cells (HSPC; ckit(+)Lin(-)Sca-1(hi)), the recipients exhibited hyperglycaemia and succumbed to diabetes. Surprisingly, lymphocyte-sufficient B6.g7 mice reconstituted with BDC2·5NOD HSPCs were protected from diabetes. In this study, we investigated the factors responsible for attenuation of diabetes in the B6.g7 recipients. Analysis of chimerism in the B6.g7 recipients showed that, although B cells and myeloid cells were 98% donor-derived, the CD4(+) T cell compartment contained ?50% host-derived cells. These host-derived CD4(+) T cells were enriched for conventional regulatory T cells (Tregs ) (CD25(+) forkhead box protein 3 (FoxP3)(+)] and also for host- derived CD4(+)CD25(-)FoxP3(-) T cells that express markers of suppressive function, CD73, FR4 and CD39. Although negative selection did not eliminate donor-derived CD4(+) T cells in the B6.g7 recipients, these cells were functionally suppressed. Thus, host-derived CD4(+) T cells that emerge in mice following myeloablation exhibit a regulatory phenoytpe and probably attenuate autoimmune diabetes. These cells may provide new therapeutic strategies to suppress autoimmunity. PMID:23795893

Rajasekaran, N; Wang, N; Hang, Y; Macaubas, C; Rinderknecht, C; Beilhack, G F; Shizuru, J A; Mellins, E D

2013-10-01

277

Inhibition of Kidney Proximal Tubular Glucose Reabsorption Does Not Prevent against Diabetic Nephropathy in Type 1 Diabetic eNOS Knockout Mice  

PubMed Central

Background and Objective Sodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect. Research Design and Methods We induced diabetes using a low dose streptozotocin protocol in 7–8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice). Results Diabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor ?1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups. Conclusion Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering. PMID:25369239

Gangadharan Komala, Muralikrishna; Gross, Simon; Mudaliar, Harshini; Huang, Chunling; Pegg, Katherine; Mather, Amanda; Shen, Sylvie; Pollock, Carol A.; Panchapakesan, Usha

2014-01-01

278

Xenogenic transplantation of human breast adipose-derived stromal vascular fraction enhances recovery of erectile function in diabetic mice.  

PubMed

The adipose tissue-derived stromal vascular fraction (SVF) is an ideal source of stem and stromal cells. The aim of this study was to examine whether and how xenogenic transplantation of human breast SVF restores erectile function in diabetic mice. Human SVF was isolated from five patients (age, 20-45 yr) undergoing reduction mammoplasty. Eight-week-old C57BL/6J mice were used, and diabetes was induced by intraperitoneal injection of streptozotocin. At 8 wk after induction of diabetes, the animals were randomly distributed into controls and diabetic mice treated with a single intracavernous injection of PBS, human SVF at different concentrations, or human SVF lysate. Two weeks later, erectile function was measured by cavernous nerve stimulation, and the penis was then harvested for biochemical examinations. Erectile function was significantly improved in diabetic mice treated with human SVF (2 × 10(5), 5 × 10(5), and 1 × 10(6) cells/20 ?l) and SVF lysate. Human SVF treatment in diabetic mice significantly increased cavernous endothelial and smooth muscle cell contents, induced eNOS phosphorylation, and restored penile nNOS-positive nerve fibers. Human SVF lysate induced secretion of angiogenic factors and expression of their receptors. Human SVF did not increase serum levels of proinflammatory cytokines. A limitation of this study was that the exact composition of the human SVF was not examined. In summary, xenogenic transplantation of human SVF did not induce systemic inflammation and successfully improved erectile function in diabetic mice through enhanced penile angiogenesis and neural regeneration. PMID:24501171

Das, Nando Dulal; Song, Kang-Moon; Yin, Guo Nan; Batbold, Dulguun; Kwon, Mi-Hye; Kwon, Ki-Dong; Kim, Woo Jean; Kim, Yeon Soo; Ryu, Ji-Kan; Suh, Jun-Kyu

2014-03-01

279

Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice.  

PubMed

Diabetic hyperglycemia increases ischemic brain damage in experimental animals and humans. The mechanisms are unclear but may involve enhanced apoptosis in penumbral regions. Estrogen is an established neuroprotectant in experimental stroke. Our previous study demonstrated that female diabetic db/db mice suffered less damage following cerebral hypoxia-ischemia (H/I) than male db/db mice. Here we investigated the effects of diabetes and estrogen apoptotic gene expression following H/I. Female db/db and nondiabetic (+/?) mice were ovariectomized (OVX) and treated with estrogen or vehicle prior to H/I; brains were analyzed for damage and bcl-2 family gene expression. OVX increased ischemic damage in +/? mice; estrogen reduced tissue injury and enhanced antiapoptotic gene expression (bcl-2 and bfl-1). db/db mice demonstrated more damage, without increased bcl-2 mRNA; bfl-1 expression appeared at 48 hours of recovery associated with infarction. To our knowledge, this is the first description of bfl-1 in the brain with localization to microglia and macrophages. Early induction of bfl-1 expression in +/? mouse brain was associated with microglia; delayed bfl-1 expression in diabetic brain was in macrophages bordering the infarct. Furthermore, estrogen replacement stimulated early postischemic expression of bcl-2 and bfl-1 and reduced damage in normoglycemic animals but failed to protect the diabetic brain. PMID:14702112

Zhang, Liqun; Nair, Aji; Krady, Kyle; Corpe, Christopher; Bonneau, Robert H; Simpson, Ian A; Vannucci, Susan J

2004-01-01

280

Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice  

PubMed Central

Diabetic hyperglycemia increases ischemic brain damage in experimental animals and humans. The mechanisms are unclear but may involve enhanced apoptosis in penumbral regions. Estrogen is an established neuroprotectant in experimental stroke. Our previous study demonstrated that female diabetic db/db mice suffered less damage following cerebral hypoxia-ischemia (H/I) than male db/db mice. Here we investigated the effects of diabetes and estrogen apoptotic gene expression following H/I. Female db/db and nondiabetic (+/?) mice were ovariectomized (OVX) and treated with estrogen or vehicle prior to H/I; brains were analyzed for damage and bcl-2 family gene expression. OVX increased ischemic damage in +/? mice; estrogen reduced tissue injury and enhanced antiapoptotic gene expression (bcl-2 and bfl-1). db/db mice demonstrated more damage, without increased bcl-2 mRNA; bfl-1 expression appeared at 48 hours of recovery associated with infarction. To our knowledge, this is the first description of bfl-1 in the brain with localization to microglia and macrophages. Early induction of bfl-1 expression in +/? mouse brain was associated with microglia; delayed bfl-1 expression in diabetic brain was in macrophages bordering the infarct. Furthermore, estrogen replacement stimulated early postischemic expression of bcl-2 and bfl-1 and reduced damage in normoglycemic animals but failed to protect the diabetic brain. PMID:14702112

Zhang, Liqun; Nair, Aji; Krady, Kyle; Corpe, Christopher; Bonneau, Robert H.; Simpson, Ian A.; Vannucci, Susan J.

2004-01-01

281

Opposite effects of angiotensins receptors type 2 and type 4 on streptozotocin induced diabetes vascular alterations in mice  

PubMed Central

Background We examined the effect of chronic administration of angiotensin IV (AngIV) on the vascular alterations induced by type 1 diabetes in mice. Methods Diabetes was induced in adult Swiss mice with a single injection of streptozotocin (STZ). Mice were treated subcutaneously with AngIV (1.4 mg/kg/day) either immediately following diabetes induction (preventive treatment), or treated with AngIV (0.01 to 1.4 mg/kg), alone or with the AT4 receptor antagonist Divalinal or the AT2 receptor antagonist PD123319, for two weeks after 4 weeks of diabetes duration (rescue treatment). Acetylcholine-induced, endothelium-dependent relaxation (EDR) was measured in isolated aortic rings preparations. Histomorphometric measurements of the media thickness were obtained, and nitric oxide (NO) and superoxide anion production were measured by electron paramagnetic resonance in aorta and mesenteric arteries. The effect of diabetes on mesenteric vascular alterations was also examined in genetically modified mice lacking the AT2 receptor. Results Induction of diabetes with STZ was associated with a progressive decrease of EDR and an increase of the aortic and mesenteric media thickness already significant after 4 weeks and peaking at week 6. Immediate treatment with AngIV fully prevented the diabetes-induced endothelial dysfunction. Rescue treatment with AngIV implemented after 4 weeks of diabetes dose-dependently restored a normal endothelial function at week 6. AngIV blunted the thickening of the aortic and mesenteric media, and reversed the diabetes-induced changes in NO and O2•– production by the vessels. The protective effect of AngIV on endothelial function was completely blunted by cotreatment with Divalinal, but not with PD123319. In contrast, both the pharmacological blockade and genetic deletion of the AT2 receptor reversed the diabetes-induced morphologic and endothelial alteration caused by diabetes. Conclusions The results suggest an opposite contribution of AT2 and AT4 receptors to the vascular alterations caused by streptozotocin-induced diabetes in mice, since chronic stimulation of AT4 by AngIV and inhibition of AT2 similarly reverse diabetes-induced endothelial dysfunction and hypertrophic remodeling, and increase NO bioavailability. PMID:24511993

2014-01-01

282

Urtica dioica extract attenuates depressive like behavior and associative memory dysfunction in dexamethasone induced diabetic mice.  

PubMed

Evidences suggest that glucocorticoids results in depression and is a risk factor for type 2 diabetes. Further diabetes induces oxidative stress and hippocampal dysfunction resulting in cognitive decline. Traditionally Urtica dioica has been used for diabetes mellitus and cognitive dysfunction. The present study investigated the effect of the hydroalcoholic extract of Urtica dioica leaves (50 and 100 mg/kg, p.o.) in dexamethasone (1 mg/kg, i.m.) induced diabetes and its associated complications such as depressive like behavior and cognitive dysfunction. We observed that mice administered with chronic dexamethasone resulted in hypercortisolemia, oxidative stress, depressive like behavior, cognitive impairment, hyperglycemia with reduced body weight, increased water intake and decreased hippocampal glucose transporter-4 (GLUT4) mRNA expression. Urtica dioica significantly reduced hyperglycemia, plasma corticosterone, oxidative stress and depressive like behavior as well as improved associative memory and hippocampal GLUT4 mRNA expression comparable to rosiglitazone (5 mg/kg, p.o.). Further, Urtica dioica insignificantly improved spatial memory and serum insulin. In conclusion, Urtica dioica reversed dexamethasone induced hyperglycemia and its associated complications such as depressive like behavior and cognitive dysfunction. PMID:24435938

Patel, Sita Sharan; Udayabanu, Malairaman

2014-03-01

283

Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice.  

PubMed

Endoplasmic reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischaemia-induced neovascularization in type II diabetes is unknown. We studied ischaemia-induced neovascularization in the hind-limb of 4-week-old db - /db- mice and their controls treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) and interleukin-1 receptor antagonist (anakinra, 0.5 µg/mouse per day) for 4 weeks. Blood pressure was similar in all groups of mice. Blood glucose, insulin levels, and body weight were reduced in db - /db- mice treated with TUDCA. Increased cholesterol and reduced adiponectin in db - /db- mice were restored by TUDCA and anakinra treatment. ER stress and inflammation in the ischaemic hind-limb in db - /db- mice were attenuated by TUDCA and anakinra treatment. Ischaemia-induced neovascularization and blood flow recovery were significantly reduced in db - /db- mice compared to control. Interestingly, neovascularization and blood flow recovery were restored in db - /db- mice treated with TUDCA or anakinra compared to non-treated db - /db- mice. TUDCA and anakinra enhanced eNOS-cGMP, VEGFR2, and reduced ERK1/2 MAP-kinase signalling, while endothelial progenitor cell number was similar in all groups of mice. Our findings demonstrate that the inhibition of ER stress and inflammation prevents impaired ischaemia-induced neovascularization in type II diabetic mice. Thus, ER stress and inflammation could be potential targets for a novel therapeutic approach to prevent impaired ischaemia-induced vascular pathology in type II diabetes. PMID:22081301

Amin, Ali; Choi, Soo-kyoung; Galan, Maria; Kassan, Modar; Partyka, Megan; Kadowitz, Philip; Henrion, Daniel; Trebak, Mohamed; Belmadani, Souad; Matrougui, Khalid

2012-06-01

284

Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes  

PubMed Central

In certain animal models of autoimmunity the isoxasol derivative leflunomide has been reported to exert a protective effect against autodestruction. In the present study, the immunomodulatory potential of the main metabolite of leflunomide, A77 1726, in experimentally induced autoimmune diabetes was investigated. The disease was induced in genetically susceptible CBA/H mice by multiple low doses of streptozotocin (MLD-SZ, 40 mg/kg per day, given intraperitoneally for 5 consecutive days). Effects of leflunomide were evaluated by two treatment protocols: mice treated with MLD-SZ were injected intraperitoneally with A77 1726 for 10 consecutive days, either during the first 10 days of the disease (early treatment), or starting from day 10 after disease induction (late treatment). Disease manifestations defined by hyperglycaemia, mononuclear infiltration into pancreas, expression of interferon-gamma (IFN-?) and inducible nitric oxide synthase (iNOS) and destruction of the islets of Langerhans were reduced in a dose-dependent fashion after early treatment with A77 1726 (dose range of 5–35 mg/kg per day). Moreover, late treatment with the high dose of the drug (25 mg/kg per day), started when the autoimmune disease was already apparent, arrested progression of ongoing inflammatory response. Analysis of the effects of A77 1726 on the adhesive interactions of spleen-derived or peripheral blood-derived mononuclear cells from MLD-SZ-treated and normal mice demonstrated that the drug inhibits both ex vivo and in vitro spontaneous mononuclear cell aggregation, thus suggesting that an important component of leflunomide's immunomodulatory action is suppression of adhesive interactions. These results demonstrate both preventive and therapeutic effects of leflunomide in a model of MLD-SZ-induced diabetes and suggest that the drug may be considered a potent therapeutic tool for autoimmune inflammatory disorders, including diabetes. PMID:10403914

STOSIC-GRUJICIC, S; DIMITRIJEVIC, M; BARTLETT, R

1999-01-01

285

Prolactin modulates the incidence of diabetes in male and female NOD mice.  

PubMed

The nonobese diabetic (NOD) mouse develops diabetes spontaneously due to autoimmune destruction of the pancreatic islets with a higher incidence in the female than the male. Prolactin (PRL), a hormone whose role has been previously focused on reproduction and lactation has been demonstrated to influence immune responses. In this study, we investigated the effect of hypoprolactinemia and hyperprolactinemia on the incidence of diabetes in male and female NOD mice. Our hypoprolactinemia model was induced from the time of weaning (21 days of age) to 112 days of age by daily injections of 200 micrograms of bromocriptine (CB-154). A hyperprolactinemic model was induced by a syngeneic anterior pituitary transplant (APT) to the kidney capsule at 35 days of age and maintained until 112 days of age. Additional experimental groups were also investigated. A group of males received pituitary transplants combined with daily subcutaneous injections of CB-154. A group of females treated with CB-154 was also given daily subcutaneous injections of 30 micrograms of oPRL. An ovariectomized (OVX-Control) group of females was also established to serve as a second control for the OVX-APT group. Bromocriptine administration did not significantly decrease plasma PRL levels compared to controls (CTRL) while APT animals had plasma PRL levels that were significantly higher (P < 0.01) than those of CTRL and CB-154 animals. These differences were observed in animals of both sexes. Bromocriptine treatment of APT groups significantly lowered plasma PRL levels from their respective controls. Plasma PRL from the OVX-Control group was markedly lower than the intact female control. The incidence of diabetes was significantly lower in female mice receiving CB-154 injections compared to the intact female CTRL group at 84, 98 and 112 days of age.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7858100

Hawkins, T A; Gala, R R; Dunbar, J C

1994-01-01

286

Polyacetylenic compounds and butanol fraction from Bidens pilosa can modulate the differentiation of helper T cells and prevent autoimmune diabetes in non-obese diabetic mice.  

PubMed

Compelling evidence suggests that infiltrating CD4+ type I helper T (Th1) cells in the pancreatic islets play a pivotal role in the progression of diabetes in non-obese diabetic (NOD) mice. We demonstrate in the present report that a butanol fraction of B. pilosa suppressed the development of diabetes, helped maintain levels of blood sugar and insulin in NOD mice in a dose-dependent manner and elevated the serum IgE levels regulated by Th2 cytokines in NOD mice. Moreover, the butanol fraction inhibited the differentiation of naive helper T (Th0) cells into Th1 cells but enhanced their transition into type II helper T (Th2) cells using an in vitro T cell differentiation assay. Two polyacetylenic compounds, 2-beta-D-glucopyranosyloxy-1-hydroxy-5(E)-tridecene-7,9,11-triyne and 3-beta-D-glucopyranosyloxy-1-hydroxy-6(E)-tetradecene-8,10,12-triyne, identified from the butanol fraction also prevented the onset of diabetes like the butanol fraction. The latter compound showed a stronger activity for T cell differentiation than the former. In summary, the butanol fraction of B. pilosa and its polyacetylenes can prevent diabetes plausibly via suppressing the differentiation of Th0 cells into Th1 cells and promoting that of Th0 cells into Th2 cells. PMID:15549660

Chang, Shu-Lin; Chang, Cicero Lee-Tian; Chiang, Yi-Ming; Hsieh, Rong-Hong; Tzeng, Chii-Ruey; Wu, Tung-Kung; Sytwu, Huey-Kang; Shyur, Lie-Fen; Yang, Wen-Chin

2004-11-01

287

Antioxidant effect of Lagerstroemia speciosa Pers (banaba) leaf extract in streptozotocin-induced diabetic mice.  

PubMed

Aqueous leaf extract of L. speciosa (banaba) effectively decreased the blood glucose in streptozotocin-induced diabetic mice after 15th day of banaba exposure. Further, banaba leaf extract have the potential to inhibit lipid peroxidation and effectively intercept/neutralize reactive oxygen species such as super oxide, H2O2 and NO based free radicals. The aqueous banaba leaf extract (150 mg/kg bodyweight) duly reduced STZ generated reactive intermediates and radical species helping to regulate normal levels of antioxidative markers like superoxide dismutase, catalase, glutathione-S-transferase and reduced glutathione. PMID:21428214

Saumya, S M; Basha, P Mahaboob

2011-02-01

288

Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice.  

PubMed

Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co-cultures prepared from WT (wild-type) mice. This protection was lost if the co-cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN. PMID:20711301

Urban, Michael J; Li, Chengyuan; Yu, Cuijuan; Lu, Yuanming; Krise, Joanna M; McIntosh, Michelle P; Rajewski, Roger A; Blagg, Brian S J; Dobrowsky, Rick T

2010-01-01

289

International Workshop on Lessons From Animal Models for Human Type 1 Diabetes: identification of insulin but not glutamic acid decarboxylase or IA2 as specific autoantigens of humoral autoimmunity in nonobese diabetic mice  

Microsoft Academic Search

Several self-antigens have been reported as targets of the autoimmune response in nonobese diabetic (NOD) mice. The aim of this workshop was to identify autoantibody assays that could provide useful markers of autoimmunity in this animal model for type 1 diabetes. More than 400 serum samples from NOD (4, 8, and 12 weeks of age and at diabetes onset), BALB\\/c,

E. Bonifacio; M. Atkinson; G. Eisenbarth; D. Serreze; T. W. H. Kay; Chan E Lee; B. Singh

2001-01-01

290

Sensitization to gliadin induces moderate enteropathy and insulitis in nonobese diabetic-DQ8 mice.  

PubMed

Celiac disease (CD) is frequently diagnosed in patients with type 1 diabetes (T1D), and T1D patients can exhibit Abs against tissue transglutaminase, the auto-antigen in CD. Thus, gliadin, the trigger in CD, has been suggested to have a role in T1D pathogenesis. The objective of this study was to investigate whether gliadin contributes to enteropathy and insulitis in NOD-DQ8 mice, an animal model that does not spontaneously develop T1D. Gliadin-sensitized NOD-DQ8 mice developed moderate enteropathy, intraepithelial lymphocytosis, and barrier dysfunction, but not insulitis. Administration of anti-CD25 mAbs before gliadin-sensitization induced partial depletion of CD25(+)Foxp3(+) T cells and led to severe insulitis, but did not exacerbate mucosal dysfunction. CD4(+) T cells isolated from pancreatic lymph nodes of mice that developed insulitis showed increased proliferation and proinflammatory cytokines after incubation with gliadin but not with BSA. CD4(+) T cells isolated from nonsensitized controls did not response to gliadin or BSA. In conclusion, gliadin sensitization induced moderate enteropathy in NOD-DQ8 mice. However, insulitis development required gliadin-sensitization and partial systemic depletion of CD25(+)Foxp3(+) T cells. This humanized murine model provides a mechanistic link to explain how the mucosal intolerance to a dietary protein can lead to insulitis in the presence of partial regulatory T cell deficiency. PMID:21911598

Galipeau, Heather J; Rulli, Nestor E; Jury, Jennifer; Huang, Xianxi; Araya, Romina; Murray, Joseph A; David, Chella S; Chirdo, Fernando G; McCoy, Kathy D; Verdu, Elena F

2011-10-15

291

Granulocyte-dendritic cell unbalance in the non-obese diabetic mice.  

PubMed

Several investigators, including ourselves, have reported lower yield of GM-CSF bone marrow-derived dendritic cells (DC) with altered MHC class II and co-stimulatory molecules expression in the non-obese diabetic (NOD) mice. However, whether this defect was intrinsic to the DC lineage and/or related to abnormal expansion of other cell types responding to GM-CSF remained an opened issue. We performed phenotypical and morphological analysis of cells from GM-CSF-supplemented-bone marrow-cultures and of freshly isolated bone marrow and blood cells from unmanipulated prediabetic NOD mice. The results show a heretofore undescribed bias towards generation of granulocytes in NOD mice, concomitant with quantitative and qualitative alterations of the DC lineage in both the bone marrow and the blood of this mouse strain. We propose that increased generation of granulocytes in NOD mice might contribute to autoimmunity. First, high numbers of granulocytes per se might favor inflammatory environment. Second, granulocytes, by interfering with DC development, might favor unbalanced antigen presenting cell function leading to T cell autoimmunity. PMID:12914754

Morin, Joëlle; Chimènes, Amélie; Boitard, Christian; Berthier, Rolande; Boudaly, Sarah

2003-05-01

292

Antidiabetic and Antioxidant Effects of Polyphenols in Brown Alga Ecklonia stolonifera in Genetically Diabetic KK-A y Mice  

Microsoft Academic Search

The dietary intake and control of blood glucose levels are very important in hyperglycemic patients and ?-glucosidase inhibitors\\u000a are a cost-effective means to preventing the progression of diabetes. In search of a natural inhibitor from food materials,\\u000a ?-glucosidase inhibitory activity and the anti-hyperglycemic effects of a brown alga, Ecklonia stolonifera, were investigated using non-insulin dependent diabetic mice. Methanolic extract of

Kunihisa Iwai

2008-01-01

293

Activation of Peroxisome Proliferator-Activated Receptor ? Inhibits Streptozotocin-Induced Diabetic Nephropathy Through Anti-Inflammatory Mechanisms in Mice  

PubMed Central

OBJECTIVE Activation of the nuclear hormone receptor peroxisome proliferator–activated receptor (PPAR)-? has been shown to improve insulin resistance, adiposity, and plasma HDL levels. Several studies have reported that activation of PPAR? is atheroprotective; however, the role of PPAR? in renal function remains unclear. Here, we report the renoprotective effects of PPAR? activation in a model of streptozotocin-induced diabetic nephropathy. RESEARCH DESIGN AND METHODS Eight-week-old male C57BL/6 mice were divided into three groups: 1) nondiabetic control mice, 2) diabetic mice, and 3) diabetic mice treated with the PPAR? agonist GW0742 (1 mg/kg/day). GW0742 was administered by gavage for 8 weeks after inducing diabetes. RESULTS GW0742 decreased urinary albumin excretion without altering blood glucose levels. Macrophage infiltration, mesangial matrix accumulation, and type IV collagen deposition were substantially attenuated by GW0742. The gene expression of inflammatory mediators in the kidney cortex, such as monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN), was also suppressed. In vitro studies demonstrated that PPAR? activation increased the expression of anti-inflammatory corepressor B-cell lymphoma-6, which subsequently suppressed MCP-1 and OPN expression. CONCLUSIONS These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPAR? agonists and support the concept that PPAR? agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy. PMID:21270242

Matsushita, Yuichi; Ogawa, Daisuke; Wada, Jun; Yamamoto, Noriko; Shikata, Kenichi; Sato, Chikage; Tachibana, Hiromi; Toyota, Noriko; Makino, Hirofumi

2011-01-01

294

Effects of polysaccharide from pumpkin on biochemical indicator and pancreatic tissue of the diabetic rabbits.  

PubMed

A water-soluble polysaccharide (PCE-CC) was obtained from pumpkin which belongs to the family Cucubitaceae by the water and ethanol extract, organic solvent fractional extraction and deproteinization. The present study was designed to investigate PCE-CC possible mechanism underlying the improvement of damaged pancreatic islets. Alloxan-induced diabetic rabbits were injected with PCE-CC for 21 days to assess effects on islet tissue morphology. After 21 days, the weights of the alloxan-induced diabetic and non-diabetic rabbits fed with diet contained PCE-CC were significantly increased as compared to the negative group. The data of blood glucose (BG), total cholesterol (TC), total triglyceride (TG) and glycosylated hemoglobin (HbA1c) indicated that PCE-CC had beneficial effects on the improvement in the control of blood glucose, serum lipid and glycosylated hemoglobin levels. Observing the pancreatic tissue of the diabetic rabbits revealed that PCE-CC could promote the regeneration of damaged pancreatic islets by stimulating ?-cell proliferation, which was accompanied by a decrease in plasma glucose levels. PCE-CC was further separated and purified to obtain PCE-CCH by ion exchange and gel chromatography. PCE-CCH was a heteropolysaccharide and consisted of glucose, galactose, arabinose, rhamnose and little amount of hexuronic acid, with a molecular weight of 1.15 × 10(5) Da. PMID:24095662

Zhang, Yongjun; Chen, Ping; Zhang, Yu; Jin, Hui; Zhu, Liyun; Li, Jia; Yao, Huiyuan

2013-11-01

295

[Effectiveness of parenteral feeding with various hydrolysates in alloxan diabetes in white rats].  

PubMed

The effect of applying various hydrolysates for parenteral feeding (caseine hydrolysate, hydrolysin L-103, aminosol, moriamine S-2) in albino rats with alloxan-induced diabetes was investigated. The assimilation of the hydrolysates introduced was found in these animals to be down by comparison with intact ones. It was only administration of nitrogenous media containing a sufficient amount of aminic nitrogen (moriamine S-2) that helped establish a positive nitrogenous balance and to prevent a loss of weight and the dry weight of the tissues. PMID:808036

Glants, R M; Skovronskaia, E V; Vovk, G P

1975-01-01

296

Bacille Calmette-Guérin/DNAhsp65 prime-boost is protective against diabetes in non-obese diabetic mice but not in the streptozotocin model of type 1 diabetes.  

PubMed

Type I diabetes is a disease caused by autoimmune destruction of the beta cells in the pancreas that leads to a deficiency in insulin production. The aim of this study was to evaluate the prophylactic potential of a prime-boost strategy involving bacille Calmette-Guérin (BCG) and the pVAXhsp65 vaccine (BCG/DNAhsp65) in diabetes induced by streptozotocin (STZ) in C57BL/6 mice and also in spontaneous type 1 diabetes in non-obese diabetic (NOD) mice. BCG/DNAhsp65 vaccination in NOD mice determined weight gain, protection against hyperglycaemia, decreased islet inflammation, higher levels of cytokine production by the spleen and a reduced number of regulatory T cells in the spleen compared with non-immunized NOD mice. In the STZ model, however, there was no significant difference in the clinical parameters. Although this vaccination strategy did not protect mice in the STZ model, it was very effective in NOD mice. This is the first report demonstrating that a prime-boost strategy could be explored as an immunomodulatory procedure in autoimmune diseases. PMID:23692306

da Rosa, L C; Chiuso-Minicucci, F; Zorzella-Pezavento, S F G; França, T G D; Ishikawa, L L W; Colavite, P M; Balbino, B; Tavares, L C B; Silva, C L; Marques, C; Ikoma, M R V; Sartori, A

2013-09-01

297

Bacille Calmette-Gu?rin/DNAhsp65 prime-boost is protective against diabetes in non-obese diabetic mice but not in the streptozotocin model of type 1 diabetes  

PubMed Central

Type I diabetes is a disease caused by autoimmune destruction of the beta cells in the pancreas that leads to a deficiency in insulin production. The aim of this study was to evaluate the prophylactic potential of a prime-boost strategy involving bacille Calmette–Guérin (BCG) and the pVAXhsp65 vaccine (BCG/DNAhsp65) in diabetes induced by streptozotocin (STZ) in C57BL/6 mice and also in spontaneous type 1 diabetes in non-obese diabetic (NOD) mice. BCG/DNAhsp65 vaccination in NOD mice determined weight gain, protection against hyperglycaemia, decreased islet inflammation, higher levels of cytokine production by the spleen and a reduced number of regulatory T cells in the spleen compared with non-immunized NOD mice. In the STZ model, however, there was no significant difference in the clinical parameters. Although this vaccination strategy did not protect mice in the STZ model, it was very effective in NOD mice. This is the first report demonstrating that a prime-boost strategy could be explored as an immunomodulatory procedure in autoimmune diseases. PMID:23692306

Rosa, L C; Chiuso-Minicucci, F; Zorzella-Pezavento, S F G; Franca, T G D; Ishikawa, L L W; Colavite, P M; Balbino, B; Tavares, L C B; Silva, C L; Marques, C; Ikoma, M R V; Sartori, A

2013-01-01

298

Importance of Sulfur-Containing Metabolites in Discriminating Fecal Extracts between Normal and Type-2 Diabetic Mice.  

PubMed

A metabolic disorder such as Type-2 Diabetes mellitus (T2DM) is a complex disease induced by genetic, environmental, and nutritional factors. The db/db mouse model, bearing a nonfunctional leptin receptor, is widely used to investigate the pathophysiology of T2DM. Fecal extracts of db/db and wild-type littermates were studied to unravel a broad spectrum of new and relevant metabolites related to T2DM as proxies of the interplay of gut microbiome and murine metabolomes. The nontargeted metabolomics approach consists of an integrated analytical concept of high-resolution mass spectrometry FT-ICR-MS, followed by UPLC-TOF-MS/MS experiments. We demonstrate that a metabolic disorder such as T2DM affects the gastrointestinal tract environment, thereby influencing different metabolic pathways and their respective metabolites in diabetic mice. Fatty acids, bile acids concerning cholic and deoxycholic acid, and steroid metabolism were highly discriminative comparing fecal meta-metabolomes of wt and db/db mice. Furthermore, sulfur-(S)-containing metabolites including N-acyl taurines were altered in diabetic mice, enabling us to focus on S-containing metabolites, especially the sulfate and taurine conjugates of bile and fatty acids. Different sulfate containing bile acids including sulfocholic acid, oxocholic acid sulfate, taurocholic acid sulfate, and cyprinol sulfate were significantly altered in diabetic mice. Moreover, we identified 12 new sulfate and taurine conjugates of hydroxylated fatty acids with significant importance in T2DM metabolism in db/db mice. PMID:24991707

Walker, Alesia; Lucio, Marianna; Pfitzner, Barbara; Scheerer, Markus F; Neschen, Susanne; de Angelis, Martin Hrab?; Hartmann, Anton; Schmitt-Kopplin, Philippe

2014-10-01

299

Improvement of antioxidant balance in diabetes mellitus type 1 mice by glutathione supplement.  

PubMed

Diabetes mellitus (DM) type 1 is a chronic disease characterized by hyperglycemia and lacking of insulin. Oxidative stress participates in development and progression of DM, in which changes of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) content were noted in DM mice. In this study, the effects of GSH supplement on anti-oxidation system in streptozotocin-induced DM type 1 Imprinting Control Region (ICR) mice were determined. The co-treatment of insulin and GSH significantly lowered the hepatic manganese superoxide dismutase (Mn-SOD), CAT, and GPx mRNA expression. Moreover, co-administration of insulin and GSH restored SOD and CAT activities to non-DM group except that of the CAT activity in the kidney. The GSH contents and GSH/GSSG ratio in the mouse livers were normalized to the normal levels by the GSH treatment and the co-administration of insulin and GSH. These observations reveal that GSH supplement potentially has the protective roles in delaying diabetic progression via the improvement of antioxidant balance. PMID:25362599

Pimson, Charinya; Chatuphonprasert, Waranya; Jarukamjorn, Kanokwan

2014-11-01

300

Coronary arterioles in type 2 diabetic (db\\/db) mice undergo a distinct pattern of remodeling associated with decreased vessel stiffness  

Microsoft Academic Search

Little is known about the impact of type 2 diabetes mellitus (DM) on coronary arteriole remodeling. The aim of this study\\u000a was to determine the mechanisms that underlie coronary arteriole structural remodeling in type 2 diabetic (db\\/db) mice. Passive\\u000a structural properties of septal coronary arterioles isolated from 12- to 16-week-old diabetic db\\/db and control mice were\\u000a assessed by pressure myography.

Paige S. Katz; Aaron J. Trask; Flavia M. Souza-Smith; Kirk R. Hutchinson; Maarten L. Galantowicz; Kevin C. Lord; James A. Stewart; Mary J. Cismowski; Kurt J. Varner; Pamela A. Lucchesi

301

Role of mTOR in podocyte function and diabetic nephropathy in humans and mice  

PubMed Central

Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy. PMID:21606591

Godel, Markus; Hartleben, Bjorn; Herbach, Nadja; Liu, Shuya; Zschiedrich, Stefan; Lu, Shun; Debreczeni-Mor, Andrea; Lindenmeyer, Maja T.; Rastaldi, Maria-Pia; Hartleben, Gotz; Wiech, Thorsten; Fornoni, Alessia; Nelson, Robert G.; Kretzler, Matthias; Wanke, Rudiger; Pavenstadt, Hermann; Kerjaschki, Dontscho; Cohen, Clemens D.; Hall, Michael N.; Ruegg, Markus A.; Inoki, Ken; Walz, Gerd; Huber, Tobias B.

2011-01-01

302

Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals  

PubMed Central

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and one of the major causes of blindness worldwide. The pathogenesis of DR has been investigated using several animal models of diabetes. These models have been generated by pharmacological induction, feeding a galactose diet, and spontaneously by selective inbreeding or genetic modification. Among the available animal models, rodents have been studied most extensively owing to their short generation time and the inherited hyperglycemia and/or obesity that affect certain strains. In particular, mice have proven useful for studying DR and evaluating novel therapies because of their amenability to genetic manipulation. Mouse models suitable for replicating the early, non-proliferative stages of the retinopathy have been characterized, but no animal model has yet been found to demonstrate all of the vascular and neural complications that are associated with the advanced, proliferative stages of DR that occur in humans. In this review, we summarize commonly used animal models of DR, and briefly outline the in vivo imaging techniques used for characterization of DR in these models. Through highlighting the ocular pathological findings, clinical implications, advantages and disadvantages of these models, we provide essential information for planning experimental studies of DR that will lead to new strategies for its prevention and treatment. PMID:22730475

Robinson, Remya; Barathi, Veluchamy A.; Chaurasia, Shyam S.; Wong, Tien Y.; Kern, Timothy S.

2012-01-01

303

Fucoxanthin promotes translocation and induction of glucose transporter 4 in skeletal muscles of diabetic\\/obese KK- A y mice  

Microsoft Academic Search

Fucoxanthin (Fx) isolated from Undaria pinnatifida suppresses the development of hyperglycemia and hyperinsulinemia of diabetic\\/obese KK-Ay mice after two weeks of feeding 0.2% Fx-containing diet. In the soleus muscle of KK-Ay mice that were fed Fx, glucose transporter 4 (GLUT4) translocation to plasma membranes from cytosol was promoted. On the other hand, Fx increased GLUT4 expression levels in the extensor

Sho Nishikawa; Masashi Hosokawa; Kazuo Miyashita

304

Modulations of cytochrome P450 expression in diabetic mice by berberine.  

PubMed

Berberine, an isoquinoline alkaloid isolated from medicinal plants such as Berberis aristata, Coptis chinesis, Coptis japonica, Coscinium fenestatun, and Hydrastis Canadensis, is widely used in Asian countries for the treatment of diabetes, hypertension, and hypercholesterolemia. Interaction between berberine and the cytochrome P450 enzymes (CYPs) has been extensively reported, but there are only a few reports of this interaction in the diabetic state. In this study, the effect of berberine on the mRNA of the CYPs in primary mouse hepatocytes and in streptozotocin (STZ)-induced diabetic mice was investigated. In primary mouse hepatocytes, berberine suppressed the induction of Cyp1a1, Cyp1a2, Cyp2e1, Cyp3a11, Cyp4a10, and Cyp4a14 mRNA expression by their prototypical inducers in a concentration-dependent fashion. However, berberine treatment alone increased the expression of Cyp2b9 and Cyp2b10 mRNA. In vivo, berberine showed the same hypoglycemic activity as metformin, an established hypoglycemic drug. The hepatic mRNA levels of Cyp1a1, Cyp2b9, Cyp2b10, Cyp3a11, Cyp4a10, and Cyp4a14 were increased in STZ-induced diabetic mice. Interestingly, berberine itself suppressed the expression of Cyp2e1, an adverse hepatic event-associated enzyme, while the expression of Cyp3a11, Cyp4a10, and Cyp4a14 were restored to normal levels by berberine. In conclusion, berberine has the potential to modify the expression of CYPs by either suppression or enhancement of CYPs' levels. Consumption of berberine as an anti-hyperglycemic compound by diabetic patients might provide an extra benefit due to its potential to restore the expression of Cyp2e1, Cyp3a, and Cyp4a to normal levels. However, an herb-drug interaction might be of concern since any berberine-containing product would definitely cause pronounced interactions based on CYP3A4 inhibition. PMID:22342832

Chatuphonprasert, Waranya; Nemoto, Nobuo; Sakuma, Tsutomu; Jarukamjorn, Kanokwan

2012-03-01

305

Identification of a novel gene for diabetic traits in rats, mice, and humans.  

PubMed

The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci. PMID:25236446

Tsaih, Shirng-Wern; Holl, Katie; Jia, Shuang; Kaldunski, Mary; Tschannen, Michael; He, Hong; Andrae, Jaime Wendt; Li, Shun-Hua; Stoddard, Alex; Wiederhold, Andrew; Parrington, John; Ruas da Silva, Margarida; Galione, Antony; Meigs, James; Hoffmann, Raymond G; Simpson, Pippa; Jacob, Howard; Hessner, Martin; Solberg Woods, Leah C

2014-09-01

306

Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans  

PubMed Central

The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci. PMID:25236446

Tsaih, Shirng-Wern; Holl, Katie; Jia, Shuang; Kaldunski, Mary; Tschannen, Michael; He, Hong; Andrae, Jaime Wendt; Li, Shun-Hua; Stoddard, Alex; Wiederhold, Andrew; Parrington, John; Ruas da Silva, Margarida; Galione, Antony; Meigs, James; Hoffmann, Raymond G.; Simpson, Pippa; Jacob, Howard; Hessner, Martin; Solberg Woods, Leah C.

2014-01-01

307

Changes in Liver Cell DNA Methylation Status in Diabetic Mice Affect Its FT-IR Characteristics  

PubMed Central

Background Lower levels of cytosine methylation have been found in the liver cell DNA from non-obese diabetic (NOD) mice under hyperglycemic conditions. Because the Fourier transform-infrared (FT-IR) profiles of dry DNA samples are differently affected by DNA base composition, single-stranded form and histone binding, it is expected that the methylation status in the DNA could also affect its FT-IR profile. Methodology/Principal Findings The DNA FT-IR signatures obtained from the liver cell nuclei of hyperglycemic and normoglycemic NOD mice of the same age were compared. Dried DNA samples were examined in an IR microspectroscope equipped with an all-reflecting objective (ARO) and adequate software. Conclusions/Significance Changes in DNA cytosine methylation levels induced by hyperglycemia in mouse liver cells produced changes in the respective DNA FT-IR profiles, revealing modifications to the vibrational intensities and frequencies of several chemical markers, including ?as –CH3 stretching vibrations in the 5-methylcytosine methyl group. A smaller band area reflecting lower energy absorbed in the DNA was found in the hyperglycemic mice and assumed to be related to the lower levels of –CH3 groups. Other spectral differences were found at 1700–1500 cm?1 and in the fingerprint region, and a slight change in the DNA conformation at the lower DNA methylation levels was suggested for the hyperglycemic mice. The changes that affect cytosine methylation levels certainly affect the DNA-protein interactions and, consequently, gene expression in liver cells from the hyperglycemic NOD mice. PMID:25019512

Vidal, Benedicto de Campos; Ghiraldini, Flavia Gerelli; Mello, Maria Luiza S.

2014-01-01

308

Type 1 Diabetes in NOD Mice Unaffected by Mast Cell Deficiency.  

PubMed

Mast cells have been invoked as important players in immune responses associated with autoimmune diseases. Based on in vitro studies, or in vivo through the use of Kit mutant mice, mast cells have been suggested to play immunological roles in direct antigen presentation to both CD4(+) and CD8(+) T cells, in the regulation of T-cell and dendritic cell migration to lymph nodes, and in Th1 versus Th2 polarization, all of which could significantly impact the immune response against self-antigens in autoimmune disease, including type 1 diabetes (T1D). Until now, the role of mast cells in the onset and incidence of T1D has only been indirectly tested through the use of low-specificity mast cell inhibitors and activators, and published studies reported contrasting results. Our three laboratories have generated independently two strains of mast cell-deficient nonobese diabetic (NOD) mice, NOD.Cpa3(Cre/+) (Heidelberg) and NOD.Kit(W-sh/W-sh) (Leuven and Boston), to address the effects of mast cell deficiency on the development of T1D in the NOD strain. Our collective data demonstrate that both incidence and progression of T1D in NOD mice are independent of mast cells. Moreover, analysis of pancreatic lymph node cells indicated that lack of mast cells has no discernible effect on the autoimmune response, which involves both innate and adaptive immune components. Our results demonstrate that mast cells are not involved in T1D in the NOD strain, making their role in this process nonessential and excluding them as potential therapeutic targets. PMID:24917576

Gutierrez, Dario A; Fu, Wenxian; Schonefeldt, Susann; Feyerabend, Thorsten B; Ortiz-Lopez, Adriana; Lampi, Yulia; Liston, Adrian; Mathis, Diane; Rodewald, Hans-Reimer

2014-11-01

309

COX-2 but Not mPGES-1 Contributes to Renal PGE2 Induction and Diabetic Proteinuria in Mice with Type-1 Diabetes  

PubMed Central

Prostaglandin E2 (PGE2) has been implicated to play a pathogenic role in diabetic nephropathy (DN) but its source remains unlcear. To elucidate whether mPGES-1, the best characterized PGE2 synthase, was involved in the development of DN, we examined the renal phenotype of mPGES-1 KO mice subjected to STZ-induced type-1 diabetes. After STZ treatment, mPGES-1 WT and KO mice presented the similar onset of diabetes as shown by similar elevation of blood glucose. Meanwhile, both genotypes of mice exhibited similar increases of urinary and renal PGE2 production. In parallel with this comparable diabetic status, the kidney injury indices including the urinary albumin excretion, kidney weight and the kidney histology (PAS staining) did not show any difference between the two genotypes. By Western-blotting and quantitative qRT-PCR, mPGES-1, mPGES-2, cPGES and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) remain unaltered following six weeks of diabetes. Finally, a selective COX-2 inhibitor celecoxib (50 mg/kg/day) was applied to the STZ-treated KO mice, which resulted in significant reduction of urinary albumin excretion (KO/STZ: 141.5±38.4 vs. KO/STZ + Celebrex: 48.7±20.8 ug/24 h, p<0.05) and the blockade of renal PGE2 induction (kidney: KO/STZ: 588.7±89.2 vs. KO/STZ + Celebrex: 340.8±58.7 ug/24 h, p<0.05; urine: KO/STZ 1667.6±421.4 vs. KO/STZ + Celebrex 813.6±199.9 pg/24 h, p<0.05), without affecting the blood glucose levels and urine volume. Taken together, our data suggests that an as yet unidentified prostaglanind E synthase but not mPGES-1 may couple with COX-2 to mediate increased renal PGE2 sythsesis in DN. PMID:24984018

Liu, Shanshan; Liu, Ying; Yang, Tianxin

2014-01-01

310

Differential gene expression in Lin-/VEGF-R2+ bone marrow-derived endothelial progenitor cells isolated from diabetic mice  

PubMed Central

Background Diabetes is known to impair the number and function of endothelial progenitor cells in the circulation, causing structural and functional alterations in the micro- and macro-vasculature. The aim of this study was to identify early diabetes-related changes in the expression of genes that have been reported to be closely involved in endothelial progenitor cell migration and function. Methods Based on review of current literature, this study examined the expression level of 35 genes that are known to be involved in endothelial progenitor cell migration and function in magnetically sorted Lin-/VEGF-R2+ endothelial progenitor cells obtained from the bone marrow of Akita mice in the early stages of diabetes (18 weeks) using RT-PCR and Western blotting. We used the Shapiro-Wilk and D’Agostino & Pearson Omnibus tests to assess normality. Differences between groups were evaluated by Student’s t-test for normally distributed data (including Welch correction in cases of unequal variances) or Mann–Whitney test for not normally distributed data. Results We observed a significant increase in the number of Lin-/VEGF-R2+ endothelial progenitor cells within the bone marrow in diabetic mice compared with non-diabetic mice. Two genes, SDF-1 and SELE, were significantly differentially expressed in diabetic Lin-/VEGF-R2+ endothelial progenitor cells and six other genes, CAV1, eNOS, CLDN5, NANOG, OCLN and BDNF, showed very low levels of expression in diabetic Lin-/VEGF-R2+ progenitor cells. Conclusion Low SDF-1 expression may contribute to the dysfunctional mobilization of bone marrow Lin-/VEGF-R2+ endothelial progenitor cells, which may contribute to microvascular injury in early diabetes. PMID:24521356

2014-01-01

311

Wound Healing Improvement with PHD-2 Silenced Fibroblasts in Diabetic Mice  

PubMed Central

Background Hypoxia-inducible factor 1? is the central regulator of the hypoxia-induced response which results in the up-regulation of angiogenic factors. Its activity is under precise regulation of prolyl-hydroxylase domain 2. We hypothesized that PHD2 silenced fibroblasts would increase the expression of angiogenic factors, which might contribute to the improvement of the diabetic wound healing. Materials and Methods 50 dB/db mice were employed and randomly assigned into five groups with 10 mice in each: group 1 (untreated cell), group 2 (PHD2 silenced cell), group 3 (L-mimosine treated cells), group 4 (nontargeting siRNA treated cells) and group 5 (sham control). Fibroblasts were cultivated from the dermis of mice in each group and treated with PHD2 targeting siRNA, L-mimosine and non-targeting siRNA respectively. A fraction of the fibroblasts were employed to verify the silencing rate of PHD2 after 48 hours. The autologous fibroblasts (treated and untreated) labeled with adenovirus-GFP were implanted around the wound (?6mm), which was created on the dorsum of each mouse. The status of wounds was recorded periodically. Ten days postoperatively, 3 mice from each group were sacrificed and wound tissues were harvested. Molecular biological examinations were performed to evaluate the expressions of cytokines. 28 days postoperatively, the remaining mice were sacrificed. Histological examinations were performed to evaluate the densities of GFP+ cells and capillaries. Results The expression of PHD2 reduced to 12.5%, and the expressions of HIF-1? and VEGFa increased significantly after PHD2 siRNA treatment. With the increasing expressions of HIF-1? and VEGFa, the time to wound closure in group 2 was less than 2 weeks. Increased numbers of GFP+ cells and capillaries were observed in group 2. Conclusion PHD2 siRNA treatment not only increased the expression of HIF1? and VEGFa, but also improved the fibroblast proliferation. These effects might contribute to the improvement of the diabetic wound healing. PMID:24376825

Cheng, Liang; Dai, Jiezhi; Wang, Chunyang; Han, Pei; Chai, Yimin

2013-01-01

312

STREPTOZOTOCIN-INDUCED DIABETES PARTIALLY ATTENUATES THE EFFECTS OF A HIGH-FAT DIET ON LIVER AND BRAIN FATTY ACID COMPOSITION IN MICE  

PubMed Central

The current study addresses the effects of a high-fat diet on liver and brain fatty acid compositions and the interaction of that diet with diabetes in a type 1 mouse model. Adult, male, normal and streptozotocin-induced diabetic C57BL/6 mice were fed standard (14% kcals from fat) or high-fat (54% kcals from fat, hydrogenated vegetable shortening and corn oil) diets for 8 weeks. Liver and whole brain total phospholipid fatty acid compositions were then determined by TLC/GC. In the liver of non-diabetic mice, the high-fat diet increased the percentages of 18:1n-9, 20:4n-6, and 22:5n-6 and decreased 18:2n-6 and 22:6n-3. Diabetes increased 16:0 in liver, and decreased 18:1n-7 and 20:4n-6. The effects of the high-fat diet on liver phospholipids in diabetic mice were similar to those in non-diabetic mice, or were of smaller magnitude. In the brain, the high-fat diet increased 18:0 and 20:4n-6 of non-diabetic, but not diabetic mice. Brain 22:5n-6 acid was increased by the high-fat diet in both non-diabetic and diabetic mice, but this increase was smaller in diabetic mice. Diabetes alone did not alter the percentage of any individual fatty acid in brain. This indicates that the effects of a high-fat diet on liver and brain phospholipid fatty acid compositions are mitigated by concomitant hyperglycemia with hypoinsulinemia. PMID:23893338

Levant, Beth; Ozias, Marlies K.; Guilford, Brianne L.; Wright, Douglas E.

2013-01-01

313

A mixture of extracts from Peruvian plants (black maca and yacon) improves sperm count and reduced glycemia in mice with streptozotocin-induced diabetes.  

PubMed

We investigated the effect of two extracts from Peruvian plants given alone or in a mixture on sperm count and glycemia in streptozotocin-diabetic mice. Normal or diabetic mice were divided in groups receiving vehicle, black maca (Lepidium meyenii), yacon (Smallanthus sonchifolius) or three mixtures of extracts black maca/yacon (90/10, 50/50 and 10/90%). Normal or diabetic mice were treated for 7?d with each extract, mixture or vehicle. Glycemia, daily sperm production (DSP), epididymal and vas deferens sperm counts in mice and polyphenol content, and antioxidant activity in each extract were assessed. Black maca (BM), yacon and the mixture of extracts reduced glucose levels in diabetic mice. Non-diabetic mice treated with BM and yacon showed higher DSP than those treated with vehicle (p?Diabetic mice treated with BM, yacon and the mixture maca/yacon increased DSP, and sperm count in vas deferens and epididymis with respect to non-diabetic and diabetic mice treated with vehicle (p?diabetic mice. Streptozotocin increased 1.43 times the liver weight that was reversed with the assessed plants extracts. In summary, streptozotocin-induced diabetes resulted in reduction in sperm counts and liver damage. These effects could be reduced with BM, yacon and the BM+yacon mixture. PMID:23489070

Gonzales, Gustavo F; Gonzales-Castañeda, Cynthia; Gasco, Manuel

2013-09-01

314

The Microbial Product Lipopolysaccharide Confers Diabetogenic Potential on the T Cell Repertoire of BDC2.5\\/NOD Mice: Implications for the Etiology of Autoimmune Diabetes  

Microsoft Academic Search

Both genetic predisposition and environmental factors participate in the etiology of Type-1 diabetes. To test the role of the microbial product lipopolysaccharide (LPS) as an environmental trigger of autoimmune diabetes, we employed transgenic (tg) BDC2.5\\/NOD mice that bear an islet-specific CD4+ T cell repertoire (>95%), but do not develop the spontaneous diabetes that typifies the NOD (nonobese diabetic) strain. LPS

Balaji Balasa; Kurt Van Gunst; Nora Sarvetnick

2000-01-01

315

Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice.  

PubMed

We have reported that exercise capacity is reduced in high fat diet (HFD)-induced diabetic mice, and that this reduction is associated with impaired mitochondrial function in skeletal muscle (SKM). However, it remains to be clarified whether the treatment of diabetes ameliorates the reduced exercise capacity. Therefore, we examined whether an insulin-sensitizing drug, pioglitazone, could improve exercise capacity in HFD mice. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated with or without pioglitazone (3mg/kg/day) to yield the following 4 groups: ND+vehicle, ND+pioglitazone, HFD+vehicle, and HFD+pioglitazone (n=10 each). After 8 weeks, body weight, plasma glucose, and insulin in the HFD+vehicle were significantly increased compared to the ND+vehicle group. Pioglitazone normalized the insulin levels in HFD-fed mice, but did not affect the body weight or plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in the HFD+vehicle, and this reduction was almost completely ameliorated in HFD+pioglitazone mice. ADP-dependent mitochondrial respiration, complex I and III activities, and citrate synthase activity were significantly decreased in the SKM of the HFD+vehicle animals, and these decreases were also attenuated by pioglitazone. NAD(P)H oxidase activity was significantly increased in the HFD+vehicle compared with the ND+vehicle, and this increase was ameliorated in HFD+pioglitazone mice. Pioglitazone improved the exercise capacity in diabetic mice, which was due to the improvement in mitochondrial function and attenuation of oxidative stress in the SKM. Our data suggest that pioglitazone may be useful as an agent for the treatment of diabetes mellitus. PMID:24964389

Takada, Shingo; Hirabayashi, Kagami; Kinugawa, Shintaro; Yokota, Takashi; Matsushima, Shouji; Suga, Tadashi; Kadoguchi, Tomoyasu; Fukushima, Arata; Homma, Tsuneaki; Mizushima, Wataru; Masaki, Yoshihiro; Furihata, Takaaki; Katsuyama, Ryoichi; Okita, Koichi; Tsutsui, Hiroyuki

2014-10-01

316

Consumption of acidic water alters the gut microbiome and decreases the risk of diabetes in NOD mice.  

PubMed

Infant formula and breastfeeding are environmental factors that influence the incidence of Type 1 Diabetes (T1D) as well as the acidity of newborn diets. To determine if altering the intestinal microbiome is one mechanism through which an acidic liquid plays a role in T1D, we placed non-obese diabetic (NOD)/ShiLtJt mice on neutral (N) or acidified H2O and monitored the impact on microbial composition and diabetes incidence. NOD-N mice showed an increased development of diabetes, while exhibiting a decrease in Firmicutes and an increase in Bacteroidetes, Actinobacteria, and Proteobacteria from as early as 2 weeks of age. NOD-N mice had a decrease in the levels of Foxp3 expression in CD4(+)Foxp3(+) cells, as well as decreased CD4(+)IL17(+) cells, and a lower ratio of IL17/IFN? CD4+ T-cells. Our data clearly indicates that a change in the acidity of liquids consumed dramatically alters the intestinal microbiome, the presence of protective Th17 and Treg cells, and the incidence of diabetes. This data suggests that early dietary manipulation of intestinal microbiota may be a novel mechanism to delay T1D onset in genetically pre-disposed individuals. PMID:24453191

Wolf, Kyle J; Daft, Joseph G; Tanner, Scott M; Hartmann, Riley; Khafipour, Ehsan; Lorenz, Robin G

2014-04-01

317

Prevention of diabetic nephropathy in Ins2(+/)?(AkitaJ) mice by the mitochondria-targeted therapy MitoQ.  

PubMed

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2(+/)?(AkitaJ) mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2(+/)?(AkitaJ) mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and ?-catenin showed a nuclear accumulation in the Ins2(+/)?(AkitaJ) mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis. PMID:20825366

Chacko, Balu K; Reily, Colin; Srivastava, Anup; Johnson, Michelle S; Ye, Yaozu; Ulasova, Elena; Agarwal, Anupam; Zinn, Kurt R; Murphy, Michael P; Kalyanaraman, Balaraman; Darley-Usmar, Victor

2010-11-15

318

Prevention of diabetic nephropathy in Ins2+/?AkitaJ mice by the mitochondria-targeted therapy MitoQ  

PubMed Central

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2+/?AkitaJ mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2+/?AkitaJ mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and ?-catenin showed a nuclear accumulation in the Ins2+/?AkitaJ mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis. PMID:20825366

Chacko, Balu K.; Reily, Colin; Srivastava, Anup; Johnson, Michelle S.; Ye, Yaozu; Ulasova, Elena; Agarwal, Anupam; Zinn, Kurt R.; Murphy, Michael P.; Kalyanaraman, Balaraman; Darley-Usmar, Victor

2010-01-01

319

Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice.  

PubMed

Autonomic neuropathy is a significant diabetic complication resulting in increased morbidity and mortality. Studies of autopsied diabetic patients and several rodent models demonstrate that the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in prevertebral ganglia is the occurrence of synaptic pathology resulting in distinctive dystrophic neurites ("neuritic dystrophy"). Our prior studies show that neuritic dystrophy is reversed by exogenous IGF-I administration without altering the metabolic severity of diabetes, i.e. functioning as a neurotrophic substance. The description of erythropoietin (EPO) synergy with IGF-I function and the recent discovery of EPO's multifaceted neuroprotective role suggested it might substitute for IGF-I in treatment of diabetic autonomic neuropathy. Our current studies demonstrate EPO receptor (EPO-R) mRNA in a cDNA set prepared from NGF-maintained rat sympathetic neuron cultures which decreased with NGF deprivation, a result which demonstrates clearly that sympathetic neurons express EPO-R, a result confirmed by immunohistochemistry. Treatment of STZ-diabetic NOD-SCID mice have demonstrated a dramatic preventative effect of EPO and carbamylated EPO (CEPO, which is neuroprotective but not hematopoietic) on the development of neuritic dystrophy. Neither EPO nor CEPO had a demonstrable effect on the metabolic severity of diabetes. Our results coupled with reported salutary effects of EPO on postural hypotension in a few clinical studies of EPO-treated anemic diabetic and non-diabetic patients may reflect a primary neurotrophic effect of EPO on the sympathetic autonomic nervous system, rather than a primary hematopoietic effect. These findings may represent a major clinical advance since EPO has been widely and safely used in anemic patients due to a variety of clinical conditions. PMID:17967455

Schmidt, Robert E; Green, Karen G; Feng, Dongyan; Dorsey, Denise A; Parvin, Curtis A; Lee, Jin-Moo; Xiao, Qinlgi; Brines, Michael

2008-01-01

320

Anti-Inflammatory and Cardioprotective Effects of Tadalafil in Diabetic Mice  

PubMed Central

Background Insulin resistance impairs nitric oxide (NO) bioavailability and obesity promotes a state of chronic inflammation and damages the vascular endothelium. Phosphodiesterase-5 inhibitors restore NO signaling and may reduce circulating inflammatory markers, and improve metabolic parameters through a number of mechanisms. We hypothesized that daily administration of the PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammation, improve fasting plasma glucose and triglyceride levels, body weight, and reduce infarct size after ischemia/reperfusion injury in obese, diabetic mice. Methods Twenty leptin receptor null (db/db) mice underwent treatment with TAD (1 mg/Kg) or 10% DMSO for 28 days. Body weight and fasting plasma glucose levels were determined weekly. Upon completion, hearts were isolated and subjected to 30 min global ischemia followed by 60 min reperfusion in a Langendorff model. Plasma samples were taken for cytokine analysis and fasting triglyceride levels. Infarct size was measured using computer morphometry of tetrazolium stained sections. Additionally, ventricular cardiomyocytes were isolated and subjected to 40 min of simulated ischemia and reoxygenation. Necrosis was determined using trypan blue exclusion and LDH release assay and apoptosis was assessed by TUNEL assay after 1 h or 18 h of reoxygenation, respectively. Results Treatment with TAD caused a reduction in infarct size in the diabetic heart (23.2±1.5 vs. 47.8±3.7%, p<0.01, n?=?6/group), reduced fasting glucose levels (292±31.8 vs. 511±19.3 mg/dL, p<0.001) and fasting triglycerides (43.3±21 vs. 129.7±29 mg/dL, p<0.05) as compared to DMSO, however body weight was not significantly reduced. Circulating tumor necrosis factor-? and interleukin-1? were reduced after treatment compared to control (257±16.51 vs. 402.3±17.26 and 150.8±12.55 vs. 264±31.85 pg/mL, respectively; P<0.001) Isolated cardiomyocytes from TAD-treated mice showed reduced apoptosis and necrosis. Conclusion We have provided the first evidence that TAD therapy ameliorates circulating inflammatory cytokines and chemokines in a diabetic animal model while improving fasting glucose levels and reducing infarct size following ischemia-reperfusion injury in the heart. PMID:23028874

Varma, Amit; Das, Anindita; Hoke, Nicholas N.; Durrant, David E.; Salloum, Fadi N.; Kukreja, Rakesh C.

2012-01-01

321

Decellularized silk fibroin scaffold primed with adipose mesenchymal stromal cells improves wound healing in diabetic mice  

PubMed Central

Introduction Silk fibroin (SF) scaffolds have been shown to be a suitable substrate for tissue engineering and to improve tissue regeneration when cellularized with mesenchymal stromal cells (MSCs). We here demonstrate, for the first time, that electrospun nanofibrous SF patches cellularized with human adipose-derived MSCs (Ad-MSCs-SF), or decellularized (D-Ad-MSCs-SF), are effective in the treatment of skin wounds, improving skin regeneration in db/db diabetic mice. Methods The conformational and structural analyses of SF and D-Ad-MSCs-SF patches were performed by scanning electron microscopy, confocal microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. Wounds were performed by a 5 mm punch biopsy tool on the mouse’s back. Ad-MSCs-SF and D-Ad-MSCs-SF patches were transplanted and the efficacy of treatments was assessed by measuring the wound closure area, by histological examination and by gene expression profile. We further investigated the in vitro angiogenic properties of Ad-MSCs-SF and D-Ad-MSCs-SF patches by affecting migration of human umbilical vein endothelial cells (HUVECs), keratinocytes (KCs) and dermal fibroblasts (DFs), through the aortic ring assay and, finally, by evaluating the release of angiogenic factors. Results We found that Ad-MSCs adhere and grow on SF, maintaining their phenotypic mesenchymal profile and differentiation capacity. Conformational and structural analyses on SF and D-Ad-MSCs-SF samples, showed that sterilization, decellularization, freezing and storing did not affect the SF structure. When grafted in wounds of diabetic mice, both Ad-MSCs-SF and D-Ad-MSCs-SF significantly improved tissue regeneration, reducing the wound area respectively by 40% and 35%, within three days, completing the process in around 10 days compared to 15–17 days of controls. RT2 gene profile analysis of the wounds treated with Ad-MSCs-SF and D-Ad-MSCs-SF showed an increment of genes involved in angiogenesis and matrix remodeling. Finally, Ad-MSCs-SF and D-Ad-MSCs-SF co-cultured with HUVECs, DFs and KCs, preferentially enhanced the HUVECs’ migration and the release of angiogenic factors stimulating microvessel outgrowth in the aortic ring assay. Conclusions Our results highlight for the first time that D-Ad-MSCs-SF patches are almost as effective as Ad-MSCs-SF patches in the treatment of diabetic wounds, acting through a complex mechanism that involves stimulation of angiogenesis. Our data suggest a potential use of D-Ad-MSCs-SF patches in chronic diabetic ulcers in humans. PMID:24423450

2014-01-01

322

Gold nanorods in an oil-base formulation for transdermal treatment of type 1 diabetes in mice  

NASA Astrophysics Data System (ADS)

Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients.Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr30651d

Nose, Keisuke; Pissuwan, Dakrong; Goto, Masahiro; Katayama, Yoshiki; Niidome, Takuro

2012-05-01

323

Insulin-Producing Cells From Adult Human Bone Marrow Mesenchymal Stem Cells Control Streptozotocin-Induced Diabetes In Nude Mice  

PubMed Central

Harvesting, expansion and directed differentiation of human bone marrow-derived mesenchymal stem cells (BM-MSCs) could provide an autologous source of surrogate ?-cells that would alleviate the limitations of availability and/or allogenic rejection following pancreatic or islet transplantation. Bone marrow cells were obtained from three adult type 2 diabetic volunteers and 3 non-diabetic donors. After 3 days in culture, adherent MSCs were expanded for 2 passages. At passage 3, differentiation was carried out in a 3-staged procedure. Cells were cultured in a glucose-rich medium containing several activation and growth factors. Cells were evaluated in-vitro by flow cytometry, immunolabelling, Rt-PCR and human insulin and c-peptide release in responses to increasing glucose concentrations. One thousand cell-clusters were inserted under the renal capsule of diabetic nude mice followed by monitoring of their diabetic status. At the end of differentiation, ~5–10% of cells were immunofluorescent for insulin, c-peptide or glucagon; insulin and c-peptide were co-expressed. Nanogold immunolabelling for electron microscopy demonstrated the presence of c-peptide in the rough endoplasmic reticulum. Insulin-producing cells (IPCs) expressed transcription factors and genes of pancreatic hormones similar to those expressed by pancreatic islets. There was a stepwise increase in human insulin and c-peptide release by IPCs in response to increasing glucose concentrations. Transplantation of IPCs into nude diabetic mice resulted in control of their diabetic status for 3 months. The sera of IPC-transplanted mice contained human insulin and c-peptide but negligible levels of mouse insulin. When the IPCs-bearing kidneys were removed, rapid return of diabetic state was noted. BM-MSCs from diabetic and non-diabetic human subjects could be differentiated without genetic manipulation to form IPCs which, when transplanted, could maintain euglycaemia in diabetic mice for 3 months. Optimization of the culture conditions are required to improve the yield of IPCs and their functional performance. PMID:22710060

Gabr, Mahmoud M.; Zakaria, Mahmoud M.; Refaie, Ayman F.; Ismail, Amani M.; Abou-El-Mahasen, Mona A.; Ashamallah, Sylvia A.; Khater, Sherry M.; El-Halawani, Sawsan M.; Ibrahim, Rana Y.; Uin, Gan Shu; Kloc, Malgorzata; Calne, Roy Y.; Ghoneim, Mohamed A.

2013-01-01

324

Antioxidant and anti-diabetic potential of Passiflora alata Curtis aqueous leaves extract in type 1 diabetes mellitus (NOD-mice).  

PubMed

Leaves of Passiflora alata Curtis were characterized for their antioxidant capacity. Antioxidant analyses of DPPH, FRAP, ABTS, ORAC and phenolic compounds were made in three different extracts: aqueous, methanol/acetone and ethanol. Aqueous extract was found to be the best solvent for recovery of phenolic compounds and antioxidant activity, when compared with methanol/acetone and ethanol. To study the anti-inflammatory properties of this extract in experimental type 1 diabetes, NOD mice were divided into two groups: the P. alata group, treated with aqueous extract of P. alata Curtis, and a non-treated control group, followed by diabetes expression analysis. The consumption of aqueous extract and water ad libitum lasted 28 weeks. The treated-group presented a decrease in diabetes incidence, a low quantity of infiltrative cells in pancreatic islets and increased glutathione in the kidney and liver (p<0.05), when compared with the diabetic and non-diabetic control-groups. In conclusion, our results suggest that the consumption of aqueous extract of P. alata may be considered a good source of natural antioxidants and compounds found in its composition can act as anti-inflammatory agents, helping in the control of diabetes. PMID:24269180

Colomeu, T C; Figueiredo, D; Cazarin, C B B; Schumacher, N S G; Maróstica, M R; Meletti, L M M; Zollner, R L

2014-01-01

325

In Vivo Hypoglycaemic Effect and Inhibitory Mechanism of the Branch Bark Extract of the Mulberry on STZ-Induced Diabetic Mice  

PubMed Central

Branch bark extract (BBE) derived from the mulberry cultivar Husang 32 (Morus multicaulis L.) with aqueous alcohol solution has been investigated as an inhibitor of ?-glycosidase in vitro. Mulberry BBE was orally administered to STZ-induced diabetic mice for three weeks, and it improved the weight gain and ameliorated the swelling of liver and kidney in diabetic mice. Obviously, mulberry BBE not only can reduce the abnormally elevated levels of serum insulin and ameliorate insulin resistance induced by STZ, but also it regulates dyslipidemia in diabetic mice. To understand this therapeutic effect and the regulatory mechanisms of BBE in diabetic mice, a qRT-PCR experiment was performed, indicating that the mulberry BBE can regulate the mRNA expression of glycometabolism genes in diabetic mice, including glucose-6-phosphatase (G6Pase), glucokinase (GCK), and phosphoenolpyruvate carboxykinase (PEPCK), thereby regulating sugar metabolism and reducing the blood glucose level in diabetic mice. The mulberry BBE can increase the mRNA expression of the genes Ins1, Ins2 and pancreatic duodenal homeobox-1 (PDX-1) and may decrease the insulin resistance in diabetic mice. Those results provide an important basis for making the best use of mulberry branch resources and producing biomedical drugs with added value. PMID:25177729

Liu, Hua-Yu; Fang, Meng; Zhang, Yu-Qing

2014-01-01

326

Tesaglitazar ameliorates non-alcoholic fatty liver disease and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient mice  

PubMed Central

Previous research has demonstrated that the dual PPAR?/? agonist tesaglitazar reduces atherosclerosis in a mouse model of hyperlipidemia by reducing both lipid content and inflammation in the aorta. However, much of the underlying mechanism of tesaglitazar in non-alcoholic fatty liver disease (NAFLD) remains less clear. The aim of the present study was to determine whether tesaglitazar attenuates NAFLD and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient (LDLr?/?) mice. Female LDLr?/? mice (3 weeks old) were induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) injection to develop an animal model of type 2 diabetes (T2DM). The mice were randomly divided into two groups: diabetic group (untreated diabetic mice, n=15) and tesaglitazar therapeutic group (n=15, 20 ?g/kg/day oral treatment for 6 weeks). Fifteen LDLr?/? mice were fed with an HFD as the control group. Tesaglitazar decreased serum glucose and lipid levels compared with the diabetic mice. Tesaglitazar significantly reduced atherosclerotic lesions, lipid accumulation in the liver, macrophage infiltration, and decreased total hepatic cholesterol and triglyceride content compared to the diabetic mice. In addition, tesaglitazar reduced inflammatory markers at both the serum and mRNA levels. Our data suggest that tesaglitazar may be effective in preventing NAFLD and atherosclerosis in a pre-existing diabetic condition by regulating glucose and lipid metabolism, and the inflammatory response. PMID:23226761

ZHANG, BU-CHUN; LI, WEI-MING; LI, XIAN-KAI; ZHU, MENG-YUN; CHE, WEN-LIANG; XU, YA-WEI

2012-01-01

327

In vivo hypoglycaemic effect and inhibitory mechanism of the branch bark extract of the mulberry on STZ-induced diabetic mice.  

PubMed

Branch bark extract (BBE) derived from the mulberry cultivar Husang 32 (Morus multicaulis L.) with aqueous alcohol solution has been investigated as an inhibitor of ?-glycosidase in vitro. Mulberry BBE was orally administered to STZ-induced diabetic mice for three weeks, and it improved the weight gain and ameliorated the swelling of liver and kidney in diabetic mice. Obviously, mulberry BBE not only can reduce the abnormally elevated levels of serum insulin and ameliorate insulin resistance induced by STZ, but also it regulates dyslipidemia in diabetic mice. To understand this therapeutic effect and the regulatory mechanisms of BBE in diabetic mice, a qRT-PCR experiment was performed, indicating that the mulberry BBE can regulate the mRNA expression of glycometabolism genes in diabetic mice, including glucose-6-phosphatase (G6Pase), glucokinase (GCK), and phosphoenolpyruvate carboxykinase (PEPCK), thereby regulating sugar metabolism and reducing the blood glucose level in diabetic mice. The mulberry BBE can increase the mRNA expression of the genes Ins1, Ins2 and pancreatic duodenal homeobox-1 (PDX-1) and may decrease the insulin resistance in diabetic mice. Those results provide an important basis for making the best use of mulberry branch resources and producing biomedical drugs with added value. PMID:25177729

Liu, Hua-Yu; Fang, Meng; Zhang, Yu-Qing

2014-01-01

328

Islet-specific T-cell clones from nonobese diabetic mice express heterogeneous T-cell receptors.  

PubMed Central

Nonobese diabetic (NOD) mice spontaneously develop a T-cell-mediated autoimmune disease that is similar in many respects to insulin-dependent diabetes mellitus in humans. T-cell clones that specifically recognize pancreatic islet cell antigens can be derived from NOD mice, and most of these have been diabetogenic upon transfer to healthy recipients. We report herein the sequences of the T-cell receptor alpha and beta chains from four NOD-derived, islet-specific clones. The sequences are quite heterogeneous--in the junctional regions, specifically--so there seems to be little hope for treating this disease with specific anti-T-cell receptor reagents. This result contrasts with the strikingly restricted junctional region sequences reported for the receptors on clones derived from mice with experimental allergic encephalomyelitis, another T-cell-mediated autoimmune disease. We discuss possible explanations for this difference. PMID:2068098

Candeias, S; Katz, J; Benoist, C; Mathis, D; Haskins, K

1991-01-01

329

Potent Anti-Diabetic Effects of MHY908, a Newly Synthesized PPAR ?/? Dual Agonist in db/db Mice  

PubMed Central

Peroxisome proliferator-activated receptor (PPAR) ?/? dual agonists have been developed to alleviate metabolic disorders and have the potential to be used as therapeutic agents for the treatment of type 2 diabetes. In this study, we investigated the effects of a newly synthesized PPAR ?/? dual agonist, 2-[4-(5-chlorobenzo [d] thiazol-2-yl) phenoxy]-2-methylpropanoic acid (MHY908) on type 2 diabetes in vitro and in vivo. To obtain initial evidence that MHY908 acts as a PPAR ?/? dual agonist, ChIP and reporter gene assays were conducted in AC2F rat liver cells, and to investigate the anti-diabetic effects and molecular mechanisms, eight-week-old, male db/db mice were allowed to eat ad libitum, placed on calorie restriction, or administered MHY908 (1 mg or 3 mg/kg/day) mixed in food for 4 weeks. Age-matched male db/m lean mice served as non-diabetic controls. It was found that MHY908 enhanced the binding and transcriptional activity of PPAR ? and ? in AC2F cells, and it reduced serum glucose, triglyceride, and insulin levels, however increased adiponectin levels without body weight gain. In addition, MHY908 significantly improved hepatic steatosis by enhancing CPT-1 levels. Remarkably, MHY908 reduced endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK) activation in the livers of db/db mice, and subsequently reduced insulin resistance. The study shows MHY908 has beneficial effects on type 2 diabetes by simultaneously activating PPAR ?/? and improving ER stress, and suggests that MHY908 could have a potent anti-diabetic effect as a PPAR ?/? dual agonist, and potential for the treatment of type 2 diabetes. PMID:24244369

Park, Min Hi; Park, Ji Young; Lee, Hye Jin; Kim, Dae Hyun; Park, Daeui; Jeong, Hyoung Oh; Park, Chan Hum; Chun, Pusoon; Moon, Hyung Ryong; Chung, Hae Young

2013-01-01

330

Defects in the Acquisition of Tumor-Killing Capability of CD8+ Cytotoxic T Cells in Streptozotocin-Induced Diabetic Mice  

PubMed Central

Emerging evidences have shown that diabetes mellitus not only raises risk but also heightens mortality rate of cancer. It is not clear, however, whether antitumor CD8+ cytotoxic T lymphocyte (CTL) response is down-modulated in diabetic hosts. We investigated the impact of hyperglycemia on CTLs' acquisition of tumor-killing capability by utilizing streptozotocin-induced diabetic (STZ-diabetic) mice. Murine diabetes was induced by intraperitoneal injection of STZ (200 mg/kg) in C57BL/6 mice, 2C-T cell receptor (TCR) transgenic and P14-TCR transgenic mice. The study found that, despite harboring intact proliferative capacity measured with CFSE labeling and MTT assay, STZ-diabetic CD8+ CTLs displayed impaired effector functions. After stimulation, STZ-diabetic CD8+ CTLs produced less perforin and TNF? assessed by intracellular staining, as well as expressed less CD103 protein. Furthermore, adoptive transfer of STZ-diabetic P14 CD8+ effector cells showed an insufficient recruitment to the B16.gp33 melanoma and inadequate production of perforin, granzyme B and TNF? determined by immunohistochemistry in the tumor milieu. As a result, STZ-diabetic CD8+ effector cells were neither able to eliminate tumor nor to improve survival of tumor-bearing mice. Taken together, our data suggest that CD8+ CTLs are crippled to infiltrate into tumors and thus fail to acquire tumor-killing capability in STZ-diabetic hosts. PMID:25390652

Chen, Shu-Ching; Su, Yu-Chia; Lu, Ya-Ting; Ko, Patrick Chow-In; Chang, Pei-Yu; Lin, Hung-Ju; Ho, Hong-Nerng; Lai, Yo-Ping

2014-01-01

331

Alcohol Facilitates CD1d Loading, Subsequent Activation of NKT Cells, and Reduces the Incidence of Diabetes in NOD Mice  

PubMed Central

Background Ethanol (‘alcohol’) is a partly hydrophobic detergent that may affect the accessibility of glycolipids thereby influencing immunological effects of these molecules. Methods The study included cellular in vitro tests using ?-galactosylceramide (?GalCer), and in vivo NOD mice experiments detecting diabetes incidence and performing behavioural and bacterial analyses. Results Alcohol in concentrations from 0.6% to 2.5% increased IL-2 production from NKT cells stimulated with ?GalCer by 60% (p<0.05). CD1d expressed on HeLa cells contained significantly increasing amounts of ?GalCer with increasing concentrations of alcohol, suggesting that alcohol facilitated the passive loading of ?GalCer to CD1d. NOD mice were found to tolerate 5% ethanol in their drinking water without signs of impairment in liver function. Giving this treatment, the diabetes incidence declined significantly. Higher numbers of CD3+CD49b+ NKT cells were found in spleen and liver of the alcohol treated compared to the control mice (p<0.05), whereas the amount of CD4+Foxp3+ regulator T cells did not differ. Increased concentrations of IFN-? were detected in 24-hour blood samples of alcohol treated mice. Behavioural studies showed no change in attitude of the ethanol-consuming mice, and bacterial composition of caecum samples was not affected by alcohol, disqualifying these as protective mechanisms. Conclusion Alcohol facilitates the uptake of glycolipids and the stimulation of NKT cells, which are known to counteract Type 1 diabetes development. We propose that this is the acting mechanism by which treatment with alcohol reduces the incidence of diabetes in NOD mice. This is corroborated by epidemiology showing beneficial effect of alcohol to reduce the severity of atherosclerosis and related diseases. PMID:21483778

Buschard, Karsten; Hansen, Axel Kornerup; Jensen, Karen; Lindenbergh-Kortleve, Dicky J.; de Ruiter, Lilian F.; Krohn, Thomas C.; Hufeldt, Majbritt R.; Vogensen, Finn K.; Aasted, Bent; Osterbye, Thomas; Roep, Bart O.; de Haar, Colin; Nieuwenhuis, Edward E.

2011-01-01

332

Restoration of the Unfolded Protein Response in Pancreatic ? Cells Protects Mice Against Type 1 Diabetes  

PubMed Central

Perturbations in endoplasmic reticulum (ER) homeostasis can evoke stress responses leading to aberrant glucose and lipid metabolism. ER dysfunction is linked to inflammatory disorders, but its role in the pathogenesis of autoimmune type 1 diabetes (T1D) remains unknown. We identified defects in the expression of unfolded protein response (UPR) mediators ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1) in ? cells from two different T1D mouse models and then demonstrated similar defects in pancreatic ? cells from T1D patients. Administration of a chemical ER stress mitigator, tauroursodeoxycholic acid (TUDCA), at the prediabetic stage resulted in a marked reduction of diabetes incidence in the T1D mouse models. This reduction was accompanied by (i) a significant decrease in aggressive lymphocytic infiltration in the pancreas, (ii) improved survival and morphology of ? cells, (iii) reduced ? cell apoptosis, (iv) preserved insulin secretion, and (v) restored expression of UPR mediators. TUDCA?s actions were dependent on ATF6 and were lost in mice with ? cell-specific deletion of ATF6. These data indicate that proper maintenance of the UPR is essential for the preservation of ? cells and that defects in this process can be chemically restored for preventive or therapeutic interventions in T1D. PMID:24225943

Engin, Feyza; Yermalovich, Alena; Nguyen, True; Hummasti, Sarah; Fu, Wenxian; Eizirik, Decio L.; Mathis, Diane; Hotamisligil, Gokhan S.

2014-01-01

333

Antidiabetic Effect of Morinda citrifolia (Noni) Fermented by Cheonggukjang in KK-Ay Diabetic Mice  

PubMed Central

Antidiabetic effects of Morinda citrifolia (aka Noni) fermented by Cheonggukjang (fast-fermented soybean paste) were evaluated using a T2DM (type 2 diabetes mellitus) murine model. Six-week-old KK-Ay/TaJcl mice were randomly divided into four groups: (1) the diabetic control (DC) group, provided with a normal mouse diet; (2) the positive control (PC) group, provided with a functional health food diet; (3) the M. citrifolia (MC) group, provided with an MC-based diet; (4) the fermented M. citrifolia (FMC) group, provided with an FMC-based diet. Over a testing period of 90 days, food and water intake decreased significantly in the FMC and PC groups compared with the DC group. Blood glucose levels in the FMC group were 211.60–252.20?mg/dL after 90 days, while those in the control group were over 400?mg/dL after 20 days. In addition, FMC supplementation reduced glycosylated hemoglobin (HbA1c) levels, enhanced insulin sensitivity, and significantly decreased serum triglycerides and low-density lipoprotein (LDL) cholesterol. Furthermore, a fermented M. citrifolia 70% ethanolic extract (FMCE) activated peroxisome proliferator-activated receptor-(PPAR-) ? and stimulated glucose uptake via stimulation of AMP-activated protein kinase (AMPK) in cultured C2C12 cells. These results suggest that FMC can be employed as a functional health food for T2DM management. PMID:22969823

Lee, So-Young; Park, So-Lim; Hwang, Jin-Taek; Yi, Sung-Hun; Nam, Young-Do; Lim, Seong-Il

2012-01-01

334

Targeting Apoptosis Signalling Kinase-1 (ASK-1) Does Not Prevent the Development of Neuropathy in Streptozotocin-Induced Diabetic Mice  

PubMed Central

Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy. PMID:25329046

Newton, Victoria L.; Ali, Sumia; Duddy, Graham; Whitmarsh, Alan J.; Gardiner, Natalie J.

2014-01-01

335

Glycogen synthase kinase-3? inhibition ameliorates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice.  

PubMed

Decreased heart rate variability (HRV) is a major risk factor for sudden death and cardiovascular disease. We previously demonstrated that parasympathetic dysfunction in the heart of the Akita type 1 diabetic mouse was due to a decrease in the level of the sterol response element-binding protein (SREBP-1). Here we demonstrate that hyperactivity of glycogen synthase kinase-3? (GSK3?) in the atrium of the Akita mouse results in decreased SREBP-1, attenuation of parasympathetic modulation of heart rate, measured as a decrease in the high-frequency (HF) fraction of HRV in the presence of propranolol, and a decrease in expression of the G-protein coupled inward rectifying K(+) (GIRK4) subunit of the acetylcholine (ACh)-activated inward-rectifying K(+) channel (IKACh), the ion channel that mediates the heart rate response to parasympathetic stimulation. Treatment of atrial myocytes with the GSK3? inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and IKACh, whereas a dominant-active GSK3? mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3? inhibitors Li(+) and/or CHIR-99021, Li(+) increased IKACh, and Li(+) and CHIR-99021 both partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. These data support the conclusion that increased GSK3? activity in the type 1 diabetic heart plays a critical role in parasympathetic dysfunction through an effect on SREBP-1, supporting GSK3? as a new therapeutic target for diabetic autonomic neuropathy. PMID:24458356

Zhang, Yali; Welzig, Charles M; Picard, Kristen L; Du, Chuang; Wang, Bo; Pan, Jen Q; Kyriakis, John M; Aronovitz, Mark J; Claycomb, William C; Blanton, Robert M; Park, Ho-Jin; Galper, Jonas B

2014-06-01

336

L-Arginine ameliorates cardiac left ventricular oxidative stress by upregulating eNOS and Nrf2 target genes in alloxan-induced hyperglycemic rats  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer L-Arginine treatment reduced the metabolic disturbances in diabetic animals. Black-Right-Pointing-Pointer Antioxidant marker proteins were found high in myocardium by L-arginine treatment. Black-Right-Pointing-Pointer Elevated antioxidant status, mediates the reduced TBA-reactivity in left ventricle. Black-Right-Pointing-Pointer L-Arginine treatment enhanced the Nrf2 and eNOS signaling in left ventricle. Black-Right-Pointing-Pointer Improved cell survival signaling by arginine, offers a novel tactic for targeting. -- Abstract: Hyperglycemia is independently related with excessive morbidity and mortality in cardiovascular disorders. L-Arginine-nitric oxide (NO) pathway and the involvement of NO in modulating nuclear factor-E2-related factor-2 (Nrf2) signaling were well established. In the present study we investigated, whether L-arginine supplementation would improve the myocardial antioxidant defense under hyperglycemia through activation of Nrf2 signaling. Diabetes was induced by alloxan monohydrate (90 mg kg{sup -1} body weight) in rats. Both non-diabetic and diabetic group of rats were divided into three subgroups and they were administered either with L-arginine (2.25%) or L-NAME (0.01%) in drinking water for 12 days. Results showed that L-arginine treatment reduced the metabolic disturbances in diabetic rats. Antioxidant enzymes and glutathione levels were found to be increased in heart left ventricles, thereby reduction of lipid peroxidation by L-arginine treatment. Heart histopathological analysis further validates the reversal of typical diabetic characteristics consisting of alterations in myofibers and myofibrillary degeneration. qRT-PCR studies revealed that L-arginine treatment upregulated the transcription of Akt and downregulated NF-{kappa}B. Notably, transcription of eNOS and Nrf2 target genes was also upregulated, which were accompanied by enhanced expression of Nrf2 in left ventricular tissue from diabetic and control rats. Under these findings, we suggest that targeting of eNOS and Nrf2 signaling by L-arginine supplementation could be used as a potential treatment method to alleviate the late diabetic complications.

Ramprasath, Tharmarajan; Hamenth Kumar, Palani; Syed Mohamed Puhari, Shanavas; Senthil Murugan, Ponniah; Vasudevan, Varadaraj [Molecular Cardiology Unit, Department of Biochemistry, Center for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai 625 021, Tamilnadu (India)] [Molecular Cardiology Unit, Department of Biochemistry, Center for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai 625 021, Tamilnadu (India); Selvam, Govindan Sadasivam, E-mail: drselvamgsbiochem@rediffmail.com [Molecular Cardiology Unit, Department of Biochemistry, Center for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai 625 021, Tamilnadu (India)

2012-11-23

337

Reactive Oxygen Species Signaling Facilitates FOXO-3a/FBXO-Dependent Vascular BK Channel ?1 Subunit Degradation in Diabetic Mice  

PubMed Central

Activity of the vascular large conductance Ca2+-activated K+ (BK) channel is tightly regulated by its accessory ?1 subunit (BK-?1). Downregulation of BK-?1 expression in diabetic vessels is associated with upregulation of the forkhead box O subfamily transcription factor-3a (FOXO-3a)–dependent F-box–only protein (FBXO) expression. However, the upstream signaling regulating this process is unclear. Overproduction of reactive oxygen species (ROS) is a common finding in diabetic vasculopathy. We hypothesized that ROS signaling cascade facilitates the FOXO-3a/FBXO-mediated BK-?1 degradation and leads to diabetic BK channel dysfunction. Using cellular biology, patch clamp, and videomicroscopy techniques, we found that reduced BK-?1 expression in streptozotocin (STZ)-induced diabetic mouse arteries and in human coronary smooth muscle cells (SMCs) cultured with high glucose was attributable to an increase in protein kinase C (PKC)-? and NADPH oxidase expressions and accompanied by attenuation of Akt phosphorylation and augmentation of atrogin-1 expression. Treatment with ruboxistaurin (a PKC? inhibitor) or with GW501516 (a peroxisome proliferator–activated receptor ? activator) reduced atrogin-1 expression and restored BK channel-mediated coronary vasodilation in diabetic mice. Our results suggested that oxidative stress inhibited Akt signaling and facilitated the FOXO-3a/FBXO-dependent BK-?1 degradation in diabetic vessels. Suppression of the FOXO-3a/FBXO pathway prevented vascular BK-?1 degradation and protected coronary function in diabetes. PMID:22586590

Lu, Tong; Chai, Qiang; Yu, Ling; d'Uscio, Livius V.; Katusic, Zvonimir S.; He, Tongrong; Lee, Hon-Chi

2012-01-01

338

Reactive oxygen species signaling facilitates FOXO-3a/FBXO-dependent vascular BK channel ?1 subunit degradation in diabetic mice.  

PubMed

Activity of the vascular large conductance Ca(2+)-activated K(+) (BK) channel is tightly regulated by its accessory ?(1) subunit (BK-?(1)). Downregulation of BK-?(1) expression in diabetic vessels is associated with upregulation of the forkhead box O subfamily transcription factor-3a (FOXO-3a)-dependent F-box-only protein (FBXO) expression. However, the upstream signaling regulating this process is unclear. Overproduction of reactive oxygen species (ROS) is a common finding in diabetic vasculopathy. We hypothesized that ROS signaling cascade facilitates the FOXO-3a/FBXO-mediated BK-?(1) degradation and leads to diabetic BK channel dysfunction. Using cellular biology, patch clamp, and videomicroscopy techniques, we found that reduced BK-?(1) expression in streptozotocin (STZ)-induced diabetic mouse arteries and in human coronary smooth muscle cells (SMCs) cultured with high glucose was attributable to an increase in protein kinase C (PKC)-? and NADPH oxidase expressions and accompanied by attenuation of Akt phosphorylation and augmentation of atrogin-1 expression. Treatment with ruboxistaurin (a PKC? inhibitor) or with GW501516 (a peroxisome proliferator-activated receptor ? activator) reduced atrogin-1 expression and restored BK channel-mediated coronary vasodilation in diabetic mice. Our results suggested that oxidative stress inhibited Akt signaling and facilitated the FOXO-3a/FBXO-dependent BK-?(1) degradation in diabetic vessels. Suppression of the FOXO-3a/FBXO pathway prevented vascular BK-?(1) degradation and protected coronary function in diabetes. PMID:22586590

Lu, Tong; Chai, Qiang; Yu, Ling; d'Uscio, Livius V; Katusic, Zvonimir S; He, Tongrong; Lee, Hon-Chi

2012-07-01

339

Mesenchymal Stem Cell-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Ameliorate Diabetic Polyneuropathy in Mice  

PubMed Central

Background. Although pathological involvements of diabetic polyneuropathy (DPN) have been reported, no dependable treatment of DPN has been achieved. Recent studies have shown that mesenchymal stem cells (MSCs) ameliorate DPN. Here we demonstrate a differentiation of induced pluripotent stem cells (iPSCs) into MSC-like cells and investigate the therapeutic potential of the MSC-like cell transplantation on DPN. Research Design and Methods. For induction into MSC-like cells, GFP-expressing iPSCs were cultured with retinoic acid, followed by adherent culture for 4 months. The MSC-like cells, characterized with flow cytometry and RT-PCR analyses, were transplanted into muscles of streptozotocin-diabetic mice. Three weeks after the transplantation, neurophysiological functions were evaluated. Results. The MSC-like cells expressed MSC markers and angiogenic/neurotrophic factors. The transplanted cells resided in hindlimb muscles and peripheral nerves, and some transplanted cells expressed S100? in the nerves. Impairments of current perception thresholds, nerve conduction velocities, and plantar skin blood flow in the diabetic mice were ameliorated in limbs with the transplanted cells. The capillary number-to-muscle fiber ratios were increased in transplanted hindlimbs of diabetic mice. Conclusions. These results suggest that MSC-like cell transplantation might have therapeutic effects on DPN through secreting angiogenic/neurotrophic factors and differentiation to Schwann cell-like cells. PMID:24319678

Kamiya, Hideki; Naruse, Keiko; Cheng, Zhao; Ito, Sachiko; Kondo, Masaki; Okawa, Tetsuji; Fujiya, Atsushi; Kato, Jiro; Suzuki, Hirohiko; Kito, Tetsutaro; Hamada, Yoji; Oiso, Yutaka; Isobe, Kenichi; Nakamura, Jiro

2013-01-01

340

Eleutheroside E, An Active Component of Eleutherococcus senticosus, Ameliorates Insulin Resistance in Type 2 Diabetic db/db Mice  

PubMed Central

Eleutheroside E (EE), a principal component of Eleutherococcus senticosus (ES), has anti-inflammatory and protective effects in ischemia heart. However, it is unknown whether it ameliorates insulin resistance and reduces hyperglycemia in diabetes. This study investigated the effect of EE-containing ES extracts, as well as EE, on hyperglycemia and insulin resistance in db/db mice. EE increased the insulin-provoked glucose uptake in C2C12 myotubes. Moreover, EE improved TNF-?-induced suppression of glucose uptake in 3T3-L1 adipocytes. Five-week-old db/db mice were fed a diet consisting of ES extract or EE for 5 weeks. Both were effective in improving serum lipid profiles and significantly decreased blood glucose and serum insulin levels. ES and EE supplementation effectively attenuated HOMA-IR. Glucose tolerance and insulin tolerance tests showed that EE increased insulin sensitivity. Immunohistochemical staining indicated that ES and EE protected pancreatic alpha and beta cells from diabetic damage. In addition, ES and EE improved hepatic glucose metabolism by upregulating glycolysis and downregulating gluconeogenesis in obese type 2 diabetic mice. These data suggest that EE mediates the hyperglycemic effects of ES by regulating insulin signaling and glucose utilization. The beneficial effects of EE may provide an effective and powerful strategy to alleviate diabetes. PMID:23690865

Ahn, Jiyun; Um, Min Young; Lee, Hyunjung; Jung, Chang Hwa; Heo, Seok Hyun; Ha, Tae Youl

2013-01-01

341

Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice  

PubMed Central

The heterogeneous cellular composition of the mammalian renal collecting duct enables regulation of fluid, electrolytes, and acid-base homeostasis, but the molecular mechanism of its development has yet to be elucidated. The Notch signaling pathway is involved in cell fate determination and has been implicated in proximal-distal patterning in the mammalian kidney. To investigate the role of Notch signaling in renal collecting duct development, we generated mice in which Mind bomb-1 (Mib1), an E3 ubiquitin ligase required for the initiation of Notch signaling, was specifically inactivated in the ureteric bud of the developing kidney. Mice lacking Mib1 in the renal collecting duct displayed increased urinary production, decreased urinary osmolality, progressive hydronephrosis, sodium wasting, and a severe urinary concentrating defect manifested as nephrogenic diabetes insipidus. Histological analysis revealed a diminished number of principal cells and corresponding increase in the number of intercalated cells. Transgenic overexpression of Notch intracellular domain reversed the altered cellular composition of mutant renal collecting duct, with principal cells occupying the entire region. Our data demonstrate that Notch signaling is required for the development of the mammalian renal collecting duct and principal cell differentiation and indicate that pathway dysregulation may contribute to distal renal tubular disorders. PMID:19855135

Jeong, Hyun-Woo; Jeon, Un Sil; Koo, Bon-Kyoung; Kim, Wan-Young; Im, Sun-Kyoung; Shin, Juhee; Cho, Yunje; Kim, Jin; Kong, Young-Yun

2009-01-01

342

SirT1 gain-of-function increases energy efficiency and prevents diabetes in mice  

PubMed Central

Summary In yeast, worms and flies, an extra copy of the gene encoding the Sirtuin Sir2 increases metabolic efficiency, as does administration of polyphenols like resveratrol, thought to act through Sirtuins. But evidence that Sirtuin gain-of-function results in increased metabolic efficiency in mammals is limited. We generated transgenic mice with moderate overexpression of SirT1, designed to mimic the Sirtuin gain-of-function that improves metabolism in C.elegans. These mice exhibit normal insulin sensitivity, but decreased food intake and locomotor activity, resulting in decreased energy expenditure. However, in various models of insulin resistance and diabetes, SirT1 transgenics display improved glucose tolerance due to decreased hepatic glucose production and increased adiponectin levels, without changes in body weight or composition. We conclude that SirT1 gain-of-function primes the organism for metabolic adaptation to insulin resistance, increasing hepatic insulin sensitivity and decreasing whole-body energy requirements. These findings have important implications for Sirtuin-based therapies in humans. PMID:18840364

Banks, Alexander S.; Kon, Ning; Knight, Colette; Matsumoto, Michihiro; Gutierrez-Juarez, Roger; Rossetti, Luciano; Gu, Wei; Accili, Domenico

2011-01-01

343

Topical application of ex vivo expanded endothelial progenitor cells promotes vascularisation and wound healing in diabetic mice.  

PubMed

Impaired wound healing leading to skin ulceration is a serious complication of diabetes and may be caused by defective angiogenesis. Endothelial progenitor cells (EPCs) can augment neovascularisation in the ischaemic tissue. Experiments were performed to test the hypothesis that locally administered EPCs can promote wound healing in diabetes. Full-thickness skin wounds were created on the dorsum of diabetic mice. EPCs were obtained from bone marrow mononuclear cells (BMMNCs) and applied topically to the wound immediately after surgery. Vehicle and non-selective BMMNCs were used as controls. Wound size was measured on days 5, 10 and 14 after treatment, followed by resection, histological analysis and quantification of vascularity. Topical application of EPCs significantly promoted wound healing, as assessed by closure rate and wound vascularity. Immunostaining revealed that transplanted EPCs induced increased expression of vascular endothelial growth factor and basic fibroblast growth factor. Few EPCs were observed in the neovasculature based on in vivo staining of the functional vasculature. Ex vivo expanded EPCs promote wound healing in diabetic mice via mechanisms involving increased local cytokine expression and enhanced neovascularisation of the wound. This strategy exploiting the therapeutic capacity of autologously derived EPCs may be a novel approach to skin repair in diabetes. PMID:22738265

Asai, Jun; Takenaka, Hideya; Ii, Masaaki; Asahi, Michio; Kishimoto, Saburo; Katoh, Norito; Losordo, Douglas W

2013-10-01

344

Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice  

PubMed Central

Diabetic nephropathy, the leading cause of end-stage renal disease, is characterized by a proapoptotic and prooxidative environment. The mechanisms by which lifestyle interventions, such as exercise, benefit diabetic nephropathy are unknown. We hypothesized that exercise inhibits early diabetic nephropathy via attenuation of the mitochondrial apoptotic pathway and oxidative damage. Type 2 diabetic db/db and normoglycemic wild-type mice were exercised for an hour everyday at a moderate intensity for 7 wk, following which renal function, morphology, apoptotic signaling, and oxidative stress were evaluated. Exercise reduced body weight, albuminuria, and pathological glomerular expansion in db/db mice independent of hyperglycemic status. Changes in renal morphology were also related to reduced caspase-3 (main effector caspase in renal apoptosis), caspase-8 (main initiator caspase of the “extrinsic” pathway) activities, and TNF-? expression. A role for the mitochondrial apoptotic pathway was unlikely as both caspase-9 activity (initiator caspase of this pathway) and expression of regulatory proteins such as Bax and Bcl-2 were unchanged. Kidneys from db/db mice also produced higher levels of superoxides and had greater oxidative damage concurrent with downregulation of superoxide dismutase (SOD) 1 and 3. Interestingly, although exercise also increased superoxides, there was also upregulation of multiple SODs that likely inhibited lipid (hydroperoxides) and protein (carbonyls and nitrotyrosine) oxidation in db/db kidneys. In conclusion, exercise can inhibit progression of early diabetic nephropathy independent of hyperglycemia. Reductions in caspase-3 and caspase-8 activities, with parallel improvements in SOD expression and reduced oxidative damage, could underlie the beneficial effects of exercise in diabetic kidney disease. PMID:19144689

Ghosh, S.; Khazaei, M.; Moien-Afshari, F.; Ang, L. S.; Granville, D. J.; Verchere, C. B.; Dunn, S. R.; McCue, P.; Mizisin, A.; Sharma, K.; Laher, I.

2009-01-01

345

Regulatory cytokine production stimulated by DNA vaccination against an altered form of glutamic acid decarboxylase 65 in nonobese diabetic mice.  

PubMed

Nonobese diabetic (NOD) mice develop a T-cell dependent autoimmune form of diabetes, in which glutamic acid decarboxylase 65 (GAD65) is an important islet target antigen. Intramuscular DNA vaccination with a plasmid encoding native GAD65 (a cytosolic antigen) did not significantly alter the incidence of diabetes, but vaccination against an altered form of GAD65 with a signal peptide (spGAD), which is secreted in vitro, was protective. The preventive effect was further enhanced by repeated injections of the spGAD plasmid. Following DNA injection into muscle GAD65 was expressed for several months, and this was not accompanied by an inflammatory response. Immunization against GAD65 was not associated with substantial alterations in cytokine production by splenic lymphocytes stimulated with immunogenic GAD65 peptides. In contrast, spGAD induced increased secretion of both interleukin 10 and interferon gamma and a striking decrease in the interferon gamma/interleukin 10 ratio in culture supernatants. Similarly, spGAD-immunized mice had higher serum interleukin 10 levels and lower serum interferon gamma levels than other groups, suggesting a systemic effect. In nondiabetic mice there was increased basal production of transforming growth factor beta(1), which was enhanced by antigenic stimulation. These alterations in regulatory cytokine production were apparent both early and late after the treatment was initiated. These findings suggest that DNA vaccination against spGAD protects NOD mice by increasing regulatory cytokine production. PMID:12682726

Glinka, Yelena; De Pooter, Renée; Croze, France; Prud'homme, Gérald J

2003-03-01

346

PDGF-BB does not accelerate healing in diabetic mice with splinted skin wounds.  

PubMed

Topical application of platelet-derived growth factor-BB (PDGF-BB) is considered to accelerate tissue repair of impaired chronic wounds. However, the vast literature is plagued with conflicting reports of its efficacy in animal models and this is often influenced by a wide array of experimental variables making it difficult to compare the results across the studies. To mitigate the confounding variables that influence the efficacy of topically applied PDGF-BB, we used a controlled full thickness splinted excisional wound model in db/db mice (type 2 diabetic mouse model) for our investigations. A carefully-defined silicone-splinted wound model, with reduced wound contraction, controlled splint and bandage maintenance, allowing for healing primarily by reepithelialization was employed. Two splinted 8 mm dorsal full thickness wounds were made in db/db mice. Wounds were topically treated once daily with either 3 µg PDGF-BB in 30 µl of 5% PEG-PBS vehicle or an equal volume of vehicle for 10 days. Body weights, wound contraction, wound closure, reepithelialization, collagen content, and wound bed inflammation were evaluated clinically and histopathologically. The bioactivity of PDGF-BB was confirmed by in vitro proliferation assay. PDGF-BB, although bioactive in vitro, failed to accelerate wound healing in vivo in the db/db mice using the splinted wound model. Considering that the predominant mechanism of wound healing in humans is by re-epithelialization, the most appropriate model for evaluating therapeutics is one that uses splints to prevent excessive wound contraction. Here, we report that PDGF-BB does not promote wound closure by re-epithelialization in a murine splinted wound model. Our results highlight that the effects of cytoactive factors reported in vivo ought to be carefully interpreted with critical consideration of the wound model used. PMID:25121729

Park, Shin Ae; Raghunathan, Vijay Krishna; Shah, Nihar M; Teixeira, Leandro; Motta, Monica J; Covert, Jill; Dubielzig, Richard; Schurr, Michael; Isseroff, Roslyn Rivkah; Abbott, Nicholas L; McAnulty, Jonathan; Murphy, Christopher J

2014-01-01

347

Immunization with soluble BDC 2.5 T cell receptor-immunoglobulin chimeric protein:antibody specificity and protection of nonobese diabetic mice against adoptive transfer of diabetes by maternal immunization  

PubMed Central

The BDC 2.5 T cell clone is specific for pancreatic beta-cell antigen presented by I-Ag7, and greatly accelerates diabetes when injected into 10-21-d-old nonobese diabetic (NOD) mice. The BDC 2.5 T cell receptor (TCR) has been solubilized as a TCR-IgG1 chimeric protein. All NOD mice immunized against BDC 2.5 TCR-IgG1 produced antibodies recognizing TCR C alpha/C beta epitopes that were inaccessible on the T cell surface. 56% of the mice produced antibodies against the BDC 2.5 clonotype that specifically blocked antigen activation of BDC 2.5 cells. We have used the adoptive transfer model of diabetes to demonstrate that maternal immunization with soluble TCR protects young mice from diabetes induced by the BDC 2.5 T cell clone. PMID:8920864

1996-01-01

348

Diabetes-induced changes in calcium homeostasis and the effects of calcium channel blockers in rat and mice nociceptive neurons  

Microsoft Academic Search

.\\u000a Aims\\/hypothesis:   Distal neuropathy is the most common complication of diabetes mellitus, making it important to reveal the cellular mechanisms\\u000a leading to its development, one of which might be the alteration in intracellular calcium homeostasis in primary and secondary\\u000a nociceptive neurons. We aimed to investigate these possible changes. \\u000a \\u000a \\u000a \\u000a Methods:   Control and streptozotocin-treated diabetic rats and mice were used. Changes in

E. Kostyuk; N. Voitenko; I. Kruglikov; A. Shmigol; V. Shishkin; A. Efimov; P. Kostyuk

2001-01-01

349

Antioxidant rich grape pomace extract suppresses postprandial hyperglycemia in diabetic mice by specifically inhibiting alpha-glucosidase  

PubMed Central

Background Postprandial hyperglycemia is an early defect of type 2 diabetes and one of primary anti-diabetic targets. Treatment of postprandial hyperglycemia can be achieved by inhibiting intestinal ?-glucosidase, the key enzyme for oligosaccharide digestion and further glucose absorption. Grape pomace is winemaking byproduct rich in bioactive food compounds such as phenolic antioxidants. This study evaluated the anti-diabetic potential of two specific grape pomace extracts by determining their antioxidant and anti-postprandial hyperglycemic activities in vitro and in vivo. Methods The extracts of red wine grape pomace (Cabernet Franc) and white wine grape pomace (Chardonnay) were prepared in 80% ethanol. An extract of red apple pomace was included as a comparison. The radical scavenging activities and phenolic profiles of the pomace extracts were determined through the measurement of oxygen radical absorbance capacity, DPPH radical scavenging activity, total phenolic content and flavonoids. The inhibitory effects of the pomace extracts on yeast and rat intestinal ?-glucosidases were determined. Male 6-week old C57BLKS/6NCr mice were treated with streptozocin to induce diabetes. The diabetic mice were then treated with vehicle or the grape pomace extrac