These are representative sample records from Science.gov related to your search topic.
For comprehensive and current results, perform a real-time search at Science.gov.
1

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

PubMed Central

Mung bean was reported as a potential antidiabetic agent while fermented food has been proposed as one of the major contributors that can reduce the risk of diabetes in Asian populations. In this study, we have compared the normoglycemic effect, glucose-induced hyperglycemic effect, and alloxan-induced hyperglycemic effect of fermented and nonfermented mung bean extracts. Our results showed that fermented mung bean extracts did not induce hypoglycemic effect on normal mice but significantly reduced the blood sugar levels of glucose- and alloxan-induced hyperglycemic mice. The serum levels of cholesterol, triglyceride (TG), and low-density lipoprotein (LDL) were also lowered while insulin secretion and antioxidant level as measured by malonaldehyde (MDA) assays were significantly improved in the plasma of the fermented mung bean-treated group in alloxan-induced hyperglycemic mouse. These results indicated that fermentation using Mardi Rhizopus sp. strain 5351 inoculums could enhance the antihyperglycemic and the antioxidant effects of mung bean in alloxan-treated mice. The improvement in the antihyperglycemic effect may also be contributed by the increased content of GABA and the free amino acid that are present in the fermented mung bean extracts. PMID:23091343

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

2012-01-01

2

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

3

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

PubMed Central

The aim of the study was to evaluate the phytochemistry and the effect of methanolic root extract (MREt) of Rauwolfia serpentina on alloxan-induced diabetic Wister male mice. Mice were divided in control (distilled water at 1?mL/kg) and alloxan-induced diabetic mice which subdivided into diabetic (distilled water at 1?mL/kg), negative (0.05% dimethyl sulfoxide at 1?mL/kg), positive (glibenclamide at 5?mg/kg) controls, and three test groups (MREt at 10, 30, and 60?mg/kg). All treatments were given orally for 14 days. Qualitatively MREt showed the presence of alkaloids, carbohydrates, flavonoids, glycosides, cardiac glycosides, phlobatannins, resins, saponins, steroids, tannins, and triterpenoids, while quantitatively extract was rich in total phenols. The flavonoids, saponins and alkaloids were also determined in root powder. MREt found effective in improving the body weights, glucose and insulin levels, insulin/glucose ratio, glycosylated and total hemoglobin in test groups as compared to diabetic control. Similarly, significantly decreased levels of total cholesterol, triglycerides, low-density lipoprotein (LDL-c), and very low-density lipoprotein (VLDL-c) cholesterols were found in test groups. Significant lipolysis with improved glycogenesis was also found in liver tissues of all test groups. ALT levels were found normal in all groups. Thus, MREt improves the glycemic, antiatherogenic, coronary risk, and cardioprotective indices in alloxan-induced diabetic mice. PMID:23365565

Azmi, Muhammad Bilal; Qureshi, Shamim A.

2012-01-01

4

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

PubMed Central

In order to avoid low absorption, incorporation, and undesirable side effects of inorganic oxovanadium compounds, the antidiabetic activities of organic oxovanadium (IV) compounds in alloxan-induced diabetic mice were investigated. Vanadyl carboxymethyl carrageenan (VOCCA) and vanadyl carboxymethyl chitosan (VOCCH) were synthesized and administrated through intragastric administration in different doses for 20 days in alloxan-induced diabetic mice. Glibenclamide was administrated as the positive control. Our results showed that low-dose group, middle-dose group, and high-dose group of VOCCA and VOCCH could significantly reduce the levels of blood glucose (P < 0.05) compared with untreated group, but not in normal mice. Besides, high-dose groups of VOCCA and VOCCH exhibited more significant hypoglycemic activities (P < 0.01). After treated with VOCCH, the oral glucose tolerance of high-dose group of VOCCH was improved compared with model control group (P < 0.05). PMID:21804857

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

2011-01-01

5

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

PubMed

Mushrooms are low calorie food with very little fat and are highly suitable for obese persons. With no starch and very low sugars, they are the 'delight of the diabetics'. Combination of herbal drugs (or isolated phytochemicals) is found to be beneficial in certain diseases when given along with conventional drugs. The aim of the present study was to evaluate the effects of aqueous extract of Pleurotus pulmonarius (Lentinaceae) (called as PP-aqu) and its interaction with glyburide in alloxan induced diabetic mice. The diabetic mice treated were with PP-aqu (500 mg/kg, p.o.) alone or combination with glyburide (10 mg/kg, p.o.) for 28 days. Blood samples were collected by orbital sinus puncture using heparinized capillary glass tubes and were analyzed for serum glucose on 0, 7th, 14th, 21st and 28th days. Body weights and mortality were noted during the study period. In oral glucose tolerance test (OGTT), glucose (2.5 g/kg, p.o.) was administered with either vehicle, PP-aqu alone or in combination with glyburide and serum glucose level analyzed at 0, 30, 60 and 120 min after drug administration. Administration of PP-aqu (500 mg/kg) and its combination with glyburide (10 mg/kg) significantly (P < 0.001) decreased serum glucose level in diabetic mice. In OGTT, glyburide or PP-aqu treatment alone or their combination produced significant (P < 0.001) increase in glucose threshold. Thus we suggest that P. pulmonarius showed potent and synergistic antihyperglycemic effect in combination with glyburide. PMID:18604261

Badole, Sachin L; Patel, Naimesh M; Thakurdesai, Prasad A; Bodhankar, Subhash L

2008-06-01

6

Protective role of three vegetable peels in alloxan induced diabetes mellitus in male mice.  

PubMed

The hitherto unknown glucose regulating role of three vegetable peels from cucurbitaceae family was evaluated. In a preliminary study, effects of ethanolic extracts of Cucurbita pepo, Cucumis sativus and Praecitrullus fistulosus peels were studied at 250 and 500 mg kg(-1) d(-1) for 15 days in the alterations in serum glucose and in hepatic lipid peroxidation (LPO) in male mice. In the pilot experiment, the effective and safe concentration of each peel was administered (p.o.) for 10 consecutive days and then on 11th and 12th days alloxan was administered along with peel extracts. The treatment was continued up to 15th day. At the end, alterations in serum glucose, insulin, triiodothyronine, thyroxine, total cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, very low density lipoprotein, hepatic lipid peroxidation, superoxide dismutase and catalase were studied. All the three peel extracts nearly reversed most of these changes induced by alloxan suggesting their possible role in ameliorating diabetes mellitus and related changes in serum lipids. However, Cucurbita pepo peel was found to be the most effective. Total polyphenols, flavonoids and ascorbic acid contents of the test peels were also estimated, which appear to be associated with the observed antidiabetic and antioxidative potentials. PMID:20614191

Dixit, Yamini; Kar, Anand

2010-09-01

7

Protective Role of Three Vegetable Peels in Alloxan Induced Diabetes Mellitus in Male Mice  

Microsoft Academic Search

The hitherto unknown glucose regulating role of three vegetable peels from cucurbitaceae family was evaluated. In a preliminary\\u000a study, effects of ethanolic extracts of Cucurbita pepo, Cucumis sativus and Praecitrullus fistulosus peels were studied at 250 and 500 mg kg?1 d?1 for 15 days in the alterations in serum glucose and in hepatic lipid peroxidation (LPO) in male mice. In the pilot experiment,\\u000a the

Yamini Dixit; Anand Kar

2010-01-01

8

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

PubMed Central

Background: Oxidative stress not only develops complications in diabetic (type 1 and type 2) but also contributes to beta cell destruction in type 2 diabetes in insulin resistance hyperglycemia. Glucose control plays an important role in the pro-oxidant/antioxidant balance. Some antidiabetic agents may by themselves have antioxidant properties independently of their role on glucose control. Objective: The present investigation draws a comparison of the protective antioxidant activity, total phenol content and the antihyperglycemic activity of the methanolic extract of Cajanus cajan root (MCC) and Tamarindus indica seeds (MTI). Materials and Methods: Antidiabetic potentials of the plant extracts were evaluated in alloxan-induced diabetic Swiss albino mice. The plant extracts at the doses of 200 and 400 mg/kg body weight was orally administered for glucose tolerance test during 1-hour study and hypoglycemic effect during 5-day study period in comparison with reference drug Metformin HCl (50 mg/kg). In vitro antioxidant potential of MCC and MTI was investigated by using 1, 1- diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity at 517 nm. Total phenolic content, total antioxidant capacity and reducing power activity was also assayed. Results: There was a significant decrease in fasting serum glucose level (P < 0.001), reduction in blood glucose level (P < 0.001) in 5-days study, observed in the alloxan-induced diabetic mice. The reduction efficacy of blood glucose level of both the extracts is proportional to their dose but MCC is more potent than MTI. Antioxidant study and quantification of phenolic compound of both the extracts revealed that they have high antioxidant capacity. Conclusion: These studies showed that MCC and MTI have both hypoglycemic and antioxidant potential but MCC is more potent than MTI. The present study suggests that both MCC and MTI could be used in managing oxidative stress. PMID:24761124

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

2014-01-01

9

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

Microsoft Academic Search

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

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

2007-01-01

10

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

11

Antidyslipidemic and Antioxidant Activities of Hibiscus rosa sinensis Root Extract in Alloxan Induced Diabetic Rats.  

PubMed

The antidyslipidemic activity of Hibiscus rosa sinensis (Malvaceae) root extract has been studied in alloxan induced diabetic rats. In this model, oral administration of root extract (500 mg/kg bw. p.o.) for 15 days resulted in significant decreased in the levels of blood glucose, plasma lipids and reactivated post heparin lipoprotein lipase activity in alloxan induced diabetic rats. Furthermore, the root extract (50-500 ?g) when tested for its antioxidant activity, inhibited the generation of super oxide anions and hydroxyl radicals, in both enzymic and non enzymic systems in vitro. The results of the present study demonstrated antidyslipidemic and antioxidant activities in root extract of H. rosa sinensis which could be used in prevention of diabetic-dyslipidemia and related complications. PMID:24381420

Kumar, Vishnu; Mahdi, Farzana; Khanna, Ashok Kumar; Singh, Ranjana; Chander, Ramesh; Saxena, Jitendra Kumar; Mahdi, Abbas Ali; Singh, Raj Kumar

2013-01-01

12

Hypoglycemic effect of aqueous extract of Parthenium hysterophorus L. in normal and alloxan induced diabetic rats  

PubMed Central

Objectives: To study the effects of Parthenium hysterophorus L. flower on serum glucose level in normal and alloxan induced diabetic rats. Materials and Methods: Albino rats were divided into six groups of six animals each, three groups of normal animals receiving different treatments consisting of vehicle, aqueous extract of Parthenium hysterophorus L. flower (100 mg/kg) and the standard antidiabetic drug, glibenclamide (0.5 mg/kg). The same treatment was given to the other three groups comprising alloxan induced diabetic animals. Fasting blood glucose level was estimated using the glucose oxidase method in normal and alloxan induced diabetic rats, before and 2 h after the administration of drugs. Results: Parthenium hysterophorus L. showed significant reduction in blood glucose level in the diabetic (P<0.01) rats. However, the reduction in blood glucose level with aqueous extract was less than with the standard drug glibenclamide. The extract showed less hypoglycemic effect in fasted normal rats, (P<0.05). Conclusion: The study reveals that the active fraction of Parthenium hysterophorus L. flower extract is very promising for developing standardized phytomedicine for diabetes mellitus. PMID:20040954

Patel, Vijay S.; Chitra, V.; Prasanna, P. Lakshmi; Krishnaraju, V.

2008-01-01

13

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

PubMed

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

Sathya, S; Kokilavani, R; Gurusamy, K

2008-10-01

14

Effect of aqueous and ethanol extracts of Cassia auriculata L. flowers on diabetes using alloxan induced diabetic rats  

Microsoft Academic Search

In the present study the antidiabetic potential of aqueous and ethanol extract of Cassia auriculata L. flowers was assessed in alloxan-induced diabetic rats. The phytochemical screening and antioxidant activity were made in these extracts. Antidiabetic agents (Flavonoids and phenolic acids) and free radical scavenging activity in water-soluble fraction of the ethanol extract was higher compared to that of aqueous extract.

F Lukmanul Hakkim; S Girija; R Senthil Kumar

2007-01-01

15

Antihyperglycemic and Antihyperlipidemic Effects of Fermented Rhynchosia nulubilis in Alloxan-induced Diabetic Rats  

PubMed Central

Alloxan administration in rats is used as a model for non-insulin dependent diabetes mellitus (NIDDM). NIDDM is a multifactorial disease, characterized by hyperglycemia and lipoprotein abnormalities. In this study, we evaluated the antihyperglycemic and antihyperlipidemic effects of fermented Rhynchosia nulubilis (FRN) through the regulation of glucose uptake in alloxan-induced rats. Fermented R. nulubilis was administered orally for 28 d at 500 mg/kg of body weight. Body weight and food intake were monitored every day. Biochemical parameters were quantified after 4 week. In the diabetic + FRN group, body weight increased significantly and blood glucose concentrations decreased when compared to those of the diabetic group. After 2 hr of administration, the oral glucose tolerance test (OGTT) indicated a significant reduction in the diabetic + FRN group compared to diabetic group. The diabetic + FRN group experienced a significant reduction in total cholesterol, triglycerides, low density lipoprotein, coronary risk factors, and malondialdehyde concentrations, with significantly increased high density lipoprotein compared to those of diabetic group. These results demonstrate that fermented R. nulubilis possesses potent antihyperglycemic and antihyperlipidemic activity in alloxan-induced diabetic rats. PMID:24278624

Kim, Min Jeong

2013-01-01

16

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

PubMed Central

Present study was carried to find out the antihyperglycemic and antihyperlipidemic activity of ethanol and aqueous extract of Thespesia populnea fruit pulp on alloxan-induced diabetic rats. Diabetes was induced in rats by administration of alloxan (150 mg/kg, i.p.). After the successful induction of experimental diabetes, the rats were divided into five groups each comprising a minimum of six rats. Phytochemical analysis and acute toxicity study of extracts was also done. The effects of extracts and metformin on fasting blood glucose and plasma lipid were examined for 28 days. Statistical analysis was carried out by using analysis of variance followed by Dunnet's multiple comparison test and paired t-test were done as the test of significance using GraphPad Prism. P?0.05 was considered as the minimal level of statistical significance. Therapeutic dose of extract was found to be 200 mg/kg on the basis of acute toxicity study. Aqueous and alcoholic extract showed a significant reduction in blood glucose levels as well as a lipid profile of diabetic rats at the end of 28th day of treatment. However, in groups treated with plant extract the reduction in the blood glucose and improvement in lipid profile was slightly less than that achieved with the standard group (metformin). From this study, it can be concluded that ethanol and aqueous extract of Thespesia populnea exhibited significant antihyperglycemic and antihyperlipidemic effects on alloxan-induced diabetic rats. PMID:24019572

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

2013-01-01

17

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

PubMed

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

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

2014-01-01

18

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

19

Antidiabetic Effect of Sida cordata in Alloxan Induced Diabetic Rats  

PubMed Central

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

20

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

21

Antidiabetic activity of ethanolic extract of tubers of Dioscorea alata in alloxan induced diabetic rats  

PubMed Central

Objective: To evaluate the antidiabetic activity of ethanolic extract of Dioscorea alata in glucose loaded and alloxan induced diabetic rats. Materials and Methods: The authenticated tubers of D. alata (DA) (JSSCPDP/2008/157) were collected from Dharmapuri, Tamil Nadu. The ethanol extract was tested for hypoglycemic activity in normal rats. In oral glucose tolerance test, glucose (3 g/kg, p.o.) was administered to non diabetic control, metformin (250 mg/kg, p.o.) and DA extract (100 and 200 mg/kg, p.o.) to treat treated rats. Diabetes mellitus was induced by alloxan monohydrate (120 mg/kg, i.p.) in physiological saline after overnight fasting for 18 hours. DA extract (100 and 200 mg/kg, p.o.) and standard drug metformin (250 mg/kg, p.o.) were administered to diabetic rats for 21 days. Fasting blood glucose level and changes in body weight were measured on days 0, 7, 14, and 21. At the end of 21st day, serum lipid profile, total protein, albumin, and creatinine were assessed. Results: In glucose loaded normal rats, the treatment with the extract of DA had shown a highly significant reduction (P < 0.001) in blood glucose levels at the doses of 100 and 200 mg/kg, respectively. The extract did not produce hypoglycemic activity at both the dose levels in normal, fasted rats. In alloxan induced diabetic rats, the body weight of the DA extract treated animals had shown a significant increase (P < 0.001) after 21 days treatment. The blood glucose level was reduced significantly by 47.48% and 52.09% after 21 days treatment at dose levels 100 and 200 mg/kg, respectively. Serum lipid levels, total protein, albumin, and creatinine were reversed toward near normal in treated rats as compared to diabetic control. Conclusion: The results indicate that ethanol extract of DA tubers possesses significant antidiabetic activity. PMID:21845005

Maithili, V.; Dhanabal, S.P.; Mahendran, S.; Vadivelan, R.

2011-01-01

22

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

23

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

PubMed

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

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

2010-01-01

24

Amelioration of oxidative stress by Tabernamontana divaricata on alloxan-induced diabetic rats  

PubMed Central

Objective: The purpose of this study was to evaluate the anti-diabetic activity of ethanol extract of Tabernamontana divaricata (L.) and its ameliorative effect on oxidative stress in alloxan-induced diabetic rats. Materials and Methods: Diabetes was induced by single intraperitoneal injection of alloxan monohydrate (140 mg/kg body weight). Methanol extract of T. divaricata was administered at the doses of 100 and 200 mg/kg body weight in diabetic induced rats including glibenclamide (3 mg/kg) as a reference drug. In the continuous 21 days treatment, fasting blood glucose level was determined on 0, 7, 14 and 21 days. On day 21, serum lipid profiles and glycosylated hemoglobin, liver antioxidant enzymes levels were estimated. Results: Experimental findings showed a significant anti-diabetic potential of the extract in terms of reduction in blood glucose levels and a correct effect on the altered biochemical parameters. Observed data were found statistically significant in correction of antioxidant enzyme level accompanied with diabetes, particularly at the dose of 200 mg/kg body weight. Conclusion: Based on the results, it can be concluded that the T. divaricata is found to be effective in type 2 diabetes in rats and to have an ameliorative effect on the associated oxidative stress. PMID:25593402

Kanthlal, S. K.; Kumar, B. Anil; Joseph, Jipnomon; Aravind, R.; Frank, P. Royal

2014-01-01

25

Hypoglycaemic and Antidiabetic Activities of Seeds of Myristica fragrans in Normoglycaemic and Alloxan-induced Diabetic Rats  

Microsoft Academic Search

The present study was designed to investigate the hypoglycaemic and antidiabetic activity of seeds of Myristica fragrans in normoglycaemic and alloxan- induced diabetic rats. The petroleum ether (60-80º C) extract of Myristica fragrans (PEMF) was administered orally in normal fasted, glucose fed (1.5 g\\/kg, p.o.) and alloxan (120 mg\\/kg, s.c.)- induced diabetic rats (n=5). The blood glucose levels were estimated

R. S. Somani; A. K. Singhai

26

Effect of Punica granatum Linn. (flowers) on blood glucose level in normal and alloxan-induced diabetic rats  

Microsoft Academic Search

‘Gulnar farsi’, male abortive flowers of Punica granatum L., are used for the treatment of diabetes mellitus in Unani medicine. Oral administration of its aqueous-ethanolic (50%, v\\/v) extract led to significant blood glucose lowering effect in normal, glucose-fed hyperglycaemic and alloxan-induced diabetic rats. This effect of the extract was maximum at 400 mg\\/kg, b.w.

M. A Jafri; M Aslam; Kalim Javed; Surender Singh

2000-01-01

27

Effects of Artemisia pallens Wall. on blood glucose levels in normal and alloxan-induced diabetic rats  

Microsoft Academic Search

Oral administration of the methanol extract of the aerial parts of Artemisia pallens Wall. (used in Indian folk medicine for the treatment of diabetes mellitus) led to significant blood glucose lowering effect in glucose-fed hyperglycaemic and alloxan-induced diabetic rats. This effect of the extract was dose dependent and significant at 100 mg\\/kg level in glucose-fed rats. In fasted normal rats,

A. Subramoniam; P. Pushpangadan; S. Rajasekharan; D. A. Evans; P. G. Latha; R. Valsaraj

1996-01-01

28

Effect of Punica granatum Linn. (flowers) on blood glucose level in normal and alloxan-induced diabetic rats.  

PubMed

'Gulnar farsi', male abortive flowers of Punica granatum L., are used for the treatment of diabetes mellitus in Unani medicine. Oral administration of its aqueous-ethanolic (50%, v/v) extract led to significant blood glucose lowering effect in normal, glucose-fed hyperglycaemic and alloxan-induced diabetic rats. This effect of the extract was maximum at 400 mg/kg, b.w. PMID:10837992

Jafri, M A; Aslam, M; Javed, K; Singh, S

2000-06-01

29

Antidiabetic effect of a black mangrove species Aegiceras corniculatum in alloxan-induced diabetic rats  

PubMed Central

Earlier ethnopharmacological records divulged the traditional usages of mangrove Aegiceras corniculatum (Linn.) Blanco distributed in coastal and estuarine areas of Southeast India. Excluding scientific knowledge of A. corniculatum against diabetes an upgrowing endocrinal disorder, our present study evaluated the effect on alloxan-induced diabetic rats. Diabetes was induced in adult rats of the Wistar strain by intraperitoneal injection of alloxan monohydrate. The experimental rats were administered with leaf suspension of A. corniculatum post orally using an intragastric tube. On completion of the 60-day treatment, a range of biochemical parameters were tested including liver hexokinase, glucose-6phosphatase and fructose 1, 6 bisphosphatase in the liver of control and allaxon-diabetic rats. As a result, A. corniculatum leaf suspension showed moderate reduction in blood glucose (from 382 ± 34 to 105 ± 35), glycosylated hemoglobin, a decrease in the activities of glucose-6 phosphatase and fructose 1, 6-bisphosphatase, and an increase activity of liver hexokinase achieved through the oral administration of extract on 100 mg/kg. The present findings support promising results in terms of antidiabetic activities establishing its candidacy for further purification of individual compound in order to understand their mechanism of action. PMID:22470894

Gurudeeban, S.; Satyavani, K.; Ramanathan, T.; Balasubramanian, T.

2012-01-01

30

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

PubMed Central

Background There are a few nutritional approaches to address the increased needs of managing diabetic conditions. Previously it has been reported that UP780, a standardized composition of aloe chromone formulated with an aloe polysaccharide, has a significant impact in reducing HbA1C, fasting blood glucose, fructosamine and plasma insulin level in humans and improved impaired glucose and insulin resistance in high-fat diet-induced and db/db non-insulin dependent diabetic mouse models. Here we describe activity of UP780 and its constituents to improve insulin sensitivity in alloxan induced insulin dependent diabetic mouse model. Materials and method Insulin dependent diabetes was induced by administering a single intraperitoneal injection of alloxan monohydrate at a dose of 150 mg/kg to CD-1 mice. Aloesin (UP394) was formulated with an Aloe vera inner leaf gel powder polysaccharide (Qmatrix) to yield a composition designated UP780. Efficacy of oral administration of UP780 at 2000 mg/kg and its constituents (aloesin at 80 mg/kg and Qmatrix at 1920 mg/kg) were evaluated in this model. Glyburide, a sulfonylurea drug used in the treatment of type 2 diabetes, was used at 5 mg/kg as a positive control. Effect of UP780 on non-diabetic normal mice was also addressed. Results Mice administered intraperitoneal alloxan monohydrate developed progressive type-1 diabetes like symptom. After 4 weeks of daily oral administration, reductions of 35.9%, 17.2% and 11.6% in fasting blood glucose levels were observed for UP780, the UP780 Aloe vera inner leaf gel polysaccharide preparation without chromone (Qmatrix), and Aloesin (UP394), treated animals respectively, compared to vehicle treated animals. UP780 has no impact on blood glucose level of non-diabetic healthy mice. UP780 showed statistically significant improvement for blood glucose clearance in oral glucose tolerance tests. Similarly, enhanced improvement in plasma insulin level and statistically significant reduction in triglyceride level was also observed for animals treated with the composition. Conclusion These findings suggest that UP780, a chromone standardized Aloe based composition, could possibly be used as a natural supplement alternative to facilitate maintenance of healthy blood glucose levels. PMID:24891878

2014-01-01

31

Serum Glucose and Malondialdehyde Levels in Alloxan Induced Diabetic Rats Supplemented with Methanolic Extract of Tacazzea Apiculata  

PubMed Central

Tacazzea apiculata is used by traditional medical practitioners for the treatment of wide range of diseases. The current work investigated the hypoglycemic and antioxidant properties of Tacazzea apiculata Oliv. on alloxan induced diabetes mellitus. Five groups (n=10) of rats were fed on commercial diet. The rats were divided into Group 1 (NUT) as non-diabetic and untreated, group 2 (NDT) as non-diabetic and treated, group 3 (DT) diabetic and treated. Group 4 (DUT) as diabetic and untreated. Group five (CP) were diabetic treated with Chlorpropamide, a drug used in the management of diabetic mellitus, with no known antioxidant property. Diabetic induction was done by intra-peritoneal injection of 100 mg/kg b. wt with alloxan. Fasting blood glucose was estimated seven days after induction to determine the severity of glucose elevation among the induced groups. Methanolic extract of T. apiculata leaf was administered to alloxan induced diabetic and non-diabetic control rats at 100mg/kg body weight for four weeks and blood glucose estimated on weekly basis. Malondialdehyde level was also estimated in the sera of the rats. Blood glucose level was monitored for additional 2 weeks post treatment. The results indicated that the extracts possess significant hypoglycemic effect on the diabetic rats (DT) having the mean glucose of (95.2 ± 9.12 mg/dl) compared to the diabetic untreated control group (DUT) with a mean glucose of (238.91 ± 4.42 mg/dl, p<0.05). The effect was sustained even on withdrawal of the extracts for two weeks. This was accompanied by a progressive increase in weight among all treated diabetic rats and non diabetic treated (DT and NDT) compared with diabetic untreated control rat (DUT) (p<0.05). A raised level in malondialdehyde was also observed among the diabetic rat prior to treatment and significantly decreased after the treatment. In conclusion the research demonstrated the hypoglycaemic and antioxidant potential of methanolic leaf extract of T. apiculata in alloxan induced rats. PMID:25598753

Gwarzo, M. Y.; Ahmadu, J. H.; Ahmad, M. B.; Dikko, A. U. A.

2014-01-01

32

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

33

Therapeutic potency of saponin rich aqueous extract of Scoparia dulcis L. in alloxan induced diabetes in rats  

PubMed Central

Background: Diabetes mellitus is major metabolic disorders of carbohydrate metabolism. This leads to alter the multiple organ system. Aims: To investigate the antidiabetic and antioxidant effects of the saponin rich aqueous extract of Scoparia dulcis (SRE-SD) using alloxan-induced hyperglycemic rat model. Material and Methods: The single dose of alloxan was injected for the induction of diabetes in rats. The SRE-SD and glibenclamide were administered for 15 consecutive days from the 3rd day of alloxan administration. Quantity of food and water intake was measured at day 0, and 18. Further, body weight was recorded and blood samples were collected at different time intervals that is, day 0, 3, 8, 13, and 18. The oxidative biomarkers (i.e. thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and nitrite (NO2?) levels were also estimated in the serum sample. Results: The SRE-SD showed a remarkable dose and time-dependent changes in alloxan-induced rise in the level of food consumption and water intake, serum glucose level, TBARS, NO2? and fall in the level of GSH. Further, significant attenuation was observed at 20 and 30 mg/kg of SRE-SD treated group. Conclusions: These findings demonstrate that SRE-SD has both antidiabetic and antioxidant effects on the experimental model of diabetes in rat. PMID:25558170

Perumal, P. Saravana; Anaswara, P. V.; Muthuraman, A.; Krishan, S.

2014-01-01

34

Effect of Ginger Extract Consumption on levels of blood Glucose, Lipid Profile and Kidney Functions in Alloxan Induced-Diabetic Rats  

Microsoft Academic Search

In recent years, ginger has become a subject of interest because of its beneficial effects on human health. The purpose of the present study was to investigate the effects of daily oral administration of ginger extract for 6 weeks on plasma glucose, lipid profile and kidney functions in alloxan -induced diabetic rats to show the ameliorating and partly curative effects

Abd-Elraheem A. Elshater; Muhammad M. A. Salman; Mahrous M. A. Moussa

35

Antiatherogenic, hepatoprotective, and hypolipidemic effects of coenzyme Q10 in alloxan-induced type 1 diabetic rats  

PubMed Central

BACKGROUND Diabetes mellitus, one of the leading metabolic syndromes, accounts for highest morbidity and mortality worldwide. In this study, we examined possible protective effect of coenzyme Q10 on lipid profile, atherogenic index, and liver enzyme markers in alloxan-induced type 1 diabetic rats. METHODS A total of 30 male rats were randomly divided into three groups; group 1 as control, group 2 diabetic untreatment, and group 3 treatments with coenzyme Q10 by 15 mg/kg i.p. daily, 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), total cholesterol (TC), low density lipoprotein (LDL), very low-density lipoprotein (VLDL), high density lipoprotein (HDL), atherogenic index, atherogenic coefficient, cardiac risk ratio, and the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) of all groups were analyzed. Data were analyzed using non-parametric Mann-Whitney test (using SPSS) and P < 0.05 was considered as significant. RESULTS Coenzyme Q10 inhibited significantly the activities of ALT (11.17%), AST (19.35%) and ALP (36.67%) and decreased FBG (21.19%), TG (37.24%), TC (17.15%), LDL (30.44%), VLDL (37.24%), atherogenic index (44.24%), atherogenic coefficient (49.69%), and cardiac risk ratio (37.97%), HDL level was significantly (33.38%) increased when treated with coenzyme Q10. CONCLUSION The findings of this study suggest that coenzyme Q10 exert beneficial effects on the lipid profile, atherogenic index, and liver enzymes activity in alloxan-induced type 1 diabetic rats. PMID:25258634

Ahmadvand, Hassan; Ghasemi-Dehnoo, Maryam

2014-01-01

36

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

37

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

38

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

PubMed

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

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

2013-01-01

39

Protective Effect of Lavandula stoechas and Rosmarinus officinalis essential oils against reproductive damage and oxidative stress in alloxan-induced diabetic rats.  

PubMed

The authors aimed in the present study to assess the protective effect of Rosmarinus officinalis essential oils (ROEO) and Lavandula stoechas essential oils (LSEO) against reproductive damage and oxidative stress in alloxan-induced diabetic male rats. Essential oil samples were obtained from the aerial parts of the plants by hydrodistillation and analyzed by the gas chromatography-mass spectrometry (GC-MS). Rats were divided into four groups: healthy control (HC); diabetic control (DC); healthy+ROEO (H+ROEO), healthy+LSEO (H+LSEO), diabetic+ROEO (D+ROEO), and diabetic+LSEO (D+LSEO). The use of GC-MS allowed to the identification of 15 and 22 compounds in ROEO and LSEO, respectively. In addition, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test showed that ROEO and LSEO had an important antioxidant capacity. In vivo, we initially found that ROEO and LSEO treatment protected against the decrease in alloxan-induced body weight gain, relative reproductive organ weights, testosterone level, as well as sperm quality decline. On the other hand, we showed that alloxan administration was accompanied by an oxidative stress status assessed by an increase of malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels, as well as a depletion of sulfhydril group content (-SH) and antioxidant enzyme activities as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in testis, epididymis, and sperm. More importantly, ROEO and LSEO treatment significantly protected against oxidative damage of the male reproductive organ systems in alloxan-induced diabetic rats. These findings suggested that ROEO and LSEO exerted a potential protective effect against alloxan-induced reproductive function damage and oxidative stress in male rat. The beneficial effect of ROEO and LSEO might be related, in part, to their antioxidant properties. PMID:25105335

Sebai, Hichem; Selmi, Slimen; Rtibi, Kais; Gharbi, Najoua; Sakly, Mohsen

2015-02-01

40

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

41

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

42

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

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

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

45

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

PubMed Central

Amaranthus spinosus Linn. (Amaranthaceae), commonly known as “Mulluharivesoppu” in Kannada, is used in the Indian traditional system of medicine for the treatment of diabetes. The present study deals with the scientific evaluation of alpha amylase and the antioxidant potential of methanol extract of A. spinosus (MEAS). The aim of this study was to investigate in vitro alpha-amylase enzyme inhibition by CNPG3 (2-chloro-4-nitrophenol ?-d-maltotrioside) and in vivo antioxidant potential of malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and total thiols (TT) in alloxan-induced diabetic rats of a methanolic extract of A. spinosus. Blood sugar was also determined in MEAS-treated alloxan-induced diabetic rats. MEAS showed significant inhibition of alpha-amylase activity and IC50 46.02 ?g/ml. Oral administration of MEAS (200 and 400 mg/kg) for 15 days showed significant reduction in the elevated blood glucose, MDA and restores GSH, CAT and TT levels as compared with a diabetic control. The present study provides evidence that the methanolic extract of A. spinosus has potent alpha amylase, anti-diabetic and antioxidant activities. PMID:23961097

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

2010-01-01

46

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

PubMed Central

The study was designed to evaluate the anti-diabetic effect of aqueous extract of Bauhinia tomentosa L. leaf on alloxan induced Wistar albino rats. Diabetes was induced in albino rat models with alloxan monohydrate (150mg/kg body weight). Aqueous leaf extract of Bauhinia tomentosa at the dose of 300 mg/kg was orally administered once a day for 30 days to the diabetic animals. In this study, glycemic parameters, lipid parameters and serum enzymes were reduced whereas the level of high-density lipoprotein-cholesterol was elevated. The extract significantly increased the total protein and glycogen level in the liver of diabetic rats. Furthermore, the liver carbohydrate metabolizing enzymes were normalized by the administration of the extracts. Histopatholgical examination results of liver, pancreas and kidney were normal in general. The above results indicated the anti-diabetic efficacy of the B.tomentosa leaf extract PMID:24826019

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

2011-01-01

47

Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans  

PubMed Central

Purpose. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. Methods. Thirty nondiabetic control rats (NC) and 30 untreated diabetic (UD) rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. Results. UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. Conclusion. Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis. PMID:25789328

Cassettari, Lucas Langoni; Spadella, César Tadeu

2015-01-01

48

l-Arginine ameliorates oxidative stress in alloxan-induced experimental diabetes mellitus  

Microsoft Academic Search

?1 of alloxan to produce experimental oxidative stress characteristic of diabetes mellitus. Hyperglycaemia and hypercholesterolaemia were observed in serum after 7 days of alloxan treatment. This was associated with a depression of glutathione (GSH) concentration as well as superoxide dismutase (SOD) and catalase (CAT) activities in the liver and brain. In addition, the thiobarbituric acid-reactive substances (TBARS) were significantly elevated,

M. A. El-Missiry; A. I. Othman; M. A. Amer

2004-01-01

49

Effect of silymarin on kidneys of rats suffering from alloxan-induced diabetes mellitus  

Microsoft Academic Search

Oxidative stress contributes to the pathogenesis of diabetes mellitus and its sequelae nephropathy. The kidneys are especially prone to damage by free radicals. We therefore tested the effect of the flavonoid mixture silymarin, a free radical scavenger, on the activity and gene expression of superoxide dismutase, glutathione peroxidase and catalase, as well as on renal tissue morphology in rats with

C. Soto; J. Pérez; V. García; E. Uría; M. Vadillo; L. Raya

2010-01-01

50

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

51

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

PubMed

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

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

2013-05-01

52

Antihyperglycemic activity of Eclipta alba leaf on alloxan-induced diabetic rats.  

PubMed

Eclipta alba, an indigenous medicinal plant, has a folk (Siddha and Ayurvedha) reputation in rural southern India as a hypoglycemic agent. In order to confirm this claim, the present study was carried out to evaluate the antihyperglycemic effect of E. alba and to study the activities of liver hexokinase and gluconeogenic enzymes such as glucose-6-phosphatase and fructose 1,6-bisphosphatase in the liver of control and alloxan-diabetic rats. Oral administration of leaf suspension of E. alba (2 and 4 g/kg body weight) for 60 days resulted in significant reduction in blood glucose (from 372.0 +/- 33.2 to 117.0 +/- 22.8), glycosylated hemoglobin HbA(1)c, a decrease in the activities of glucose-6 phosphatase and fructose 1,6-bisphosphatase, and an increase in the activity of liver hexokinase. E. alba at dose of 2 g/kg body weight exhibited better sugar reduction than 4 g/kg body weight. Thus, the present study clearly shows that the oral administration of E. alba possess potent antihyperglycemic activity. PMID:15369623

Ananthi, J; Prakasam, A; Pugalendi, K V

2003-01-01

53

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

54

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

55

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

56

Diabetic state-induced modification of resting membrane potential and conductance in diaphragm muscle of alloxan and diabetic KK-CA y mice  

Microsoft Academic Search

Summary  The electrical properties of skeletal muscle membranes were investigated in genetically diabetic KK-CAy mice and alloxan-induced diabetic ddY mice. Using isolated phrenic nerve-diaphragm muscle or sciatic nerve-gastrocnemius muscle in situ preparations, nerve-stimulated twitch tensions (the maximal value) were obtained at lower voltage pulse in diabetic KK-CAy mice than in normal ddY mice. The diabetic state reduced resting membrane potentials (1.7–4.0

M. Kimura; I. Kimura; T. Nakamura; H. Nojima

1988-01-01

57

Autologous circulating angiogenic cells treated with osteopontin and delivered via a collagen scaffold enhance wound healing in the alloxan-induced diabetic rabbit ear ulcer model  

PubMed Central

Introduction Diabetic foot ulceration is the leading cause of amputation in people with diabetes mellitus. Peripheral vascular disease is present in the majority of patients with diabetic foot ulcers. Despite standard treatments there exists a high amputation rate. Circulating angiogenic cells previously known as early endothelial progenitor cells are derived from peripheral blood and support angiogenesis and vasculogenesis, providing a potential topical treatment for non-healing diabetic foot ulcers. Methods A scaffold fabricated from Type 1 collagen facilitates topical cell delivery to a diabetic wound. Osteopontin is a matricellular protein involved in wound healing and increases the angiogenic potential of circulating angiogenic cells. A collagen scaffold seeded with circulating angiogenic cells was developed. Subsequently the effect of autologous circulating angiogenic cells that were seeded in a collagen scaffold and topically delivered to a hyperglycemic cutaneous wound was assessed. The alloxan-induced diabetic rabbit ear ulcer model was used to determine healing in response to the following treatments: collagen seeded with autologous circulating angiogenic cells exposed to osteopontin, collagen seeded with autologous circulating angiogenic cells, collagen alone and untreated wound. Stereology was used to assess angiogenesis in wounds. Results The cells exposed to osteopontin and seeded on collagen increased percentage wound closure as compared to other groups. Increased angiogenesis was observed with the treatment of collagen and collagen seeded with circulating angiogenic cells. Conclusions These results demonstrate that topical treatment of full thickness cutaneous ulcers with autologous circulating angiogenic cells increases wound healing. Cells exposed to the matricellular protein osteopontin result in superior wound healing. The wound healing benefit is associated with a more efficient vascular network. This topical therapy provides a potential novel therapy for the treatment of non-healing diabetic foot ulcers in humans. PMID:24444259

2013-01-01

58

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

PubMed Central

Moringa oleifera (MO) is used for a number of therapeutic purposes. This raises the question of safety and possible toxicity. The objective of the study was to ascertain the safety and possible metabolic toxicity in comparison with metformin, a known drug associated with acidosis. Animals confirmed with diabetes were grouped into 2 groups. The control group only received oral dose of PBS while the test group was treated with ethanolic extract of MO orally twice daily for 5-6 days. Data showed that the extract significantly lowered glucose level to normal values and did not cause any significant cytotoxicity compared to the control group (P = 0.0698); there was no gain in weight between the MO treated and the control groups (P > 0.8115). However, data showed that treatment with an ethanolic extract of MO caused a decrease in bicarbonate (P < 0.0001), and more than twofold increase in anion gap (P < 0.0001); metformin treatment also decreased bicarbonate (P < 0.0001) and resulted in a threefold increase in anion gap (P < 0.0001). Conclusively, these data show that while MO appears to have antidiabetic and noncytotoxic properties, it is associated with statistically significant anion gap acidosis in alloxan induced type 2 diabetic rats. PMID:25548560

2014-01-01

59

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

PubMed

Moringa oleifera (MO) is used for a number of therapeutic purposes. This raises the question of safety and possible toxicity. The objective of the study was to ascertain the safety and possible metabolic toxicity in comparison with metformin, a known drug associated with acidosis. Animals confirmed with diabetes were grouped into 2 groups. The control group only received oral dose of PBS while the test group was treated with ethanolic extract of MO orally twice daily for 5-6 days. Data showed that the extract significantly lowered glucose level to normal values and did not cause any significant cytotoxicity compared to the control group (P = 0.0698); there was no gain in weight between the MO treated and the control groups (P > 0.8115). However, data showed that treatment with an ethanolic extract of MO caused a decrease in bicarbonate (P < 0.0001), and more than twofold increase in anion gap (P < 0.0001); metformin treatment also decreased bicarbonate (P < 0.0001) and resulted in a threefold increase in anion gap (P < 0.0001). Conclusively, these data show that while MO appears to have antidiabetic and noncytotoxic properties, it is associated with statistically significant anion gap acidosis in alloxan induced type 2 diabetic rats. PMID:25548560

Omabe, Maxwell; Nwudele, Chibueze; Omabe, Kenneth Nwobini; Okorocha, Albert Egwu

2014-01-01

60

Comparative Effects of Some Medicinal Plants: Anacardium occidentale, Eucalyptus globulus, Psidium guajava, and Xylopia aethiopica Extracts in Alloxan-Induced Diabetic Male Wistar Albino Rats.  

PubMed

Insulin therapy and oral antidiabetic agents/drugs used in the treatment of diabetes mellitus have not sufficiently proven to control hyperlipidemia, which is commonly associated with the diabetes mellitus. Again the hopes that traditional medicine and natural plants seem to trigger researchers in this area is yet to be discovered. This research was designed to compare the biochemical effects of some medicinal plants in alloxan-induced diabetic male Wistar rats using named plants that are best at lowering blood glucose and hyperlipidemia and ameliorating other complications of diabetes mellitus by methods of combined therapy. The results obtained showed 82% decrease in blood glucose concentration after the 10th hour to the fortieth hour. There was significant increase P < 0.05 in the superoxide dismutase activity of the test group administered 100?mg/kg of A. Occidentale. There was no significant difference P > 0.05 recorded in the glutathione peroxidase activity of E. globulus (100?mg/kg) when compared to the test groups of P. guajava (250?mg/kg) and X. aethiopica (250?mg/kg). Catalase activity showed significant increase P < 0.05 in the catalase activity, compared to test groups. While at P > 0.05, there was no significant difference seen between test group and treated groups. Meanwhile, degree of significance was observed in other parameters analysed. The biochemical analysis conducted in this study showed positive result, attesting to facts from previous works. Though these individual plants extracts exhibited significant increase in amelorating diabetes complication and blood glucose control compared to glibenclamide, a synthetic antidiabetic drug. Greater performance was observed in the synergy groups. Therefore, a poly/combined formulation of these plants extracts yielded significant result as well as resolving some other complications associated with diabetics. PMID:25525518

Okpashi, Victor Eshu; Bayim, Bayim Peter-Robins; Obi-Abang, Margaret

2014-01-01

61

Comparative Effects of Some Medicinal Plants: Anacardium occidentale, Eucalyptus globulus, Psidium guajava, and Xylopia aethiopica Extracts in Alloxan-Induced Diabetic Male Wistar Albino Rats  

PubMed Central

Insulin therapy and oral antidiabetic agents/drugs used in the treatment of diabetes mellitus have not sufficiently proven to control hyperlipidemia, which is commonly associated with the diabetes mellitus. Again the hopes that traditional medicine and natural plants seem to trigger researchers in this area is yet to be discovered. This research was designed to compare the biochemical effects of some medicinal plants in alloxan-induced diabetic male Wistar rats using named plants that are best at lowering blood glucose and hyperlipidemia and ameliorating other complications of diabetes mellitus by methods of combined therapy. The results obtained showed 82% decrease in blood glucose concentration after the 10th hour to the fortieth hour. There was significant increase P < 0.05 in the superoxide dismutase activity of the test group administered 100?mg/kg of A. Occidentale. There was no significant difference P > 0.05 recorded in the glutathione peroxidase activity of E. globulus (100?mg/kg) when compared to the test groups of P. guajava (250?mg/kg) and X. aethiopica (250?mg/kg). Catalase activity showed significant increase P < 0.05 in the catalase activity, compared to test groups. While at P > 0.05, there was no significant difference seen between test group and treated groups. Meanwhile, degree of significance was observed in other parameters analysed. The biochemical analysis conducted in this study showed positive result, attesting to facts from previous works. Though these individual plants extracts exhibited significant increase in amelorating diabetes complication and blood glucose control compared to glibenclamide, a synthetic antidiabetic drug. Greater performance was observed in the synergy groups. Therefore, a poly/combined formulation of these plants extracts yielded significant result as well as resolving some other complications associated with diabetics. PMID:25525518

Okpashi, Victor Eshu; Bayim, Bayim Peter-Robins; Obi-Abang, Margaret

2014-01-01

62

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

PubMed Central

Background: Diabetes mellitus, becoming the third killer of mankind after cancer and cardiovascular diseases, is one of the most challenging diseases facing health care professionals today. That is why; there has been a growing interest in the therapeutic use of natural products for diabetes, especially those derived from plants. Aim: To evaluate the anti-diabetic activity together with the accompanying biological effects of the fractions and the new natural compounds of Hyphaene thebaica (HT) epicarp. Materials and Methods: 500 g of coarsely powdered of (HT) fruits epicarp were extracted by acetone. The acetone crude extract was fractionated with methanol and ethyl acetate leaving a residual water-soluble fraction WF. The anti-diabetic effects of the WF and one of its compounds of the acetone extract of the (HT) epicarp were investigated in this study using 40 adult male rats. Results: Phytochemical investigation of active WF revealed the presence of ten different flavonoids, among which two new natural compounds luteolin 7-O-[6”-O-?-Lrhamnopyranosyl]-?-D-galactopyranoside 3 and chrysoeriol 7-O-?-D-galactopyranosyl(1?2)-?-L-arabinofuranoside 5 were isolated. Supplementation of the WF improved glucose and insulin tolerance and significantly lowered blood glycosylated hemoglobin levels. On the other hand, compound 5 significantly reduced AST and ALT levels of liver, respectively. Likewise, the kidney functions were improved for both WF and compound 5, whereby both urea and creatinine levels in serum were highly significant Conclusion: The results justify the use of WF and compound 5 of the (HT) epicarp as anti-diabetic agent, taking into consideration that the contents of WF were mainly flavonoids PMID:23598921

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

2013-01-01

63

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

Microsoft Academic Search

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

P. Dhar; D. Bhattacharyya; S. Ghosh

2006-01-01

64

Hypoglycaemic effects of methanolic extract of Canscora decussata (Schult) whole-plant in normal and alloxan-induced diabetic rabbits.  

PubMed

In present study hypoglycaemic effects of the crude powdered C. decussata and its methanolic extract (ME) in alloxan diabetic rabbits were evaluated. The hypoglycaemic effect was measured by blood glucose, insulin level, HbA1c and his to pathology of pancreas. Glucose lowering effect of the ME was studied in diabetic rabbits. The effects of extract on blood glucose, body weight, food in take, fluid intake, OGTT were also evaluated. The results showed that 0.5,1 and 2g/kg of the powder significantly decreased blood glucose levels in normal rabbits and diabetic rabbits at the intervals checked. Oral intake of pioglitazone also reduced the levels in these rabbits. Synergistic hypoglycaemic effect of 600mg/kg of ME with different doses of insulin (2 & 3unit/kg, s/c) further reduced blood glucose levels of treated alloxan-diabetic rabbits. The oral glucose tolerance test revealed lowered area under curve values in ME treated rabbits. Treatment with ME (400 and 600 mg/kg) for 30 days showed highly significant decrease in blood glucose level by augmenting insulin secretion, HbA1cand significant increase in body weight, serum insulin levels in treated diabetic rabbits. Histopathology study showed regeneration of ?-cells. These studies have, therefore, supported the traditional use of this herb in diabetic patients. PMID:25553693

Irshad, Nadeem; Akhtar, Muhammad Shoaib; Bashir, Sajid; Hussain, Azhar; Shafiq, Muhammad; Iqbal, Javeid; Malik, Abdul

2015-01-01

65

Taurine ameliorate alloxan induced oxidative stress and intrinsic apoptotic pathway in the hepatic tissue of diabetic rats.  

PubMed

Oxidative stress is associated with various diabetic complications and taurine plays an important role in ameliorating those difficulties. In the present study we, therefore, investigated whether taurine plays any beneficial role against diabetes induced liver dysfunction and if it does, what cellular mechanism it follows during protective action. Induction of diabetes by alloxan (ALX) (at a dose of 120mg/kg body weight, i.p., once) reduced body weight and plasma insulin level, enhanced blood glucose and serum markers related to hepatic injury, accelerated ROS production, disturbed the intra-cellular antioxidant machineries and disintegrated hepatic cells near central vein. This pathophysiology leads to apoptotic cell death as evidenced from DNA fragmentation and TUNEL aasay. Studies on the mechanism of apoptosis showed that ALX accelerated the markers of mitochondrial dependent apoptotic pathway (enhanced cytochrome C release in cytosol from mitochondria, altered the expression of Bax, Bcl-2, Apaf-1, caspase-9, caspase-3). Treatment with taurine (1% w/v for three weeks) post-hyperglycemia, however, could restore all the alteration caused by ALX. Moreover, taurine activates hepatic PI3Kinase, Akt, hexokinase and augments the translocation of GLUT 2 to hepatic membrane in diabetic rats. Combining all, as a potential therapeutic, taurine may normalize the complications of diabetic liver injury. PMID:23092809

Rashid, Kahkashan; Das, Joydeep; Sil, Parames C

2013-01-01

66

Effect of walnut leaf, coriander and pomegranate on blood glucose and histopathology of pancreas of alloxan induced diabetic rats.  

PubMed

Mechanism of most of herbal used for diabetes mellitus treatment has not been well defined. This study was performed to investigate hypoglycemic effect of walnut leaf (Juglans regia L.), coriander leaf (Coriandrum sativum L.) or pomegranate seed (Punica granatum L.), and their possible role on pancreatic tissue. Diabetes mellitus was induced in 20 adult male Sprague Dawley rats and the animals were divided into four groups; three of them fed a diet supplemented with about 15 gram (60 g/ kg body weight /day) of mentioned plants for 15 days. The fourth diabetic untreated group (positive control) and a non-diabetic group (negative control) received standard diet. Blood glucose was measured every day and on the last day pancreases were isolated and stained with hematoxylin & eosin (H&E) and Gomeri aldehyde fuchsin (GAF). Histomorphology and following morphometric factors were studied; Volume density of beta cells, volume density of islets, percent of beta cells, number of islets per square centimeter and average area of islets. The results of this study indicate that only walnut leaf was able to reduce blood glucose significantly compared with diabetic untreated group (9.029 vs. 14.358 mmol/l) (P<0.05). Hypercellularity of islets tissue, increased hyperchromic nucleus in pancreatic islets of this group was obvious. Density of islets in pancreatic tissue, percent of beta cells and islets size increased significantly in this group in comparison with diabetic untreated group which may signify regeneration of islets or beta cells in group received walnut leaf (P<0.05). PMID:20161893

Jelodar, Gholamali; Mohsen, Maleki; Shahram, Sirus

2007-01-01

67

Hypoglycemic and antioxidant effects of leaf essential oil of Pelargonium graveolens L’Hér. 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

68

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

69

Effect of biologically synthesized gold nanoparticles on alloxan-induced diabetic rats-an in vivo approach.  

PubMed

Development of novel antidiabetic agents using various organic compounds and biomolecules has been in practice for a long time. Recently, nanomaterials are also being used in antidiabetic studies for their unique properties such as small size, biocompatibility and ability to penetrate cell membrane for carrying drugs. Herein, in vivo antidiabetic activity of gold nanoparticles (AuNPs) synthesized using the antidiabetic potent plant Gymnema sylvestre R. Br on wistar albino rats has been evaluated. The formation of AuNPs and their morphology were confirmed using spectroscopic and microscopic analyses, respectively. The treatment of AuNPs has shown significant reduction in blood glucose level on diabetic rats. AuNPs were also tested for its anti-inflammatory effect by estimating the serum levels of tumor necrosis factor-alpha (TNF-?), interleukin-6 (IL-6) and high-sensitive C-reactive protein (CRP). PMID:25092583

Karthick, V; Kumar, V Ganesh; Dhas, T Stalin; Singaravelu, G; Sadiq, A Mohamed; Govindaraju, K

2014-10-01

70

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

71

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

72

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

73

Protective effect of gallic acid on alloxan-induced oxidative stress and osmotic fragility in rats.  

PubMed

In the present study, we investigated the antioxidant effect of gallic acid (GA) on membrane lipid peroxidation and osmotic fragility in alloxan-induced diabetic Wistar rats. GA was administered orally at doses of 5, 10, and 20 mg/kg body weight for 45 days, after which liver and kidney tissues were analyzed for the degree of lipid peroxidation, reduced glutathione, and the activities of antioxidants such as catalase, superoxide dismutase, and glutathione peroxidase. Administration of GA to alloxan-induced diabetic rats reduced the blood glucose level with an increase in the level of insulin. Liver and kidney tissues from diabetic animals exhibited disturbances in antioxidant defense compared with normal rats. GA at a dose of 20 mg/kg b.w. showed a significant effect than that of the other doses. In addition, the results revealed that GA protected the integrity of erythrocyte membrane in diabetic rats as demonstrated by lower percentage of hemolysis and resistance to hydrogen peroxide-induced peroxidation. The anti-hyperglycemic activity of GA in alloxan-induced diabetic rats was also comparable with glibenclamide, a reference drug. These results suggest that GA could provide a beneficial effect on diabetes by decreasing oxidative stress-related diabetic complications. PMID:24064907

Ramkumar, Km; Vijayakumar, Rs; Vanitha, P; Suganya, N; Manjula, C; Rajaguru, P; Sivasubramanian, S; Gunasekaran, P

2014-06-01

74

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

SciTech Connect

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

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

2012-01-15

75

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

76

Effects of allogenic fetal pancreatic tissue transplantation on regeneration of islet cells in recipient rats with alloxan-induced diabetes mellitus.  

PubMed

The linear parameters and number of Langerhans islets were evaluated in rats with alloxaninduced diabetes mellitus after transplantation of fetal pancreatic tissue to the anterior chamber of the eye. The islets significantly increased in size by week 3 after surgery and a trend to an increase in their number was observed. PMID:25573370

Kulikov, D A; Kulikov, A V; Arkhipova, L V; Smirnova, G N; Dreval', A V; Tikhonova, L P; Gaivoronskii, I V; Sukhikh, G T

2015-01-01

77

Evaluation of anti-oxidative effects of propofol in experimental diabetes  

Microsoft Academic Search

This study was designed to evaluate the serum oxidative status during general anaesthesia established with propofol in alloxan-induced\\u000a diabetic mice. Sixty mice were randomly allocated into two equal groups. The mice in the diabetic group were injected intraperitoneally\\u000a with alloxan. Diabetic and normal mice were further divided into five treatment groups of six mice per group. The control\\u000a group consisted

Abdonnaser Mohebbi; Fariba Ghasemian; Mohamad-Hosein Maftoonian; Ahmad-Reza Mohammadnia; Saeed Habibian Dehkordi; Maryam Matboo-Riahi

78

Evidence for a major role for glucagon in regulation of plasma glucose in conscious, nondiabetic, and alloxan-induced diabetic rabbits.  

PubMed

Effects of glucagon immunoneutralization on plasma glucose, insulin, and glucagon were studied 2-4 h after intravenous injection of a high-affinity, monoclonal glucagon antibody into normal as well as moderately and severely alloxan (ALX)-induced diabetic rabbits (n = 5-7). A monoclonal trinitrophenyl antibody was used in control studies. Endogenous glucagon was completely neutralized as evidenced by undetectable levels of free glucagon and high plasma glucagon-binding capacities. In postabsorbtive normal rabbits, glucagon neutralization decreased plasma glucose by 2.2 +/- 0.3 mmol/l, and the resulting plasma levels of insulin and glucagon (indirectly measured) were 8 +/- 3 and 640 +/- 129% of baseline, respectively. However, when euglycemia was maintained by means of glucose infusion (steady-state plasma glucose and glucose infusion rate: 6.6 +/- 0.1 mmol/l and 3.0 +/- 0.4 mg.kg-1.min-1), both plasma insulin and glucagon remained unaltered. Thus, the glucose infusion rate accurately reflects glucagon's contribution to postabsorbtive glucose production. In both moderately and severely diabetic rabbits, immunoneutralization of glucagon decreased plasma glucose by approximately 8 mmol/l, leading to euglycemia (7.3 +/- 1.1 mmol/l) and reduced hyperinsulinemia (41 +/- 9% of baseline) in the former and to partial restoration of euglycemia (12.7 +/- 1.8 mmol/l) and unchanged insulin levels in the latter group of diabetic rabbits (P < 0.05 vs. controls in all studies). No significant changes were observed in control studies. In conclusion, glucagon is an important regulator of postabsorbtive glucose production in normal rabbits and plays an important role in the maintenance of hyperglycemia in ALX-induced diabetic rabbits. PMID:8690155

Brand, C L; Jørgensen, P N; Svendsen, I; Holst, J J

1996-08-01

79

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

80

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

SciTech Connect

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

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

1988-01-01

81

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

Microsoft Academic Search

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

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

2003-01-01

82

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

83

Hypoglycemic Effect of Combination of Azadirachta indica A. Juss. and Gynura procumbens (Lour.) Merr. Ethanolic Extracts Standardized by Rutin and Quercetin in Alloxan-induced Hyperglycemic Rats  

PubMed Central

Purpose: Exploration of plant combinations could be an alternative approach for diabetes treatment. The aim of this study is to evaluate the hypoglycemic effect of combination of A. indica and G. procumbens ethanolic extracts in alloxan-induced diabetic rats. Methods: Powder of A. indica and G. procumbens leaves were macerated with ethanol 70%. Determination of rutin in A. indica and quercetin in G. procumbens were performed by TLC-densitometry. Hyperglycemia in rats was induced by an intraperitoneal injection of alloxan monohydrate at a single dose of 150 mg/kgBW. The rats were treated with 3 dosage variation of combinations for 15 days. Hypoglycemic effect was evaluated by estimating the blood glucose levels and the rats pancreas histological study. Results: A. indica contained 2.90±0.15% of rutin and G. procumbens contained 18.86±0.86% of quercetin. Combination at the ratio of 50mg/kgBW A. indica:112.5mg/kgBW G. procumbens showed the highest hypoglycemic effect: 68.74±4.83% (preprandial) and 73.91±3.18% (postprandial). Histological studies indicated that this combination improved the morphology of the islets of Langerhans and ? cells. It also increased insulin expression and decreased the elevated-glucose concentrations. Conclusion: This study showed that combination of both extracts has better hypoglycemic effect than the single treatment of A. indica or G. procumbens. Combination of both extracts was potential to develop as a blood glucose-lowering agent for diabetic patients. PMID:25671197

Sunarwidhi, Anggit Listyacahyani; Sudarsono, Sudarsono; Nugroho, Agung Endro

2014-01-01

84

Effects of parabiosis of obese with diabetes and normal mice  

Microsoft Academic Search

Summary  Parabiosis of obese (ob\\/ob) with diabetes (db\\u000a2J\\/db2J) mice caused the obese partner to become hypoglycemic, to lose weight and to die of starvation, while no abnormal changes were observed in the diabetes partner. The striking similarity of this response to that observed in normal mice in parabiosis with diabetes mice suggests that obese mice are like normal mice in

D. L. Coleman

1973-01-01

85

Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice.  

PubMed

It has been established that insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice results from a CD4+ and CD8+ T cell-dependent autoimmune process directed against the pancreatic beta cells. The precise roles that beta cell-reactive CD8+ and CD4+ T cells play in the disease process, however, remain ill defined. Here we have investigated whether naive beta cell-specific CD8+ and CD4+ T cells can spontaneously accumulate in pancreatic islets, differentiate into effector cells, and destroy beta cells in the absence of other T cell specificities. This was done by introducing Kd- or I-Ag7-restricted beta cell-specific T cell receptor (TCR) transgenes that are highly diabetogenic in NOD mice (8.3- and 4.1-TCR, respectively), into recombination-activating gene (RAG)-2-deficient NOD mice, which cannot rearrange endogenous TCR genes and thus bear monoclonal TCR repertoires. We show that while RAG-2(-/-) 4.1-NOD mice, which only bear beta cell-specific CD4+ T cells, develop diabetes as early and as frequently as RAG-2+ 4.1-NOD mice, RAG-2(-/-) 8.3-NOD mice, which only bear beta cell-specific CD8+ T cells, develop diabetes less frequently and significantly later than RAG-2(+) 8.3-NOD mice. The monoclonal CD8+ T cells of RAG-2(-/-) 8.3-NOD mice mature properly, proliferate vigorously in response to antigenic stimulation in vitro, and can differentiate into beta cell-cytotoxic T cells in vivo, but do not efficiently accumulate in islets in the absence of a CD4+ T cell-derived signal, which can be provided by splenic CD4+ T cells from nontransgenic NOD mice. These results demonstrate that naive beta cell- specific CD8+ and CD4+ T cells can trigger diabetes in the absence of other T or B cell specificities, but suggest that efficient recruitment of naive diabetogenic beta cell-reactive CD8+ T cells to islets requires the assistance of beta cell-reactive CD4+ T cells. PMID:9362527

Verdaguer, J; Schmidt, D; Amrani, A; Anderson, B; Averill, N; Santamaria, P

1997-11-17

86

Spontaneous Autoimmune Diabetes in Monoclonal T Cell Nonobese Diabetic Mice  

PubMed Central

It has been established that insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice results from a CD4+ and CD8+ T cell–dependent autoimmune process directed against the pancreatic beta cells. The precise roles that beta cell–reactive CD8+ and CD4+ T cells play in the disease process, however, remain ill defined. Here we have investigated whether naive beta cell–specific CD8+ and CD4+ T cells can spontaneously accumulate in pancreatic islets, differentiate into effector cells, and destroy beta cells in the absence of other T cell specificities. This was done by introducing Kd– or I-Ag7–restricted beta cell–specific T cell receptor (TCR) transgenes that are highly diabetogenic in NOD mice (8.3- and 4.1-TCR, respectively), into recombination-activating gene (RAG)-2–deficient NOD mice, which cannot rearrange endogenous TCR genes and thus bear monoclonal TCR repertoires. We show that while RAG-2?/? 4.1-NOD mice, which only bear beta cell–specific CD4+ T cells, develop diabetes as early and as frequently as RAG-2+ 4.1-NOD mice, RAG-2?/? 8.3-NOD mice, which only bear beta cell–specific CD8+ T cells, develop diabetes less frequently and significantly later than RAG-2+ 8.3-NOD mice. The monoclonal CD8+ T cells of RAG-2?/? 8.3-NOD mice mature properly, proliferate vigorously in response to antigenic stimulation in vitro, and can differentiate into beta cell–cytotoxic T cells in vivo, but do not efficiently accumulate in islets in the absence of a CD4+ T cell–derived signal, which can be provided by splenic CD4+ T cells from nontransgenic NOD mice. These results demonstrate that naive beta cell– specific CD8+ and CD4+ T cells can trigger diabetes in the absence of other T or B cell specificities, but suggest that efficient recruitment of naive diabetogenic beta cell–reactive CD8+ T cells to islets requires the assistance of beta cell–reactive CD4+ T cells. PMID:9362527

Verdaguer, Joan; Schmidt, Dennis; Amrani, Abdelaziz; Anderson, Brad; Averill, Nuzhat; Santamaria, Pere

1997-01-01

87

Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice  

Microsoft Academic Search

Aims\\/hypothesis  1,25-dihydroxyvitamin D3, the active form of vitamin D, prevents Type 1 diabetes in non-obese diabetic (NOD) mice. Epidemiological data show a threefold increase in human Type 1 diabetes when vitamin D deficiency was present in the first months of life. To evaluate whether a similar dietary deficiency affects diabetes incidence in NOD mice, we generated NOD mice with vitamin D

A. Giulietti; C. Gysemans; K. Stoffels; E. van Etten; B. Decallonne; L. Overbergh; R. Bouillon; C. Mathieu

2004-01-01

88

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

89

Decreased thyroidal response to thyrotropin in diabetic mice  

SciTech Connect

The effect of diabetes mellitus on the synthesis and secretion of thyroid hormone ws investigated in mice with streptozotocin-induced diabetes. Thyroid glands were labeled in vivo with 131I for 2 h. In control animals, TSH stimulated the synthesis of PB127I and 131I-labeled iodothyronines and simultaneously decreased the proportion of 131I-. These effects of TSH were not observed in diabetic animals but were demonstrable in diabetic animals treated with insulin. For studies of hormone secretion, labeled thyroid glands were cultured in vitro in medium containing 1 mM mononitrotyrosine. The rate of the hydrolysis of labeled thyroglobulin was measured as the proportion of 131I-labeled iodotyrosines and 131I-labeled iodothyronines recovered at the end of culture and was used as an index of thyroid secretion. TSH in vivo stimulated the rate of thyroglobulin hydrolysis for 6 h, with a peak occurring after 2 h. The diabetic mice had a diminished response to TSH, which improved on treatment with insulin. The addition of TSH and insulin to the culture medium significantly increased the rate of thyroglobulin hydrolysis in glands of diabetic mice over that resulting from the addition of dibutyryl cAMP alone. The generation of thyroidal cAMP in response to TSH was higher in diabetic mice than in controls. The rise in plasma T4 and T3 2 h after the administration of TSH was less in diabetic mice than in control mice or diabetic mice treated with insulin. Our studies, therefore, indicate that the thyroidal response to TSH is decreased in diabetes mellitus. The defect appears to be at a step beyond the generation of cAMP.

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

1981-11-01

90

Trigonella foenum graecum seed powder protects against histopathological abnormalities in tissues of diabetic rats  

Microsoft Academic Search

Trigonella foenum graecum is a well-known hypoglycemic agent used in traditional Indian medicines. It was previously reported that oral administration of its seed powder for 3 weeks to alloxan diabetic rats stabilized glucose homeostasis and free radical metabolism in liver and kidney. In the present study, we further investigated the effects of 3 weeks alloxan induced diabetes on the histological

Shalini Thakran; M. R. Siddiqui; Najma Z. Baquer

2004-01-01

91

Glucose intolerance and diabetes following antigen-specific insulitis in diabetes-susceptible "humanized" transgenic mice.  

PubMed

The genetic contribution of antigen-presenting molecules and the environmental ignition of an antigen-specific immune attack to pancreatic beta-cells define autoimmune diabetes. We focused here on generating an antigen-specific model of autoimmune diabetes in humanized double-transgenic mice carrying antigen-presenting HLA-DQ8 diabetes-linked haplotype and expressing human autoantigen GAD65 in pancreatic beta-cells using a relatively diabetes-susceptible strain of mice. Double transgenic (DQ8-GAD65) mice and controls were immunized with cDNA encoding human GAD65 in adenoviral vectors and monitored for glucose intolerance and diabetes. Human-GAD65 immunization induced insulitis, glucose intolerance and diabetes in double-transgenic mice, while controls were insulitis free and glucose tolerant. Glucose intolerance 10 weeks post-immunization was followed by diabetes later on in most animals. Destructive insulitis characterized by inflammation and apoptosis correlated with the diabetes outcome. Humoral immune responses to hGAD65 were sustained in mice with diabetes while transient in non-responders. Insulitis was massive in mice with diabetes while mild in non-responders by the end of the study. Our results show for the first time the occurrence of antigen-specific induced insulitis, impaired glucose homeostasis and diabetes after immunization with a clinically relevant, human autoantigen in the context of HLA-DQ8 diabetes-susceptibility transgenes and human GAD65 expression in beta-cells. This animal model will facilitate studies of mechanisms of disease involved in development of autoimmunity to GAD65 in the context of HLA-DQ8. Furthermore, this model would be ideal for testing therapeutic strategies aimed at preventing human beta-cell loss and/or restoring function in the setting of autoimmune diabetes. PMID:20350527

Elagin, Raya B; Jaume, Juan C

2010-04-23

92

Therapeutic effects of dehydroepiandrosterone (dhea) in diabetic mice  

Microsoft Academic Search

Dehydroepiandrosterone (DHEA), a major adrenal secretory steroid in humans, was therapeutic when fed in a concentration of 0.4% to C57BL\\/KsJ mice with either non-insulin-dependent or insulin-dependent diabetes. Genetically diabetic (db\\/db) mice of both sexes develop obesity and a glucose intolerance and hyperglycemia associated with insulin resistance by 2 mo of age, and exhibit beta-cell necrosis and islet atrophy by 4

D. L. Coleman; E. H. Leiter; R. W. Schwizer

1982-01-01

93

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

94

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

95

Islet-infiltrating lymphocytes from prediabetic NOD mice rapidly transfer diabetes to NOD-scid\\/scid mice  

Microsoft Academic Search

In an effort to study the development of diabetes in NOD mice, our laboratory developed a novel adoptive transfer model using NOD-scid\\/scid (NOD-scid) mice as recipients of islet-infiltrating lymphocytes from donor prediabetic female NOD mice. We first confirmed previous results that demonstrated that splenocytes of diabetic and prediabetic female NOD mice could transfer diabetes to NOD-scid mice. We demonstrated that

P. W. Rohane; A. Shimada; D. T. Kim; C. T. Edwards; B. Charlton; L. D. Shultz; C. G. Fathman

1995-01-01

96

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

97

Experimental diabetes in neonatal mice induces early peripheral sensorimotor neuropathy.  

PubMed

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

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

2014-08-22

98

GSK3 INHIBITION PREVENTS LEARNING DEFICITS IN DIABETIC MICE  

PubMed Central

There is an increasing awareness that diabetes has an impact on the central nervous system, with reports of impaired learning, memory and mental flexibility being more common in diabetic subjects than in the general population. Insulin-deficient diabetic mice also display learning deficits associated with defective insulin-signaling in the brain and increased activity of GSK3. In the present study, AR-A014418, a GSK3? inhibitor and TX14(A), a neurotrophic factor with GSK3 inhibitory properties, were tested against the development of learning deficits in mice with insulin-deficient diabetes. Treatments were started at onset of diabetes and continued for 10 weeks. Treatment with AR-A014418 or TX14(A) prevented the development of learning deficits, assessed by the Barnes maze, while only AR-A014418 prevented memory deficits, as assessed by the object recognition test. Diabetes-induced increased levels of amyloid beta protein and phosphorylated tau were not significantly affected by the treatments. However the diabetes-induced decrease in synaptophysin, a presynaptic protein marker of hippocampal plasticity, was partially prevented by both treatments. These results suggest a role for GSK3 and/or reduced neurotrophic support in the development of cognitive deficits in diabetic mice that are associated with synaptic damage. PMID:23362012

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

2012-01-01

99

Traditional plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice  

Microsoft Academic Search

Summary  The effects on glucose homeostasis of eleven plants used as traditional treatments for diabetes mellitus were evaluated in normal and streptozotocin diabetic mice. Dried leaves of agrimony (Agrimonia eupatoria), alfalfa (Medicago saliva), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), lady's mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of

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

1990-01-01

100

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

101

Trigonella foenum graecum (fenugreek) seed powder improves glucose homeostasis in alloxan diabetic rat tissues by reversing the altered glycolytic, gluconeogenic and lipogenic enzymes  

Microsoft Academic Search

Trigonella foenum graecum (fenugreek) seed powder has been suggested to have potential antidiabetic effects. The effect of oral administration of Trigonella whole seed powder (5% in the diet) for 21 days on glycolytic, gluconeogenic and NADPlinked lipogenic enzymes were studied in liver and kidney tissues of alloxan-induced diabetic Wistar rats. Diabetic rats were characterised by a 4fold higher blood glucose

Jayadev Raju; Dhananjay Gupta; Araga R. Rao; Pramod K. Yadava; Najma Z. Baquer

2001-01-01

102

Anti-Diabetic Effects of CTB-APSL Fusion Protein in Type 2 Diabetic Mice  

PubMed Central

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

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

2014-01-01

103

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

104

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

PubMed

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

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

2014-03-01

105

Mitochondrial Dysfunction and Apoptosis in Cumulus Cells of Type I Diabetic Mice  

E-print Network

Mitochondrial Dysfunction and Apoptosis in Cumulus Cells of Type I Diabetic Mice Qiang Wang1 demonstrated in diabetic mice; however, the potential pathways by which maternal diabetes exerts its effects of maternal diabetes on the mitochondrial status in cumulus cells. We found an increased frequency

106

Hypoglycemic effects of Murraya koenigii on normal and alloxan-diabetic rabbits  

Microsoft Academic Search

In past there have been many medicinal plants, which have been used in traditional medicines for their antidiabetic properties without any scientific support and pharmacological evidence. The aqueous extract of Murraya koenigii leaves has been taken to evaluate the hypoglycemic activity in normal and alloxan induced diabetic rabbits. This plant is promising as it is widely and regularly used as

Achyut Narayan Kesari; Rajesh Kumar Gupta; Geeta Watal

2005-01-01

107

Artificial Pancreas Using Living Beta Cells: Effects on Glucose Homeostasis in Diabetic Rats  

Microsoft Academic Search

An artificial pancreas consisting of beta cells cultured on synthetic semipermeable hollow fibers was tested in rats with alloxan-induced diabetes. When implanted ex vivo as arteriovenous shunts in the circulatory system these devices lowered concentrations of plasma glucose from 533 to between 110 and 130 milligrams per 100 milliliters, increased concentrations of plasma insulin, and restored intravenous glucose tolerance tests

William L. Chick; John J. Perna; Vilma Lauris; David Low; Pierre M. Galletti; Georg Panol; Anthony D. Whittemore; Arthur A. Like; Clark K. Colton; Michael J. Lysaght

1977-01-01

108

Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice.  

PubMed

Differences in susceptibility to diabetic nephropathy (DN) between mouse strains with identical levels of hyperglycemia correlate with renal levels of oxidative stress, shown previously to play a central role in the pathogenesis of DN. Susceptibility to DN appears to be genetically determined, but the critical genes have not yet been identified. Overexpression of the enzyme glyoxalase 1 (Glo1), which prevents posttranslational modification of proteins by the glycolysis-derived ?-oxoaldehyde, methylglyoxal (MG), prevents hyperglycemia-induced oxidative stress in cultured cells and model organisms. In this study, we show that in nondiabetic mice, knockdown of Glo1 increases to diabetic levels both MG modification of glomerular proteins and oxidative stress, causing alterations in kidney morphology indistinguishable from those caused by diabetes. We also show that in diabetic mice, Glo1 overexpression completely prevents diabetes-induced increases in MG modification of glomerular proteins, increased oxidative stress, and the development of diabetic kidney pathology, despite unchanged levels of diabetic hyperglycemia. Together, these data indicate that Glo1 activity regulates the sensitivity of the kidney to hyperglycemic-induced renal pathology and that alterations in the rate of MG detoxification are sufficient to determine the glycemic set point at which DN occurs. PMID:24062246

Giacco, Ferdinando; Du, Xueliang; D'Agati, Vivette D; Milne, Ross; Sui, Guangzhi; Geoffrion, Michele; Brownlee, Michael

2014-01-01

109

Protection of Nonobese Diabetic Mice from Diabetes by Intranasal or Subcutaneous Administration of Insulin Peptide B(9-23)  

Microsoft Academic Search

The observation that overt type I diabetes is often preceded by the appearance of insulin autoantibodies and the reports that prophylactic administration of insulin to biobreeding diabetes-prone (BB-DP) rats, nonobese diabetic (NOD) mice, and human subjects results in protection from diabetes suggest that an immune response to insulin is involved in the process of beta cell destruction. We have recently

Dylan Daniel; Dale R. Wegmann

1996-01-01

110

Rotavirus Infection of Infant and Young Adult Nonobese Diabetic Mice Involves Extraintestinal Spread and Delays Diabetes Onset?  

PubMed Central

Rotaviruses have been implicated as a possible viral trigger for exacerbations in islet autoimmunity, suggesting they might modulate type 1 diabetes development. In this study, the ability of rotavirus strain RRV to infect the pancreas and affect insulitis and diabetes was examined in nonobese diabetic (NOD) mice, an experimental model of type 1 diabetes. Mice were inoculated either orally or intraperitoneally as infants or young adults. In infant mice inoculated orally, rotavirus antigen was detected in pancreatic macrophages outside islets and infectious virus was found in blood cells, pancreas, spleen, and liver. Extraintestinal RRV spread and pancreatic presence of infectious virus also occurred in intraperitoneally inoculated infant and adult mice. The initiation of insulitis was unaltered by infection. The onset of diabetes was delayed in infant mice inoculated orally and infant and adult mice inoculated intraperitoneally. In contrast, adult mice inoculated orally showed no evidence of pancreatic RRV, the lowest rate of detectable RRV replication, and no diabetes modulation. Thus, the ability of RRV infection to modulate diabetes development in infant and young adult NOD mice was related to the overall extent of detectable virus replication and the presence of infectious virus extraintestinally, including in the pancreas. These studies show that RRV infection of infant and young adult NOD mice provides significant protection against diabetes. As these findings do not support the hypothesis that rotavirus triggers autoimmunity related to type 1 diabetes, further research is needed to resolve this issue. PMID:17428851

Graham, Kate L.; O'Donnell, Joanne A.; Tan, Yan; Sanders, Natalie; Carrington, Emma M.; Allison, Janette; Coulson, Barbara S.

2007-01-01

111

The DPP4 inhibitor linagliptin delays the onset of diabetes and preserves ?-cell mass in non-obese diabetic mice.  

PubMed

Recent data indicate that dipeptidyl peptidase 4 (DPP4) inhibitors have anti-inflammatory and ?-cell-sparing effects in animal models of type 1 diabetes. To evaluate the effects of the DPP4 inhibitor linagliptin on ?-cell mass and insulinitis, we examined the progression of diabetes (blood glucose >11 ?mmol/l) in non-obese diabetic (NOD) mice with terminal stereological assessment of cellular pancreatic changes. Female NOD mice were fed a normal chow diet or a diet containing linagliptin 0.083 ?g/kg chow for 60 days. At study end, the incidence of diabetes in linagliptin-treated mice was reduced by almost 50% compared with vehicle (10 of 31 mice vs 18 of 30 mice, P=0.021). The total islet mass and total ?-cell mass, identified by insulin immunoreactivity, were greater in non-diabetic linagliptin-treated mice compared with non-diabetic vehicle-treated mice (P<0.01 for both) but were greatly reduced in diabetic mice irrespective of treatment. No changes were seen in the ?, ? and ? endocrine cell pool. Moreover, the total mass of lymphocyte insulinitis was significantly reduced in linagliptin-treated mice compared with vehicle. The data indicate that linagliptin treatment delays the onset of diabetes in NOD mice by protecting ?-cell mass. PMID:22761275

Jelsing, Jacob; Vrang, Niels; van Witteloostuijn, Søren B; Mark, Michael; Klein, Thomas

2012-09-01

112

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

113

Hypoglycaemic action of stevioside and a barley and brewer’s yeast based preparation in the experimental model on mice  

PubMed Central

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 1ml/100g (III-placebo). Glycaemia was measured before and after 7-day treatment with stevioside or BBCr in the following conditions: fasting, 30min after glucose load (I) or 45min 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

2011-01-01

114

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

115

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

Microsoft Academic Search

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

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

1987-01-01

116

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

117

Altered Metabolic Signature in Pre-Diabetic NOD Mice  

PubMed Central

Altered metabolism proceeding seroconversion in children progressing to Type 1 diabetes has previously been demonstrated. We tested the hypothesis that non-obese diabetic (NOD) mice show a similarly altered metabolic profile compared to C57BL/6 mice. Blood samples from NOD and C57BL/6 female mice was collected at 0, 1, 2, 3, 4, 5, 6, 7, 9, 11, 13 and 15 weeks and the metabolite content was analyzed using GC-MS. Based on the data of 89 identified metabolites OPLS-DA analysis was employed to determine the most discriminative metabolites. In silico analysis of potential involved metabolic enzymes was performed using the dbSNP data base. Already at 0 weeks NOD mice displayed a unique metabolic signature compared to C57BL/6. A shift in the metabolism was observed for both strains the first weeks of life, a pattern that stabilized after 5 weeks of age. Multivariate analysis revealed the most discriminative metabolites, which included inosine and glutamic acid. In silico analysis of the genes in the involved metabolic pathways revealed several SNPs in either regulatory or coding regions, some in previously defined insulin dependent diabetes (Idd) regions. Our result shows that NOD mice display an altered metabolic profile that is partly resembling the previously observation made in children progressing to Type 1 diabetes. The level of glutamic acid was one of the most discriminative metabolites in addition to several metabolites in the TCA cycle and nucleic acid components. The in silico analysis indicated that the genes responsible for this reside within previously defined Idd regions. PMID:22514744

Madsen, Rasmus; Banday, Viqar Showkat; Moritz, Thomas; Trygg, Johan; Lejon, Kristina

2012-01-01

118

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

PubMed Central

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

Raafat, K.; Samy, W.

2014-01-01

119

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

120

Antidiabetic activity of isoquercetin in diabetic KK -Ay mice  

PubMed Central

Background Tartary buckwheat bran is an important natural source of quercetin and isoquercetin. Quercetin and isoquercetin are both powerful ?-glucosidase inhibitors. Although the IC50 of isoquercetin as ?-glucosidase inhibitor was much higher than that of quercetin, the bioavailability of isoquercetin was higher than that of quercetin. Hence, we are interested in the antidiabetic effect of isoquercetin in diabetic KK -Ay mice. Methods The hypoglycemic effect of isoquercetin in a type 2 diabetic animal model (KK-Ay mice) was studied. Isoquercetin was administrated at doses of 50, 100 and 200 mg/kg for 35 days. Results It was found that fasting blood glucose concentration was decreased with the 200 mg/kg group (p < 0.01) the most efficient compared with the diabetic control group. In addition, there was significant decrease in plasma C-peptide, triglyceride, total cholesterol and blood urea nitrogen levels after 35 days. Meanwhile, glucose tolerance was improved, and the immunoreactive of pancreatic islets ?-cells was promoted. Conclusions These results suggest that isoquercetin had a regulative role in blood glucose level and lipids, and improved the function of pancreatic islets. Isoquercetin may be useful in the treatment of type 2 diabetes mellitus. PMID:22133267

2011-01-01

121

Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice.  

PubMed

Type 1 diabetes (T1D) results from the autoimmune-mediated destruction of pancreatic ?-cells, leading to deficiency of insulin production. Successful islet transplantation can normalise hyperglycaemia in T1D patients; however, the limited availability of the islets, loss of islet cell mass through apoptosis after islet isolation and potential autoimmune destruction of the transplanted islets prevent the widespread use of this procedure. Therefore, the search for novel and cost-effective agents that can prevent or treat T1D is extremely important to decrease the burden of morbidity from this disease. In the present study, we discovered that ( - )-epigallocatechin gallate (EGCG, 0·05 % in drinking-water), the primary polyphenolic component in green tea, effectively delayed the onset of T1D in non-obese diabetic (NOD) mice. At 32 weeks of age, eight (66·7 %) out of twelve mice in the control group developed diabetes, whereas only three (25 %) out of twelve mice in the EGCG-treated group became diabetic (P < 0·05). Consistently, mice supplemented with EGCG had significantly higher plasma insulin levels and survival rate but lower glycosylated Hb concentrations compared with the control animals. EGCG had no significant effects on food or water intake and body weight in mice, suggesting that the glucose-lowering effect was not due to an alteration in these parameters. While EGCG did not modulate insulitis, it elevated the circulating anti-inflammatory cytokine IL-10 level in NOD mice. These findings demonstrate that EGCG may be a novel, plant-derived compound capable of reducing the risk of T1D. PMID:21144096

Fu, Zhuo; Zhen, Wei; Yuskavage, Julia; Liu, Dongmin

2011-04-01

122

Diabetes-Resistant NOR Mice Are More Severely Affected by Streptozotocin Compared to the Diabetes-Prone NOD Mice: Correlations with Liver and Kidney GLUT2 Expressions  

PubMed Central

Nonobese Diabetic (NOD) mice are susceptible strains for Type 1 diabetes development, and Nonobese Diabetes-Resistant (NOR) mice are defined as suitable controls for NOD mice in non-MHC-related research. Diabetes is often accelerated in NOD mice via Streptozotocin (STZ). STZ is taken inside cells via GLUT2 transmembrane carrier proteins, the major glucose transporter isoforms in pancreatic beta cells, liver, kidneys, and the small intestine. We observed severe adverse effects in NOR mice treated with STZ compared to NOD mice that were made diabetic with a similar dose. We suggested that the underlying mechanism could be differential GLUT2 expressions in pancreatic beta cells, yet immunofluorescent and immunohistochemical studies revealed similar GLUT2 expression levels. We also detected GLUT2 expression profiles in NOD and NOR hepatic and renal tissues by western blot analysis and observed considerably higher GLUT2 expression levels in liver and kidney tissues of NOR mice. Although beta cell GLUT2 expression levels are frequently evaluated as a marker predicting STZ sensitivity in animal models, we report here very different diabetic responses to STZ in two different animal strains, in spite of similar initial GLUT2 expressions in beta cells. Furthermore, use of NOR mice in STZ-mediated experimental diabetes settings should be considered accordingly. PMID:25699277

Kahraman, S.; Aydin, C.; Elpek, G. O.; Dirice, E.; Sanlioglu, A. D.

2015-01-01

123

Diabetes Reduces Aortic Endothelial Gap Junctions in ApoE-deficient Mice: Simvastatin Exacerbates the Reduction  

PubMed Central

We examined the endothelial gap junctions in diabetic hyperlipidemic mice. Male apolipoprotein E (apoE)-deficient mice were made diabetic by streptozotocin. Three weeks later, the animals were treated with simvastatin for 2 weeks. The expression of aortic gap junctions in the non-diabetic (n=10), untreated diabetic (n=10), and simvastatin-treated diabetic animals (n=6) was analyzed. There was a >4-fold increase in serum cholesterol level and >50% increase in plaque areas in the diabetic mice, regardless of simvastatin treatment. Western blotting of aortae showed reduced expression of connexin37 (Cx37) and Cx40 in the diabetic mice, which were further decreased in the simvastatin-treated diabetic mice. Immunoconfocal microscopy showed that endothelial gap junctions made of Cx37 and Cx40 were both reduced in the untreated diabetic mice compared with the non-diabetic mice (decrease: Cx37, 41%; Cx40, 42%; both p<0.01). The reduction was greater in the simvastatin-treated mice (decrease in treated diabetic vs non-diabetic: Cx37, 61%; Cx40, 79%; both p<0.01; decrease in treated diabetic vs untreated diabetic: Cx37, 34%; Cx40, 63%; both p<0.01). Cx37 and Cx40 were decreased in the endothelium of plaque surface. Cx43 appeared in the medial layer and inner layer of the intima. All three connexins were rarely expressed in monocytes/macrophages inside the plaques. In conclusion, in apoE-deficient mice, streptozotocin-induced diabetes is associated with downregulation of endothelial Cx37 and Cx40 gap junctions. Short-term treatment with simvastatin exacerbates the downregulation. (J Histochem Cytochem 56:745–752, 2008) PMID:18443364

Hou, Charles Jia-Yin; Tsai, Cheng-Ho; Su, Cheng-Huang; Wu, Yih-Jer; Chen, Su-Jen; Chiu, Jing-Jing; Shiao, Ming-Shi; Yeh, Hung-I

2008-01-01

124

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

125

Impaired response of mature adipocytes of diabetic mice to hypoxia.  

PubMed

Adipose tissue contains various cells such as infiltrated monocytes/macrophages, endothelial cells, preadipocytes, and adipocytes. Adipocytes have an endocrine function by secreting adipokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-?, leptin, and adiponectin. Dysregulation of adipokines in adipose tissues leads to a chronic low-grade inflammation which could result in atherosclerosis, hypertension, and type 2 diabetes. A sustained inflammatory state, which is characterized by prolonged persistence of macrophages and neutrophils, is found in diabetic wounds. In addition, subcutaneous adipocytes are enormously increased in amount clinically in type 2 diabetes. However, the function of subcutaneous adipocytes, which play an important role in injured tissue subjected to hypoxia, has not been well characterized in vitro due to the difficulty of maintaining mature adipocytes in culture using conventional methods because of their buoyancy. In this study, we established a novel in vitro culture method of mature adipocytes by enclosing them in a hyaluronan (HA) based hydrogel to study their role in response to stress such as hypoxia. BrdU labeling and Ki67 immunostaining experiments showed that hydrogel enclosed mature adipocytes proliferate in vitro. Both mRNA and protein expression analyses for hypoxia regulated genes, such as vascular endothelial growth factor (VEGF) and heme oxygenase 1 (HO1), showed that mature adipocytes of wild type mice respond to hypoxia. In contrast, mature adipocytes of diabetic db/db and TallyHo mice did not efficiently respond to hypoxia. Our studies suggest that mature adipocytes are functionally active cells, and their abnormal function to hypoxia can be one of underlining mechanisms in type 2 diabetes. PMID:21777581

Hong, Seok Jong; Jin, Da P; Buck, Donald W; Galiano, Robert D; Mustoe, Thomas A

2011-10-01

126

Impaired response of mature adipocytes of diabetic mice to hypoxia  

SciTech Connect

Adipose tissue contains various cells such as infiltrated monocytes/macrophages, endothelial cells, preadipocytes, and adipocytes. Adipocytes have an endocrine function by secreting adipokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-{alpha}, leptin, and adiponectin. Dysregulation of adipokines in adipose tissues leads to a chronic low-grade inflammation which could result in atherosclerosis, hypertension, and type 2 diabetes. A sustained inflammatory state, which is characterized by prolonged persistence of macrophages and neutrophils, is found in diabetic wounds. In addition, subcutaneous adipocytes are enormously increased in amount clinically in type 2 diabetes. However, the function of subcutaneous adipocytes, which play an important role in injured tissue subjected to hypoxia, has not been well characterized in vitro due to the difficulty of maintaining mature adipocytes in culture using conventional methods because of their buoyancy. In this study, we established a novel in vitro culture method of mature adipocytes by enclosing them in a hyaluronan (HA) based hydrogel to study their role in response to stress such as hypoxia. BrdU labeling and Ki67 immunostaining experiments showed that hydrogel enclosed mature adipocytes proliferate in vitro. Both mRNA and protein expression analyses for hypoxia regulated genes, such as vascular endothelial growth factor (VEGF) and heme oxygenase 1 (HO1), showed that mature adipocytes of wild type mice respond to hypoxia. In contrast, mature adipocytes of diabetic db/db and TallyHo mice did not efficiently respond to hypoxia. Our studies suggest that mature adipocytes are functionally active cells, and their abnormal function to hypoxia can be one of underlining mechanisms in type 2 diabetes.

Hong, Seok Jong, E-mail: seok-hong@northwestern.edu; Jin, Da P.; Buck, Donald W.; Galiano, Robert D.; Mustoe, Thomas A., E-mail: tmustoe@nmh.org

2011-10-01

127

Traditional plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice.  

PubMed

The effects on glucose homeostasis of eleven plants used as traditional treatments for diabetes mellitus were evaluated in normal and streptozotocin diabetic mice. Dried leaves of agrimony (Agrimonia eupatoria), alfalfa (Medicago sativa), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), lady's mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra) were studied. Each plant material was supplied in the diet (6.25% by weight) and some plants were additionally supplied as decoctions or infusions (1 g/400 ml) in place of drinking water to coincide with the traditional method of preparation. Food and fluid intake, body weight gain, plasma glucose and insulin concentrations in normal mice were not altered by 12 days of treatment with any of the plants. After administration of streptozotocin (200 mg/kg i.p.) on day 12 the development of hyperphagia, polydipsia, body weight loss, hyperglycaemia and hypoinsulinaemia were not affected by blackberry, celandine, lady's mantle or lily of the valley. Garlic and liquorice reduced the hyperphagia and polydipsia but did not significantly alter the hyperglycaemia or hypoinsulinaemia. Treatment with agrimony, alfalfa, coriander, eucalyptus and juniper reduced the level of hyperglycaemia during the development of streptozotocin diabetes. This was associated with reduced polydipsia (except coriander) and a reduced rate of body weight loss (except agrimony). Alfalfa initially countered the hypoinsulinaemic effect of streptozotocin, but the other treatments did not affect the fall in plasma insulin. The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice. PMID:2210118

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

1990-08-01

128

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

129

Inhibition of macrophage migration inhibitory factor reduces diabetic nephropathy in type II diabetes mice.  

PubMed

Macrophage migration inhibitory factor (MIF) plays a critical role in inflammation and is elevated in diabetic kidney. However, whether MIF plays a causative role in diabetic nephropathy (DN) remains unclear. In the present study, we have demonstrated that after treatment of 8-week-old diabetic db/db and nondiabetic db/m mice with the MIF inhibitor ISO-1 (20 mg/kg) for 8 weeks, there was a significant decrease in blood glucose, albuminuria, extracellular matrix accumulation, epithelial-mesenchymal transition (EMT), and macrophage activation in the kidney of db/db mice. Incubation of macrophages with MIF induced the production of proinflammatory cytokines, including interleukin (IL) 6, IL-1?, tumor necrosis factor ? (TNF-?). The conditioned media (CM) of MIF-activated macrophages and TNF-? induced by MIF caused podocyte damage. Moreover, CM from MIF-activated macrophages induced EMT of renal tubular cells, and this effect was blocked by ISO-1. Thus, MIF inhibition may be a potential therapeutic strategy for DN. This effect may be attributable to its inhibitory effect on macrophage activation in the diabetic kidney. PMID:24958012

Wang, Zhigang; Wei, Meng; Wang, Meng; Chen, Lei; Liu, Hua; Ren, Yi; Shi, Kehui; Jiang, Hongli

2014-12-01

130

Baicalein Protects against Type 2 Diabetes via Promoting Islet ?-Cell Function in Obese Diabetic Mice  

PubMed Central

In both type 1 (T1D) and type 2 diabetes (T2D), the deterioration of glycemic control over time is primarily caused by an inadequate mass and progressive dysfunction of ?-cell, leading to the impaired insulin secretion. Here, we show that dietary supplementation of baicalein, a flavone isolated from the roots of Chinese herb Scutellaria baicalensis, improved glucose tolerance and enhanced glucose-stimulated insulin secretion (GSIS) in high-fat diet (HFD-) induced middle-aged obese mice. Baicalein had no effect on food intake, body weight gain, circulating lipid profile, and insulin sensitivity in obese mice. Using another mouse model of type 2 diabetes generated by high-fat diet (HFD) feeding and low doses of streptozotocin injection, we found that baicalein treatment significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in these middle-aged obese diabetic mice, which are associated with the improved islet ?-cell survival and mass. In the in vitro studies, baicalein significantly augmented GSIS and promoted viability of insulin-secreting cells and human islets cultured either in the basal medium or under chronic hyperlipidemic condition. These results demonstrate that baicalein may be a naturally occurring antidiabetic agent by directly modulating pancreatic ?-cell function. PMID:25147566

Fu, Yu; Jia, Zhenquan; Zhen, Wei; Zhou, Kequan; Gilbert, Elizabeth

2014-01-01

131

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

132

Protective effects of polysaccharides from Lilium lancifolium on streptozotocin-induced diabetic mice.  

PubMed

In this study, the protective effect of Lilium lancifolium polysaccharides (LLP) on streptozotocin (STZ)-induced diabetic mice and possible mechanism were investigated. The diabetic mice were administered with LLP for 28 days. The results showed that oral administration of LLP could significantly decrease blood glucose level and increase body weight loss in STZ-induced diabetic mice. LLP also significantly increased the activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) and decreased the level of malondialdehyde (MDA) in serum, liver, and kidney in STZ-induced diabetic mice. Moreover, histopathological examination showed that LLP could markedly improve the structure integrity of pancreatic islet tissue in STZ-induced diabetic mice. However, LLP had no significant effect on organ weight of liver and pancreas of diabetic mice, but significantly decreased kidney weight compared with diabetic control mice. This study suggested that LLP had hypoglycemic and antioxidant properties and could provide protective effect on STZ-induced diabetic mice. PMID:24508917

Zhang, Ting; Gao, Jie; Jin, Zheng-Yu; Xu, Xue-Ming; Chen, Han-Qing

2014-04-01

133

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

E-print Network

Gene Expression Profiles of Nondiabetic and Diabetic Obese Mice Suggest a Role of Hepatic Lipogenic Kathryn L. Schueler,1 Fei Zou,2 Brian S. Yandell,3 and Alan D. Attie1 Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice

Attie, Alan D.

134

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

Microsoft Academic Search

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 30days

Atef M. Al-Attar; Talal A. Zari

2010-01-01

135

Protection of inactivated influenza virus vaccine against lethal influenza virus infection in diabetic mice  

Microsoft Academic Search

Influenza virus infection frequently causes complications and some excess mortality in the patients with diabetes. Vaccination is an effective measure to prevent influenza virus infection. In this paper, antibody response and protection against influenza virus infection induced by vaccination were studied in mouse model of diabetes. Healthy and diabetic BALB\\/c mice were immunized once or twice with inactivated influenza virus

Qiang Zhu; Haiyan Chang; Yan Chen; Fang Fang; Changyong Xue; Fenghua Zhang; Meizhen Qiu; Hanzhong Wang; Bin Wang; Ze Chen

2005-01-01

136

Elimination of insulitis and augmentation of islet beta cell regeneration via induction of chimerism in overtly diabetic NOD mice  

Microsoft Academic Search

Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from autoreactive T cell destruction of insulin-producing ? cells. Cure of type 1 diabetes may require both reversal of auto-immunity and regeneration of ? cells. Induction of chimerism via allogeneic hematopoietic cell transplantation has been shown to reestablish tolerance in both prediabetic and diabetic NOD mice. However, it

Chunyan Zhang; Ivan Todorov; C.-L. Lin; Mark Atkinson; Fouad Kandeel; Stephen Forman; Defu Zeng

2007-01-01

137

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

138

Diabetes provides an unfavorable environment for muscle mass and function after muscle injury in mice.  

PubMed

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 injection of a myotoxic agent (cardiotoxin). Neuromuscular function was evaluated by examining in situ isometric contractile properties of regenerating muscles in response to nerve stimulation 14, 28 and 56 days after myotoxic injury. We found that STZ-induced diabetes reduces muscle weight and absolute maximal tetanic force in both regenerating and uninjured muscles (p = 0.0001). Moreover, it increases specific maximal tetanic force and tetanic fusion in regenerating and uninjured muscles (p = 0.04). In the Akita mice, diabetes decreases muscle weight and absolute maximal tetanic force, and increases tetanic fusion in both regenerating and uninjured muscles (p < or = 0.003). Interestingly, STZ-induced diabetes exerts more marked effects than diabetes of genetic origin, in particular on muscle weight. This reduction in muscle mass was not due to an increased expression of the atrogenes MuRF1 and atrogin-1 during STZ-induced diabetes. The present study in mice demonstrates that both models of diabetes impair regenerating muscles as well as uninjured muscles. Regenerating fast muscles are weaker, lighter and slower in diabetic compared with nondiabetic mice. PMID:17890896

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

2007-01-01

139

Increased galectin-1 expression in muscle of Astragalus polysaccharide-treated Type 1 diabetic mice  

Microsoft Academic Search

In order to investigate the immunopharmacological function of Astragalus polysaccharide (APS) in Type 1 diabetes mellitus\\u000a (T1DM), multiple low-dose streptozotocin-induced diabetic mice and normal mice were administered either APS or saline intraperitoneally\\u000a once daily. The changes in galectin-1 expression in different organs of the mice were detected by ELISA, Real-time fluorescence\\u000a quantitative RT-PCR and Western blot. The percentages of apoptotic

Xingjian Zhou; Yancheng Xu; Guoming Yang; Fang Li

2011-01-01

140

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.; Köhler, S. Eleonore

2014-01-01

141

Autoimmune diabetes and resistance to xenograft transplantation tolerance in NOD mice.  

PubMed

Costimulation blockade induces prolonged rat islet and skin xenograft survival in C57BL/6 mice. Nonobese diabetic (NOD) mice, which are used to model human autoimmune diabetes, are resistant to costimulation blockade-induced allograft tolerance. We tested the hypothesis that NOD mice would also be resistant to costimulation blockade-induced rat xenograft tolerance. We report that rat islet xenograft survival is short in spontaneously diabetic NOD mice treated with a tolerizing regimen of donor-specific transfusion and anti-CD154 antibody. Rat islet xenograft survival is only marginally longer in chemically diabetic NOD mice treated with costimulation blockade but is prolonged further in NOD Idd congenic mice bearing C57-derived chromosome 3 loci. Reciprocally, the presence of NOD-derived chromosome 3 loci shortens islet xenograft survival in tolerized C57BL/6 mice. Islet xenograft survival is longer in tolerized NOD.CD4a(-/-) and (NOD x C57BL/6)F1 mice than in NOD mice but still much shorter than in C57BL/6 mice. Skin xenograft survival in (NOD x C57BL/6)F1 mice treated with costimulation blockade is short, suggesting a strong genetic resistance to skin xenograft tolerance induction. We conclude that the resistance of NOD mice to xenograft tolerance induction involves some mechanisms that also participate in the expression of autoimmunity and other mechanisms that are distinct. PMID:15616017

Gordon, Ethel J; Wicker, Linda S; Peterson, Laurence B; Serreze, David V; Markees, Thomas G; Shultz, Leonard D; Rossini, Aldo A; Greiner, Dale L; Mordes, John P

2005-01-01

142

Pancreatic IL-10 induces diabetes in NOD.B6 Idd3 Idd10 mice.  

PubMed

Transgenic NOD backcross mice expressing pancreatic interleukin 10 (IL-10) were crossed and backcrossed to NOD.B6 Idd3 Idd10 mice, which have diabetes-resistance alleles at Idd3 and Idd10 on chromosome 3 and have a very low frequency diabetes and insulitis. Insulitis and diabetes developed in almost all IL-10 transgenic backcross 1 (BC1) mice of the H2g(7/g7) haplotype regardless of the allelic status at Idd3 and Idd10. Furthermore, diabetes occurred in 23% of IL-10 transgenic H2g(7/d) BC1 mice. These results indicate that pancreatic IL-10 is able to overcome the diabetes protection afforded by C57BL/6 (B6)-derived alleles at Idd3 and Idd10 as well as the absence of NOD MHC homozygosity, if other non-MHC NOD-derived Idd alleles are provided. PMID:9543182

Lee, M S; Wicker, L S; Peterson, L B; Sarvetnick, N

1997-01-01

143

Induction of Diabetes in Aged C57B6 Mice Results in Severe Nephropathy  

PubMed Central

Kidney aging is a slowly progressive process that is postulated to be accelerated by intervening diseases, such as diabetes, due in part to the addition of excessive stress and inflammation from the intervening disease to the underlying aging process. This hypothesis was tested by inducing diabetes with streptozotocin in 18-month-old, aging mice. After 4 months of diabetes, these mice developed severe albuminuria, elevated creatinine levels, and renal lesions including extensive apoptotic cell death, glomerulosclerosis, afferent and efferent hyalinosis, and tubulointerstitial inflammation and fibrosis. These symptoms were associated with elevated oxidative stress. The presence of endoplasmic reticulum (ER) stress in 22-month-old diabetic kidneys resulted in up-regulation of C/EBP homologous protein (CHOP), which may play a role in increasing kidney lesions because CHOP-deficient proximal tubular cells were resistant to ER stress-induced cell death, and CHOP-deficient mice were protected from diabetic nephropathy. Moreover, CHOP-deficient mice did not develop albuminuria as they aged. Inflammation, another key component of progressive diabetic nephropathy, was prominent in 22-month-old diabetic kidneys. The expression of tumor-necrosis factor-? in 22-month-old diabetic kidneys may play a role in inflammation, ER stress, and apoptosis. Thus, diabetes may accelerate the underlying kidney aging process present in old mice. PMID:20363923

Wu, Jin; Zhang, Ruihua; Torreggiani, Massimo; Ting, Adrian; Xiong, Huabao; Striker, Gary E.; Vlassara, Helen; Zheng, Feng

2010-01-01

144

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

145

Estrogen treatment predisposes to severe and persistent vaginal candidiasis in diabetic mice  

PubMed Central

Background Increased levels of estrogen and diabetes mellitus separately predispose to vaginal candidiasis (VC). However, the compounding effect of estrogen on the severity and persistence of VC in diabetic females is not clear. Methods To address this issue, a diabetic mouse model with estrogen-maintained VC was developed and evaluated for vaginal fungal burden (VFB) and immune competence at different time points throughout the study period. Results Blood glucose levels in estrogen-treated diabetic mice were consistently lower than that in untreated counterparts. Estrogen-treated C. albicans-infected non-diabetic mice experienced persistent episodes of VC as compared with naïve controls (P?diabetic mice was significantly greater than that in non-diabetic counterparts (P?diabetic mice were significantly higher (P?diabetic counterparts. Statistically significant (P?diabetic and non-diabetic mice as compared with controls. Levels of expression of the inhibitory molecule CD152 on vaginal and splenic T cells isolated from estrogen-treated C. albicans infected mice was significantly higher than that in naive untreated controls (P?diabetic females may protect against the progression of DM on the one hand and predispose to severe and persistent VC on the other. The later outcome could be related to the immunosuppressed status of the host. PMID:24401317

2014-01-01

146

Sotagliflozin improves glycemic control in nonobese diabetes-prone mice with type 1 diabetes  

PubMed Central

Purpose Oral agents are needed that improve glycemic control without increasing hypoglycemic events in patients with type 1 diabetes (T1D). Sotagliflozin may meet this need, because this compound lowers blood glucose through the insulin-independent mechanisms of inhibiting kidney SGLT2 and intestinal SGLT1. We examined the effect of sotagliflozin on glycemic control and rate of hypoglycemia measurements in T1D mice maintained on a low daily insulin dose, and compared these results to those from mice maintained in better glycemic control with a higher daily insulin dose alone. Materials and methods Nonobese diabetes-prone mice with cyclophosphamide-induced T1D were randomized to receive one of four daily treatments: 0.2 U insulin/vehicle, 0.05 U insulin/vehicle, 0.05 U insulin/2 mg/kg sotagliflozin or 0.05 U insulin/30 mg/kg sotagliflozin. Insulin was delivered subcutaneously by micro-osmotic pump; the day after pump implantation, mice received their first of 22 once-daily oral doses of sotagliflozin or vehicle. Glycemic control was monitored by measuring fed blood glucose and hemoglobin A1c levels. Results Blood glucose levels decreased rapidly and comparably in the 0.05 U insulin/sotagliflozin-treated groups and the 0.2 U insulin/vehicle group compared to the 0.05 U insulin/vehicle group, which had significantly higher levels than the other three groups from day 2 through day 23. A1c levels were also significantly higher in the 0.05 U insulin/vehicle group compared to the other three groups on day 23. Importantly, the 0.2 U insulin/vehicle group had, out of 100 blood glucose measurements, 13 that were <70 mg/dL compared to one of 290 for the other three groups combined. Conclusion Sotagliflozin significantly improved glycemic control, without increasing the rate of hypoglycemia measurements, in diabetic mice maintained on a low insulin dose. This sotagliflozin-mediated improvement in glycemic control was comparable to that achieved by raising the insulin dose alone, but was not accompanied by the increased rate of hypoglycemia measurements observed with the higher insulin dose.

Powell, David R; Doree, Deon; Jeter-Jones, Sabrina; Ding, Zhi-Ming; Zambrowicz, Brian; Sands, Arthur

2015-01-01

147

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice.  

PubMed

Diabetes mellitus is characterized by hyperglycemia and its associated complications, including cardiomyopathy. Metformin, in addition to lowering blood glucose levels, provides cardioprotection for diabetic subjects. Glycolysis is essential to cardiac metabolism and its reduction may contribute to diabetic cardiomyopathy. Hexokinase (HK) and phosphofructokinase (PFK), rate-limiting enzymes of glycolysis, are downregulated in cardiac muscle from diabetic subjects, playing a central role on the decreased glucose utilization in the heart of diabetic subjects. Thus, the aim of this study was to determine whether metformin modulates heart HK and PFK from diabetic mice. Diabetes was induced by streptozotocin injection on male Swiss mice, which were treated for three consecutive days with 250 mg/kg metformin before evaluating HK and PFK activity, expression, and intracellular distribution on the heart of these subjects. We show that metformin abrogates the downregulation of HK and PFK in the heart of streptozotocin-induced diabetic mice. This effect is not correlated to alteration on the enzymes' transcription and expression. However, the intracellular distribution of both enzymes is altered in diabetic hearts that show increased activity of the soluble fraction when compared to the particulate fraction. Moreover, this pattern is reversed upon the treatment with metformin, which is correlated with the effects of the drug on the enzymes activity. Altogether, our results support evidences that metformin alter the intracellular localization of HK and PFK augmenting glucose utilization by diabetic hearts and, thus, conferring cardiac protection to diabetic subjects. PMID:22730258

Da Silva, Daniel; Ausina, Priscila; Alencar, Edgard M; Coelho, Wagner S; Zancan, Patricia; Sola-Penna, Mauro

2012-09-01

148

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

149

Connective Tissue Growth Factor Is Necessary for Retinal Capillary Basal Lamina Thickening in Diabetic Mice  

PubMed Central

Experimental prevention of basal lamina (BL) thickening of retinal capillaries ameliorates early vascular changes caused by diabetes. Connective tissue growth factor (CTGF) is upregulated early in diabetes in the human retina and is a potent inducer of expression of BL components. We hypothesize that CTGF is causally involved in diabetes-induced BL thickening of retinal capillaries. To test this hypothesis, we compared the effects of streptozotocin (STZ)-induced diabetes on retinal capillary BL thickness between wild-type mice (CTGF+/+) and mice lacking one functional CTGF allele (CTGF+/?). Differences in BL thickness were calculated by quantitative analysis of electron microscopic images of transversally sectioned capillaries in and around the inner nuclear layer of the retina. We show that BL thickening was significant in diabetic CTGF+/+ mice compared with control CTGF+/+ mice, whereas diabetes did not significantly induce BL thickening in CTGF+/? mice. We conclude that CTGF expression is necessary for diabetes-induced BL thickening and suggest that reduction of CTGF levels may be protective against the development of diabetic retinopathy. (J Histochem Cytochem 56:785–792, 2008) PMID:18474939

Kuiper, Esther J.; van Zijderveld, Rogier; Roestenberg, Peggy; Lyons, Karen M.; Goldschmeding, Roel; Klaassen, Ingeborg; Van Noorden, Cornelis J.F.; Schlingemann, Reinier O.

2008-01-01

150

Connective tissue growth factor is necessary for retinal capillary basal lamina thickening in diabetic mice.  

PubMed

Experimental prevention of basal lamina (BL) thickening of retinal capillaries ameliorates early vascular changes caused by diabetes. Connective tissue growth factor (CTGF) is upregulated early in diabetes in the human retina and is a potent inducer of expression of BL components. We hypothesize that CTGF is causally involved in diabetes-induced BL thickening of retinal capillaries. To test this hypothesis, we compared the effects of streptozotocin (STZ)-induced diabetes on retinal capillary BL thickness between wild-type mice (CTGF+/+) and mice lacking one functional CTGF allele (CTGF+/-). Differences in BL thickness were calculated by quantitative analysis of electron microscopic images of transversally sectioned capillaries in and around the inner nuclear layer of the retina. We show that BL thickening was significant in diabetic CTGF+/+ mice compared with control CTGF+/+ mice, whereas diabetes did not significantly induce BL thickening in CTGF+/- mice. We conclude that CTGF expression is necessary for diabetes-induced BL thickening and suggest that reduction of CTGF levels may be protective against the development of diabetic retinopathy. PMID:18474939

Kuiper, Esther J; van Zijderveld, Rogier; Roestenberg, Peggy; Lyons, Karen M; Goldschmeding, Roel; Klaassen, Ingeborg; Van Noorden, Cornelis J F; Schlingemann, Reinier O

2008-08-01

151

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

152

Protective effect of brain-derived neurotrophic factor on pancreatic islets in obese diabetic mice  

Microsoft Academic Search

We have previously demonstrated that brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and energy expenditure in obese diabetic db\\/db mice. In the present study, the effect of BDNF treatment on pancreatic islets of db\\/db mice was examined, using vehicle-treated pair-fed db\\/db mice as controls. Brain-derived neurotrophic factor (10 mg\\/kg) or vehicle was subcutaneously administered to male db\\/db mice for 4

Mitsugu Yamanaka; Yasushi Itakura; Tadashi Inoue; Atsushi Tsuchida; Tsutomu Nakagawa; Hiroshi Noguchi; Mutsuo Taiji

2006-01-01

153

Deletion of Aldose Reductase from Mice Inhibits Diabetes-Induced Retinal Capillary Degeneration and Superoxide Generation  

PubMed Central

Purpose Pharmacologic inhibition of aldose reductase (AR) previously has been studied with respect to diabetic retinopathy with mixed results. Since drugs can have off-target effects, we studied the effects of AR deletion on the development and molecular abnormalities that contribute to diabetic retinopathy. Since recent data suggests an important role for leukocytes in the development of the retinopathy, we determined also if AR in leukocytes contributes to leukocyte-mediated death of retinal endothelial cells in diabetes. Methods Wild-type (WT; C57BL/6J) and AR deficient (AR?/?) mice were made diabetic with streptozotocin. Mice were sacrificed at 2 and 10 months of diabetes to evaluate retinal vascular histopathology, to quantify retinal superoxide production and biochemical and physiological abnormalities in the retina, and to assess the number of retinal endothelial cells killed by blood leukocytes in a co-culture system. Results Diabetes in WT mice developed the expected degeneration of retinal capillaries, and increased generation of superoxide by the retina. Leukocytes from diabetic WT mice also killed more retinal endothelial cells than did leukocytes from nondiabetic animals (p<0.0001). Deletion of AR largely (P<0.05) inhibited the diabetes-induced degeneration of retinal capillaries, as well as the increase in superoxide production by retina. AR-deficiency significantly inhibited the diabetes-induced increase in expression of inducible nitric oxide synthase (iNOS) in retina, but had no significant effect on expression of intercellular adhesion molecule-1 (ICAM-1), phosphorylated p38 MAPK, or killing of retinal endothelial cells by leukocytes. Conclusions AR contributes to the degeneration of retinal capillaries in diabetic mice. Deletion of the enzyme inhibits the diabetes-induced increase in expression of iNOS and of superoxide production, but does not correct a variety of other pro-inflammatory abnormalities associated with the development of diabetic retinopathy. PMID:23614016

Tang, Jie; Du, Yunpeng; Petrash, J. Mark; Sheibani, Nader; Kern, Timothy S.

2013-01-01

154

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

155

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

156

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

NASA Astrophysics Data System (ADS)

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.

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

2014-11-01

157

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

158

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

159

Kinin receptor agonism restores hindlimb postischemic neovascularization capacity in diabetic mice.  

PubMed

Limb ischemia is a major complication of thromboembolic diseases. Diabetes worsens prognosis by impairing neovascularization. Genetic or pharmacological inactivation of the kallikrein-kinin system aggravates limb ischemia in nondiabetic animals, whereas angiotensin I-converting enzyme/kininase II inhibition improves outcome. The role of kinins in limb ischemia in the setting of diabetes is not documented. We assessed whether selective activation of kinin receptors by pharmacological agonists can influence neovascularization in diabetic mice with limb ischemia and have a therapeutic effect. Selective pseudopeptide kinin B1 or B2 receptor agonists resistant to peptidase action were administered by osmotic minipumps at a nonhypotensive dosage for 14 days after unilateral femoral artery ligation in mice previously rendered diabetic by streptozotocin. Comparison was made with ligatured, nonagonist-treated nondiabetic and diabetic mice. Diabetes reduced neovascularization, assessed by microangiography and histologic capillary density analysis, by roughly 40%. B1 receptor agonist or B2 receptor agonist similarly restored neovascularization in diabetic mice. Neovascularization in agonist-treated diabetic mice was indistinguishable from nondiabetic mice. Both treatments restored blood flow in the ischemic hindfoot, measured by laser-Doppler perfusion imaging. Macrophage infiltration increased 3-fold in the ischemic gastrocnemius muscle during B1 receptor agonist or B2 receptor agonist treatment, and vascular endothelial growth factor (VEGF) level increased 2-fold. Both treatments increased, by 50-100%, circulating CD45/CD11b-positive monocytes and CD34(+)/VEGFR2(+) progenitor cells. Thus, selective pharmacological activation of B1 or B2 kinin receptor overcomes the effect of diabetes on postischemic neovascularization and restores tissue perfusion through monocyte/macrophage mobilization. Kinin receptors are potential therapeutic targets in limb ischemia in diabetes. PMID:25398240

Desposito, Dorinne; Potier, Louis; Chollet, Catherine; Gobeil, Fernand; Roussel, Ronan; Alhenc-Gelas, Francois; Bouby, Nadine; Waeckel, Ludovic

2015-02-01

160

Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23).  

PubMed

The observation that overt type I diabetes is often preceded by the appearance of insulin autoantibodies and the reports that prophylactic administration of insulin to biobreeding diabetes-prone (BB-DP) rats, nonobese diabetic (NOD) mice, and human subjects results in protection from diabetes suggest that an immune response to insulin is involved in the process of beta cell destruction. We have recently reported that islet-infiltrating cells isolated from NOD mice are enriched for insulin-specific T cells, that insulin-specific T cell clones are capable of adoptive transfer of diabetes, and that epitopes present on residues 9-23 of the B chain appear to be dominant in this spontaneous response. In the experiments described in this report, the epitope specificity of 312 independently isolated insulin-specific T cell clones was determined and B-(9-23) was found to be dominant, with 93% of the clones exhibiting specificity toward this peptide and the remainder to an epitope on residues 7-21 of the A chain. On the basis of these observations, the effect of either subcutaneous or intranasal administration of B-(9-23) on the incidence of diabetes in NOD mice was determined. The results presented here indicate that both subcutaneous and intranasal administration of B-(9-23) resulted in a marked delay in the onset and a decrease in the incidence of diabetes relative to mice given the control peptide, tetanus toxin-(830-843). This protective effect is associated with reduced T-cell proliferative response to B-(9-23) in B-(9-23)-treated mice. PMID:8570667

Daniel, D; Wegmann, D R

1996-01-23

161

Hypertension Is a Conditional Factor for the Development of Cardiac Hypertrophy in Type 2 Diabetic Mice  

PubMed Central

Background Type 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice. Methods Thereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII) for 4 wks to induce mild hypertension (n?=?9–10 per group). Left ventricular (LV) function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immuno)histochemical analysis to assess effects on hypertrophy, fibrosis and inflammation. Results Vehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01) and cardiomyocyte size (+53% and +31%, p<0.001). This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK), while accumulation of Advanced Glycation End products (AGEs) and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice. Conclusions Collectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling. PMID:24416343

Brouwers, Olaf; Janssen, Ben J. A.; Derks, Wouter J. A.; Brouns, Agnieszka E.; Munts, Chantal; Schalkwijk, Casper G.; van der Vusse, Ger J.; van Nieuwenhoven, Frans A.

2014-01-01

162

Rotavirus Infection Accelerates Type 1 Diabetes in Mice with Established Insulitis?  

PubMed Central

Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet ? cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with the monkey rotavirus strain RRV delays diabetes development. Here, the effect of RRV infection on diabetes development once insulitis is established was determined. NOD and NOD8.3 TCR mice were inoculated with RRV aged ?12 and 5 weeks, respectively. Diabetes onset was significantly accelerated in both models (P < 0.024), although RRV infection was asymptomatic and confined to the intestine. The degree of diabetes acceleration was related to the serum antibody titer to RRV. RRV-infected NOD mice showed a possible trend toward increased insulitis development. Infected males showed increased CD8+ T-cell proportions in islets. Levels of ?-cell major histocompatibility complex class I expression and islet tumor necrosis factor alpha mRNA were elevated in at least one model. NOD mouse exposure to mouse rotavirus in a natural experiment also accelerated diabetes. Thus, rotavirus infection after ?-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of ? cells to immune recognition and activation of autoreactive T cells by proinflammatory cytokines. The timing of infection relative to mouse age and degree of insulitis determines whether diabetes onset is delayed, unaltered, or accelerated. PMID:18417562

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

2008-01-01

163

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

SciTech Connect

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

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

2012-10-26

164

Dietary supplementation with cacao liquor proanthocyanidins prevents elevation of blood glucose levels in diabetic obese mice  

Microsoft Academic Search

ObjectiveEffective approaches should be established to prevent the onset of type 2 diabetes mellitus, which has been increasing in developed countries. The present study examined whether dietary supplementation with cacao liquor proanthocyanidins (CLPr) could prevent elevation of blood glucose levels in mice with diabetes mellitus and obesity.

Makoto Tomaru; Hirohisa Takano; Naomi Osakabe; Akiko Yasuda; Ken-ichiro Inoue; Rie Yanagisawa; Tsuneto Ohwatari; Hiroshi Uematsu

2007-01-01

165

DPP-4 (CD26) Inhibitor Alogliptin Inhibits Atherosclerosis in Diabetic Apolipoprotein E-Deficient Mice  

PubMed Central

Dipeptidyl peptidase-4 (DPP-4 or CD26) inhibitors, a new class of anti-diabetic compounds, are effective in treatment of hyperglycemia. Since atherosclerosis-related cardiovascular diseases are the major complications of diabetes, it is important to determine the effect of DPP-4 inhibitors on atherosclerosis. In this study, nondiabetic and diabetic apolipoprotein E (apoE)-deficient mice were treated with DPP-4 inhibitor alogliptin for 24 weeks and atherosclerotic lesions in aortic origins were examined. Results showed that diabetes significantly increased atherosclerotic lesions, but alogliptin treatment reduced atherosclerotic lesions in diabetic mice. Metabolic studies showed that diabetes increased plasma glucose and alogliptin treatment reduced glucose. Furthermore, immunohistochemistry study showed that diabetes increased IL-6 and IL-1? protein expression in atherosclerotic plaques, but alogliptin treatment attenuated diabetes-augmented IL-6 and IL-1? expression. In consistence with the observations from the mouse models, our in vitro studies showed that alogliptin inhibited toll-like receptor (TLR)4-mediated upregulation of IL-6, IL-1?, and other proinflammatory cytokines by mononuclear cells. Taken together, our findings showed that alogliptin inhibited atherosclerosis in diabetic apoE-deficient mice and the actions of alogliptin on both glucose and inflammation may contribute to the inhibition. PMID:21558879

Ta, Nga N.; Schuyler, Corinne A.; Li, Yanchun; Lopes-Virella, Maria F.; Huang, Yan

2011-01-01

166

Indomethacin reverses decreased hippocampal cell proliferation in streptozotocin-induced diabetic mice.  

PubMed

Diabetes in humans and animals is accompanied by chronic low-grade inflammation, which could be a possible mediator of developing neuropathology and neurobehavioral deficits. The objective of the present study determined if decreasing inflammation could reverse diabetes-induced decreases in hippocampal cell proliferation, one aspect of hippocampal neurogenesis. C57BL/6J mice were made diabetic by administering streptozotocin (STZ; 195 mg/kg). STZ mice or vehicle controls received chronic treatment with the non-steroidal anti-inflammatory drug indomethacin (2 mg/kg for 14 days). Levels of glucose, corticosterone and cytokines were measured from plasma, cell proliferation was measured using BrdU incorporation in the hippocampus and TNF-?R1 and TNF-?R2 mRNA was measured using real-time PCR. STZ-induced diabetes increased plasma levels of glucose and corticosterone and decreased body weight. Cell proliferation in the hippocampus was reduced in diabetic mice by 50 %. The decreased level of cell proliferation was reversed by chronic treatment with indomethacin without changes to corticosterone and glucose levels. Plasma TNF-? levels increased in diabetic mice and were normalized by indomethacin treatment whereas IL-1 and IL-6 levels were unchanged by diabetes or indomethacin. In contrast, plasma levels of the cytokines IL-10 and IFN-gamma decreased in diabetic mice and were not affected by indomethacin treatment. STZ-induced diabetes decreased hippocampal expression of TNF-?R2 but not TNF-?R1 mRNA. Indomethacin ameliorated the effects of STZ on hippocampal neurogenesis independent of corticosterone and glycemic control, possibly by mediating the proinflammatory cytokine TNF-?. Inflammation is a potential novel pharmacological target for alleviating neurobehavioral complications arising from diabetes. PMID:25160865

Ho, Nancy; Brookshire, Bethany R; Clark, Janet E; Lucki, Irwin

2015-04-01

167

Carnosine treatment largely prevents alterations of renal carnosine metabolism in diabetic mice.  

PubMed

Recently, we identified an allelic variant of human carnosinase 1 (CN1) that results in increased enzyme activity and is associated with susceptibility for diabetic nephropathy in humans. Investigations in diabetic (db/db) mice showed that carnosine ameliorates glucose metabolism effectively. We now investigated the renal carnosinase metabolism in db/db mice. Kidney CN1 activity increased with age and was significantly higher in diabetic mice compared to controls. Increased CN1 activity did not affect renal carnosine levels, but anserine concentrations were tenfold lower in db/db mice compared to controls (0.24±0.2 vs. 2.28±0.3 nmol/mg protein in controls; p<0.001). Homocarnosine concentrations in kidney tissue were low in both control and db/db mice (below 0.1 nmol/mg protein, p=n.s.). Carnosine treatment for 4 weeks substantially decreased renal CN1 activity in diabetic mice (0.32±0.3 in non-treated db/db vs. 0.05±0.05 ?mol/mg/h in treated db/db mice; p<0.01) close to normal activities. Renal anserine concentrations increased significantly (0.24±0.2 in non-treated db/db vs. 5.7±1.2 ?mol/mg/h in treated db/db mice; p<0.01), while carnosine concentrations remained unaltered (53±6.4 in non-treated vs. 61±15 nmol/mg protein in treated db/db mice; p=n.s.). Further, carnosine treatment halved proteinuria and reduced vascular permeability to one-fifth in db/db mice. In renal tissue of diabetic mice carnosinase activity is significantly increased and anserine concentrations are significantly reduced compared to controls. Carnosine treatment largely prevents the alterations of renal carnosine metabolism. PMID:21833769

Peters, Verena; Schmitt, Claus P; Zschocke, Johannes; Gross, Marie-Luise; Brismar, Kerstin; Forsberg, Elisabete

2012-06-01

168

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

NASA Astrophysics Data System (ADS)

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

Peplow, Philip V.; Chung, Tzu-Yun; Baxter, G. David

2011-08-01

169

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

Microsoft Academic Search

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

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

2001-01-01

170

Hypoglycemic effect of DL-aminocarnitine in streptozotocin diabetic mice: inhibition of gluconeogenesis  

SciTech Connect

DL-Aminocarnitine and palmitoyl-DL-aminocarnitine are potent, non-covalent inhibitors of carnitine palmitoyl transferase. In both diabetic and non-diabetic fasted mice, DL-aminocarnitine (0.3 mmol/kg) and palmitoyl-DL-aminocarnitine (0.1 mmol/kg) decrease the blood concentration of ketone bodies to levels observed in fed control mice. Both carnitine palmitoyltransferase inhibitors also normalize plasma glucose levels in diabetic mice. The hypoglycemic effect is maximal at 8 hours, the continues for at least 12 hours. In the present studies the authors have used (/sup 14/C)alanine, a pyruvate precursor, to prove the effect of aminocarnitine on gluconeogenesis. Diabetic mice given L-(U-/sup 14/C)alanine (1 mmol/kg) by intraperitoneal injection convert 10-15% of the administered dose to (/sup 14/C)glucose after 10 min; less than 0.1% of the radioactivity is recovered in glycogen. If 0.3 mmol/kg aminocarnitine is given subcutaneously 1 hr prior to giving (/sup 14/C)analine, the radioactivity recovered in plasma glucose is reduced by approximately 40%. The authors conclude that the hypoglycemic effect of DL-aminocarnitine in diabetic mice is due, at least in part, to inhibition of gluconeogenesis. The possibility that aminocarnitine also stimulates glucose utilization in diabetic animals is not excluded.

Jenkins, D.L.; Griffith, O.W.

1986-05-01

171

Sonoporation of the Minicircle-VEGF 165 for Wound Healing of Diabetic Mice  

Microsoft Academic Search

Purpose  The purpose of this study is to examine the efficiency of sonoporation with minicircle DNA for the skin wound healing in diabetic\\u000a mice.\\u000a \\u000a \\u000a \\u000a Methods  Minicircle DNA containing the human VEGF165 was constructed and tested in vitro. Diabetes was induced in 2-week old male C57BL\\/6J mice via streptozotocin (STZ) injection. 6 mm circular skin wounds were\\u000a made on the mice back. After the

C. S. Yoon; H. S. Jung; M. J. Kwon; S. H. Lee; C. W. Kim; M. K. Kim; M. Lee; J. H. Park

2009-01-01

172

Dietary Chinese quince polyphenols suppress generation of ?-dicarbonyl compounds in diabetic KK-A(y) mice.  

PubMed

Many dietary polyphenols can provide health benefits, such as antioxidant and antidiabetic effects, and can down-regulate the progression of glycation (one cause of diabetic complications). Chinese quince (CQ) is rich in polyphenols, especially procyanidins. A few studies have indicated that CQ has an effect on diabetes. In this study, a procyanidin-rich extract was prepared from Chinese quince fruit (CQE), and its effects were investigated and compared with those of green tea extract (GTE) in type 2 diabetes model KK-A(y) mice. Mice were provided one of two high-fat (HF) diets for 4 weeks: a HF diet containing 0.5% CQE or a HF diet containing 0.5% GTE. Blood glucose was suppressed in mice fed CQE and GTE during the experimental period (p < 0.05), although the effect of CQE was weaker than that of GTE. Intake of CQE had no effect on the blood insulin level, whereas GTE decreased the insulin level. Body weight gain was suppressed in mice fed CQE similarly to mice fed GTE (p < 0.05). Hepatic lipid content and ?-dicarbonyl compounds in the kidney were reduced in mice fed CQE and GTE (p < 0.05). These results suggest that intake of CQE could moderate type 2 diabetes and diabetic complications. PMID:23730977

Nagahora, Nozomi; Ito, Yoshiaki; Nagasawa, Takashi

2013-07-10

173

DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice.  

PubMed

Dipeptidyl peptidase-4 (DPP-4 or CD26) inhibitors, a new class of antidiabetic compounds, are effective in the treatment of hyperglycemia. Because atherosclerosis-related cardiovascular diseases are the major complications of diabetes, it is important to determine the effect of DPP-4 inhibitors on atherosclerosis. In this study, nondiabetic and diabetic apolipoprotein E-deficient mice were treated with DPP-4 inhibitor alogliptin for 24 weeks, and atherosclerotic lesions in aortic origins were examined. Results showed that diabetes significantly increased atherosclerotic lesions, but alogliptin treatment reduced atherosclerotic lesions in diabetic mice. Metabolic studies showed that diabetes increased plasma glucose and that alogliptin treatment reduced glucose. Furthermore, immunohistochemistry study showed that diabetes increased interleukin-6 (IL-6) and IL-1? protein expression in atherosclerotic plaques, but alogliptin treatment attenuated diabetes-augmented IL-6 and IL-1? expression. In consistence with the observations from the mouse models, our in vitro studies showed that alogliptin-inhibited toll-like receptor 4 (TLR-4)-mediated upregulation of IL-6, IL-1?, and other proinflammatory cytokines by mononuclear cells. Taken together, our findings showed that alogliptin-inhibited atherosclerosis in diabetic apolipoprotein E-deficient mice and that the actions of alogliptin on both glucose and inflammation may contribute to the inhibition. PMID:21558879

Ta, Nga N; Schuyler, Corinne A; Li, Yanchun; Lopes-Virella, Maria F; Huang, Yan

2011-08-01

174

Glycogen synthase kinase-3 inhibition prevents learning deficits in diabetic mice.  

PubMed

There is an increasing awareness that diabetes has an impact on the central nervous system, with reports of impaired learning, memory, and mental flexibility being more common in diabetic subjects than in the general population. Insulin-deficient diabetic mice also display learning deficits associated with defective insulin-signaling in the brain and increased activity of GSK3. In the present study, AR-A014418, a GSK3? inhibitor, and TX14(A), a neurotrophic factor with GSK3 inhibitory properties, were tested against the development of learning deficits in mice with insulin-deficient diabetes. Treatments were started at onset of diabetes and continued for 10 weeks. Treatment with AR-A014418 or TX14(A) prevented the development of learning deficits, assessed by the Barnes maze, but only AR-A014418 prevented memory deficits, as assessed by the object recognition test. Diabetes-induced increased levels of amyloid ? protein and phosphorylated tau were not significantly affected by the treatments. However, the diabetes-induced decrease in synaptophysin, a presynaptic protein marker of hippocampal plasticity, was partially prevented by both treatments. These results suggest a role for GSK3 and/or reduced neurotrophic support in the development of cognitive deficits in diabetic mice that are associated with synaptic damage. PMID:23362012

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

2013-04-01

175

Anti-diabetic effects of rice hull smoke extract on glucose-regulating mechanism in type 2 diabetic mice  

Technology Transfer Automated Retrieval System (TEKTRAN)

The aim of this study is to determine the protective effect of a liquid rice hull smoke extract (RHSE) against type 2 diabetes induced by a high fat diet administered to mice. Dietary administration of 0.5% or 1% RHSE for 7 weeks results in significantly reduced blood glucose and triglyceride and to...

176

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

PubMed Central

Objective of the Study Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. Methodology and Principal Findings Streptozotocin (STZ)-induced diabetes in apolipoprotein E?/? mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. Conclusions Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications. PMID:23755169

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

2013-01-01

177

Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice.  

PubMed

Advanced glycation end products (AGEs) are implicated in beta-cell oxidant stress. Diet-derived AGE (dAGE) are shown to contribute to end-organ toxicity attributed to diabetes. To assess the role of dAGE on type 1 diabetes, NOD mice were exposed to a high-AGE diet (H-AGE) and to a nutritionally similar diet with approximate fivefold-lower levels of N(epsilon)-carboxymethyllysine (CML) and methylglyoxal-derivatives (MG) (L-AGE). Suppression of serum CML and MG in L-AGE-fed mice was marked by suppression of diabetes (H-AGE mice >94% vs. L-AGE mice 33% in founder [F](0), 14% in F(1), and 13% in F(2) offspring, P < 0.006) and by a delay in disease onset (4-month lag). Survival for L-AGE mice was 76 vs. 0% after 44 weeks of H-AGE mice. Reduced insulitis in L-AGE versus H-AGE mice (P < 0.01) was marked by GAD- and insulin-unresponsive pancreatic interleukin (IL)-4-positive CD4+ cells compared with the GAD- and insulin-responsive interferon (IFN)-gamma-positive T-cells from H-AGE mice (P < 0.005). Splenocytes from L-AGE mice consisted of GAD- and insulin-responsive IL-10-positive CD4+ cells compared with the IFN-gamma-positive T-cells from H-AGE mice (P < 0.005). Therefore, high AGE intake may provide excess antigenic stimulus for T-cell-mediated diabetes or direct beta-cell injury in NOD mice; both processes are ameliorated by maternal or neonatal exposure to L-AGE nutrition. PMID:12765955

Peppa, Melpomeni; He, Cijiang; Hattori, Masakazu; McEvoy, Robert; Zheng, Feng; Vlassara, Helen

2003-06-01

178

A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice  

PubMed Central

Whereas an important role of free radicals and oxidants in peripheral diabetic neuropathy is well established, the contribution of nitrosative stress and, in particular, of the highly reactive oxidant peroxynitrite, has not been properly explored. Our previous findings implicate peroxynitrite in diabetes-associated motor and sensory nerve conduction deficits and peripheral nerve energy deficiency and poly(ADP-ribose) polymerase activation associated with Type 1 diabetes. In this study the role of nitrosative stress in diabetic sensory neuropathy is evaluated. The peroxynitrite decomposition catalyst Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin (FP15) was administered to control and streptozotocin (STZ)-diabetic mice at the dose of 5 mg kg?1 day?1 (FP15), for 3 weeks after initial 3 weeks without treatment. Mice with 6-week duration of diabetes developed clearly manifest thermal hypoalgesia (paw withdrawal, tail-flick, and hot plate tests), mechanical hypoalgesia (tail pressure Randall–Sellito test), tactile allodynia (flexible von Frey filament test), and ~38% loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, grey matter of spinal cord, and dorsal root ganglion neurons. FP15 treatment was associated with alleviation of thermal and mechanical hypoalgesia. Tactile response threshold tended to increase in response to peroxynitrite decomposition catalyst treatment, but still remained ~59% lower compared with non-diabetic controls. Intraepidermal nerve fiber density was 25% higher in FP15-treated than in untreated diabetic rats, but the difference between two groups did not achieve statistical significance (p=0.054). Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglion neurons of peroxynitrite decomposition catalyst-treated diabetic mice were markedly reduced. In conclusion, nitrosative stress plays an important role in sensory neuropathy associated with Type 1 diabetes. The findings provide rationale for further studies of peroxynitrite decomposition catalysts in a long-term diabetic model. PMID:17644085

Drel, Viktor R.; Pacher, Pal; Vareniuk, Igor; Pavlov, Ivan; Ilnytska, Olga; Lyzogubov, Valeriy V.; Tibrewala, Jyoti; Groves, John T.; Obrosova, Irina G.

2008-01-01

179

Effect of Hominis Placenta on cutaneous wound healing in normal and diabetic mice  

PubMed Central

BACKGROUND/OBJECTIVES The number of diabetic patients has recently shown a rapid increase, and delayed wound healing is a major clinical complication in diabetes. In this study, the wound healing effect of Hominis placenta (HP) treatment was investigated in normal and streptozotocin-induced diabetic mice. MATERIALS/METHODS Four full thickness wounds were created using a 4 mm biopsy punch on the dorsum. HP was injected subcutaneously at the middle region of the upper and lower wounds. Wounds were digitally photographed and wound size was measured every other day until the 14th day. Wound closure rate was analyzed using CANVAS 7SE software. Wound tissues were collected on days 2, 6, and 14 after wounding for H/E, immunohistochemistry for FGF2, and Masson's trichrome staining for collagen study. RESULTS Significantly faster wound closure rates were observed in the HP treated group than in normal and diabetes control mice on days 6 and 8. Treatment with HP resulted in reduced localization of inflammatory cells in wounded skin at day 6 in normal mice and at day 14 in diabetic mice (P < 0.01). Expression of fibroblast growth factor (FGF) 2 showed a significant increase in the HP treated group on day 14 in both normal (P < 0.01) and diabetic mice (P < 0.05). In addition, HP treated groups showed a thicker collagen layer than no treatment groups, which was remarkable on the last day, day 14, in both normal and diabetic mice. CONCLUSIONS Taken together, HP treatment has a beneficial effect on acceleration of cutaneous wound healing via regulation of the entire wound healing process, including inflammation, proliferation, and remodeling. PMID:25110560

Park, Ji-Yeun; Lee, Jiyoung; Jeong, Minsu; Min, Seorim; Kim, Song-Yi; Lee, Hyejung; Lim, Yunsook

2014-01-01

180

Exendin-4 improves resistance to Listeria monocytogenes infection in diabetic db/db mice  

PubMed Central

The incidence of diabetes mellitus is increasing among companion animals. This disease has similar characteristics in both humans and animals. Diabetes is frequently identified as an independent risk factor for infections associated with increased mortality. In the present study, homozygous diabetic (db/db) mice were infected with Listeria (L.) monocytogenes and then treated with the anti-diabetic drug exendin-4, a glucagon-like peptide 1 analogue. In aged db/db mice, decreased CD11b+ macrophage populations with higher lipid content and lower phagocytic activity were observed. Exendin-4 lowered high lipid levels and enhanced phagocytosis in macrophages from db/db mice infected with L. monocytogenes. Exendin-4 also ameliorated obesity and hyperglycemia, and improved ex vivo bacteria clearance by macrophages in the animals. Liver histology examined during L. monocytogenes infection indicated that abscess formation was much milder in exendin-4-treated db/db mice than in the control animals. Moreover, mechanistic studies demonstrated that expression of ATP binding cassette transporter 1, a sterol transporter, was higher in macrophages isolated from the exendin-4-treated db/db mice. Overall, our results suggest that exendin-4 decreases the risk of infection in diabetic animals by modifying the interaction between intracellular lipids and phagocytic macrophages. PMID:23000581

Liu, Hsien Yueh; Chung, Chih-Yao; Yang, Wen-Chin; Liang, Chih-Lung; Wang, Chi-Young; Chang, Chih-Yu

2012-01-01

181

Ecklonia cava Inhibits Glucose Absorption and Stimulates Insulin Secretion in Streptozotocin-Induced Diabetic Mice  

PubMed Central

Aims of study. Present study investigated the effect of Ecklonia cava (EC) on intestinal glucose uptake and insulin secretion. Materials and methods. Intestinal Na+-dependent glucose uptake (SGU) and Na+-dependent glucose transporter 1 (SGLT1) protein expression was determined using brush border membrane vesicles (BBMVs). Glucose-induced insulin secretion was examined in pancreatic ?-islet cells. The antihyperglycemic effects of EC, SGU, and SGLT1 expression were determined in streptozotocin (STZ)-induced diabetic mice. Results. Methanol extract of EC markedly inhibited intestinal SGU of BBMV with the IC50 value of 345??g/mL. SGLT1 protein expression was dose dependently down regulated with EC treatment. Furthermore, insulinotrophic effect of EC extract was observed at high glucose media in isolated pancreatic ?-islet cells in vitro. We next conducted the antihyperglycemic effect of EC in STZ-diabetic mice. EC supplementation markedly suppressed SGU and SGLT1 abundance in BBMV from STZ mice. Furthermore, plasma insulin level was increased by EC treatment in diabetic mice. As a result, EC supplementation improved postprandial glucose regulation, assessed by oral glucose tolerance test, in diabetic mice. Conclusion. These results suggest that EC play a role in controlling dietary glucose absorption at the intestine and insulinotrophic action at the pancreas contributing blood glucose homeostasis in diabetic condition. PMID:22645628

Kim, Hye Kyung

2012-01-01

182

Ecklonia cava Inhibits Glucose Absorption and Stimulates Insulin Secretion in Streptozotocin-Induced Diabetic Mice.  

PubMed

Aims of study. Present study investigated the effect of Ecklonia cava (EC) on intestinal glucose uptake and insulin secretion. Materials and methods. Intestinal Na(+)-dependent glucose uptake (SGU) and Na(+)-dependent glucose transporter 1 (SGLT1) protein expression was determined using brush border membrane vesicles (BBMVs). Glucose-induced insulin secretion was examined in pancreatic ?-islet cells. The antihyperglycemic effects of EC, SGU, and SGLT1 expression were determined in streptozotocin (STZ)-induced diabetic mice. Results. Methanol extract of EC markedly inhibited intestinal SGU of BBMV with the IC(50) value of 345??g/mL. SGLT1 protein expression was dose dependently down regulated with EC treatment. Furthermore, insulinotrophic effect of EC extract was observed at high glucose media in isolated pancreatic ?-islet cells in vitro. We next conducted the antihyperglycemic effect of EC in STZ-diabetic mice. EC supplementation markedly suppressed SGU and SGLT1 abundance in BBMV from STZ mice. Furthermore, plasma insulin level was increased by EC treatment in diabetic mice. As a result, EC supplementation improved postprandial glucose regulation, assessed by oral glucose tolerance test, in diabetic mice. Conclusion. These results suggest that EC play a role in controlling dietary glucose absorption at the intestine and insulinotrophic action at the pancreas contributing blood glucose homeostasis in diabetic condition. PMID:22645628

Kim, Hye Kyung

2012-01-01

183

Placental growth factor-2 gene transfer by electroporation restores diabetic sensory neuropathy in mice.  

PubMed

Placental growth factor-2 (PlGF-2) exhibits neurotrophic activity in dorsal root ganglion (DRG) neurons through the neuropilin-1 (NP-1) receptor in vitro. To examine the potential utility of PlGF-2 therapy for treating diabetic neuropathy, we performed intramuscular PlGF-2 gene transfer by electroporation, and examined its effects on sensory neuropathy in diabetic mice. PlGF-2 was overexpressed in the tibial anterior (TA) muscles of streptozotocin-induced diabetic mice with hypoalgesia using a PlGF-2 plasmid injection with electroporation. The nociceptive threshold was measured using a paw-pressure test. In addition, we overexpressed PlGF-1, an isoform of PlGF that does not bind NP-1. The sciatic nerve and skin were examined 3weeks after PlGF-2 electro-gene transfer. The overexpression and secretion of PlGF-2 in TA muscles were confirmed by an increase in PlGF levels in TA muscles and plasma, and strongly PlGF positive myofibers in TA muscles. Two weeks after electro-gene transfer into the bilateral TA muscles, the previously elevated nociceptive threshold was found to be significantly decreased in all treated mice. PlGF-1 gene transfer by electroporation did not significantly decrease the nociceptive threshold in diabetic mice. No increase in the number of endoneurial vessels in the sciatic nerve was found in the PlGF-2 plasmid-electroporated mice. A reduction of area of immunoreactivity in epidermal nerves in diabetic mice was restored by PlGF-2 gene transfer. These findings suggest that PlGF-2 electro-gene therapy can significantly ameliorate sensory deficits (i.e. hypoalgesia) in diabetic mice through NP-1 in DRG and peripheral nerves. PMID:21056561

Murakami, Tatsufumi; Imada, Yoshimi; Kawamura, Mai; Takahashi, Tomoko; Fujita, Yoshiaki; Sato, Eiji; Yoshitomi, Hironori; Sunada, Yoshihide; Nakamura, Akihiro

2011-01-01

184

Plasminogen activator inhibitor-1 is involved in impaired bone repair associated with diabetes in female mice.  

PubMed

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

185

Antidiabetic potential of Citrus sinensis and Punica granatum peel extracts in alloxan treated male mice.  

PubMed

An investigation on the effects of four different concentrations of peel extract from Citrus sinensis (CS) or Punica granatum (PG) in male mice revealed the maximum glucose lowering and antiperoxidative activities at 25 mg/kg of CS and 200 mg/kg of PG. In a separate experiment their potential was evaluated with respect to the regulation of alloxan induced diabetes mellitus. While a single dose of alloxan (120 mg/kg) increased the serum levels of glucose and alpha-amylase activity, rate of water consumption and lipid peroxidation (LPO) in hepatic, cardiac and renal tissues with a parallel decrease in serum insulin level, administration of 25 mg/kg of CS or 200 mg/kg of PG was found to normalize all the adverse changes induced by alloxan, revealing the antidiabetic and anti peroxidative potential of test fruit peel extracts. Subsequent phytochemical analysis indicated that the high content of total polyphenols in the test peels might be related to the antidiabetic and antiperoxidative effects of the test peels. PMID:18806305

Parmar, Hamendra Singh; Kar, Anand

2007-01-01

186

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

187

CD8+ T cell tolerance in nonobese diabetic mice is restored by insulin-dependent diabetes resistance alleles.  

PubMed

Although candidate genes controlling autoimmune disease can now be identified, a major challenge that remains is defining the resulting cellular events mediated by each locus. In the current study we have used NOD-InsHA transgenic mice that express the influenza hemagglutinin (HA) as an islet Ag to compare the fate of HA-specific CD8+ T cells in diabetes susceptible NOD-InsHA mice with that observed in diabetes-resistant congenic mice having protective alleles at insulin-dependent diabetes (Idd) 3, Idd5.1, and Idd5.2 (Idd3/5 strain) or at Idd9.1, Idd9.2, and Idd9.3 (Idd9 strain). We demonstrate that protection from diabetes in each case is correlated with functional tolerance of endogenous islet-specific CD8+ T cells. However, by following the fate of naive, CFSE-labeled, islet Ag-specific CD8+ (HA-specific clone-4) or CD4+ (BDC2.5) T cells, we observed that tolerance is achieved differently in each protected strain. In Idd3/5 mice, tolerance occurs during the initial activation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes where CD25+ regulatory T cells (Tregs) effectively prevent their accumulation. In contrast, resistance alleles in Idd9 mice do not prevent the accumulation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes, indicating that tolerance occurs at a later checkpoint. These results underscore the variety of ways that autoimmunity can be prevented and identify the elimination of islet-specific CD8+ T cells as a common indicator of high-level protection. PMID:16034108

Martinez, Xavier; Kreuwel, Huub T C; Redmond, William L; Trenney, Rebecca; Hunter, Kara; Rosen, Hugh; Sarvetnick, Nora; Wicker, Linda S; Sherman, Linda A

2005-08-01

188

Evaluation of anti-hyperglycemic and hypoglycemic effect of Trigonella foenum- graecum Linn, Ocimum sanctum Linn and Pterocarpus marsupium Linn in normal and alloxanized diabetic rats  

Microsoft Academic Search

The hypoglycemic effect of the aqueous (Aq) extract of the bark of Pterocarpus marsupium (PM) and alcoholic (Alc) extract of seeds of Trigonella foenum-graecum (FG) and leaves of Ocimum sanctum (OS) was investigated in both normal and alloxan-induced diabetic rats. The Aq extract of PM (1 g\\/kg PO) significantly (P<0.001) reduced the blood sugar levels from 72.32±5.62 to 61.35±1.2 mg%

V Vats; J. K Grover; S. S Rathi

2002-01-01

189

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

PubMed Central

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

Min, Seong Won; Han, Ji Sook

2014-01-01

190

Phlorofucofuroeckol A isolated from Ecklonia cava alleviates postprandial hyperglycemia in diabetic mice.  

PubMed

This study was designed to investigate whether phlorofucofuroeckol A inhibited ?-glucosidase and ?-amylase activities and alleviated postprandial hyperglycemia in diabetic mice. Phlorofucofuroeckol A that was isolated from Ecklonia cava (brown algae) demonstrated prominent inhibitory effects against ?-glucosidase and ?-amylase activities. The IC50 values of phlorofucofuroeckol A against ?-glucosidase and ?-amylase were 19.52 and 6.34?M, respectively. These inhibitory activities of phlorofucofuroeckol A were higher than those of acarbose, which was used as a positive control. Increases in postprandial blood glucose levels were significantly more suppressed in the group administered phlorofucofuroeckol A compared to the control group in both diabetic and normal mice. Moreover, the area under the curve was significantly lower after phlorofucofuroeckol A administration (2296 versus 2690mmolmin/l) in the diabetic mice. These results suggested that phlorofucofuroeckol A is a potent ?-glucosidase inhibitor and can alleviate the postprandial hyperglycemia that is caused by starch. PMID:25680946

You, Han-Nui; Lee, Hyun-Ah; Park, Mi-Hwa; Lee, Ji-Hyeok; Han, Ji-Sook

2015-04-01

191

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

PubMed Central

OBJECTIVE The therapeutic potential of exendin-4, an agonist of the glucagon-like peptide-1 receptor (GLP-1R), on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic mice was investigated. RESEARCH DESIGN AND METHODS The presence of the GLP-1R in lumbar dorsal root ganglion (DRG) was evaluated by immunohistochemical analyses. DRG neurons were dissected from C57BL6/J mice and cultured with or without Schwann cell–conditioned media in the presence or absence of GLP-1 (7–37) or exendin-4. Then neurite outgrowth was determined. In animal-model experiments, mice were made diabetic by STZ administration, and after 12 weeks of diabetes, exendin-4 (10 nmol/kg) was intraperitoneally administered once daily for 4 weeks. Peripheral nerve function was determined by the current perception threshold and motor and sensory nerve conduction velocity (MNCV and SNCV, respectively). Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated. RESULTS The expression of the GLP-1R in DRG neurons was confirmed. GLP-1 (7–37) and exendin-4 significantly promoted neurite outgrowth of DRG neurons. Both GLP-1R agonists accelerated the impaired neurite outgrowth of DRG neurons cultured with Schwann cell–conditioned media that mimicked the diabetic condition. At the doses used, exendin-4 had no effect on blood glucose or HbA1c levels. Hypoalgesia and delayed MNCV and SNCV in diabetic mice were improved by exendin-4 without affecting the reduced SNBF. The decreased IENFDs in sole skins of diabetic mice were ameliorated by exendin-4. CONCLUSIONS Our findings indicate that exendin-4 ameliorates the severity of DPN, which may be achieved by its direct actions on DRG neurons and their axons. PMID:21810596

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

2011-01-01

192

Fluorofenidone Attenuates Diabetic Nephropathy and Kidney Fibrosis in db\\/db Mice  

Microsoft Academic Search

Background\\/Aims: Fluorofenidone [1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD], a novel pyridone agent, showed potent antifibrotic properties. The aim of the present study was to investigate the effects of AKF-PD on diabetic nephropathy and kidney fibrosis, and to obtain an insight into its mechanisms of action. Methods: We administered AKF-PD to diabetic db\\/db mice for 12 weeks. Moreover, we performed in vitro cultures using murine

Ling Hao Wang; Ji Shi Liu; Wang Bin Ning; Qiong Jing Yuan; Fang Fang Zhang; Zhang Zhe Peng; Miao Miao Lu; Ren Na Luo; Xiao Fu; Gao Yun Hu; Zhao He Wang; Li Jian Tao

2011-01-01

193

Systemic administration of high-molecular weight hyaluronan stimulates wound healing in genetically diabetic mice.  

PubMed

Hyaluronic acid (HA), an essential component of the extracellular matrix, is an efficient space filler that maintains hydration, serves as a substrate for assembly of proteoglycans and is involved in wound healing. Although numerous pieces of evidence demonstrate beneficial effects in promoting wound healing in diabetes, a systemic approach has never been tested. We used an incisional wound healing model in genetically diabetic mice to test the effects of systemic injection of HA. Diabetic (n=56) and normoglycemic (n=56) mice were subjected to incision and randomized (8 groups of 7 animals each) to receive HA at different doses, 7.5, 15 and 30mg/kg/i.p., or vehicle (0.9% NaCl solution) for 12days. At the end of the experiment animals were sacrificed and skin wounds were excised for histological, biochemical and molecular analysis. Histology revealed that the most effective dose to improve wound repair and angiogenesis in diabetic mice was 30mg/kg. Furthermore HA injection (30mg/kg) improved the altered healing pattern in diabetic animals, increased skin remodeling proteins TGF-? and transglutaminase-II and restored the altered expression of cyclin B1/Cdc2 complex. Evaluation of skin from diabetic animals injected with HA revealed also an increase in HA content, suggesting that systemic injection may be able to restore the reduced intracellular HA pool of diabetic mice. Finally HA markedly improved skin mechanical properties. These promising results, if confirmed in a clinical setting, may improve the care and management of diabetic patients. PMID:21447385

Galeano, Mariarosaria; Polito, Francesca; Bitto, Alessandra; Irrera, Natasha; Campo, Giuseppe M; Avenoso, Angela; Calò, Margherita; Lo Cascio, Patrizia; Minutoli, Letteria; Barone, Mauro; Squadrito, Francesco; Altavilla, Domenica

2011-07-01

194

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

195

NOD congenic mice genetically protected from autoimmune diabetes remain resistant to transplantation tolerance induction.  

PubMed

The loss of self-tolerance leading to autoimmune type 1 diabetes in the NOD mouse model involves at least 19 genetic loci. In addition to their genetic defects in self-tolerance, NOD mice resist peripheral transplantation tolerance induced by costimulation blockade using donor-specific transfusion and anti-CD154 antibody. Hypothesizing that these two abnormalities might be related, we investigated whether they could be uncoupled through a genetic approach. Diabetes-resistant NOD and C57BL/6 stocks congenic for various reciprocally introduced Idd loci were assessed for their ability to be tolerized. Surprisingly, in NOD congenic mice that are almost completely protected from diabetes, costimulation blockade failed to prolong skin allograft survival. In reciprocal C57BL/6 congenic mice with NOD-derived Idd loci, skin allograft survival was readily prolonged by costimulation blockade. These data indicate that single or multiple combinations of evaluated Idd loci that dramatically reduce diabetes frequency do not correct resistance to peripheral transplantation tolerance induced by costimulation blockade. We suggest that mechanisms controlling autoimmunity and transplantation tolerance in NOD mice are not completely overlapping and are potentially distinct, or that the genetic threshold for normalizing the transplantation tolerance defect is higher than that for preventing autoimmune diabetes. PMID:12540603

Pearson, Todd; Markees, Thomas G; Wicker, Linda S; Serreze, David V; Peterson, Laurence B; Mordes, John P; Rossini, Aldo A; Greiner, Dale L

2003-02-01

196

Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice  

PubMed Central

Endothelial cell progenitors, angioblasts, have been detected in the peripheral blood of adult humans, mice, and rabbits. These cells have been shown to incorporate into the endothelium of newly forming blood vessels in pathological and nonpathological conditions. Here we investigated the possibility that the CD34-expressing leukocytes (CD34+ cells) that appear to be enriched for angioblasts could be used to accelerate the rate of blood-flow restoration in nondiabetic and diabetic mice undergoing neovascularization due to hindlimb ischemia. CD34+ cells did not accelerate the restoration of flow in nondiabetic mice, but dramatically increased it in diabetic mice. Furthermore, CD34+ cells derived from type 1 diabetics produced fewer differentiated endothelial cells in culture than did their type 2 diabetic– or nondiabetic-derived counterparts. In vitro experiments suggest that hyperglycemia per se does not alter the ability of angioblasts to differentiate or of angioblast-derived endothelial cells to proliferate. In contrast, hyperinsulinemia may enhance angioblast differentiation but impair angioblast-derived endothelial cell survival or proliferation. Our findings suggest that CD34+ cells may be a useful tool for therapeutic angiogenesis in diabetics. PMID:10953032

Schatteman, Gina C.; Hanlon, Heather D.; Jiao, Chunhua; Dodds, Sherry G.; Christy, Barbara A.

2000-01-01

197

Genetic analysis of autoimmune type 1 diabetes mellitus in mice  

Microsoft Academic Search

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

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

1991-01-01

198

The effects of DPP-IV inhibition in NOD mice with overt diabetes.  

PubMed

Sitagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor that exerts an anti-hyperglycaemic effect by preventing degradation of glucagon-like peptide 1 with subsequent ?-cell stimulation and potential regeneration. We tested whether sitagliptin therapy in symptomatic non-obese diabetic (NOD) mice would lead to changes in the immune cell profile, improve ?-cell survival and induce diabetes remission. Flow cytometry analysis of immune cells in the spleen and peripheral lymph nodes, immunohistology of the pancreas and DPP-IV activity were investigated in diabetic NOD mice, either treated or non-treated with sitagliptin, at 0, 7, 14 and 28 days after hyperglycaemia onset, and in non-diabetic NOD controls. While compared to diabetic controls sitagliptin prevented increase of the CD8+/CD4+ ratio in pancreatic nodes after four weeks (0.443 ± 0.067 vs. 0.544 ± 0.131; P < 0.05), the population of Tregs in lymph nodes increased from day 0 to 28 in both treated and non-treated diabetic groups (8 ± 1.76 vs. 13.45 ± 5.07 % and 8 ± 1.76 vs. 13.19 ± 5.58 %, respectively). The severity of islet infiltration was similar in both diabetic groups and decreased in parallel with ?-cell loss. Surprisingly, sitagliptin blocked the DPP-IV activity only temporarily (on day 7, 277.68 ± 89.2 vs. 547.40 ± 94.04 ng/ml in the diabetic control group) with no apparent effect later on. In conclusion, sitagliptin administered after the onset of overt hyperglycaemia in NOD mice had only a marginal immunological effect and did not lead to diabetes remission. Failure to block DPP-IV over time represents an important finding that requires further explanation. PMID:23890479

Vargová, L; Zacharovová, K; Dovolilová, E; Vojtová, L; Cimburek, Z; Saudek, F

2013-01-01

199

Vitreous Fluid of db\\/db Mice Exhibits Alterations in Angiogenic and Metabolic Factors Consistent with Early Diabetic Retinopathy  

Microsoft Academic Search

Background: This study evaluated the postulate that the vitreous of diabetic db\\/db mice, a genetic model of type 2 diabetes that manifests hyperglycemia and insulin resistance, exhibits alterations in angiogenic and metabolic factors that reflect abnormalities in the retinal microvasculature participatory in the pathogenesis of diabetic retinopathy. Methods: Vitreous obtained from db\\/db and age-matched nondiabetic db\\/m mice was analyzed by

Margo P. Cohen; Elizabeth Hud; Elizabeth Shea; Clyde W. Shearman

2008-01-01

200

Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice  

Microsoft Academic Search

Summary  The diabetes syndromes produced by the two single gene mutations, obese (ob), and diabetes (db) are identical when both genes are expressed on the same inbred background, whereas on different backgrounds the syndrome changes from a severeobesity, moderate-diabetes to a severe life-shortening diabetes. The same initial sequence of events occurs in both conditions. Increased secretion of insulin and hyperphagia is

D. L. Coleman

1978-01-01

201

MicroRNA-29b inhibits diabetic nephropathy in db/db mice.  

PubMed

Inflammation and its consequent fibrosis are two main features of diabetic nephropathy (DN), but target therapy on these processes for DN remains yet ineffective. We report here that miR-29b is a novel therapeutic agent capable of inhibiting progressive renal inflammation and fibrosis in type 2 diabetes in db/db mice. Under diabetic conditions, miR-29b was largely downregulated in response to advanced glycation end (AGE) product, which was associated with upregulation of collagen matrix in mesangial cells via the transforming growth factor-? (TGF-?)/Smad3-dependent mechanism. These pathological changes were reversed by overexpressing miR-29b, but enhanced by knocking-down miR-29b. Similarly, loss of renal miR-29b was associated with progressive diabetic kidney injury, including microalbuminuria, renal fibrosis, and inflammation. Restored renal miR-29b by the ultrasound-based gene therapy was capable of attenuating diabetic kidney disease. Further studies revealed that inhibition of Sp1 expression, TGF-?/Smad3-dependent renal fibrosis, NF-?B-driven renal inflammation, and T-bet/Th1-mediated immune response may be mechanisms associated with miR-29b treatment in db/db mice. In conclusion, miR-29b may play a protective role in diabetic kidney disease and may have therapeutic potential for diabetic kidney complication. PMID:24445937

Chen, Hai-Yong; Zhong, Xiang; Huang, Xiao R; Meng, Xiao-Ming; You, Yongke; Chung, Arthur Ck; Lan, Hui Y

2014-04-01

202

NaoXinTong Inhibits the Development of Diabetic Retinopathy in db/db Mice  

PubMed Central

Buchang NaoXinTong capsule (NXT) is a Chinese Materia Medica standardized product extracted from 16 Chinese traditional medical herbs and widely used for treatment of patients with cerebrovascular and cardiovascular diseases in China. Formation of microaneurysms plays an important role in the development of diabetic retinopathy. In this study, we investigated if??NXT can protect diabetic mice against the development of diabetic retinopathy. The db/db mice (~6 weeks old), a diabetic animal model, were divided into two groups and fed normal chow or plus NXT for 14 weeks. During the treatment, fasting blood glucose levels were monthly determined. After treatment, retinas were collected to determine retinal thickness, accumulation of carbohydrate macromolecules, and caspase-3 (CAS-3) expression. Our results demonstrate that administration of NXT decreased fasting blood glucose levels. Associated with the decreased glucose levels, NXT blocked the diabetes-induced shrink of multiple layers, such as photoreceptor layer and outer nuclear/plexiform layers, in the retina. NXT also inhibited the diabetes-induced expression of CAS-3 protein and mRNA, MMP-2/9 and TNF? mRNA, accumulation of carbohydrate macromolecules, and formation of acellular capillaries in the retina. Taken together, our study shows that NXT can inhibit the development of diabetic retinopathy and suggests a new potential application of NXT in clinic.

Liu, Mengyang; Pan, Quan; Chen, Yuanli; Yang, Xiaoxiao; Zhao, Buchang; Jia, Lifu; Zhu, Yan; Han, Jihong; Li, Xiaoju; Duan, Yajun

2015-01-01

203

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

Microsoft Academic Search

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

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

2001-01-01

204

Diabetes accelerates retinal ganglion cell dysfunction in mice lacking sigma receptor 1  

PubMed Central

Purpose Sigma receptor 1 (?R1) is a non-opioid transmembrane protein that may act as a molecular chaperone at the endoplasmic reticulum–mitochondrial membrane. Ligands for ?R1, such as (+)-pentazocine [(+)-PTZ], confer marked retinal neuroprotection in vivo and in vitro. Recently we analyzed the retinal phenotype of mice lacking ?R1 (?R1 KO) and observed normal retinal morphology and function in young mice (5–30 weeks) but diminished negative scotopic threshold responses (nSTRs), retinal ganglion cell (RGC) loss, and disruption of optic nerve axons consistent with inner retinal dysfunction by 1 year. These data led us to test the hypothesis that ?R1 may be critical in forestalling chronic retinal stress; diabetes was used as the model of chronic stress. Methods To determine whether ?R1 is required for (+)-PTZ neuroprotective effects, primary RGCs isolated from wild-type (WT) and ?R1 KO mice were exposed to xanthine–xanthine oxidase (10 µM:2 mU/ml) to induce oxidative stress in the presence or absence of (+)-PTZ. Cell death was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. To assess effects of chronic stress on RGC function, diabetes was induced in 3-week C57BL/6 (WT) and ?R1 KO mice, using streptozotocin to yield four groups: WT nondiabetic (WT non-DB), WT diabetic (WT-DB), ?R1 KO non-DB, and ?R1 KO-DB. After 12 weeks of diabetes, when mice were 15-weeks old, intraocular pressure (IOP) was recorded, electrophysiologic testing was performed (including detection of nSTRs), and the number of RGCs was counted in retinal histological sections. Results In vitro studies showed that (+)-PTZ could not prevent oxidative stress-induced death of RGCs harvested from ?R1 KO mice but afforded robust protection against death of RGCs harvested from WT mice. In the studies of chronic stress induced by diabetes, the IOP measured in the four mouse groups was within the normal range; however, there was a significant increase in the IOP of ?R1 KO-DB mice (16±0.5 mmHg) compared to the other groups tested (?R1 KO non-DB, WT non-DB, WT-DB: ~12±0.6 mmHg). Regarding electrophysiologic testing, the nSTRs of ?R1 KO non-DB mice were similar to WT non-DB mice at 15 weeks; however, they were significantly lower in ?R1 KO-DB mice (5±1 µV) compared to the other groups, including, notably, ?R1 KO-nonDB (12±2 µV). As expected, the number of RGCs in ?R1 KO non-DB mice was similar to WT non-DB mice at 15 weeks, but under chronic stress of diabetes there were fewer RGCs in retinas of ?R1 KO-DB mice. Conclusions This is the first report showing unequivocally that the neuroprotective effects of (+)-PTZ require ?R1. ?R1 KO mice show normal retinal structure and function at young ages; however, when subjected to the chronic stress of diabetes, there is an acceleration of retinal functional deficits in ?R1 KO mice such that ganglion cell dysfunction is observed at a much earlier age than nondiabetic ?R1 KO mice. The data support the hypothesis that ?R1 plays a key role in modulating retinal stress and may be an important target for retinal disease. PMID:23233788

Ha, Yonju; Saul, Alan; Tawfik, Amany; Zorrilla, Eric P.; Ganapathy, Vadivel

2012-01-01

205

Insulin autoantibodies are associated with islet inflammation but not always related to diabetes progression in NOD congenic mice.  

PubMed

Susceptibility to diabetes in humans and nonobese diabetic (NOD) mice is believed to arise from the combined effect of multiple genetic loci, resulting in immune-mediated destruction of the insulin-secreting beta-cells. Insulin autoantibodies (IAAs) are often present in humans for years, and in NOD mice for weeks, before the onset of diabetes. We have evaluated the expression of IAAs in NOD mice and in diabetes-resistant NOD congenic strains to characterize the association of autoantibody expression with insulitis and diabetes. In NOD congenic strains with genes that contribute to protection from insulitis and diabetes (Idd3, Idd5, Idd10, and Idd18), the prevalence of IAAs is reduced relative to NOD mice. In contrast, NOD.B10 Idd9 mice have a high prevalence of IAAs and a high degree of insulitis, despite a nearly complete resistance to diabetes. These data indicate that IAA expression is a phenotype that is associated with insulitis and correlates with overall disease progression in some strains of congenic mice but not in others. It is likely that patients with type 1 diabetes will also show non-major histocompatibility complex genetically determined variation in expression of autoantibodies and progression to diabetes. PMID:12606534

Robles, David T; Eisenbarth, George S; Dailey, Natalie J M; Peterson, Laurence B; Wicker, Linda S

2003-03-01

206

Retinal Neurodegeneration in db/db Mice at the Early Period of Diabetes  

PubMed Central

Purpose. To describe both the functional and pathological alternations in neurosensory retina in a murine model of spontaneous type 2 diabetes (db/db mouse). Methods. db/db (BKS/DB?/?) mice and heterozygous littermates (as control group) at various ages (12, 16, 20, 24, and 28 weeks) were inspected with pattern electroretinogram (PERG), fundus fluorescein angiography (FFA), and optical coherence tomography (OCT). Histological markers of neuroinflammation (IBA-1 and F4/80) were evaluated by immunohistochemistry. In addition, levels of retinal ganglion cell death were measured by terminal dUTP nick-end labeling (TUNEL). Results. Significant alternations of PERG responses and increased retinal ganglion cells (RGCs) apoptosis were observed in diabetic db/db mice for 20-week period when compared with control group. IBA-1 and F4/80 expression in microglia/macrophages became evidently for 24-week period, thus supporting the PERG findings. Furthermore, obvious thinning of nasal and dorsal retina in 28-week-old db/db mice was also revealed by OCT. No visible retinal microvascular changes were detected by FFA throughout the experiments on db/db mice. Conclusions. Diabetic retina underwent neurodegenerative changes in db/db mice, which happened at retinal ganglion cell layer and inner nuclear layer. But there was no obvious abnormality in retinal vasculature on db/db mice.

Yang, Qin; Xu, Yidan; Xie, Ping; Cheng, Haixia; Song, Qinglu; Su, Tu; Yuan, Songtao; Liu, Qinghuai

2015-01-01

207

Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice  

PubMed Central

Angiotensin-converting enzyme 2 (ACE2) is located in several tissues and is highly expressed in renal proximal tubules, where it degrades the vasoconstrictor angiotensin II (ANG II) to ANG-(1–7). Accumulating evidence supports protective roles of ACE2 in several disease states, including diabetic nephropathy. A disintegrin and metalloprotease (ADAM) 17 is involved in the shedding of several transmembrane proteins, including ACE2. Our previous studies showed increased renal ACE2, ADAM17 expression, and urinary ACE2 in type 2 diabetic mice (Chodavarapu H, Grobe N, Somineni HK, Salem ES, Madhu M, Elased KM. PLoS One 8: e62833, 2013). The aim of the present study was to determine the effect of insulin on ACE2 shedding and ADAM17 in type 1 diabetic Akita mice. Results demonstrate increased renal ACE2 and ADAM17 expression and increased urinary ACE2 fragments (?70 kDa) and albumin excretion in diabetic Akita mice. Immunostaining revealed colocalization of ACE2 with ADAM17 in renal tubules. Renal proximal tubular cells treated with ADAM17 inhibitor showed reduced ACE2 shedding into the media, confirming ADAM17-mediated shedding of ACE2. Treatment of Akita mice with insulin implants for 20 wk normalized hyperglycemia and decreased urinary ACE2 and albumin excretion. Insulin also normalized renal ACE2 and ADAM17 but had no effect on tissue inhibitor of metalloproteinase 3 (TIMP3) protein expression. There was a positive linear correlation between urinary ACE2 and albuminuria, blood glucose, plasma creatinine, glucagon, and triglycerides. This is the first report showing an association between hyperglycemia, cardiovascular risk factors, and increased shedding of urinary ACE2 in diabetic Akita mice. Urinary ACE2 could be used as a biomarker for diabetic nephropathy and as an index of intrarenal ACE2 status. PMID:24452639

Salem, Esam S. B.; Grobe, Nadja

2014-01-01

208

The Altered Renal and Hepatic Expression of Solute Carrier Transporters (SLCs) in Type 1 Diabetic Mice.  

PubMed

Diabetes mellitus is a chronic metabolic disorder that significantly affects human health and well-being. The Solute carrier transporters (SLCs), particularly the Organic anion/cation transporters (Oats/Octs/Octns), Organic anion transporting polypeptides (Oatps) and Oligopeptide transporters (Pepts) are essential membrane proteins responsible for cellular uptake of many endogenous and exogenous substances such as clinically important drugs. They are widely expressed in mammalian key organs especially the kidney and liver, in which they facilitate the influx of various drug molecules, thereby determining their distribution and elimination in body. The altered expression of SLCs in diabetes mellitus could have a profound and clinically significant influence on drug therapies. In this study, we extensively investigated the renal and hepatic expression of twenty essential SLCs in the type 1 diabetic Ins2Akita murine model that develops both hyperglycemia and diabetes-related complications using real-time PCR and immunoblotting analysis. We found that the renal expression of mOatp1a1, mOatp1a6, mOat1, mOat3, mOat5, mOct2 and mPept2 was decreased; while that of mPept1 was increased at the mRNA level in the diabetic mice compared with non-diabetic controls. We found up-regulated mRNA expression of mOatp1a4, mOatp1c1, mOctn2, mOct3 and mPept1 as well as down-regulation of mOatp1a1 in the livers of diabetic mice. We confirmed the altered protein expression of several SLCs in diabetic mice, especially the decreased renal and hepatic expression of mOatp1a1. We also found down-regulated protein expression of mOat3 and mOctn1 in the kidneys as well as increased protein expression of mOatp1a4 and mOct3 in the livers of diabetic mice. Our findings contribute to better understanding the modulation of SLC transporters in type 1 diabetes mellitus, which is likely to affect the pharmacokinetic performance of drugs that are transported by these transporters and therefore, forms the basis of future therapeutic optimization of regimens in patients with type 1 diabetes mellitus. PMID:25789863

Xu, Chenghao; Zhu, Ling; Chan, Ting; Lu, Xiaoxi; Shen, Weiyong; Gillies, Mark C; Zhou, Fanfan

2015-01-01

209

The Altered Renal and Hepatic Expression of Solute Carrier Transporters (SLCs) in Type 1 Diabetic Mice  

PubMed Central

Diabetes mellitus is a chronic metabolic disorder that significantly affects human health and well-being. The Solute carrier transporters (SLCs), particularly the Organic anion/cation transporters (Oats/Octs/Octns), Organic anion transporting polypeptides (Oatps) and Oligopeptide transporters (Pepts) are essential membrane proteins responsible for cellular uptake of many endogenous and exogenous substances such as clinically important drugs. They are widely expressed in mammalian key organs especially the kidney and liver, in which they facilitate the influx of various drug molecules, thereby determining their distribution and elimination in body. The altered expression of SLCs in diabetes mellitus could have a profound and clinically significant influence on drug therapies. In this study, we extensively investigated the renal and hepatic expression of twenty essential SLCs in the type 1 diabetic Ins2Akita murine model that develops both hyperglycemia and diabetes-related complications using real-time PCR and immunoblotting analysis. We found that the renal expression of mOatp1a1, mOatp1a6, mOat1, mOat3, mOat5, mOct2 and mPept2 was decreased; while that of mPept1 was increased at the mRNA level in the diabetic mice compared with non-diabetic controls. We found up-regulated mRNA expression of mOatp1a4, mOatp1c1, mOctn2, mOct3 and mPept1 as well as down-regulation of mOatp1a1 in the livers of diabetic mice. We confirmed the altered protein expression of several SLCs in diabetic mice, especially the decreased renal and hepatic expression of mOatp1a1. We also found down-regulated protein expression of mOat3 and mOctn1 in the kidneys as well as increased protein expression of mOatp1a4 and mOct3 in the livers of diabetic mice. Our findings contribute to better understanding the modulation of SLC transporters in type 1 diabetes mellitus, which is likely to affect the pharmacokinetic performance of drugs that are transported by these transporters and therefore, forms the basis of future therapeutic optimization of regimens in patients with type 1 diabetes mellitus. PMID:25789863

Xu, Chenghao; Zhu, Ling; Chan, Ting; Lu, Xiaoxi; Shen, Weiyong; Gillies, Mark C.; Zhou, Fanfan

2015-01-01

210

Brain-Derived Neurotrophic Factor Reduces Blood Glucose Level in Obese Diabetic Mice but Not in Normal Mice  

Microsoft Academic Search

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family. However, it is not yet known if BDNF works on the endocrine system itself. Here we report that BDNF improves hyperglycemia in obese diabetic animals. BDNF reduced the blood glucose level in obesedb\\/dbdiabetic mice in which the effect of BDNF was age-dependent and high under the condition of hyperinsulinemia,

Michiko Ono; Junji Ichihara; Takeshi Nonomura; Yasushi Itakura; Mutsuo Taiji; Chikao Nakayama; Hiroshi Noguchi

1997-01-01

211

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

212

The dynamic changes of endoplasmic reticulum stress pathway markers GRP78 and CHOP in the hippocampus of diabetic mice.  

PubMed

Diabetic encephalopathy has recently been recognized late complication of diabetes resulting in progressive cognitive deficits. Emerging evidence has indicated that endoplasmic reticulum (ER) stress-mediated apoptosis is involved in the pathogenesis of diabetic eye and kidney as well as non-diabetic neurodegeneration. However, there was little direct evidence for the involvement of ER stress in diabetic encephalopathy up to now. In the present work, we investigated the role of ER stress in the pathogenesis of diabetic encephalopathy. Our results have demonstrated the existence of ER stress in the hippocampus of streptozotocin (STZ)-induced diabetic mice. STZ injection i.p. rapidly induced up-regulation of the ER stress marker, the prosurvival chaperone glucose-regulated protein 78 (GRP78), as early as 6-24h and persisted at least for up to 72h in the hippocampus of mice, indicating the UPR activation soon after STZ administration. The increased expression of GRP78 in hippocampal cells is to relieve the ER stress. With the development of diabetes, the expression of GRP78 decreases while the expression of UPR-associated proapoptotic transcriptional regulator C/EBP homologous protein (CHOP) increases significantly in the hippocampal neurons of diabetic mice from 1 week after STZ administration to 12 weeks/the end of the study. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells in the hippocampus of diabetic mice were largely colocalized with NeuN- and CHOP-positive cells, indicating that the up-regulation of CHOP in hippocampal neurons of diabetic mice may promote neuronal apoptosis and account for the damaged learning and memory ability of diabetic mice. Therefore, our study provides evidence that ER stress may play an important role in the pathogenesis of neuronal degeneration and may contribute to cognitive dysfunction of diabetic encephalopathy. PMID:25529350

Zhao, Yongmei; Yan, Ying; Zhao, Zhiwei; Li, Sen; Yin, Jie

2015-02-01

213

Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice.  

PubMed

The branched-chain amino acids (BCAA) accumulated in type 2 diabetes are independent contributors to insulin resistance. The activity of branched-chain ?-keto acid dehydrogenase (BCKD) complex, rate-limiting enzyme in BCAA catabolism, is reduced in diabetic states, which contributes to elevated BCAA concentrations. However, the mechanisms underlying decreased BCKD activity remain poorly understood. Here, we demonstrate that mitochondrial phosphatase 2C (PP2Cm), a newly identified BCKD phosphatase that increases BCKD activity, was significantly downregulated in ob/ob and type 2 diabetic mice. Interestingly, in adiponectin (APN) knockout (APN(-/-)) mice fed with a high-fat diet (HD), PP2Cm expression and BCKD activity were significantly decreased, whereas BCKD kinase (BDK), which inhibits BCKD activity, was markedly increased. Concurrently, plasma BCAA and branched-chain ?-keto acids (BCKA) were significantly elevated. APN treatment markedly reverted PP2Cm, BDK, BCKD activity, and BCAA and BCKA levels in HD-fed APN(-/-) and diabetic animals. Additionally, increased BCKD activity caused by APN administration was partially but significantly inhibited in PP2Cm knockout mice. Finally, APN-mediated upregulation of PP2Cm expression and BCKD activity were abolished when AMPK was inhibited. Collectively, we have provided the first direct evidence that APN is a novel regulator of PP2Cm and systematic BCAA levels, suggesting that targeting APN may be a pharmacological approach to ameliorating BCAA catabolism in the diabetic state. PMID:25071024

Lian, Kun; Du, Chaosheng; Liu, Yi; Zhu, Di; Yan, Wenjun; Zhang, Haifeng; Hong, Zhibo; Liu, Peilin; Zhang, Lijian; Pei, Haifeng; Zhang, Jinglong; Gao, Chao; Xin, Chao; Cheng, Hexiang; Xiong, Lize; Tao, Ling

2015-01-01

214

Anti-diabetic effects of polysaccharides from Talinum triangulare in streptozotocin (STZ)-induced type 2 diabetic male mice.  

PubMed

The present study evaluated the anti-diabetic effects of the polysaccharides obtained from Talinum triangulare (TTP). Two TTP doses (150 mg/kg and 300 mg/kg · bw/d) were administered orally to normal and streptozotocin (STZ)-induced type 2 diabetic male Kunming mice, respectively. The TTP hypoglycemic and hypolipidemic effects were evaluated by testing the fast blood glucose (FBG) level, fasting serum insulin (FINS), and serum lipids (TC, TG, HDL, LDL) as well as the body, hepar and kidney weights. After four weeks administration, the low-dose group 150 mg/kg · bw/d) and high-dose group (300 mg/kg · bw/d) showed a marked FBG fall rate of 29.85% and 41.18% (FBG fall rate% = ((Diabetic control--TTP group)/Diabetic control) × 100%). The results of FBG and serum lipids indicate that TTP possess significant hypoglycemic effect, but no significant hypolipidemic effect. These results suggest the potential use of TTP as a functional food for the treatment of type 2 diabetic mellitus (T2DM). PMID:25236607

Xu, Wei; Zhou, Qing; Yin, Jiao-jiao; Yao, Yong; Zhang, Jiu-liang

2015-01-01

215

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...

216

Anti-diabetic activity of a leaf extract prepared from Salacia reticulata in mice.  

PubMed

The effects of a water extract prepared from the leaves of Salacia reticulata on the absorption of sugars in normal and type 1 diabetic mice were investigated. The simultaneous oral administration of the extract at a dose of 1.0 mg/mouse with maltose or sucrose inhibited the postprandial elevation of the plasma glucose and insulin levels and intestinal alpha-glucosidase activities in mice. In addition, the supply of a 0.01% solution of the extract as drinking water prevented the elevation of the plasma glucose level and intestinal alpha-glucosidase activities in type 1 diabetic mice. This treatment also prevented the elevation of the plasma, pancreatic, and kidney lipid peroxide levels, lowering of the plasma insulin level, and elevation of the kidney aldose reductase activities in diabetic mice. These results suggest that the water extract of the leaves of S. reticulata could be a beneficial food material for the prevention of diabetes and obesity because of its multiple effects. PMID:19420711

Yoshino, Kyoji; Miyauchi, Yuko; Kanetaka, Takashi; Takagi, Yasutaka; Koga, Kunimasa

2009-05-01

217

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

218

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

219

Anti-obesity and anti-diabetic effects of acacia polyphenol in obese diabetic KKAy mice fed high-fat diet  

Microsoft Academic Search

Acacia polyphenol (AP) extracted from the bark of the black wattle tree (Acacia meansii )i s rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. The present study investigated the anti-obesity\\/anti-diabetic effects of AP using obese diabetic KKAy mice. KKAy mice received either normal diet, high-fat diet or high-fat diet with additional AP for 7 weeks. After the end

Nobutomo Ikarashi; Takahiro Toda; Takehiro Okaniwa; Kiyomi Ito; Wataru Ochiai; Kiyoshi Sugiyama

2010-01-01

220

Marrow-Derived Cells Regulate the Development of Early Diabetic Retinopathy and Tactile Allodynia in Mice  

PubMed Central

The hypothesis that marrow-derived cells, and specifically proinflammatory proteins in those cells, play a critical role in the development of diabetes-induced retinopathy and tactile allodynia was investigated. Abnormalities characteristic of the early stages of retinopathy and allodynia were measured in chimeric mice lacking inducible nitric oxide synthase (iNOS) or poly(ADP-ribosyl) polymerase (PARP1) in only their marrow-derived cells. Diabetes-induced capillary degeneration, proinflammatory changes, and superoxide production in the retina and allodynia were inhibited in diabetic animals in which iNOS or PARP1 was deleted from bone marrow cells only. Of the various marrow cells, neutrophils (and monocytes) play a major role in retinopathy development, because retinal capillary degeneration likewise was significantly inhibited in diabetic mice lacking the receptor for granulocyte colony-stimulating factor in their marrow-derived cells. Immunodepletion of neutrophils or monocytes inhibited the endothelial death otherwise observed when coculturing leukocytes from wild-type diabetic animals with retinal endothelium. iNOS and PARP1 are known to play a role in inflammatory processes, and we conclude that proinflammatory processes within marrow-derived cells play a central role in the development of diabetes complications in the retina and nerve. PMID:22923475

Li, Guangyuan; Veenstra, Alexander A.; Talahalli, Ramaprasad R.; Wang, Xiaoqi; Gubitosi-Klug, Rose A.; Sheibani, Nader; Kern, Timothy S.

2012-01-01

221

Impaired cytokine expression, neutrophil infiltration and bacterial clearance in response to urinary tract infection in diabetic mice.  

PubMed

Diabetic patients have increased susceptibility to infections, and urinary tract infections (UTI) are the most common type in women with diabetes mellitus. Knowledge of bacterial clearance effectiveness following UTI in diabetics is sparse. In this study, the effects of diabetes on bacterial clearance efficiency and components of the innate immune system in response to UTI in a murine model were investigated. Streptozotocin-induced diabetic and control female C57BL/6J mice were infected with uropathogenic Escherichia coli, and bacterial load, expression of chemokines, and neutrophil infiltration in the bladder over time were investigated. Expression levels of histone deacetylases were also measured to address a potential mechanism underlying the phenotype. Bacterial clearance during UTI was significantly prolonged in diabetic mice relative to controls. Neutrophil infiltration in bladder tissue and urine, and both mRNA and protein expression of chemokines MIP-2, KC, MCP-1 and IL-6 in bladder tissue were diminished at early time points after infection in diabetic mice relative to controls. In addition, mRNA levels of histone deacetylases 1-5 were increased in diabetic mice. This is the first study to show an association of impaired bacterial clearance in diabetic mice with suppression of UTI-induced chemokine expression and neutrophil infiltration in the bladder. PMID:25663347

Ozer, Ahmet; Altuntas, Cengiz Z; Bicer, Fuat; Izgi, Kenan; Hultgren, Scott J; Liu, Guiming; Daneshgari, Firouz

2015-04-01

222

Red clover extract ameliorates dyslipidemia in streptozotocin-induced diabetic C57BL/6 mice by activating hepatic PPAR?.  

PubMed

The effects of red clover extract and its bioactive components, biochanin A and formononetin, on the blood glucose and lipid levels of streptozotocin (STZ) induced-diabetic mice were investigated. Male diabetic C57BL/6 mice were induced by multiple low-dose STZ administration and then treated with red clover extract or isoflavones for a period of 3?weeks. Red clover extract had no significant effect on lowering the blood glucose levels of STZ-diabetic mice. Similarly, biochanin A and formononetin exerted no hypoglycemic effect. However, the serum triglycerides, total cholesterols and low-density lipoprotein-cholesterol levels for STZ-diabetic mice receiving red clover extract were significantly lower than that of untreated STZ-diabetic mice. In addition, treatment with biochanin A or formononetin significantly ameliorated these lipid profiles in diabetic mice. The mRNA expression of two target genes transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR) ? were determined by semi-quantitative RT-PCR and biochanin A or formononetin were found to significantly down-regulate hepatic APOC3 expression, whereas they had no significant effect on hepatic APOA5 expression. Thus we conclude that red clover extract and biochanin A or formononetin significantly ameliorate the lipid profiles of STZ-diabetic mice and these effects are achieved at least in part by activating hepatic PPAR?. PMID:22084061

Qiu, Longxin; Ye, Hong; Chen, Limei; Hong, Yamin; Zhong, Fojin; Zhang, Tingting

2012-06-01

223

Rapid onset of cardiomyopathy in STZ-induced female diabetic mice involves the downregulation of pro-survival Pim-1  

PubMed Central

Background Diabetic women are five times more likely to develop congestive heart failure compared with two fold for men. The underlying mechanism for this gender difference is not known. Here we investigate the molecular mechanisms responsible for this female disadvantage and attempt safeguarding cardiomyocytes viability and function through restoration of pro-survival Pim-1. Methods and Results Diabetes was induced by injection of streptozotocin in CD1 mice of both genders. Functional and dimensional parameters measurement using echocardiography revealed diastolic dysfunction in female diabetic mice within 8 weeks after STZ-induced diabetes. This was associated with significant downregulation of pro-survival Pim-1 and upregulation of pro-apoptotic Caspase-3, microRNA-1 and microRNA-208a. Male diabetic mice did not show any significant changes at this time point (P?diabetic). Further, the onset of ventricular remodelling was quicker in female diabetic mice showing marked left ventricular dilation, reduced ejection fraction and poor contractility (P?diabetic at 12 and 16 weeks of STZ-induced diabetes). Molecular analysis of samples from human diabetic hearts confirmed the results of pre-clinical studies, showing marked downregulation of Pim-1 in the female diabetic heart (P?diabetic). Finally, in vitro restoration of Pim-1 reversed the female disadvantage in diabetic cardiomyocytes. Conclusions We provide novel insights into the molecular mechanisms behind the rapid onset of cardiomyopathy in female diabetics. These results suggest the requirement for the development of gender-specific treatments for diabetic cardiomyopathy. PMID:24685144

2014-01-01

224

GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice.  

PubMed Central

Although glutamic acid decarboxylase (GAD) has been implicated in IDDM, there is no direct evidence showing GAD-reactive T cells are diabetogenic in vivo. To address this issue, 3-wk-old NOD mice received two injections of purified rat brain GAD; one mouse rapidly developed diabetes 3 wk later. Splenocytes from this mouse showed a proliferative response to purified GAD, and were used to generate a CD4+ T cell line, designated 5A, that expresses TCRs encoding Vbeta2 and Vbeta12. 5A T cells exhibit a MHC restricted proliferative response to purified GAD, as well as GAD65 peptide 524-543. After antigen-specific stimulation, 5A T cells secrete IFNgamma and TNFalpha/beta, but not IL-4. They are also cytotoxic against NOD-derived hybridoma cells (expressing I-Ag7) that were transfected with rat GAD65, but not nontransfected hybridoma cells. Adoptive transfer of 5A cells into NOD/SCID mice produced insulitis in all mice. Diabetes occurred in 83% of the mice. We conclude that GAD injection in young NOD mice may, in some cases, provoke diabetes due to the activation of diabetogenic T cells reactive to GAD65 peptides. Our data provide direct evidence that GAD65 autoimmunity may be a critical event in the pathogenesis of IDDM. PMID:9421467

Zekzer, D; Wong, F S; Ayalon, O; Millet, I; Altieri, M; Shintani, S; Solimena, M; Sherwin, R S

1998-01-01

225

The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension.  

PubMed

Diabetic nephropathy is the leading cause of end-stage renal disease in humans in the Western world. The recent development of Na+-glucose cotransporter 2 (SGLT2) inhibitors offers a new antidiabetic therapy via enhanced glucose excretion. Whether this strategy exerts beneficial effects on the development of type 2 diabetic nephropathy is still largely unclear. We investigated the effects of the specific SGLT2 inhibitor empagliflozin in BTBR.Cg-Lep/WiscJ (BTBR ob/ob) mice, which spontaneously develop type 2 diabetic nephropathy. In the first experiment, BTBR ob/ob mice received either a diet containing 300 ppm empagliflozin or equicaloric placebo chow for 12 wk. In the second experiment, BTBR ob/ob mice received 1 ?g·kg body wt(-1)·day(-1) ANG II to induce arterial hypertension and were separated into the same two diet groups for 6 wk. In both experiments, empagliflozin treatment enhanced glucosuria, thereby lowering blood glucose. Independently of hypertension, empagliflozin reduced albuminuria in diabetic mice. However, empagliflozin treatment affected diabetes-related glomerular hypertrophy, markers of renal inflammation, and mesangial matrix expansion only in BTBR ob/ob mice without hypertension. In summary, empagliflozin demonstrated significant antihyperglycemic effects, differentially ameliorating early features of diabetic nephropathy in BTBR ob/ob mice with and without hypertension. PMID:24944269

Gembardt, Florian; Bartaun, Christoph; Jarzebska, Natalia; Mayoux, Eric; Todorov, Vladimir T; Hohenstein, Bernd; Hugo, Christian

2014-08-01

226

Multi-Tissue Computational Modeling Analyzes Pathophysiology of Type 2 Diabetes in MKR Mice  

PubMed Central

Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective. PMID:25029527

Kumar, Amit; Harrelson, Thomas; Lewis, Nathan E.; Gallagher, Emily J.; LeRoith, Derek; Shiloach, Joseph; Betenbaugh, Michael J.

2014-01-01

227

Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice  

NASA Astrophysics Data System (ADS)

Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus. glucose | GW4064 | farnesoid X receptor-VP16 | triglyceride | cholesterol

Zhang, Yanqiao; Lee, Florence Ying; Barrera, Gabriel; Lee, Hans; Vales, Charisse; Gonzalez, Frank J.; Willson, Timothy M.; Edwards, Peter A.

2006-01-01

228

Diabetes  

MedlinePLUS

... version of this page please turn Javascript on. Diabetes What is Diabetes? Too Much Glucose in the Blood Diabetes means ... high, causing pre-diabetes or diabetes. Types of Diabetes There are three main kinds of diabetes: type ...

229

SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabetic db/db mice.  

PubMed

Diabetic nephropathy is currently the most common cause of end-stage renal disease. Diabetic nephropathy patients, whether insulin dependent or not, develop fibrotic changes in glomeruli that manifest as overt nephropathy. Previously, we demonstrated that 5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-methyl-1H-pyrrol-1-yl]prop-1-en-1-yl}-N-(methylsulfonyl)benzamide (SMP-534) reduces extracellular matrix (ECM) production induced by transforming growth factor-beta (TGF-beta) in vitro and prevents the accumulation of ECM in glomeruli in rat Thy-1 nephritis models. In this study, we examined the long-term effects of SMP-534 on renal insufficiency and glomerulosclerosis in db/db mice, which are models of type 2 diabetes. A diet containing SMP-534 was given to the mice from the age of 9 to 25 wk, and blood and urine analysis were performed at 8, 17, and 25 wk. At the end of study, kidney tissues were analyzed histologically. Treatment with SMP-534 dose dependently suppressed the increase of urinary albumin and type IV collagen excretion in db/db mice. The renal histological analysis showed that SMP-534 dose dependently suppressed the increase of mesangial expansion in the kidney. In the immunohistological analysis, fibronectin and type IV collagen expression were lower in SMP-534-treated db/db mice compared with vehicle-treated db/db mice. This study suggested that SMP-534 ameliorated the increase of ECM production in kidney of db/db mice, possibly through the inhibition of TGF-beta action. Hence, antifibrotic agents such as SMP-534 might be a new therapeutic option for the treatment of diabetic nephropathy. PMID:16278277

Sugaru, Eiji; Nakagawa, Tsutomu; Ono-Kishino, Michiko; Nagamine, Jun; Tokunaga, Teruhisa; Kitoh, Makoto; Hume, W Ewan; Nagata, Ryu; Taiji, Mutsuo

2006-04-01

230

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

231

ER Stress and Autophagy Dysfunction Contribute to Fatty Liver in Diabetic Mice  

PubMed Central

Diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are often identified in patients simultaneously. Recent evidence suggests that endoplasmic reticulum (ER) stress and autophagy dysfunction play an important role in hepatocytes injury and hepatic lipid metabolism, however the mechanistic interaction between diabetes and NAFLD is largely unknown. In this study, we used a diabetic mouse model to study the interplay between ER stress and autophagy during the pathogenic transformation of NAFLD. The coexist of inflammatory hepatic injury and hepatic accumulation of triglycerides (TGs) stored in lipid droplets indicated development of steatohepatitis in the diabetic mice. The alterations of components for ER stress signaling including ATF6, GRP78, CHOP and caspase12 indicated increased ER stress in liver tissues in early stage but blunted in the later stage during the development of diabetes. Likewise, autophagy functioned well in the early stage but suppressed in the later stage. The inactivation of unfolded protein response and suppression of autophagy were positively related to the development of steatohepatitis, which linked to metabolic abnormalities in the compromised hepatic tissues in diabetic condition. We conclude that the adaption of ER stress and impairment of autophagy play an important role to exacerbate lipid metabolic disorder contributing to steatohepatitis in diabetes.

Zhang, Quan; Li, Yan; Liang, Tingting; Lu, Xuemian; Zhang, Chi; Liu, Xingkai; Jiang, Xin; Martin, Robert C.; Cheng, Mingliang; Cai, Lu

2015-01-01

232

Short term supplementation of dietary antioxidants selectively regulates the inflammatory responses during early cutaneous wound healing in diabetic mice  

PubMed Central

Background Diabetic foot ulcers are serious complications for diabetic patients, yet the precise mechanism that underlines the treatment of these diabetic complications remains unclear. We hypothesized that dietary antioxidant supplementation with vitamin C, combined either with vitamin E or with vitamin E and NAC, improves delayed wound healing through modulation of blood glucose levels, oxidative stress, and inflammatory response. Methods Diabetes was induced by administration of alloxan monohydrate. Mice were divided into 4 groups; CON (non-diabetic control mice fed AIN 93 G purified rodent diet), DM (diabetic mice fed AIN 93 G purified rodent diet), VCE (diabetic mice fed 0.5% vitamin C and 0.5% vitamin E supplemented diet), and Comb (diabetic mice fed 0.5% vitamin C, 0.5% vitamin E, and 2.5% NAC supplemented diet). After 10 days of dietary antioxidant supplementation, cutaneous full-thickness excisional wounds were performed, and the rate of wound closure was examined. TBARS as lipid peroxidation products and vitamin E levels were measured in the liver. Expression levels of oxidative stress and inflammatory response related proteins were measured in the cutaneous wound site. Results Dietary antioxidant supplementation improved blood glucose levels and wound closure rate and increased liver vitamin E, but not liver TBARS levels in the diabetic mice as compared to those of the CON. In addition, dietary antioxidant supplementation modulated the expression levels of pI?B?, HO-1, CuZnSOD, iNOS and COX-2 proteins in the diabetic mice. Conclusions These findings demonstrated that delayed wound healing is associated with an inflammatory response induced by hyperglycaemia, and suggests that dietary antioxidant supplementation may have beneficial effects on wound healing through selective modulation of blood glucose levels, oxidative stress, and inflammatory response. PMID:22088091

2011-01-01

233

Effects of ursolic acid on glucose metabolism, the polyol pathway and dyslipidemia in non-obese type 2 diabetic mice.  

PubMed

Ursolic acid (UA) is a pentacyclic triterpenoid compound that naturally occurs in fruits, leaves and flowers of medicinal herbs. This study investigated the dose-response efficacy of UA (0.01 and 0.05%) on glucose metabolism, the polyol pathway and dyslipidemia in streptozotocin/nicotinamide-induced diabetic mice. Supplement with both UA doses reduced fasting blood glucose and plasma triglyceride levels in non-obese type 2 diabetic mice. High-dose UA significantly lowered plasma free fatty acid, total cholesterol and VLDL-cholesterol levels compared with the diabetic control mice, while LDL-cholesterol levels were reduced with both doses. UA supplement effectively decreased hepatic glucose-6-phosphatase activity and increased glucokinase activity, the glucokinase/glucose-6-phosphatase ratio, GLUT2 mRNA levels and glycogen content compared with the diabetic control mice. UA supplement attenuated hyperglycemia-induced renal hypertrophy and histological changes. Renal aldose reductase activity was higher, whereas sorbitol dehydrogenase activity was lower in the diabetic control group than in the non-diabetic group. However, UA supplement reversed the biochemical changes in polyol pathway to normal values. These results demonstrated that low-dose UA had preventive potency for diabetic renal complications, which could be mediated by changes in hepatic glucose metabolism and the renal polyol pathway. High-dose UA was more effective anti-dyslipidemia therapy in non-obese type 2 diabetic mice. PMID:25059036

Lee, Jin; Lee, Hae-In; Seo, Kown-Il; Cho, Hyun Wook; Kim, Myung-Joo; Park, Eun-Mi; Lee, Mi-Kyung

2014-07-01

234

Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice.  

PubMed

Schistosoma mansoni soluble egg antigens (SEA) profoundly regulate the infected host's immune system. We previously showed that SEA prevents type 1 diabetes in NOD mice and that splenocytes from SEA-treated mice have reduced ability to transfer diabetes to NOD.scid recipients. To further characterize the mechanism of diabetes prevention we examined the cell types involved and showed that CD25(+) T-cell depletion of splenocytes from SEA-treated donors restored their ability to transfer diabetes. Furthermore, SEA treatment increased the number and proportional representation of Foxp3(+) T cells in the pancreas of NOD mice. We have used in vitro systems to analyze the effect of SEA on the development of NOD Foxp3(+) T cells. We find that SEA can induce Foxp3 expression in naïve T cells in a TGF-beta-dependent manner. Foxp3 induction requires the presence of DC, which we also show are modified by SEA to upregulate C-type lectins, IL-10 and IL-2. Our studies show that SEA can have a direct effect on CD4(+) T cells increasing expression of TGF-beta, integrin beta8 and galectins. These effects of SEA on DC and T cells may act in synergy to induce Foxp3(+) Treg in the NOD mouse. PMID:19291704

Zaccone, Paola; Burton, Oliver; Miller, Nigel; Jones, Frances M; Dunne, David W; Cooke, Anne

2009-04-01

235

CD4+ beta islet cell-reactive T cell clones that suppress autoimmune diabetes in nonobese diabetic mice  

PubMed Central

We report the isolation of a panel of CD4+ T helper type 1 autoreactive T cell clones from the spleen of unprimed nonobese diabetic mice, a murine model of human insulin-dependent diabetes mellitus. The T cell clones express a diverse repertoire of T cell receptors, three of which recognize beta islet cell autoantigen(s). The islet cell-reactive T cell clones inhibit adoptive transfer of insulin-dependent diabetes mellitus and intraislet lymphocytic infiltration. The protective capacity of the T cell clones correlates with their ability to produce a novel immunoregulatory activity that potently inhibits in vitro allogeneic mixed lymphocyte reaction. The partially purified activity significantly inhibited the adoptive transfer of diabetes. Our work provides evidence in support of the existence of T helper type 1, CD4+ T cells reactive to beta islet cell autoantigens that have acquired a protective instead of a diabetogenic effector function. These T cells mediate their protective action in part by production of an immunoregulatory activity capable of down-regulating immune responses, and they are likely to represent a population of regulatory T cells that normally plays a role in maintaining peripheral tolerance. PMID:7790825

1995-01-01

236

Immunotherapy with Tolerogenic Dendritic Cells Alone or in Combination with Rapamycin Does Not Reverse Diabetes in NOD Mice.  

PubMed

Type 1 diabetes is a metabolic disease caused by autoimmunity towards ? -cells. Different strategies have been developed to restore ? -cell function and to reestablish immune tolerance to prevent and cure the disease. Currently, there is no effective treatment strategy to restore endogenous insulin secretion in patients with type 1 diabetes. This study aims to restore insulin secretion in diabetic mice with experimental antigen-specific immunotherapy alone or in combination with rapamycin, a compound well known for its immunomodulatory effect. Nonobese diabetic (NOD) mice develop spontaneous type 1 diabetes after 12 weeks of age. Autologous tolerogenic dendritic cells-consisting in dendritic cells pulsed with islet apoptotic cells-were administered to diabetic NOD mice alone or in combination with rapamycin. The ability of this therapy to revert type 1 diabetes was determined by assessing the insulitis score and by measuring both blood glucose levels and C-peptide concentration. Our findings indicate that tolerogenic dendritic cells alone or in combination with rapamycin do not ameliorate diabetes in NOD mice. These results suggest that alternative strategies may be considered for the cure of type 1 diabetes. PMID:23555060

Pujol-Autonell, Irma; Ampudia, Rosa M; Monge, Pau; Lucas, Anna M; Carrascal, Jorge; Verdaguer, Joan; Vives-Pi, Marta

2013-01-01

237

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

238

Aqueous Extract from Pepino (Solanum muricatum Ait.) Attenuated Hyperlipidemia and Cardiac Oxidative Stress in Diabetic Mice.  

PubMed

This study examined the lipid-lowering and cardiac protective effects of aqueous extract of pepino (Solanum muricatum Ait.) in type 2 diabetic mice. Pepino at 1, 2, or 5% was supplied for 8 weeks. Results showed that pepino significantly decreased water intake and epididymal fat pad weight in diabetic mice (P < 0.05). Pepino treatments also significantly reduced plasma glucose and insulin levels, HOMA-IR index, and improved oral glucose tolerance (P < 0.05). Plasma and hepatic levels of triglyceride and total cholesterol (TC) were higher in diabetic groups when compared with normal group (P < 0.05), pepino treatments at 2 and 5% decreased triglyceride and TC levels in both plasma and liver (P < 0.05). Diabetes enhanced mRNA expression of resistin and diacylglycerol acyltransferase1 (DGAT1) in epididymal fat pad (P < 0.05); however, pepino intake significantly suppressed mRNA expression of resistin and DGAT1 in epididymal fat pad (P < 0.05). Pepino intake significantly reduced reactive oxygen species level, increased glutathione level, and retained glutathione peroxidase and catalase activities in cardiac tissues (P < 0.05). These findings suggest that pepino could be considered as a functional food for the alleviation of type 2 diabetes. PMID:24527264

Wang, Zhi-Hong; Hsu, Cheng-Chin; Yin, Mei-Chin

2012-01-01

239

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

240

Improvement of diabetes, obesity and hypertension in type 2 diabetic KKA{sup y} mice by bis(allixinato)oxovanadium(IV) complex  

SciTech Connect

Previously, we found that bis(allixinato)oxovanadium(IV) (VO(alx){sub 2}) exhibits a potent hypoglycemic activity in type 1-like diabetic mice. Since the enhancement of insulin sensitivity is involved in one of the mechanisms by which vanadium exerts its anti-diabetic effects, VO(alx){sub 2} was further tested in type 2 diabetes with low insulin sensitivity. The effect of oral administration of VO(alx){sub 2} was examined in obesity-linked type 2 diabetic KKA{sup y} mice. Treatment of VO(alx){sub 2} for 4 weeks normalized hyperglycemia, glucose intolerance, hyperinsulinemia, hypercholesterolemia and hypertension in KKA{sup y} mice; however, it had no effect on hypoadiponectinemia. VO(alx){sub 2} also improved hyperleptinemia, following attenuation of obesity in KKA{sup y} mice. This is the first example in which a vanadium compound improved leptin resistance in type 2 diabetes by oral administration. On the basis of these results, VO(alx){sub 2} is proposed to enhance not only insulin sensitivity but also leptin sensitivity, which in turn improves diabetes, obesity and hypertension in an obesity-linked type 2 diabetic animal.

Adachi, Yusuke [Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414 (Japan); Yoshikawa, Yutaka [Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414 (Japan); Yoshida, Jiro [Healthcare Institute, Wakunaga Pharmaceutical Co. Ltd, 1624 Shimokotachi, Koda-cho, Takatagun, Hiroshima 739-1195 (Japan); Kodera, Yukihiro [Healthcare Institute, Wakunaga Pharmaceutical Co. Ltd, 1624 Shimokotachi, Koda-cho, Takatagun, Hiroshima 739-1195 (Japan)]. E-mail: kodera_y@wakunaga.co.jp; Katoh, Akira [Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, 3-3-1 Kitamachi, Kichijoji, Musashino-shi, Tokyo 180-8633 (Japan)]. E-mail: katoh@st.seikei.ac.jp; Takada, Jitsuya [Research Reactor Institute, Kyoto University, Osaka 590-0494 (Japan)]. E-mail: takada@hl.rri.kyoto-u.ac.jp; Sakurai, Hiromu [Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414 (Japan)]. E-mail: sakurai@mb.kyoto-phu.ac.jp

2006-07-07

241

The PKD Inhibitor CID755673 Enhances Cardiac Function in Diabetic db/db Mice  

PubMed Central

The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy. PMID:25798941

Venardos, Kylie; De Jong, Kirstie A.; Elkamie, Mansour; Connor, Timothy; McGee, Sean L.

2015-01-01

242

Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice.  

PubMed

Diabetic peripheral neuropathy is a common complication of long-standing diabetes mellitus. To mimic clinical trials in which patients with diabetes enrolled have advanced peripheral neuropathy, we investigated the effect of sildenafil, a specific inhibitor of phosphodiesterase type 5 enzyme, on long term peripheral neuropathy in middle aged male mice with type II diabetes. Treatment of diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 36 weeks with sildenafil significantly increased functional blood vessels and regional blood flow in the sciatic nerve, concurrently with augmentation of intra-epidermal nerve fiber density in the skin and myelinated axons in the sciatic nerve. Functional analysis showed that the sildenafil treatment considerably improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal stimulus sensitivity compared with the saline treatment. In vitro studies showed that mouse dermal endothelial cells (MDE) cultured under high glucose levels exhibited significant down regulation of angiopoietin 1 (Ang1) expression and reduction of capillary-like tube formation, which were completely reversed by sildenafil. In addition, incubation of dorsal root ganglia (DRG) neurons with conditioned medium harvested from MDE under high glucose levels suppressed neurite outgrowth, where as conditional medium harvested from MDE treated with sildenafil under high glucose levels did not inhibit neurite outgrowth of DRG neurons. Moreover, blockage of the Ang1 receptor, Tie2, with a neutralized antibody against Tie2 abolished the beneficial effect of sildenafil on tube formation and neurite outgrowth. Collectively, our data indicate that sildenafil has a therapeutic effect on long term peripheral neuropathy of middle aged diabetic mice and that improvement of neurovascular dysfunction by sildenafil likely contributes to the amelioration of nerve function. The Ang1/Tie2 signaling pathway may play an important role in these restorative processes. PMID:25689401

Wang, Lei; Chopp, Michael; Szalad, Alexandra; Jia, LongFei; Lu, XueRong; Lu, Mei; Zhang, Li; Zhang, Yi; Zhang, RuiLan; Zhang, Zheng Gang

2015-01-01

243

The Role of TNF-? in Mice with Type 1- and 2- Diabetes  

PubMed Central

Background Previously, we have demonstrated that short-term treatment of new onset diabetic Non-obese diabetic (NOD) mice, mice that are afflicted with both type 1 (T1D) and type 2 (T2D) diabetes with either Power Mix (PM) regimen or alpha1 antitrypsin (AAT) permanently restores euglycemia, immune tolerance to self-islets and normal insulin signaling. Methodology and Principal Findings To search for relevant therapeutic targets, we have applied genome wide transcriptional profiling and systems biology oriented bioinformatics analysis to examine the impact of the PM and AAT regimens upon pancreatic lymph node (PLN) and fat, a crucial tissue for insulin dependent glucose disposal, in new onset diabetic non-obese diabetic (NOD) mice. Systems biology analysis identified tumor necrosis factor alpha (TNF-?) as the top focus gene hub, as determined by the highest degree of connectivity, in both tissues. In PLNs and fat, TNF-? interacted with 53% and 32% of genes, respectively, associated with reversal of diabetes by previous treatments and was thereby selected as a therapeutic target. Short-term anti-TNF-? treatment ablated a T cell-rich islet-invasive and beta cell-destructive process, thereby enhancing beta cell viability. Indeed anti-TNF-? treatment induces immune tolerance selective to syngeneic beta cells. In addition to these curative effects on T1D anti-TNF-? treatment restored in vivo insulin signaling resulting in restoration of insulin sensitivity. Conclusions In short, our molecular analysis suggested that PM and AAT both may act in part by quenching a detrimental TNF-? dependent effect in both fat and PLNs. Indeed, short-term anti-TNF-? mAb treatment restored enduring euglycemia, self-tolerance, and normal insulin signaling. PMID:22606220

Awdeh, Zuheir; Qipo, Andi; Fan, Zhigang; Hanidziar, Dusan; Putheti, Prabhakar; Shi, Hang; Csizuadia, Eva; Libermann, Towia A.; Strom, Terry B.

2012-01-01

244

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

245

Experimental protection of diabetic mice against Lethal P. aeruginosa infection by bacteriophage.  

PubMed

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 × 10(8)?CFU, resulting in a fatal bacteremia within 48?hrs. A single i.p. injection of 3 × 10(9)?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 × 10(9)?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

246

Cardioprotective effect of the PPAR ligand tetradecylthioacetic acid in type 2 diabetic mice.  

PubMed

Tetradecylthioacetic acid (TTA) is a novel peroxisome proliferator-activated receptor (PPAR) ligand with marked hypolipidemic and insulin-sensitizing effects in obese models. TTA has recently been shown to attenuate dyslipidemia in patients with type 2 diabetes, corroborating the potential for TTA in antidiabetic therapy. In a recent study on normal mice, we showed that TTA increased myocardial fatty acid (FA) oxidation, which was associated with decreased cardiac efficiency and impaired postischemic functional recovery. The aim of the present study was, therefore, to elucidate the effects of TTA treatment (0.5%, 8 days) on cardiac metabolism and function in a hyperlipidemic type 2 diabetic model. We found that TTA treatment increased myocardial FA oxidation, not only in nondiabetic (db/+) mice but also in diabetic (db/db) mice, despite a clear lipid-lowering effect. Although TTA had deleterious effects in hearts from nondiabetic mice (decreased efficiency and impaired mitochondrial respiratory capacity), these effects were not observed in db/db hearts. In db/db hearts, TTA improved ischemic tolerance, an effect that is most likely related to the antioxidant property of TTA. The present study strongly advocates the need for investigation of the cardiac effects of PPAR ligands used in antidiabetic/hypolipidemic therapy, because of their pleiotropic properties. PMID:21421822

Khalid, Ahmed M; Hafstad, Anne Dragøy; Larsen, Terje S; Severson, David L; Boardman, Neoma; Hagve, Martin; Berge, Rolf K; Aasum, Ellen

2011-06-01

247

Impaired Musculoskeletal Response to Age and Exercise in PPAR??/? Diabetic Mice  

PubMed Central

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

2014-01-01

248

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

249

Maintenance of Normoglycemia in Diabetic Mice by Subcutaneous Xenografts of Encapsulated Islets  

NASA Astrophysics Data System (ADS)

The goal of islet transplantation in human diabetes is to maintain the islet grafts in the recipients without the use of immunosuppression. One approach is to encapsulate the donor islets in permselective membranes. Hollow fibers fabricated from an acrylic copolymer were used to encapsulate small numbers of rat islets that were immobilized in an alginate hydrogel for transplantation in diabetic mice. The fibers were biocompatible, prevented rejection, and maintained normoglycemia when transplanted intraperitoneally; hyperglycemia returned when the fibers were removed at 60 days. Normoglycemia was also maintained by subcutaneous implants that had an appropriately constructed outer surface on the fibers.

Lacy, Paul E.; Hegre, Orion D.; Gerasimidi-Vazeou, Andriani; Gentile, Frank T.; Dionne, Keith E.

1991-12-01

250

Dietary polyherbal supplementation decreases CD3(+) cell infiltration into pancreatic islets and prevents hyperglycemia in nonobese diabetic mice.  

PubMed

Type 1 diabetes mellitus results from autoimmune-mediated destruction of pancreatic islet ?-cells, a process associated with inflammatory signals. We hypothesized that dietary supplementation with botanicals known to contain anti-inflammatory properties would prevent losses in functional ?-cell mass in nonobese diabetic (NOD) mice, a rodent model of autoimmune-mediated islet inflammation that spontaneously develops diabetes. Female NOD mice, a model of spontaneous autoimmune diabetes, were fed a diet supplemented with herbal extracts (1.916 g total botanical extracts per 1 kg of diet) over a 12-week period. The mice consumed isocaloric matched diets without (controls) and with polyherbal supplementation (PHS) ad libitum starting at a prediabetic stage (age 6 weeks) for 12 weeks. Control mice developed hyperglycemia (>180 mg/dL) within 16 weeks (n = 9). By contrast, mice receiving the PHS diet did not develop hyperglycemia by 18 weeks (n = 8). Insulin-positive cell mass within pancreatic islets was 31.9% greater in PHS mice relative to controls. We also detected a 26% decrease in CD3(+) lymphocytic infiltration in PHS mice relative to mice consuming a control diet. In vitro assays revealed reduced ?-cell expression of the chemokines CCL2 and CXCL10 after overnight PHS addition to the culture media. We conclude that dietary PHS delays initiation of autoimmune-mediated ?-cell destruction and subsequent onset of diabetes mellitus by diminishing islet inflammatory responses. PMID:25640963

Burke, Susan J; Karlstad, Michael D; Conley, Caroline P; Reel, Danielle; Whelan, Jay; Jason Collier, J

2015-04-01

251

An aqueous extract of Portulaca oleracea ameliorates diabetic nephropathy through suppression of renal fibrosis and inflammation in diabetic db/db mice.  

PubMed

Diabetic nephropathy is one of the most common microvascular complications of diabetes and the leading cause of end-stage renal disease. In the present study, we investigated the renoprotective effect of the aqueous extract of Portulaca oleracea (AP) on diabetic nephropathy accelerated by renal fibrosis and inflammation in type 2 diabetic db/db mice. The mice were treated with AP (300 mg/kg/day, p.o.) for ten weeks to examine the long-term effects on diabetic nephropathy and renal dysfunction. We found that AP treatment markedly lowered blood glucose to 412 ± 11.4 mg/dl and plasma creatinine level to 2.3 ± 0.8 mg/dl compared to db/db mice (p < 0.05, p < 0.01, respectively). This study also showed that treatment with AP significantly decreased water intake and urine volume in diabetic db/db mice (p < 0.05). In immunohistological study, the renal expression of transforming growth factor-?1 (TGF-?1), advanced glycation end products (AGE), and intercellular adhesion molecule (ICAM)-1 markedly increased in the renal cortex of untreated db/db mice (p < 0.01). In contrast, AP treatment significantly reduced these expressions to 50 ± 2.1%, 48 ± 2.8%, 61 ± 1.1%, respectively (p < 0.01). Furthermore, NF-?B p65 activation in renal tissues markedly increased in untreated db/db mice, which was significantly suppressed by AP treatment. Taken together, these findings suggest that AP attenuates diabetic nephropathy through inhibition of renal fibrosis and inflammation in db/db mice. PMID:22745066

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

2012-01-01

252

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

253

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

254

Contribution of neural cell death to depressive phenotypes of streptozotocin-induced diabetic mice  

PubMed Central

Major depression disorder (MDD) or depression is highly prevalent in individuals with diabetes, and the depressive symptoms are more severe and less responsive to antidepressant therapies in these patients. The underlying mechanism is little understood. We hypothesized that the pathophysiology of comorbid depression was more complex than that proposed for MDD and that neural cell death played a role in the disease severity. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic mice. These mice had blood glucose levels threefold above controls and exhibited depressive phenotypes as judged by a battery of behavioral tests, thus confirming the comorbidity in mice. Immunohistological studies showed markedly increased TUNEL-positive cells in the frontal cortex and hippocampus of the comorbid mice, indicating apoptosis. This finding was supported by increased caspase-3 and decreased Bcl-2 proteins in these brain regions. In addition, the serum brain-derived neurotrophic factor (BDNF) level of comorbid mice was reduced compared with controls, further supporting the neurodegenerative change. Mechanistic analyses showed an increased expression of mitochondrial fission genes fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1), and a decreased expression of mitochondrial fusion genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optical atrophy 1 (Opa1). Representative assessment of the proteins Drp1 and Mfn2 mirrored the mRNA changes. The data demonstrated that neural cell death was associated with the depressive phenotype of comorbid mice and that a fission-dominant expression of genes and proteins mediating mitochondrial dynamics played a role in the hyperglycemia-induced cell death. The study provides new insight into the disease mechanism and could aid the development of novel therapeutics aimed at providing neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes. PMID:24764190

Chen, Cheng; Wang, Yun; Zhang, Juan; Ma, Lian; Gu, Jiang; Ho, Guyu

2014-01-01

255

Dietary Saury Oil Reduces Hyperglycemia and Hyperlipidemia in Diabetic KKAy Mice and in Diet-Induced Obese C57BL\\/6J Mice by Altering Gene Expression  

Microsoft Academic Search

We investigated the effect of saury oil on the alleviation of metabolic syndrome in mice. Saury oil contains 18% (w\\/w\\/) n-3\\u000a polyunsaturated fatty acids (n-3 PUFA) and 35% (w\\/w) monounsaturated fatty acids (MUFA). Diabetic KKAy mice were fed a 10%\\u000a soybean oil diet (control) or a 10% saury oil diet for 4 weeks, and diet-induced obese C57BL\\/6J mice were fed a

Zhi-Hong Yang; Hiroko Miyahara; Shuhei Takemura; Akimasa Hatanaka

2011-01-01

256

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

257

Quantitative phosphoproteomic analysis of T cell receptor signaling in diabetes prone and resistant mice.  

PubMed

Type 1 diabetes, in human patients and NOD mice, results from an 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

2010-06-01

258

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

259

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

260

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

PubMed

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

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

2014-01-01

261

Immunomodulatory and Antidiabetic Effects of a New Herbal Preparation (HemoHIM) on Streptozotocin-Induced Diabetic Mice  

PubMed Central

HemoHIM (a new herbal preparation of three edible herbs: Angelica gigas Nakai, Cnidium officinale Makino, and Paeonia japonica Miyabe) was developed to protect immune, hematopoietic, and self-renewal tissues against radiation. This study determined whether or not HemoHIM could alter hyperglycemia and the immune response in diabetic mice. Both nondiabetic and diabetic mice were orally administered HemoHIM (100?mg/kg) once a day for 4 weeks. Diabetes was induced by single injection of streptozotocin (STZ, 200?mg/kg, i.p.). In diabetic mice, HemoHIM effectively improved hyperglycemia and glucose tolerance compared to the diabetic control group as well as elevated plasma insulin levels with preservation of insulin staining in pancreatic ?-cells. HemoHIM treatment restored thymus weight, white blood cells, lymphocyte numbers, and splenic lymphocyte populations (CD4+ T and CD8+ T), which were reduced in diabetic mice, as well as IFN-? production in response to Con A stimulation. These results indicate that HemoHIM may have potential as a glucose-lowering and immunomodulatory agent by enhancing the immune function of pancreatic ?-cells in STZ-induced diabetic mice. PMID:25045390

Kim, Jong-Jin; Choi, Jina; Lee, Mi-Kyung; Kang, Kyung-Yun; Paik, Man-Jeong; Jo, Sung-Kee; Jung, Uhee; Park, Hae-Ran; Yee, Sung-Tae

2014-01-01

262

Antihyperglycaemic effects of ethanol extracts of Carica papaya and Pandanus amaryfollius leaf in streptozotocin-induced diabetic mice  

Microsoft Academic Search

Diabetes mellitus is a global disease that is increasing in an alarming rate. The present study was undertaken to study the antidiabetic effect of the ethanol extracts of Carica papaya and Pandanus amaryfollius on streptozotocin-induced diabetic mice. The results of the present study indicated that there was no significant difference in the body weight of the treated groups when compared

Sreenivasan Sasidharan; Vello Sumathi; Naidu Rameshwar Jegathambigai; Lachimanan Yoga Latha

2011-01-01

263

Adiponectin retards the progression of diabetic nephropathy in db/db mice by counteracting angiotensin II.  

PubMed

Adiponectin is a multifunctional adipokine with insulin-sensitizing, anti-inflammatory, and vasoprotective properties. Epidemiology studies have, however, shown that high levels of serum adiponectin are associated with kidney disease progression. We, therefore, examined the effect of adiponectin administration on the progression of glomerulosclerosis in the obese diabetic (db/db) mouse, a model of type II diabetes. Recombinant human adiponectin was administered intraperitoneally at a dose of 30 or 150 ?g per day from weeks 18 to 20. Rosiglitazone administered by gavage at 20 mg/kg body weight (BW) daily served as a therapeutic control. Untreated uninephrectomized db/db mice developed progressive albuminuria and glomerular matrix expansion, associated with increased expression of transforming growth factor beta 1 (TGF?1), plasminogen activator inhibitor type 1 (PAI-1), collagen I (Col I), and fibronectin (FN). Treatment with adiponectin at either dose reduced the increases in albuminuria and markers of renal fibrosis seen in db/db mice, without affecting BW and blood glucose. Renal expressions of tumor necrosis factor-? (TNF-?) and monocyte-chemoattractant protein-1 (MCP-1) and urinary TNF-? levels, the markers of renal inflammation, were increased in diabetic mice, whereas adiponectin treatment significantly reduced the levels of these markers. Furthermore, adiponectin obliterated the stimulatory effects of angiotensin II (Ang II), but not the total effect of TGF?1, on the mRNA expression of PAI-1, Col I, and FN by cultured glomerular mesangial cells. These observations suggest that adiponectin treatment reduces glomerulosclerosis resulting from type II diabetes probably through its anti-inflammatory and angiotensin-antagonistic effects. Thus, adiponectin has therapeutic implications in the prevention of progression of diabetic nephropathy. PMID:24744899

Guo, Xiaohua; Zhou, Guangyu; Guo, Meizi; Cheung, Alfred K; Huang, Yufeng; Beddhu, Srinivasan

2014-02-01

264

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

PubMed Central

Background Type-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites. Results Transporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice. Conclusion A severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels. PMID:22524730

2012-01-01

265

Adiponectin retards the progression of diabetic nephropathy in db/db mice by counteracting angiotensin II  

PubMed Central

Abstract Adiponectin is a multifunctional adipokine with insulin?sensitizing, anti?inflammatory, and vasoprotective properties. Epidemiology studies have, however, shown that high levels of serum adiponectin are associated with kidney disease progression. We, therefore, examined the effect of adiponectin administration on the progression of glomerulosclerosis in the obese diabetic (db/db) mouse, a model of type II diabetes. Recombinant human adiponectin was administered intraperitoneally at a dose of 30 or 150 ?g per day from weeks 18 to 20. Rosiglitazone administered by gavage at 20 mg/kg body weight (BW) daily served as a therapeutic control. Untreated uninephrectomized db/db mice developed progressive albuminuria and glomerular matrix expansion, associated with increased expression of transforming growth factor beta 1 (TGF?1), plasminogen activator inhibitor type 1 (PAI?1), collagen I (Col I), and fibronectin (FN). Treatment with adiponectin at either dose reduced the increases in albuminuria and markers of renal fibrosis seen in db/db mice, without affecting BW and blood glucose. Renal expressions of tumor necrosis factor?? (TNF??) and monocyte?chemoattractant protein?1 (MCP?1) and urinary TNF?? levels, the markers of renal inflammation, were increased in diabetic mice, whereas adiponectin treatment significantly reduced the levels of these markers. Furthermore, adiponectin obliterated the stimulatory effects of angiotensin II (Ang II), but not the total effect of TGF?1, on the mRNA expression of PAI?1, Col I, and FN by cultured glomerular mesangial cells. These observations suggest that adiponectin treatment reduces glomerulosclerosis resulting from type II diabetes probably through its anti?inflammatory and angiotensin–antagonistic effects. Thus, adiponectin has therapeutic implications in the prevention of progression of diabetic nephropathy. PMID:24744899

Guo, Xiaohua; Zhou, Guangyu; Guo, Meizi; Cheung, Alfred K; Huang, Yufeng; Beddhu, Srinivasan

2014-01-01

266

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)

2005-06-01

267

Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice  

Microsoft Academic Search

We hypothesized that formation of advanced glycation end products (AGEs) associated with diabetes reduces matrix degradation by metalloproteinases (MMPs) and contributes to the impairment of ischemia-induced angiogenesis. Mice were treated or not with streptozotocin (40 mg\\/kg) and streptozotocin plus aminoguanidine (AGEs formation blocker, 50 mg\\/kg). After 8 weeks of treatment, hindlimb ischemia was induced by right femoral artery ligature. Plasma

Radia Tamarat; Jean-Sébastien Silvestre; Maya Huijberts; Joelle Benessiano; Teni G. Ebrahimian; Micheline Duriez; Marie-Paule Wautier; Jean Luc Wautier; Bernard I. Lévy

2003-01-01

268

Two diallyl sulphides derived from garlic inhibit meticillin-resistant Staphylococcus aureus infection in diabetic mice  

Microsoft Academic Search

The inhibitory effect of diallyl sulphide (DAS) and diallyl disulphide (DADS) against meticillin-resistant Staphylococcus aureus (MRSA) infection in diabetic mice was studied. The influence of these agents on the plasma levels of fibronectin, C-reactive protein (CRP), fibrinogen, interleukin (IL)-6 and tumour necrosis factor-a (TNF-a), and on the activity of plasminogen activator inhibitor-1 (PAI-1), antithrombin III (AT-III) and protein C, in

Shih-Ming Tsao; Wen-Hu Liu; Mei-Chin Yin

2007-01-01

269

Immune responses to an encapsulated allogeneic islet {beta}-cell line in diabetic NOD mice  

SciTech Connect

Our goal is to develop effective islet grafts for treating type 1 diabetes. Since human islets are scarce, we evaluated the efficacy of a microencapsulated insulin-secreting conditionally transformed allogeneic {beta}-cell line ({beta}TC-tet) in non-obese diabetic mice treated with tetracycline to inhibit cell growth. Relatively low serum levels of tetracycline controlled proliferation of {beta}TC-tet cells without inhibiting effective control of hyperglycemia in recipients. There was no significant host cellular reaction to the allografts or host cell adherence to microcapsules, and host cytokine levels were similar to those of sham-operated controls. We conclude that encapsulated allogeneic {beta}-cell lines may be clinically relevant, because they effectively restore euglycemia and do not elicit a strong cellular immune response following transplantation. To our knowledge, this is First extensive characterization of the kinetics of host cellular and cytokine responses to an encapsulated islet cell line in an animal model of type 1 diabetes.

Black, Sasha P. [Charles River Laboratories, Pre-clinical Services Montreal, Senneville, Que., H9X 3R3 (Canada)]. E-mail: Sasha.Black@ca.crl.com; Constantinidis, Ioannis [Department of Medicine, Division of Endocrinology, University of Florida, Gainesville, FL 32610 (United States); Cui, Hong [Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322 (United States); Tucker-Burden, Carol [Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322 (United States); Weber, Collin J. [Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322 (United States); Safley, Susan A. [Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322 (United States)

2006-02-03

270

Role of Metformin in Suppressing 1,2-Dimethylhydrazine-Induced Colon Cancer in Diabetic and Non-Diabetic Mice: Effect on Tumor Angiogenesis and Cell Proliferation  

PubMed Central

Several studies indicated that type 2 diabetes mellitus and insulin resistance are associated with increased colon cancer risk. Recently, studies suggest that metformin can reduce cancer risk in diabetic or non-diabetic patients with unclear mechanisms. This work aimed to determine the effect of metformin on chemically-induced colon cancer in mice. Colon cancer was induced using 1,2-dimethylhydrazine (DMH, 20 mg/kg/week, s.c.) for fifteen weeks. Experiment I: healthy mice were fed with basal diet for four weeks and then allocated into seven groups, (i) saline, (ii) DMH, (iii) oxaliplatin, (iv–v): metformin (100 or 200 mg/kg) and (vi–vii): oxaliplatin+metformin (100 or 200 mg/kg), respectively. Experiment II: type 2 diabetes mellitus was induced by injection of STZ (30 mg/kg) after four weeks of high-fat feeding and then mice were allocated into seven groups similar to those reported in experiment I. Examination of the colonic tissue at the end of the experiment highlighted an increase in angiogenic markers and cell proliferation and showed a greater immunostaining for insulin growth factor I receptors and CD34 in the colon of diabetic mice compared to non-diabetics. In general, metformin downregulated tumor angiogenesis and augmented the antitumor effect of oxaliplatin. Overall, the current results showed that metformin protected against DMH-induced colon cancer in non-diabetic and diabetic mice. This therapeutic effect was, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms. PMID:24971882

Zaafar, Dalia K.; Zaitone, Sawsan A.; Moustafa, Yasser M.

2014-01-01

271

Treated of type 1 diabetes mellitus in non-obese diabetic mice by transplantation of allogeneic bone marrow and pancreatic tissue  

SciTech Connect

Non-obese diabetic (NOD) mice provide a model for type 1 diabetes mellitus. We previously showed that allogeneic bone marrow transplantation (ABMT) can prevent and treat insulitis and overt diabetes in NOD mice. However, ABMT alone could not be used to treat overt diabetes in NOD mice whose islets had been completely destroyed. To provide insulin-producing cells, pancreatic tissue from newborn mice was grafted under the renal capsules in combination with ABMT. The aims of concomitant ABMT are as follows. (i) It induces immunological tolerance to the donor-type major histocompatibility complex determinants and permits the host to accept subsequent pancreatic allografts from the bone marrow donor. (ii) ABMT replaces abnormal stem cells with normal stem cells. After transplantation of bone marrow plus newborn pancreas, NOD mice showed reduction of the glycosuria and a normal response in the glucose-tolerance test. Immunohistological study revealed the presence of clustered insulin-containing beta cells in the grafted pancreatic transplants. ABMT may become a viable treatment of established type 1 diabetes mellitus in humans.

Yasumizu, R.; Sugiura, K.; Iwai, H.; Inaba, M.; Makino, S.; Ida, T.; Imura, H.; Hamashima, Y.; Good, R.A.; Ikehara, S.

1987-09-01

272

Overexpression of STAMP2 suppresses atherosclerosis and stabilizes plaques in diabetic mice  

PubMed Central

Our research aims to evaluate the function of the STAMP2 gene, an important trigger in insulin resistance (IR), and explore its role in macrophage apoptosis in diabetic atherosclerotic vulnerable plaques. The characteristics of diabetic mice were measured by serial metabolite and pathology tests. The level of STAMP2 was measured by RT-PCR and Western blot. The plaque area, lipid and collagen content of brachiocephalic artery plaques were measured by histopathological analyses, and the macrophage apoptosis was measured by TUNEL. Correlation of STAMP2/Akt signaling pathway and macrophage apoptosis was validated by Ad-STAMP2 transfection and STAMP2 siRNA inhibition. The diabetic mice showed typical features of IR, hyperglycaemia. Overexpression of STAMP2 ameliorated IR and decreased serum glucose level. In brachiocephalic lesions, lipid content, macrophage quantity and the vulnerability index were significantly decreased by overexpression of STAMP2. Moreover, the numbers of apoptotic cells and macrophages in lesions were both significantly decreased. In vitro, both mRNA and protein expressions of STAMP2 were increased under high glucose treatment. P-Akt was highly expressed and caspase-3 was decreased after overexpression of STAMP2. However, expression of p-Akt protein was decreased and caspase-3 was increased when STAMP2 was inhibited by siRNA. STAMP2 overexpression could exert a protective effect on diabetic atherosclerosis by reducing IR and diminishing macrophage apoptosis. PMID:24467451

Wang, Jia; Han, Lu; Wang, Zhi-hao; Ding, Wen-yuan; Shang, Yuan-yuan; Tang, Meng-xiong; Li, Wen-bo; Zhang, Yun; Zhang, Wei; Zhong, Ming

2014-01-01

273

Nearby Construction Impedes the Progression to Overt Autoimmune Diabetes in NOD Mice  

PubMed Central

Construction nearby animal houses has sporadically been reported to affect various aspects of animal health. Most of the reports have focussed on the impact on stress hormone levels and the hypersensitivity of animals relative to humans. There has also been an anecdotal report on the impact of construction on autoimmune diabetes in NOD mice. Here, we describe that nearby construction significantly impedes the progression to overt diabetes in female NOD mice offspring. We demonstrate that this was not due to a genetic drift or to particularities associated with our specific mouse colony. Interestingly, although the glycemia levels remained low in mice born from mothers subject to construction stress during gestation, we detected an active autoimmune reaction towards pancreatic islet cells, as measured by both the degree of insulitis and the presence of insulin autoantibody levels in the serum. These results suggest that the external stress imposed during embryonic development does not prevent but significantly delays the autoimmune process. Together, our findings emphasize the impact of surrounding factors during in vivo studies and are in agreement with the hypothesis that both environmental and genetic cues contribute to autoimmune diabetes development. PMID:23691516

Hillhouse, Erin E.; Chabot-Roy, Geneviève; Guyon, Marie-Josée; Tessier, Nathalie; Boulay, Maryse; Liscourt, Patricia

2013-01-01

274

Activation of ?-opioid receptor exerts the glucose-homeostatic effect in streptozotocin-induced diabetic mice.  

PubMed

Opioid and its receptors play important roles in glucose homeostasis. However, few reports were available for the study of ?-opioid receptor in glucose regulation. In our study, we found that the blood glucose of diabetic mice dropped significantly following the treatment with U50,488H (a selective ?-opioid receptor agonist). This phenomenon was time-dependent and associated with the coincident alteration of Glut4 translocation in the skeleton muscles. U50,488H increased the serum adiponectin, but not serum insulin in diabetic mice. U50,488H increased the AdipoR1 expression at both mRNA and protein levels. It also promoted AMPK phosphorylation and Glut4 translocation. All these effects were abolished by nor-BNI (a selective ?-opioid receptor antagonist). These findings suggest that activation of ?-opioid receptor reduces hyperglycemia in streptozotocin-induced diabetic mice. This effect is associated with the translocation of Glut4 and might be relevant to increased adiponectin, AdipoR1, and AMPK phosphorylation. PMID:25186835

Shang, Yulong; Guo, Fan; Li, Juan; Fan, Rong; Ma, Xinliang; Wang, Yuemin; Feng, Na; Yin, Yue; Jia, Min; Zhang, Shumiao; Zhou, Jingjun; Wang, Hongbing; Pei, Jianming

2015-02-01

275

Manganese supplementation protects against diet-induced diabetes in wild type mice by enhancing insulin secretion.  

PubMed

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; McClain, Donald A

2013-03-01

276

Recovery from diabetes in neonatal mice after a low-dose streptozotocin treatment  

SciTech Connect

Highlights: ? We monitored long-term beta cell regeneration in neonatal mice treated with low dose STZ. ? Low-dose STZ neonatal female mice recovered blood glucose in 150 days. ? Glucose intolerance of the STZ treated mice significantly improved in 150 days. -- Abstract: Administration of streptozotocin (STZ) induces destruction of ?-cells and is widely used as an experimental animal model of type I diabetes. In neonatal rat, after low-doses of STZ-mediated destruction of ?-cells, ?-cells regeneration occurs and reversal of hyperglycemia was observed. However, in neonatal mice, ?-cell regeneration seems to occur much slowly compared to that observed in the rat. Here, we described the time dependent quantitative changes in ?-cell mass during a spontaneous slow recovery of diabetes induced in a low-dose STZ mice model. We then investigated the underlying mechanisms and analyzed the cell source for the recovery of ?-cells. We showed here that postnatal day 7 (P7) female mice treated with 50 mg/kg STZ underwent the destruction of a large proportion of ?-cells and developed hyperglycemia. The blood glucose increased gradually and reached a peak level at 500 mg/dl on day 35–50. This was followed by a spontaneous regeneration of ?-cells. A reversal of non-fasting blood glucose to the control value was observed within 150 days. However, the mice still showed impaired glucose tolerance on day 150 and day 220, although a significant improvement was observed on day 150. Quantification of the ?-cell mass revealed that the ?-cell mass increased significantly between day 100 and day 150. On day 150 and day 220, the ?-cell mass was approximately 23% and 48.5% of the control, respectively. Of the insulin-positive cells, 10% turned out to be PCNA-positive proliferating cells. Our results demonstrated that, ?-cell duplication is one of the cell sources for ?-cell regeneration.

Kataoka, Masateru; Kawamuro, Yuki; Shiraki, Nobuaki [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan)] [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); Miki, Rika; Sakano, Daisuke [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan) [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); The Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); Yoshida, Tetsu; Yasukawa, Takanori; Kume, Kazuhiko [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan)] [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); Kume, Shoen, E-mail: skume@kumamoto-u.ac.jp [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan) [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); The Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan)

2013-01-18

277

Diabetes-Induced Impairment in Visual Function in Mice: Contributions of p38 MAPK, RAGE, Leukocytes, and Aldose Reductase  

PubMed Central

Purpose. Visual function is impaired in diabetes, but molecular causes of this dysfunction are not clear. We assessed effects of diabetes on visual psychophysics in mice, and tested the effect of therapeutic approaches reported previously to inhibit vascular lesions of the retinopathy. Methods. We used the optokinetic test to assess contrast sensitivity and spatial frequency threshold in diabetic C57Bl/6J mice and age-matched nondiabetic controls between 2 and 10 months of diabetes. Contributions of p38 MAP kinase (MAPK), receptor for advanced glycation end products (RAGE), leukocytes, and aldose reductase (AR) to the defect in contrast sensitivity were investigated. Cataract, a potential contributor to reductions in vision, was scored. Results. Diabetes of 2 months' duration impaired contrast sensitivity and spatial frequency threshold in mice. The defect in contrast sensitivity persisted for at least 10 months, and cataract did not account for this impairment. Diabetic mice deficient in AR were protected significantly from development of the diabetes-induced defects in contrast sensitivity and spatial frequency threshold. In contrast, pharmacologic inhibition of p38 MAPK or RAGE, or deletion of inducible nitrous oxide synthase (iNOS) from bone marrow-derived cells did not protect the visual function in diabetes. Conclusions. Diabetes reduces spatial frequency threshold and contrast sensitivity in mice, and the mechanism leading to development of these defects involves AR. The mechanism by which AR contributes to the diabetes-induced defect in visual function can be probed by identifying which molecular abnormalities are corrected by AR deletion, but not other therapies that do not correct the defect in visual function. PMID:23920367

Lee, Chieh Allen; Li, Guangyuan; Patel, Mansi D.; Petrash, J. Mark; Benetz, Beth Ann; Veenstra, Alex; Amengual, Jaume; von Lintig, Johannes; Burant, Christopher J.; Tang, Johnny; Kern, Timothy S.

2014-01-01

278

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

279

Caffeine Consumption Prevents Diabetes-Induced Memory Impairment and Synaptotoxicity in the Hippocampus of NONcZNO10/LTJ Mice  

PubMed Central

Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A1 and A2A receptors) emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7–11 months when kept under an 11% fat diet. Caffeine (1 g/l) was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25), mainly glutamatergic (vesicular glutamate transporters), and increased astrogliosis (GFAP immunoreactivity) compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A2A receptors and down-regulated A1 receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes. PMID:22514596

Duarte, João M. N.; Agostinho, Paula M.; Carvalho, Rui A.; Cunha, Rodrigo A.

2012-01-01

280

Knockout of the TauT Gene Predisposes C57BL/6 Mice to Streptozotocin-Induced Diabetic Nephropathy  

PubMed Central

Diabetic nephropathy is the leading cause of end stage renal disease in the world. Although tremendous efforts have been made, scientists have yet to identify an ideal animal model that can reproduce the characteristics of human diabetic nephropathy. In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus. This hypothesis was tested in vivo in TauT heterozygous (TauT+/-) and homozygous (TauT-/-) knockout in C57BL/6 background mice. We have shown that alteration of the TauT gene (also known as SLC6A6) has a substantial effect on the susceptibility to development of extensive diabetic kidney disease in both TauT+/- and TauT-/-mouse models of diabetes. These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis. Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations. Our results demonstrated that both homozygous and heterozygous TauT gene deletion predispose C57BL/6 mice to develop end-stage diabetic kidney disease, which closely replicates the pathological features of diabetic nephropathy in human diabetic patients. PMID:25629817

Han, Xiaobin; Patters, Andrea B.; Ito, Takashi; Schaffer, Stephen W.; Chesney, Russell W.

2015-01-01

281

Hypoglycemic activity and potential mechanism of a polysaccharide from the loach in streptozotocin-induced diabetic mice.  

PubMed

The present study was designed to investigate the hypoglycemic activity and the potential mechanisms of Misgurnus anguillicaudatus polysaccharide (MAP) in streptozotocin-induced diabetic mice. MAP oral administration significantly decreased the blood levels of glucose, TC, TG, LDL-C, and increased the blood levels of HDL-C and insulin in diabetic mice, concurrent with increases in body weights and pancreatic insulin contents. Moreover, MAP reversed the increased mRNA expressions of PEPCK and the reduced glycogen contents in the liver of diabetic mice. Concurrently, MAP exhibited potent anti-inflammatory and anti-oxidative activities, as evidenced by the decreased blood levels of TNF-?, IL-6, monocyte chemoattractant protein-1, MDA, and also the elevated SOD and GPx activities in the serum of diabetic mice. Furthermore, MAP also significantly improved the blood markers of the impaired liver function and renal function in diabetic mice. Altogether, these results suggest that MAP may be a potential therapeutic option for type 1 diabetes. PMID:25659690

Zhou, Jun; Yan, Junyan; Bai, Zhaoshuai; Li, Kaicheng; Huang, Kaixun

2015-05-01

282

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

283

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

284

Phosphodiesterase-5 (PDE5) is a Therapeutic Target for Peripheral Neuropathy in Diabetic Mice  

PubMed Central

Peripheral neuropathy is a common and major complication of diabetes, the underlying mechanisms of which are not fully understood. Using a mouse model of type II diabetes, the present study investigated the role of phosphodiesterase-5 (PDE5) in peripheral neuropathy. BKS.Cg-m+/+Leprdb/J (db/db) mice were treated with sildenafil, a specific inhibitor of PDE5, at doses of 2 and 10 mg/kg or saline. Levels of PDE5 and morphometric parameters in sciatic nerve tissue as well as the motor and sensory function were measured in these mice. In diabetic mice, PDE5 expression in sciatic nerve tissue was significantly upregulated, while the myelin sheath thickness, myelin basic protein (MBP), and subcutaneous nerve fibers were significantly reduced. Treatment with sildenafil, significantly improved neurological function, assayed by motor and sensory conducting velocities and thermal and mechanical noxious stimuli, concomitantly with increases in myelin sheath thickness, MBP levels, and subcutaneous nerve fibers. In vitro, hyperglycemia upregulated PDE5 in Schwann cells, and reduced Schwann cell proliferation, migration and expression of brain-derived neurotrophic factor (BDNF). Blockage of PDE5 with sildenafil, increased cGMP, and completely abolished the effect of hyperglycemia on Schwann cells. Sildenafil upregulated cGMP-dependent protein kinase G1 (PKG1), whereas inhibition of PKG1 with a PKG inhibitor, KT5823, suppressed the inhibitory effect of sildenafil on Schwann cells. These data indicate that hyperglycemia substantially upregulates PDE5 expression and that the cGMP/PKG signaling pathway activated by sildenafil mediates the beneficial effects of sildenafil on diabetic peripheral neuropathy. PMID:21820491

Wang, Lei; Chopp, Michael; Szalad, Alexandra; Liu, Zhongwu; Bolz, Marianne; Ãlvarez, Francisco Moniche; Lu, Mei; Zhang, Li; Cui, Yisheng; Zhang, Rui Lan; Zhang, Zheng Gang

2011-01-01

285

Modulation of AT-1R/MAPK cascade by an olmesartan treatment attenuates diabetic nephropathy in streptozotocin-induced diabetic mice.  

PubMed

There is increasing evidence that angiotensin (Ang)-II plays an unprecedented role in diabetic complications. It could also be an important therapeutic target for ameliorating various diseases, especially diabetic nephropathy (DN). We therefore studied the beneficial effects of olmesartan, an Ang-II type 1 receptor (AT-1R) blocker in streptozotocin (150 mg/kg, BW)-induced diabetic kidney disease in mice. The diabetic kidney mice displayed upregulated protein expression levels of AT-1R, AT-2R, ERK-1/2, p-p38 MAPK, p-MAPKAPK-2, ET-1, p-JNK, p-c-Jun, TGF-?1, and gp91-phox, and all of these effects were expectedly downregulated by an olmesartan treatment. Also, immunohistochemical analysis, and Azan-Mallory and HE staining were performed to examine the expression of collagen-III and fibronectin, renal fibrosis, and hypertrophy, respectively. Furthermore, olmesartan treatment significantly abrogated the downregulation of ACE-2 and Ang-(1-7) mas R protein expression in diabetic kidney mice. Considering all these findings together, the AT-1R/MAPK pathway might be a potential therapeutic target in diabetes kidney disease, and olmesartan treatment could have beneficial effects on DN by modulating the AT-1R/MAPK pathway. PMID:21827824

Lakshmanan, Arun Prasath; Thandavarayan, Rajarajan A; Watanabe, Kenichi; Sari, Flori R; Meilei, Harima; Giridharan, Vijayasree V; Sukumaran, Vijayakumar; Soetikno, Vivian; Arumugam, Somasundaram; Suzuki, Kenji; Kodama, Makoto

2012-01-01

286

Hepatic Circadian-Clock System Altered by Insulin Resistance, Diabetes and Insulin Sensitizer in Mice  

PubMed Central

Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor ? (PPAR?) rather than PPAR?. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

Yang, Shih-Hsien; Shieh, Kun-Ruey

2015-01-01

287

Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice.  

PubMed

Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor ? (PPAR?) rather than PPAR?. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

Tseng, Huey-Ling; Yang, Shu-Chuan; Yang, Shih-Hsien; Shieh, Kun-Ruey

2015-01-01

288

Transmaternal bisphenol A exposure accelerates diabetes type 1 development in NOD mice.  

PubMed

Diabetes mellitus type 1 is an autoimmune disease with a genetic predisposition that is triggered by environmental factors during early life. Epidemiological studies show that bisphenol A (BPA), an endocrine disruptor, has been detected in about 90% of all analyzed human urine samples. In this study, BPA was found to increase the severity of insulitis and the incidence of diabetes in female non obese diabetic (NOD) mice offspring after transmaternal exposure through the dams' drinking water (0, 0.1, 1, and 10mg/l). Both the severity of insulitis in the pancreatic islets at 11 weeks of age and the diabetes prevalence at 20 weeks were significantly increased for female offspring in the highest exposure group compared to the control group. Increased numbers of apoptotic cells, a reduction in tissue resident macrophages and an increase in regulatory T cells were observed in islets prior to insulitis development in transmaternally exposed offspring. The detectable apoptotic cells were identified as mostly glucagon producing alpha-cells but also tissue resident macrophages and beta-cells. In the local (pancreatic) lymph node neither regulatory T cell nor NKT cell populations were affected by maternal BPA exposure. Maternal BPA exposure may have induced systemic immune changes in offspring, as evidenced by alterations in LPS- and ConA-induced cytokine secretion in splenocytes. In conclusion, transmaternal BPA exposure, in utero and through lactation, accelerated the spontaneous diabetes development in NOD mice. This acceleration appeared to be related to early life modulatory effects on the immune system, resulting in adverse effects later in life. PMID:24189131

Bodin, Johanna; Bølling, Anette Kocbach; Becher, Rune; Kuper, Frieke; Løvik, Martinus; Nygaard, Unni Cecilie

2014-02-01

289

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

290

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice  

Microsoft Academic Search

Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in

L. Weiss; M. Zeira; S. Reich; M. Har-Noy; R. Mechoulam; S. Slavin; R. Gallily

2006-01-01

291

Omega-3 polyunsaturated fatty acids preserve retinal function in type 2 diabetic mice  

PubMed Central

Objective: Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (?-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of ?-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM). Design: Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks–26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either ?-3 or ?-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet. Results: The ?-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a ?-6PUFA-rich diet. There was also an enhanced ability of ?-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of ?-3PUFAs. Conclusion: This study identifies beneficial effects of dietary ?-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As ?-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing ?-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM. PMID:23448719

Sapieha, P; Chen, J; Stahl, A; Seaward, M R; Favazza, T L; Juan, A M; Hatton, C J; Joyal, J-S; Krah, N M; Dennison, R J; Tang, J; Kern, T S; Akula, J D; Smith, L E H

2012-01-01

292

Anti-CD3 mAb treatment cures PDL1-/-.NOD mice of diabetes but precipitates fatal myocarditis.  

PubMed

Anti-CD3 mAb is an effective therapy that can reverse diabetes in NOD mice and has therapeutic potential in patients with type 1 diabetes (T1D). We administered anti-CD3 to PDL1-/-.NOD mice in order to determine whether this treatment would reverse the development of diabetes in these mice. Mice injected with anti-CD3 mAb neonatally were protected from T1D. However, all of these anti-CD3 mAb treated PDL1-/-.NOD mice developed a wasting disease between 12 and 20 weeks of age with sudden deterioration and weight loss, leading to death within 3-5 days of development of illness. Histology revealed severe inflammation in the heart and skeletal muscles. These results suggest that deficiency of PDL1 in NOD background has the potential to lead to immune-mediated tissue damage in organs other than the pancreas, but this cannot be appreciated in PDL1-/-.NOD mice as the mice develop T1D at an early age and die from diabetes prior to manifesting other autoimmune diseases. PMID:21498129

Mfarrej, Bechara; Keir, Mary; Dada, Shirine; Trikudanathan, Subbulaxmi; Sayegh, Mohamed H; Sharpe, Arlene H; Guleria, Indira

2011-07-01

293

Chlorogenic Acid Improves Late Diabetes through Adiponectin Receptor Signaling Pathways in db/db Mice  

PubMed Central

The aim of this study was to examine the effects of chlorogenic acid (CGA) on glucose and lipid metabolism in late diabetic db/db mice, as well as on adiponectin receptors and their signaling molecules, to provide evidence for CGA in the prevention of type 2 diabetes. We randomly divided 16 female db/db mice into db/db-CGA and db/db-control (CON) groups equally; db/m mice were used as control mice. The mice in both the db/db-CGA and db/m-CGA groups were administered 80 mg/kg/d CGA by lavage for 12 weeks, whereas the mice in both CON groups were given equal volumes of phosphate-buffered saline (PBS) by lavage. At the end of the intervention, we assessed body fat and the parameters of glucose and lipid metabolism in the plasma, liver and skeletal muscle tissues as well as the levels of aldose reductase (AR) and transforming growth factor-?1 (TGF-?1) in the kidneys and measured adiponectin receptors and the protein expression of their signaling molecules in liver and muscle tissues. After 12 weeks of intervention, compared with the db/db-CON group, the percentage of body fat, fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) in the db/db-CGA group were all significantly decreased; TGF-?1 protein expression and AR activity in the kidney were both decreased; and the adiponectin level in visceral adipose was increased. The protein expression of adiponectin receptors (ADPNRs), the phosphorylation of AMP-activated protein kinase (AMPK) in the liver and muscle, and the mRNA and protein levels of peroxisome proliferator-activated receptor alpha (PPAR-?) in the liver were all significantly greater. CGA could lower the levels of fasting plasma glucose and HbA1c during late diabetes and improve kidney fibrosis to some extent through the modulation of adiponectin receptor signaling pathways in db/db mice. PMID:25849026

Jin, Shasha; Chang, Cuiqing; Zhang, Lantao; Liu, Yang; Huang, Xianren; Chen, Zhimin

2015-01-01

294

Oxytocin Treatment Prevents the Cardiomyopathy Observed in Obese Diabetic Male db/db Mice.  

PubMed

Oxytocin (OT) is involved in the regulation of energy metabolism and in the activation of cardioprotective mechanisms. We evaluated whether chronic treatment with OT could prevent the metabolic and cardiac abnormalities associated with diabetes and obesity using the db/db mice model. Four-week-old male db/db mice and their lean nondiabetic littermates (db/+) serving as controls were treated with OT (125 ng/kg · h) or saline vehicle for a period of 12 weeks. Compared with db/+ mice, the saline-treated db/db mice developed obesity, hyperglycemia, and hyperinsulinemia. These mice also exhibited a deficient cardiac OT/natriuretic system and developed systolic and diastolic dysfunction resulting from cardiomyocyte hypertrophy, fibrosis, and apoptosis. These abnormalities were associated with increased reactive oxygen species (ROS) production, inflammation, and suppressed 5'-adenosine monophosphate kinase signaling pathway. The db/db mice displayed reduced serum levels of adiponectin and adipsin and elevated resistin. OT treatment increased circulating OT levels, significantly reduced serum resistin, body fat accumulation (19%; P < .001), fasting blood glucose levels by (23%; P < .001), and improved glucose tolerance and insulin sensitivity. OT also normalized cardiac OT receptors, atrial natriuretic peptide, and brain natriuretic peptide, expressions and prevented systolic and diastolic dysfunction as well as cardiomyocyte hypertrophy, fibrosis, and apoptosis. Furthermore, OT reduced cardiac oxidative stress and inflammation and normalized the 5'-adenosine monophosphate-activated protein kinase signaling pathway. The complete normalization of cardiac structure and function by OT treatment in db/db mice contrasted with only partial improvement of hyperglycemia and hyperinsulinemia. These results indicate that chronic treatment with OT partially improves glucose and fat metabolism and reverses abnormal cardiac structural remodeling, preventing cardiac dysfunction in db/db mice. PMID:25562615

Plante, Eric; Menaouar, Ahmed; Danalache, Bogdan A; Yip, Denis; Broderick, Tom L; Chiasson, Jean-Louis; Jankowski, Marek; Gutkowska, Jolanta

2015-04-01

295

Immunomodulation therapy of diabetes by oral administration of a surfactin lipopeptide in NOD mice.  

PubMed

Type 1 diabetes mellitus (T1DM) is considered an autoimmune disease, which can be attenuated by modulation of immune pathway from Th1- to Th2-type through vaccination. WH1fungin surfactin is a Bacillus-produced natural immunomodulator. NOD mice were orally treated with 5mg/kg or 25mg/kg WH1fungin once a week for total 4 weeks. After the final administration, the diabetes incidence and the anti-inflammatory roles of WH1fungin were investigated by immunohistochemistry, FACS and ELISA. The results showed oral WH1fungin obviously resulted in a WH1fungin-unspecific suppression of T1DM. Diabetes incidence was significantly reduced when compared to phosphate buffered saline (PBS) control. Mice in the control group began to be onset of diabetes at week 15, following with an increased mortality from week 16 to 28. At the end of observation, the diabetes incidence reached to 81% at week 30, while only 25% in WH1fungin groups. The splenocytes assay showed oral WH1fungin could suppress T cells proliferation, down-regulate amounts of activated CD8(+) T cells with the production of tumor necrosis factor (TNF)-? and interferon (IFN)-?, and increase CD4(+)CD25(+)FOXP3(+) regulator T cells (Tregs). The serum assay revealed oral WH1fungin down-regulated TNF-? and IgG2a but increased interleukin (IL)-10 and IgG1 in mice. All of these data showed oral WH1fungin tended to switch the immune response from Th1- to Th2-type. The further surveys revealed that less IFN-? but more transfer growth factor (TGF)-? were found in the islets of mice with oral WH1fungin when compared to that in the control group. As a result, the normal islet architecture and slight inflammatory cells infiltration was observed with a slight insulitis in the oral WH1fungin groups. These results demonstrate that oral WH1fungin might be a novel therapeutic approach for the prevention of T1DM. PMID:25239487

Gao, Zhenqiu; Zhao, Xiuyun; Yang, Tao; Shang, Jun; Shang, Long; Mai, Haizhe; Qi, Gaofu

2014-11-28

296

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

297

SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2Akita diabetic mice  

PubMed Central

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-Ins2Akita diabetic mice, which exhibit progressive diabetic nephropathy (DN), but not in DN-resistant C57BL/6- Ins2Akita (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

2015-01-01

298

Berberine Nanosuspension Enhances Hypoglycemic Efficacy on Streptozotocin Induced Diabetic C57BL/6 Mice  

PubMed Central

Berberine (Ber), an isoquinoline derivative alkaloid and active ingredient of Coptis, has been demonstrated to possess antidiabetic activities. However its low oral bioavailability restricts its clinical application. In this report, Ber nanosuspension (Ber-NS) composed of Ber and D-?-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by high pressure homogenization technique. Antidiabetic effects of Ber-NS relative to efficacy of bulk Ber were evaluated in streptozotocin (STZ) induced diabetic C57BL/6 mice. The particle size and zeta potential of Ber-NS were 73.1 ± 3.7?nm and 6.99 ± 0.17?mV, respectively. Ber-NS (50?mg/kg) treatment via oral gavage for 8 weeks resulted in a superior hypoglycemic and total cholesterol (TC) and body weight reduction effects compared to an equivalent dose of bulk Ber and metformin (Met, 300?mg/kg). These data indicate that a low dosage Ber-NS decreases blood glucose and improves lipid metabolism in type 2 diabetic C57BL/6 mice. These results suggest that the delivery of Ber as a nanosuspension is a promising approach for treating type 2 diabetes.

Wang, Zhiping; Wu, Junbiao; Zhou, Qun; Wang, Yifei; Chen, Tongsheng

2015-01-01

299

Lentivectors Encoding Immunosuppressive Proteins Genetically Engineer Pancreatic ? Cells to Correct Diabetes in Allogeneic Mice  

PubMed Central

The effectiveness of genetic engineering with lentivectors to protect transplanted cells from allogeneic rejection was examined using, as a model, type 1 diabetes treatment with ? cell transplantation, whose widespread use has been limited by the requirement for sustained immunosuppressive treatment to prevent graft rejection. We examined whether lentivectors expressing select immunosuppressive proteins encoded by the adenoviral genome early region 3 (AdE3) would protect transplanted ? cells from an alloimmune attack. The insulin-producing ? cell line ?TC-tet (C3HeB/FeJ-derived) was transduced with lentiviruses encoding the AdE3 proteins gp19K and RID?/?. The efficiency of lentiviral transduction of ?TC-tet cells exceeded 85%. Lentivector expression of gp19K decreased surface class I MHC expression by over 90%, while RID?/? expression inhibited cytokine-induced Fas upregulation by over 75%. ?TC-tet cells transduced with gp19K and RID?/? lentivectors, but not with a control lentivector, provided prolonged correction of hyperglycemia after transplantation into diabetic BALB/c SCID mice reconstituted with allogeneic immune effector cells or into diabetic allogeneic BALB/c mice. Thus, genetic engineering of ? cells using gp19K and RID?/? expressing lentiviral vectors may provide an alternative that has the potential to eliminate or reduce treatment with the potent immunosuppressive agents currently necessary for prolonged engraftment with transplanted islets. PMID:19112449

Kojaoghlanian, Tsoline; Joseph, Aviva; Follenzi, Antonia; Zheng, Jian Hua; Leiser, Margarita; Fleischer, Norman; Horwitz, Marshall S.; DiLorenzo, Teresa P.; Goldstein, Harris

2010-01-01

300

Transient Neonatal Diabetes Mellitus Gene Zac1 Impairs Insulin Secretion in Mice through Rasgrf1  

PubMed Central

The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies ?60% of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1 misexpression in pancreatic ? cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/Plagl1 target gene in murine ? cells. Doubling Zac1 expression reduced Rasgrf1 expression, the stimulus-induced activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and, ultimately, insulin secretion. Normalizing Rasgrf1 expression reversed this phenotype. Moreover, the transplantation of Zac1-overexpressing ? cells failed to reinstate euglycemia in experimental diabetic mice. In contrast, Zac1 expression did not interfere with the signaling of the glucagon-like peptide 1 receptor (GLP-1R), and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy. PMID:22547676

Hoffmann, Anke

2012-01-01

301

Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice.  

PubMed

Induction of long-term tolerance to ?-cell autoantigens has been investigated both in animal models and in human type 1 diabetes (T1D) in order to prevent the disease. As regards external compounds, the dietary plant protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was lowered. Intranasal gliadin also rescued a fraction of prediabetic 13-week-old NOD mice from progressing to clinical onset of diabetes compared to OVA-treated controls. Vaccination with i.n. gliadin led to an induction of CD4(+)Foxp3(+) T cells and even more significant induction of ?? T cells in mucosal, but not in non-mucosal lymphoid compartments. This prevention strategy was characterized by an increased proportion of IL-10 and a decreased proportion of IL-2, IL-4 and IFN-?-positive CD4(+)Foxp3(+) T cells, and IFN-?-positive ?? T cells, preferentially in mucosal lymphoid organs. In conclusion, i.n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D. PMID:24728138

Funda, David P; Fundova, Petra; Hansen, Axel Kornerup; Buschard, Karsten

2014-01-01

302

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

303

Type 2 diabetes aggravates Alzheimer's disease-associated vascular alterations of the aorta in mice.  

PubMed

Vascular risk factors are associated with a higher incidence of dementia. In fact, diabetes mellitus is considered a main risk factor for Alzheimer's disease (AD) and both diseases are characterized by vascular dysfunction. However, the underlying mechanisms remain largely unknown. Here, the effects of high-sucrose-induced type 2 diabetes (T2D) in the aorta of wild type (WT) and triple-transgenic AD (3xTg-AD) mice were investigated. 3xTg-AD mice showed a significant decrease in body weight and an increase in postprandial glycemia, glycated hemoglobin (HbA1c), and vascular nitrotyrosine, superoxide anion (O2•-), receptor for the advanced glycation end products (RAGE) protein, and monocyte chemoattractant protein-1 (MCP-1) levels when compared to WT mice. High-sucrose intake caused a significant increase in body weight, postprandial glycemia, HbA1c, triglycerides, plasma vascular cell adhesion molecule 1 (VCAM-1), and vascular nitrotyrosine, O2•-, RAGE, and MCP-1 levels in both WT and 3xTg-AD mice when compared to the respective control group. Also, a significant decrease in nitric oxide-dependent vasorelaxation was observed in 3xTg-AD and sucrose-treated WT mice. In conclusion, AD and T2D promote similar vascular dysfunction of the aorta, this effect being associated with elevated oxidative and nitrosative stress and inflammation. Also, AD-associated vascular alterations are potentiated by T2D. These findings support the idea that metabolic alterations predispose to the onset and progression of dementia. PMID:25471187

Sena, Cristina M; Pereira, Ana M; Carvalho, Cristina; Fernandes, Rosa; Seiça, Raquel M; Oliveira, Catarina R; Moreira, Paula I

2015-01-01

304

Attenuation of atherosclerotic lesions in diabetic apolipoprotein E-deficient mice using gene silencing of macrophage migration inhibitory factor  

PubMed Central

Macrophage migration inhibitory factor (MIF) involves the pathogenesis of atherosclerosis (AS) and increased plasma MIF levels in diabetes mellitus (DM) patients are associated with AS. Here, we have been suggested that MIF could be a critical contributor for the pathological process of diabetes-associated AS by using adenovirus-mediated RNA interference. First, streptozotocin (STZ)-induced diabetic animal model was constructed in 114 apolipoprotein E-deficient mice (apoE?/? mice) fed on a regular chow diet. Then, the animals were randomly divided into three groups: Adenovirus-mediated MIF interference (Ad-MIFi), Ad-enhanced green fluorescent protein (EGFP) and normal saline (NS) group (n ? 33/group). Non-diabetic apoE?/? mice (n = 35) were served as controls. Ad-MIFi, Ad-EGFP and NS were, respectively, injected into the tail vein of mice from Ad-MIFi, Ad-EGFP and NS group, which were injected repeatedly 4 weeks later. Physical, biochemical, morphological and molecular parameters were measured. The results showed that diabetic apoE?/? mice had significantly aggravated atherosclerotic lesions. MIF gene interference attenuated atherosclerotic lesions and stabilized atheromatous plaque, accompanied by the decreased macrophages and lipids deposition and inflammatory cytokines production, improved glucose intolerance and plasma cholesterol level, the decreased ratio of matrix matalloproteinase-2/tissue inhibitor of metalloproteinase-1 and plaque instability index. An increased expression of MIF and its ligand CD74 was also detected in the diabetic patients with coronary artery disease. The results suggest that MIF gene interference is able to inhibit atherosclerotic lesions and increase plaque stability in diabetic apoE?/?mice. MIF inhibition could be a novel and promising approach to the treatment of DM-associated AS. PMID:25661015

Sun, Hui; Zhang, XianJun; Zhao, Lei; Zhen, Xi; Huang, ShanYing; Wang, ShaSha; He, Hong; Liu, ZiMo; Xu, NaNa; Yang, FaLin; Qu, ZhongHua; Ma, ZhiYong; Zhang, Cheng; Zhang, Yun; Hu, Qin

2015-01-01

305

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

306

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

307

Hypoglycemic and hypolipidemic effects of neohesperidin derived from Citrus aurantium L. in diabetic KK-A(y) mice.  

PubMed

The present study is to investigate the possible hypoglycemic and hypolipidemic effects of neohesperidin (NHP) derived from Citrus aurantium L. in vivo. KK-A(y) mice were used as the diabetic experimental model, whereas C57BL/6 mice were used as normal control for a 6-week study. Treatment of NHP significantly decreased fasting glucose, serum glucose, and glycosylated serum protein (GSP) in KK-A(y) mice. It significantly elevated oral glucose tolerance and insulin sensitivity and decreased insulin resistance in the diabetic mice. In addition, NHP significantly decreased serum triglycerides (TG), total cholesterol (TCH), leptin level, and liver index in the KK-A(y) mice. NHP also inhibited lipid accumulation in the liver and decreased the size of epididymal adipocyte in the KK-A(y) mice. Gene expression of stearoyl-CoA desaturase 1 (SCD-1) and fatty acid synthase (FAS) were significantly inhibited, whereas the expression of acyl-CoA oxidase (ACOX) was significantly induced by NHP treatment in the liver of KK-A(y) mice. In addition, elevated level of phosphorylation of hepatic AMPK was observed in NHP-treated mice. Therefore, the activation of the AMPK pathway and regulation of its target genes, including SCD-1, FAS, and ACOX, may play important roles in the hypoglycemic and hypolipidemic effects of NHP in vivo, and NHP may have great potential in the prevention of diabetes and its complications. PMID:25620042

Jia, Sheng; Hu, Ying; Zhang, Wenna; Zhao, Xiaoyong; Chen, Yanhong; Sun, Chongde; Li, Xian; Chen, Kunsong

2015-03-11

308

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

309

Toll-like receptor 3 is critical for coxsackievirus B4-induced type 1 diabetes in female NOD mice.  

PubMed

Group B coxsackieviruses (CVBs) are involved in triggering some cases of type 1 diabetes mellitus (T1DM). However, the molecular mechanism(s) responsible for this remain elusive. Toll-like receptor 3 (TLR3), a receptor that recognizes viral double-stranded RNA, is hypothesized to play a role in virus-induced T1DM, although this hypothesis is yet to be substantiated. The objective of this study was to directly investigate the role of TLR3 in CVB-triggered T1DM in nonobese diabetic (NOD) mice, a mouse model of human T1DM that is widely used to study both spontaneous autoimmune and viral-induced T1DM. As such, we infected female wild-type (TLR3(+/+)) and TLR3 knockout (TLR3(-/-)) NOD mice with CVB4 and compared the incidence of diabetes in CVB4-infected mice with that of uninfected counterparts. We also evaluated the islets of uninfected and CVB4-infected wild-type and TLR3 knockout NOD mice by immunohistochemistry and insulitis scoring. TLR3 knockout mice were markedly protected from CVB4-induced diabetes compared with CVB4-infected wild-type mice. CVB4-induced T-lymphocyte-mediated insulitis was also significantly less severe in TLR3 knockout mice compared with wild-type mice. No differences in insulitis were observed between uninfected animals, either wild-type or TLR3 knockout mice. These data demonstrate for the first time that TLR3 is 1) critical for CVB4-induced T1DM, and 2) modulates CVB4-induced insulitis in genetically prone NOD mice. PMID:25422874

McCall, Kelly D; Thuma, Jean R; Courreges, Maria C; Benencia, Fabian; James, Calvin B L; Malgor, Ramiro; Kantake, Noriko; Mudd, William; Denlinger, Nathan; Nolan, Bret; Wen, Li; Schwartz, Frank L

2015-02-01

310

Food restriction by intermittent fasting induces diabetes and obesity and aggravates spontaneous atherosclerosis development in hypercholesterolaemic mice.  

PubMed

Different regimens of food restriction have been associated with protection against obesity, diabetes and CVD. In the present study, we hypothesised that food restriction would bring benefits to atherosclerosis- and diabetes-prone hypercholesterolaemic LDL-receptor knockout mice. For this purpose, 2-month-old mice were submitted to an intermittent fasting (IF) regimen (fasting every other day) over a 3-month period, which resulted in an overall 20 % reduction in food intake. Contrary to our expectation, epididymal and carcass fat depots and adipocyte size were significantly enlarged by 15, 72 and 68 %, respectively, in the IF mice compared with the ad libitum-fed mice. Accordingly, plasma levels of leptin were 50 % higher in the IF mice than in the ad libitum-fed mice. In addition, the IF mice showed increased plasma levels of total cholesterol (37 %), VLDL-cholesterol (195 %) and LDL-cholesterol (50 %). As expected, in wild-type mice, the IF regimen decreased plasma cholesterol levels and epididymal fat mass. Glucose homeostasis was also disturbed by the IF regimen in LDL-receptor knockout mice. Elevated levels of glycaemia (40 %), insulinaemia (50 %), glucose intolerance and insulin resistance were observed in the IF mice. Systemic inflammatory markers, TNF-? and C-reactive protein, were significantly increased and spontaneous atherosclerosis development were markedly increased (3-fold) in the IF mice. In conclusion, the IF regimen induced obesity and diabetes and worsened the development of spontaneous atherosclerosis in LDL-receptor knockout mice. Although being efficient in a wild-type background, this type of food restriction is not beneficial in the context of genetic hypercholesterolaemia. PMID:24176004

Dorighello, Gabriel G; Rovani, Juliana C; Luhman, Christopher J F; Paim, Bruno A; Raposo, Helena F; Vercesi, Anibal E; Oliveira, Helena C F

2014-03-28

311

Activated protein C inhibits pancreatic islet inflammation, stimulates T regulatory cells, and prevents diabetes in non-obese diabetic (NOD) mice.  

PubMed

Activated protein C (aPC) is a natural anticoagulant with strong cyto-protective and anti-inflammatory properties. aPC inhibits pancreatic inflammation and preserves functional islets after intraportal transplantation in mice. Whether aPC prevents the onset or development of type 1 diabetes (T1D) is unknown. In this study, when human recombinant aPC was delivered intraperitoneally, twice weekly for 10 weeks (from week 6 to 15) to non-obese diabetic (NOD) mice, a model for T1D, the incidence of diabetes was reduced from 70% (saline control) to 7.6% by 26 weeks of age. Islets of aPC-treated mice exhibited markedly increased expression of insulin, aPC/protein C, endothelial protein C receptor, and matrix metalloproteinase (MMP)-2 when examined by immunostaining. The insulitis score in aPC-treated mice was 50% less than that in control mice. T regulatory cells (Tregs) in the spleen, pancreatic islets, and pancreatic lymph nodes were increased 37, 53, and 59%, respectively, in NOD mice following aPC treatment. These Tregs had potent suppressor function and, after adoptive transfer, delayed diabetes onset in NOD.severe combined immunodeficiency mice. The culture of NOD mouse spleen cells with aPC reduced the secretion of inflammatory cytokines interleukin (IL)-1? and interferon-? but increased IL-2 and transforming growth factor-?1, two cytokines required for Treg differentiation. In summary, our results indicate that aPC prevents T1D in the NOD mouse. The aPC mechanism of action is complex, involving induction of Treg differentiation, inhibition of inflammation, and possibly direct cyto-protective effects on ? cells. PMID:22447930

Xue, Meilang; Dervish, Suat; Harrison, Leonard C; Fulcher, Gregory; Jackson, Christopher J

2012-05-11

312

Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: modulation of spontaneous 60-kDa heat shock protein autoimmunity.  

PubMed

Nonobese diabetic (NOD) mice develop insulitis and diabetes through a process involving autoimmunity to the 60-kDa heat shock protein (HSP60). Treatment of NOD mice with HSP60 or with peptides derived from HSP60 inhibits this diabetogenic process. We now report that NOD diabetes can be inhibited by vaccination with a DNA construct encoding human HSP60, with the pcDNA3 empty vector, or with an oligonucleotide containing the CpG motif. Prevention of diabetes was associated with a decrease in the degree of insulitis and with down-regulation of spontaneous proliferative T cell responses to HSP60 and its peptide p277. Moreover, both the pcDNA3 vector and the CpG oligonucleotide induced specific Abs, primarily of the IgG2b isotype, to HSP60 and p277, and not to other islet Ags (glutamic acid decarboxylase or insulin) or to an unrelated recombinant Ag expressed in bacteria (GST). The IgG2b isotype of the specific Abs together with the decrease in T cell proliferative responses indicate a shift of the autoimmune process to a Th2 type in treated mice. These results suggest that immunostimulation by bacterial DNA motifs can modulate spontaneous HSP60 autoimmunity and inhibit NOD diabetes. PMID:11086048

Quintana, F J; Rotem, A; Carmi, P; Cohen, I R

2000-12-01

313

Lotus (Nelumbo nucifera Gaertn) plumule polysaccharide ameliorates pancreatic islets loss and serum lipid profiles in non-obese diabetic mice.  

PubMed

To unravel possible protective effects of a newly isolated lotus plumule polysaccharide (LPPS) on type 1 diabetes (T1D), this study isolated LPPS and administered it to non-obese diabetic (NOD) female mice for 15 weeks. Oral glucose tolerance, serum ketone body, glucose, insulin, and lipid levels, as well as pancreatic islet cell numbers and the insulin secretion ability of the experimental mice were determined. The results showed that LPPS administration in vivo significantly (P<0.05) increased pancreatic islet cell numbers and slightly enhanced the basal insulin secretion ability compared to the control group. LPPS administration improved serum lipid profiles in the diabetic mice via relatively increasing serum high density lipoprotein-cholesterol, but decreasing low density lipoprotein-cholesterol and total cholesterol levels. The present study suggests that LPPS supplementation may ameliorate T1D progress and its complications through protecting pancreatic islets and modulating serum lipid profiles. PMID:23707471

Liao, Chun-Huei; Lin, Jin-Yuarn

2013-08-01

314

Prevention of Type I Diabetes in Nonobese Diabetic Mice by Late Intervention with Nonhypercalcemic Analogs of 1,25-Dihydroxyvitamin D3 in Combination with a Short Induction Course of Cyclosporin A  

Microsoft Academic Search

In nonobese diabetic (NOD) mice, type I diabetes can be prevented without generalized immunosuppression by nonhypercalcemic ana- logs of vitamin D3 when treatment is started early, i.e. before the autoimmune attack, reflected by insulitis, occurs. The aim of this study was to investigate whether these substances can arrest pro- gression to clinically overt diabetes when administered in a more advanced

KRISTINA M. CASTEELS; CHANTAL MATHIEU; MARK WAER; DIRK VALCKX; LUT OVERBERGH; JOS M. LAUREYS; ROGER BOUILLON

1998-01-01

315

Ay allele promotes azoxymethane-induced colorectal carcinogenesis by macrophage migration in hyperlipidemic/diabetic KK mice.  

PubMed

The incidence of colorectal cancer has been increasing and is associated with obesity and diabetes. We have found that type 2 diabetes model KK-Ay/TaJcl (KK-Ay) mice develop tumors within a short period after treatment with azoxymethane (AOM). However, factors that contribute to the promotion of carcinogenesis have not been clarified. Therefore, we looked at the genetic background of KK-Ay, including two genetic characteristics of KK/TaJcl (KK) mice and C57BL/6J-Ham-Ay/+ (Ay) mice, compared with other non-obese and non-diabetic mouse strains C57BL/6J and ICR, and induced colorectal premalignant lesions, aberrant crypt foci (ACF), and tumors using AOM (150 ?g/mouse/week for 4 weeks and 200 ?g/mouse/week for 6 weeks, respectively). The mice with a diabetes feature, KK-Ay and KK, developed significantly more ACF, 67 and 61 per mouse, respectively, whereas ICR, Ay, and C57BL/6J mice developed 42, 24, and 18 ACF/mouse, respectively, at 17 weeks of age. Serum insulin and triglyceride levels in KK-Ay and KK mice were quite high compared with other non-diabetic mouse strains. Interestingly, KK-Ay mice developed more colorectal tumors (2.7 ± 2.3 tumor/mouse) than KK mice (1.2 ± 1.1 tumor/mouse) at 25 weeks of age, in spite of similar diabetic conditions. The colon cancers that developed in both KK-Ay and KK mice showed similar activation of ?-catenin signaling. However, mRNA levels of inflammatory factors related to the activation of macrophages were significantly higher in colorectal cancer of KK-Ay mice than in KK. These data indicate that factors such as insulin resistance and dyslipidemia observed in obese and diabetic patients could be involved in susceptibility to colorectal carcinogenesis. In addition, increase of tumor-associated macrophages may play important roles in the stages of promotion of colorectal cancer. PMID:23551905

Ito, Kumiko; Ishigamori, Rikako; Mutoh, Michihiro; Ohta, Toshihiro; Imai, Toshio; Takahashi, Mami

2013-07-01

316

Supplementary effect by harvest period of Lentinus edodes on the levels of blood glucose and serum lipid in diabetic KK mice  

Technology Transfer Automated Retrieval System (TEKTRAN)

This study was carried out to investigate the effect of Lentinus edodes which were harvested at different times of maturity on blood glucose and lipid levels in diabetic mice. The diabetic KK mice were fed diet supplemented with Lentinus edodes harvested early (LE) or late (LL) for eight weeks, and ...

317

Importance of GAD65 peptides and IA g7 in the development of insulitis in nonobese diabetic mice  

Microsoft Academic Search

Insulin-dependent diabetes mellitus (IDDM) develops in nonobese diabetic (NOD) mice through the destruction of the B cells\\u000a in pancreatic Langerhans islets by islet autoantigen-specific T cells. The islet autoantigen glutamic acid decarboxylase 65\\u000a (GAD65) is thought to be a major target autoantigen in IDDM. In the present report, we established GAD65-specific T-cell clones\\u000a using overlapping peptides that cover the amino

Takeshi Ogino; Keisuke Sato; Naoyuki Miyokawa; Shoji Kimura; Makoto Katagiri

2000-01-01

318

Antihyperglycaemic activity of 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal in diabetic mice  

PubMed Central

Abstract We have recently generated lipophilic D-xylose derivatives that increase the rate of glucose uptake in cultured skeletal muscle cells in an AMP-activated protein kinase (AMPK)-dependent manner. The derivative 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal (EH-36) stimulated the rate of glucose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of cultured myotubes. The present study aimed at investigating potential antihyperglycaemic effects of EH-36 in animal models of diabetes. Two animal models were treated subcutaneously with EH-36: streptozotocin-induced diabetes in C57BL/6 mice (a model of insulin-deficient type 1 diabetes), and spontaneously diabetic KKAy mice (Kuo Kondo rats carrying the Ay yellow obese gene; insulin-resistant type 2 diabetes). The in vivo biodistribution of glucose in control and treated mice was followed with the glucose analogue 2-deoxy-2-[18F]-D-glucose; the rate of glucose uptake in excised soleus muscles was measured with [3H]-2-deoxy-D-glucose. Pharmacokinetic parameters were determined by non-compartmental analysis of the in vivo data. The effective blood EH-36 concentration in treated animals was 2 ?M. It reduced significantly the blood glucose levels in both types of diabetic mice and also corrected the typical compensatory hyperinsulinaemia of KKAy mice. EH-36 markedly increased glucose transport in vivo into skeletal muscle and heart, but not to adipose tissue. This stimulatory effect was mediated by Thr172-phosphorylation in AMPK. Biochemical tests in treated animals and acute toxicological examinations showed that EH-36 was well tolerated and not toxic to the mice. These findings indicate that EH-36 is a promising prototype molecule for the development of novel antidiabetic drugs. PMID:21564514

Gruzman, Arie; Elgart, Anna; Viskind, Olga; Billauer, Hana; Dotan, Sharon; Cohen, Guy; Mishani, Eyal; Hoffman, Amnon; Cerasi, Erol; Sasson, Shlomo

2012-01-01

319

Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade.  

PubMed

The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2±2.3 mmHg vs. 117.1±2.2 mmHg; p?=?0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2±2.5 mmHg and 105.0±3.2 mmHg, respectively, vs. 117.1±2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3±9.6 µg/24 h vs. 170.8±34.2 µg/24 h; p?=?0.002) reaching levels similar to those of non-diabetic controls (34.4±10.6 µg/24 h), whereas the reduction by single treatment with either telmisartan (97.8±26.4 µg/24 h) or riociguat (97.1±15.7 µg/24 h) was not statistically significant. The combination treatment led to a significant (p<0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment. PMID:22900035

Ott, Ina M; Alter, Markus L; von Websky, Karoline; Kretschmer, Axel; Tsuprykov, Oleg; Sharkovska, Yuliya; Krause-Relle, Katharina; Raila, Jens; Henze, Andrea; Stasch, Johannes-Peter; Hocher, Berthold

2012-01-01

320

Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II Receptor Blockade  

PubMed Central

The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2±2.3 mmHg vs. 117.1±2.2 mmHg; p?=?0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2±2.5 mmHg and 105.0±3.2 mmHg, respectively, vs. 117.1±2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3±9.6 µg/24 h vs. 170.8±34.2 µg/24 h; p?=?0.002) reaching levels similar to those of non-diabetic controls (34.4±10.6 µg/24 h), whereas the reduction by single treatment with either telmisartan (97.8±26.4 µg/24 h) or riociguat (97.1±15.7 µg/24 h) was not statistically significant. The combination treatment led to a significant (p<0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment. PMID:22900035

von Websky, Karoline; Kretschmer, Axel; Tsuprykov, Oleg; Sharkovska, Yuliya; Krause-Relle, Katharina; Raila, Jens; Henze, Andrea; Stasch, Johannes-Peter; Hocher, Berthold

2012-01-01

321

Effect of Green Tea Extract/Poly-?-Glutamic Acid Complex in Obese Type 2 Diabetic Mice  

PubMed Central

Background The increasing prevalence of type 2 diabetes mellitus (T2DM) is associated with the rapid spread of obesity. Obesity induces insulin resistance, resulting in ?-cell dysfunction and thus T2DM. Green tea extract (GTE) has been known to prevent obesity and T2DM, but this effect is still being debated. Our previous results suggested that circulating green tea gallated catechins (GCs) hinders postprandial blood glucose lowering, regardless of reducing glucose and cholesterol absorption when GCs are present in the intestinal lumen. This study aimed to compare the effect of GTE with that of GTE coadministered with poly-?-glutamic acid (?-PGA), which is likely to inhibit the intestinal absorption of GCs. Methods The db/db mice and age-matched nondiabetic mice were provided with normal chow diet containing GTE (1%), ?-PGA (0.1%), or GTE+?-PGA (1%:0.1%) for 4 weeks. Results In nondiabetic mice, none of the drugs showed any effects after 4 weeks. In db/db mice, however, weight gain and body fat gain were significantly reduced in the GTE+?-PGA group compared to nondrug-treated db/db control mice without the corresponding changes in food intake and appetite. Glucose intolerance was also ameliorated in the GTE+?-PGA group. Histopathological analyses showed that GTE+?-PGA-treated db/db mice had a significantly reduced incidence of fatty liver and decreased pancreatic islet size. Neither GTE nor ?-PGA treatment showed any significant results. Conclusion These results suggest that GTE+?-PGA treatment than GTE or ?-PGA alone may be a useful tool for preventing both obesity and obesity-induced T2DM. PMID:23807923

Bae, Ki-Cheor; Park, Jae-Hyung; Na, Ann-Yae; Kim, Sun-Joo; Ahn, Shinbyoung; Kim, Sang-Pyo; Oh, Byung-Chul; Cho, Ho-Chan

2013-01-01

322

The H1-receptor antagonist cetirizine ameliorates high-fat diet-induced glucose intolerance in male C57BL/6 mice, but not diabetes outcome in female non-obese diabetic (NOD) mice.  

PubMed

Abstract Background. It has been proposed that the histamine 1-receptor (H1-receptor) not only promotes allergic reactions, but also modulates innate immunity and autoimmune reactions. In line with this, we have recently reported that the H1-receptor antagonist cetirizine partially counteracts cytokine-induced beta-cell signaling and destruction. Therefore, the aim of this study was to determine whether cetirizine affects diabetes in NOD mice, a model for human type 1 diabetes, and glucose intolerance in high-fat diet C57BL/6 mice, a model for human glucose intolerance. Methods. Female NOD mice were treated with cetirizine in the drinking water (25 mg/kg body weight) from 9 until 30 weeks of age during which precipitation of diabetes was followed. Male C57BL/6 mice were given a high-fat diet from 5 weeks of age. When the mice were 12 weeks of age cetirizine was given for 2 weeks in the drinking water. The effects of cetirizine were analyzed by blood glucose determinations, glucose tolerance tests, and insulin sensitivity tests. Results. Cetirizine did not affect diabetes development in NOD mice. On the other hand, cetirizine treatment for 1 week protected against high-fat diet-induced hyperglycemia. The glucose tolerance after 2 weeks of cetirizine treatment was improved in high-fat diet mice. We observed no effect of cetirizine on the insulin sensitivity of high-fat diet mice. Conclusion. Our results suggest a protective effect of cetirizine against high-fat diet-induced beta-cell dysfunction, but not against autoimmune beta-cell destruction. PMID:25291144

Anvari, Ebrahim; Wang, Xuan; Sandler, Stellan; Welsh, Nils

2015-03-01

323

The H1-receptor antagonist cetirizine ameliorates high-fat diet-induced glucose intolerance in male C57BL/6 mice, but not diabetes outcome in female non-obese diabetic (NOD) mice  

PubMed Central

Background It has been proposed that the histamine 1-receptor (H1-receptor) not only promotes allergic reactions, but also modulates innate immunity and autoimmune reactions. In line with this, we have recently reported that the H1-receptor antagonist cetirizine partially counteracts cytokine-induced beta-cell signaling and destruction. Therefore, the aim of this study was to determine whether cetirizine affects diabetes in NOD mice, a model for human type 1 diabetes, and glucose intolerance in high-fat diet C57BL/6 mice, a model for human glucose intolerance. Methods Female NOD mice were treated with cetirizine in the drinking water (25 mg/kg body weight) from 9 until 30 weeks of age during which precipitation of diabetes was followed. Male C57BL/6 mice were given a high-fat diet from 5 weeks of age. When the mice were 12 weeks of age cetirizine was given for 2 weeks in the drinking water. The effects of cetirizine were analyzed by blood glucose determinations, glucose tolerance tests, and insulin sensitivity tests. Results Cetirizine did not affect diabetes development in NOD mice. On the other hand, cetirizine treatment for 1 week protected against high-fat diet-induced hyperglycemia. The glucose tolerance after 2 weeks of cetirizine treatment was improved in high-fat diet mice. We observed no effect of cetirizine on the insulin sensitivity of high-fat diet mice. Conclusion Our results suggest a protective effect of cetirizine against high-fat diet-induced beta-cell dysfunction, but not against autoimmune beta-cell destruction. PMID:25291144

Anvari, Ebrahim; Wang, Xuan; Sandler, Stellan

2015-01-01

324

Effect of Tumor Necrosis Factor o~ on Insulin-dependent Diabetes Mellitus in NOD Mice. I. The Early Development of Autoimmunity and the Diabetogenic Process  

Microsoft Academic Search

Summary Tumor necrosis factor (TNF) ot is a cytokine that has potent immune regulatory functions. To assess the potential role of this cytokine in the early development of autoimmunity, we investigated the effect of TNF on the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice, a spontaneous murine model for autoimmune, insulin-dependent type I diabetes. Treatment of

Xiao-Dong Yang; Roland Tisch; Steven M. Singer; Zhu A. Cao; Roland S. Liblau; Robert D. Schreiber; Hugh O. McDevitt

325

A low carbohydrate, high fiber diet containing a processed maize by-product increases the incidence and advances the onset of diabetes in NOD mice  

Microsoft Academic Search

Type I diabetes is reported to be caused by a combination of genetic predisposition, diet and immune exposure. Small animal models, such as the Non-obese diabetic (NOD) mouse, are often used to test potential therapies that may prevent, delay or cure the disease. This model of Type 1 diabetes may require large numbers of mice to demonstrate the effects of

Robert B Elliott; Nicola J Beckman; Olivia D Andersen; Marija Muzina; Stephen JM Skinner

326

Maternal dietary n-6/n-3 fatty acid ratio affects type 1 diabetes development in the offspring of non-obese diabetic mice.  

PubMed

Environment factors, including maternal or infant dietary nutrition have been reported to have an influence on the pathogenesis of type 1 diabetes. In the present study, to investigate the effect of maternal or post-weaning offspring's nutrition, in particular the essential fatty acid ratio (n-6/n-3) on the development of type 1 diabetes, we prepared two kinds of chows with n-6/n-3 ratios of 3.0 (L) and 14.5 (H), and provided them to mothers of non-obese diabetic (NOD) mice during gestation and lactation and to the offspring after weaning. The n-6/n-3 ratios in breast milk and erythrocyte membrane of NOD offspring became nearly the same with that of the maternal diet at 2 weeks after birth. In the L chow-fed offspring from L chow-fed mother (LLL), levels of insulitis were higher than those in the H chow-fed offspring from H chow-fed mother (HHH) at 4 weeks of age, while the levels in the LLL offspring became lower than those in the HHH after 6 weeks. Early insulin autoantibody expressions were found from 2 to 6 weeks in the HHH offspring, but not in the LLL. The LLL offspring exhibited strong suppression of overt diabetes development in regard to the onset and accumulated incidence of diabetes compared to the HHH. The study with combined L and H chows during gestation, lactation in mother and in post-weaning offspring revealed that only the LLH chow significantly suppressed the development of diabetes with similar kinetics to LLL chow, although the other combinations may delay the onset of diabetes. The present findings suggest that n-6/n-3 ratio of the maternal diet during gestation and lactation rather than that of offspring after weaning strongly affects the development of overt diabetes in NOD mice. PMID:20846138

Kagohashi, Yukiko; Abiru, Norio; Kobayashi, Masakazu; Hashimoto, Michio; Shido, Osamu; Otani, Hiroki

2010-12-01

327

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

328

Oral Administration of the High-Chromium Yeast Improve Blood Plasma Variables and Pancreatic Islet Tissue in Diabetic Mice  

Microsoft Academic Search

The in vivo effects of oral administration of the high-chromium yeast to healthy and diabetic mice are described. Given that\\u000a these complexes are proposed to function by potentiating the actions of insulin and activating the insulin receptor kinase,\\u000a changes in lipid and carbohydrate metabolism would be expected. After 15 weeks administration (500 ?g Cr\\/kg body mass) to\\u000a healthy mice, abnormal metabolism and

Lu Liu; Wen Jin; Jia-ping Lv

2010-01-01

329

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice.  

PubMed

Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, noncompetitive allosteric inhibitors, were used to pharmacologically blockade CXCR1/2. Transient blockade of said receptors was effective in preventing inflammation-mediated damage in MLD-STZ and in preventing and reversing diabetes in NOD mice. Blockade of CXCR1/2 was associated with inhibition of insulitis and modification of leukocytes distribution in blood, spleen, bone marrow, and lymph nodes. Among leukocytes, CXCR2(+) myeloid cells were the most decreased subpopulations. Together these results identify CXCR1/2 chemokine receptors as "master regulators" of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving residual ?-cells holds the potential to make a significant change in the approach to management of human T1D. PMID:25315007

Citro, Antonio; Valle, Andrea; Cantarelli, Elisa; Mercalli, Alessia; Pellegrini, Silvia; Liberati, Daniela; Daffonchio, Luisa; Kastsiuchenka, Olga; Ruffini, Pier Adelchi; Battaglia, Manuela; Allegretti, Marcello; Piemonti, Lorenzo

2015-04-01

330

BBT improves glucose homeostasis by ameliorating ?-cell dysfunction in type 2 diabetic mice.  

PubMed

Impaired glucose-stimulated insulin secretion (GSIS) and increasing ?-cell death are two typical dysfunctions of pancreatic ?-cells in individuals that are destined to develop type 2 diabetes, and improvement of ?-cell function through GSIS enhancement and/or inhibition of ?-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting ?-cells from cytokine- or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca(2) (+) channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on ?-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored ?-cell functions as indicated by the increased plasma insulin level and decrease in the ?-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research. PMID:25572265

Yao, Xin-Gang; Xu, Xin; Wang, Gai-Hong; Lei, Min; Quan, Ling-Ling; Cheng, Yan-Hua; Wan, Ping; Zhou, Jin-Pei; Chen, Jing; Hu, Li-Hong; Shen, Xu

2015-03-01

331

Trim27-deficient mice are susceptible to streptozotocin-induced diabetes?  

PubMed Central

Tumor necrosis factor ? (TNF-?) plays an important role in cell proliferation and apoptosis, and defects in TNF-?-induced apoptosis are associated with various diseases. TRIM27 is a tripartite motif (TRIM) protein containing RING finger, B-box, and coiled-coil domains. We recently reported that TRIM27 positively regulates TNF-?-induced apoptosis through deubiquitination of receptor-interacting protein 1 (RIP1). Multiple studies have suggested a link between TNF-? pathway and various diseases, such as diabetes and colitis. Here, we report that Trim27-deficient mice were susceptible to streptozotocin (STZ)-induced diabetes, a mouse model of diabetes. Infiltration of T cells and cleaved caspase-3 signals were enhanced, and ?-cell mass was decreased in Trim27-deficient islets compared to wild-type islets. On the other hand, Trim27-mutation did not affect the dextran sodium sulphate (DSS)-induced colitis. These data support the idea that the TRIM27 mutation is responsible for the development of certain types of diseases. PMID:24392305

Zaman, Mohammad Mahabub-Uz; Shinagawa, Toshie; Ishii, Shunsuke

2013-01-01

332

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

PubMed

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

2012-07-01

333

Small-Molecule Inhibitors of PKR Improve Glucose Homeostasis in Obese Diabetic Mice  

PubMed Central

Obesity and metabolic diseases appear as clusters, often featuring high risk for insulin resistance and type 2 diabetes, and constitute a major global health problem with limited treatment options. Previous studies have shown that double-stranded RNA–dependent kinase, PKR, plays an important role in the nutrient/pathogen-sensing interface, and acts as a key modulator of chronic metabolic inflammation, insulin sensitivity, and glucose homeostasis in obesity. Recently, pathological PKR activation was also demonstrated in obese humans, strengthening its prospects as a potential drug target. Here, we investigate the use of two structurally distinct small-molecule inhibitors of PKR in the treatment of insulin resistance and type 2 diabetes in cells and in a mouse model of severe obesity and insulin resistance. Inhibition of PKR reduced stress-induced Jun NH2-terminal kinase activation and insulin receptor substrate 1 serine phosphorylation in vitro and in vivo. In addition, treatment with both PKR inhibitors reduced adipose tissue inflammation, improved insulin sensitivity, and improved glucose intolerance in mice after the establishment of obesity and insulin resistance. Our findings suggest that pharmacologically targeting PKR may be an effective therapeutic strategy for the treatment of insulin resistance and type 2 diabetes. PMID:24150608

Nakamura, Takahisa; Arduini, Alessandro; Baccaro, Brenna; Furuhashi, Masato; Hotamisligil, Gökhan S.

2014-01-01

334

CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice  

PubMed Central

Background & Aims Gastroparesis is a well-recognized complication of diabetes. In diabetics, up-regulation of heme oxygenase-1 (HO1) in gastric macrophages protects against oxidative stress-induced damage. Loss of up-regulation of HO1, the subsequent increase in oxidative stress, and loss of Kit delays gastric emptying; this effect is reversed by induction of HO1. Macrophages have pro- and anti-inflammatory activities, depending on their phenotype. We investigated the number and phenotype of gastric macrophages in NOD/ShiLtJ (NOD) mice after onset of diabetes, when delayed gastric emptying develops, and after induction of HO1 to reverse delay. Methods Four groups of NOD and db/db mice were studied: non-diabetic, diabetic with normal emptying, diabetic with delayed gastric emptying, and diabetic with delayed gastric emptying reversed by the HO1 inducer hemin. Whole-mount samples from stomach were labeled in triplicate with antisera against F4/80, HO1, and CD206 and macrophages were quantified in stacked confocal images. Markers for macrophage subtypes were measured by quantitative PCR. Results Development of diabetes was associated with an increased number of macrophages and up-regulation of HO1 in CD206+ M2 macrophages. Onset of delayed gastric emptying did not alter the total number of macrophages, but there was a selective loss of CD206+/HO1+ M2 macrophages. Normalization of gastric emptying was associated with re-population of CD206+/HO1+ M2 macrophages. Conclusion CD206+ M2-macrophages that express HO1 appear to be required for prevention of diabetes-induced delayed gastric emptying. Induction of HO1 in macrophages might be a therapeutic option for patients with diabetic gastroparesis. PMID:20178793

Choi, Kyoung Moo; Kashyap, Purna C.; Dutta, Nirjhar; Stoltz, Gary J.; Ordog, Tamas; Donohue, Terez Shea; Bauer, Anthony J.; Linden, David R.; Szurszewski, Joseph H.; Gibbons, Simon J.; Farrugia, Gianrico

2010-01-01

335

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

336

Quantitative proteomic and functional analysis of liver mitochondria from high fat diet (HFD) diabetic mice.  

PubMed

Insulin resistance plays a major role in the development of type 2 diabetes and obesity and affects a number of biological processes such as mitochondrial biogenesis. Though mitochondrial dysfunction has been linked to the development of insulin resistance and pathogenesis of type 2 diabetes, the precise mechanism linking the two is not well understood. We used high fat diet (HFD)-induced obesity dependent diabetes mouse models to gain insight into the potential pathways altered with metabolic disease, and carried out quantitative proteomic analysis of liver mitochondria. As previously reported, proteins involved in fatty acid oxidation, branched chain amino acid degradation, tricarboxylic acid cycle, and oxidative phosphorylation were uniformly up-regulated in the liver of HFD fed mice compared with that of normal diet. Further, our studies revealed that retinol metabolism is distinctly down-regulated and the mitochondrial structural proteins-components of mitochondrial inter-membrane space bridging (MIB) complex (Mitofilin, Sam50, and ChChd3), and Tim proteins-essential for protein import, are significantly up-regulated in HFD fed mice. Structural and functional studies on HFD and normal diet liver mitochondria revealed remodeling of HFD mitochondria to a more condensed form with increased respiratory capacity and higher ATP levels compared with normal diet mitochondria. Thus, it is likely that the structural remodeling is essential to accommodate the increased protein content in presence of HFD: the mechanism could be through the MIB complex promoting contact site and crista junction formation and in turn facilitating the lipid and protein uptake. PMID:24030101

Guo, Yurong; Darshi, Manjula; Ma, Yuliang; Perkins, Guy A; Shen, Zhouxin; Haushalter, Kristofer J; Saito, Rintaro; Chen, Ai; Lee, Yun Sok; Patel, Hemal H; Briggs, Steven P; Ellisman, Mark H; Olefsky, Jerrold M; Taylor, Susan S

2013-12-01

337

Lentivectors encoding immunosuppressive proteins genetically engineer pancreatic beta-cells to correct diabetes in allogeneic mice.  

PubMed

The effectiveness of genetic engineering with lentivectors to protect transplanted cells from allogeneic rejection was examined using, as a model, type 1 diabetes treatment with beta-cell transplantation, whose widespread use has been limited by the requirement for sustained immunosuppressive treatment to prevent graft rejection. We examined whether lentivectors expressing select immunosuppressive proteins encoded by the adenoviral genome early region 3 (AdE3) would protect transplanted beta-cells from an alloimmune attack. The insulin-producing beta-cell line beta TC-tet (C3HeB/FeJ-derived) was transduced with lentiviruses encoding the AdE3 proteins gp19K and RID alpha/beta. The efficiency of lentiviral transduction of beta TC-tet cells exceeded 85%. Lentivector expression of gp19K decreased surface class I major histocompatibility complex expression by over 90%, whereas RID alpha/beta expression inhibited cytokine-induced Fas upregulation by over 75%. beta TC-tet cells transduced with gp19K and RID alpha/beta lentivectors, but not with a control lentivector, provided prolonged correction of hyperglycemia after transplantation into diabetic BALB/c severe combined immunodeficient mice reconstituted with allogeneic immune effector cells or into diabetic allogeneic BALB/c mice. Thus, genetic engineering of beta-cells using gp19K- and RID alpha/beta-expressing lentiviral vectors may provide an alternative that has the potential to eliminate or reduce treatment with the potent immunosuppressive agents necessary at present for prolonged engraftment with transplanted islets. PMID:19112449

Kojaoghlanian, T; Joseph, A; Follenzi, A; Zheng, J H; Leiser, M; Fleischer, N; Horwitz, M S; DiLorenzo, T P; Goldstein, H

2009-03-01

338

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

339

Differential Proteomic Analysis of the Pancreas of Diabetic db/db Mice Reveals the Proteins Involved in the Development of Complications of Diabetes Mellitus  

PubMed Central

Type 2 diabetes mellitus is characterized by hyperglycemia and insulin-resistance. Diabetes results from pancreatic inability to secrete the insulin needed to overcome this resistance. We analyzed the protein profile from the pancreas of ten-week old diabetic db/db and wild type mice through proteomics. Pancreatic proteins were separated in two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and significant changes in db/db mice respect to wild type mice were observed in 27 proteins. Twenty five proteins were identified by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) and their interactions were analyzed using search tool for the retrieval of interacting genes/proteins (STRING) and database for annotation, visualization and integrated discovery (DAVID). Some of these proteins were Pancreatic ?-amylase, Cytochrome b5, Lithostathine-1, Lithostathine-2, Chymotrypsinogen B, Peroxiredoxin-4, Aspartyl aminopeptidase, Endoplasmin, and others, which are involved in the metabolism of carbohydrates and proteins, as well as in oxidative stress, and inflammation. Remarkably, these are mostly endoplasmic reticulum proteins related to peptidase activity, i.e., they are involved in proteolysis, glucose catabolism and in the tumor necrosis factor-mediated signaling pathway. These results suggest mechanisms for insulin resistance, and the chronic inflammatory state observed in diabetes. PMID:24886809

Pérez-Vázquez, Victoriano; Guzmán-Flores, Juan M.; Mares-Álvarez, Daniela; Hernández-Ortiz, Magdalena; Macías-Cervantes, Maciste H.; Ramírez-Emiliano, Joel; Encarnación-Guevara, Sergio

2014-01-01

340

Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice  

PubMed Central

Poly(ADP-ribose) polymerase (PARP) activation has been implicated in the pathogenesis of diabetic complications, including nephropathy and peripheral neuropathy. This study aimed at evaluating the manifestations of both complications in diabetic Akita mice, a model of Type 1 (insulin-dependent) diabetes, and their amenability to treatment with the potent PARP inhibitor, 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427). Male non-diabetic C57Bl6/J and diabetic C57Bl/6-Ins2Akita/J (Akita) mice were maintained with or without treatment with GPI-15427, 30 mg/kg/day, for 4 weeks starting from 16 weeks of age. Sixteen week-old Akita mice displayed sensory nerve conduction velocity (SNCV) deficit, whereas the motor nerve conduction velocity (MNCV) tended to decrease, but the difference with controls did not achieve statistical significance. They also developed thermal and mechanical hypoalgesia and tactile allodynia. SNCV deficit, mechanical hypoalgesia, and tactile allodynia progressed with age whereas the severity of thermal hypoalgesia was similar in 16- and 20-week-old Akita mice. PARP inhibition alleviated, although it did not completely reverse, SNCV deficit, thermal and mechanical hypoalgesia and tactile allodynia. Sixteen-week-old Akita mice displayed MNCV deficit (41.3±2.5 vs. 51.0±1.2 m/sec in non-diabetic controls, P<0.01), axonal atrophy of myelinated fibers, kidney hypertrophy, and albuminuria. MNCV slowing, axonal atrophy, and kidney hypertrophy, but not albuminuria, were less severe inGPI-15427-treated age-matched Akitamice. Neuroprotective and nephroprotective effects of PARP inhibition were not due to alleviation of diabetic hyperglycemia, or peripheral nerve p38 mitogen-activated protein kinase activation. GPI-15427 did not affect any variables in control mice. In conclusion, the findings support an important role for PARP activation in diabetic peripheral neuropathy and kidney hypertrophy associated with Type 1 diabetes, and provide rationale for development and further studies of PARP inhibitors, for the prevention and treatment of these complications. PMID:21617845

DREL, VIKTOR R.; PACHER, PAL; STAVNIICHUK, ROMAN; XU, WEIZHENG; ZHANG, JIE; KUCHMEROVSKA, TAMARA M.; SLUSHER, BARBARA; OBROSOVA, IRINA G.

2012-01-01

341

Genetic disassociation of autoimmunity and resistance to costimulation blockade-induced transplantation tolerance in nonobese diabetic mice.  

PubMed

Curing type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD x C57BL/6)F(1) mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F(1) mice shared the dendritic cell maturation defects and abnormal CD4(+) T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects. PMID:12816997

Pearson, Todd; Markees, Thomas G; Serreze, David V; Pierce, Melissa A; Marron, Michele P; Wicker, Linda S; Peterson, Laurence B; Shultz, Leonard D; Mordes, John P; Rossini, Aldo A; Greiner, Dale L

2003-07-01

342

The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice.  

PubMed

In recent years, new and effective therapeutic agents for blood glucose control have been added to standard diabetes therapies: dipeptidyl peptidase-4 (DPP-4) inhibitors, which prolong the bioavailability of the endogenously secreted incretin hormone glucagon-like peptide-1 (GLP-1). Full-thickness excisional wounding was performed in wild-type (C57BL/6J) and diabetic [C57BL/6J-obese/obese (ob/ob)] mice. DPP-4 activity was inhibited by oral administration of linagliptin during healing. Wound tissue was analyzed by using histological, molecular, and biochemical techniques. In healthy mice, DPP-4 was constitutively expressed in the keratinocytes of nonwounded skin. After skin injury, DPP-4 expression declined and was lowest during the most active phase of tissue reassembly. In contrast, in ob/ob mice, we observed increasing levels of DPP-4 at late time points, when delayed tissue repair still occurs. Oral administration of the DPP-4 inhibitor linagliptin strongly reduced DPP-4 activity, stabilized active GLP-1 in chronic wounds, and improved healing in ob/ob mice. At day 10 postwounding, linagliptin-treated ob/ob mice showed largely epithelialized wounds characterized by the absence of neutrophils. In addition, DPP-4 inhibition reduced the expression of the proinflammatory markers cyclooxygenase-2 and macrophage inflammatory protein-2, but enhanced the formation of myofibroblasts in healing wounds from ob/ob mice. Our data suggest a potentially beneficial role of DPP-4 inhibition in diabetes-affected wound healing. PMID:22493041

Schürmann, Christoph; Linke, Andreas; Engelmann-Pilger, Kerstin; Steinmetz, Cornelia; Mark, Michael; Pfeilschifter, Josef; Klein, Thomas; Frank, Stefan

2012-07-01

343

Chronic Ingestion of Advanced Glycation End Products Induces Degenerative Spinal Changes and Hypertrophy in Aging Pre-Diabetic Mice  

PubMed Central

Intervertebral disc (IVD) degeneration and pathological spinal changes are major causes of back pain, which is the top cause of global disability. Obese and diabetic individuals are at increased risk for back pain and musculoskeletal complications. Modern diets contain high levels of advanced glycation end products (AGEs), cyto-toxic components which are known contributors to obesity, diabetes and accelerated aging pathologies. There is little information about potential effects of AGE rich diet on spinal pathology, which may be a contributing cause for back pain which is common in obese and diabetic individuals. This study investigated the role of specific AGE precursors (e.g. methylglyoxal-derivatives (MG)) on IVD and vertebral pathologies in aging C57BL6 mice that were fed isocaloric diets with standard (dMG+) or reduced amounts of MG derivatives (dMG-; containing 60-70% less dMG). dMG+ mice exhibited a pre-diabetic phenotype, as they were insulin resistant but not hyperglycemic. Vertebrae of dMG+ mice displayed increased cortical-thickness and cortical-area, greater MG-AGE accumulation and ectopic calcification in vertebral endplates. IVD morphology of dMG+ mice exhibited ectopic calcification, hypertrophic differentiation and glycosaminoglycan loss relative to dMG- mice. Overall, chronic exposure to dietary AGEs promoted age-accelerated IVD degeneration and vertebral alterations involving ectopic calcification which occurred in parallel with insulin resistance, and which were prevented with dMG- diet. This study described a new mouse model for diet-induced spinal degeneration, and results were in support of the hypothesis that chronic AGE ingestion could be a factor contributing to a pre-diabetic state, ectopic calcifications in spinal tissues, and musculoskeletal complications that are more generally known to occur with chronic diabetic conditions. PMID:25668621

Illien-Jünger, Svenja; Lu, Young; Qureshi, Sheeraz A.; Hecht, Andrew C.; Cai, Weijing; Vlassara, Helen; Striker, Gary E.; Iatridis, James C.

2015-01-01

344

Chronic ingestion of advanced glycation end products induces degenerative spinal changes and hypertrophy in aging pre-diabetic mice.  

PubMed

Intervertebral disc (IVD) degeneration and pathological spinal changes are major causes of back pain, which is the top cause of global disability. Obese and diabetic individuals are at increased risk for back pain and musculoskeletal complications. Modern diets contain high levels of advanced glycation end products (AGEs), cyto-toxic components which are known contributors to obesity, diabetes and accelerated aging pathologies. There is little information about potential effects of AGE rich diet on spinal pathology, which may be a contributing cause for back pain which is common in obese and diabetic individuals. This study investigated the role of specific AGE precursors (e.g. methylglyoxal-derivatives (MG)) on IVD and vertebral pathologies in aging C57BL6 mice that were fed isocaloric diets with standard (dMG+) or reduced amounts of MG derivatives (dMG-; containing 60-70% less dMG). dMG+ mice exhibited a pre-diabetic phenotype, as they were insulin resistant but not hyperglycemic. Vertebrae of dMG+ mice displayed increased cortical-thickness and cortical-area, greater MG-AGE accumulation and ectopic calcification in vertebral endplates. IVD morphology of dMG+ mice exhibited ectopic calcification, hypertrophic differentiation and glycosaminoglycan loss relative to dMG- mice. Overall, chronic exposure to dietary AGEs promoted age-accelerated IVD degeneration and vertebral alterations involving ectopic calcification which occurred in parallel with insulin resistance, and which were prevented with dMG- diet. This study described a new mouse model for diet-induced spinal degeneration, and results were in support of the hypothesis that chronic AGE ingestion could be a factor contributing to a pre-diabetic state, ectopic calcifications in spinal tissues, and musculoskeletal complications that are more generally known to occur with chronic diabetic conditions. PMID:25668621

Illien-Jünger, Svenja; Lu, Young; Qureshi, Sheeraz A; Hecht, Andrew C; Cai, Weijing; Vlassara, Helen; Striker, Gary E; Iatridis, James C

2015-01-01

345

Hypoglycemic effect of catalpol on high-fat diet/streptozotocin-induced diabetic mice by increasing skeletal muscle mitochondrial biogenesis.  

PubMed

Catalpol, an iridoid glycoside, exists in the root of Radix Rehmanniae. Some studies have shown that catalpol has a remarkable hypoglycemic effect in the streptozotocin-induced diabetic model, but the underlying mechanism for this effect has not been fully elucidated. Because mitochondrial dysfunction plays a vital role in the pathology of diabetes and because improving mitochondrial function may offer a new approach for the treatment of diabetes, this study was designed. Catalpol was orally administered together with metformin to high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice daily for 4 weeks. Body weight (BW), fasting blood glucose (FBG) level, and glucose disposal (IPGTT) were measured during or after the treatment. The results showed a dose-dependent reduction of FBG level with no apparent changes in BW through four successive weeks of catalpol administration. Catalpol treatment substantially reduced serum total cholesterol and triglyceride levels in the diabetic mice. In addition, catalpol efficiently increased mitochondrial ATP production and reversed the decrease of mitochondrial membrane potential and mtDNA copy number in skeletal muscle tissue. Furthermore, catalpol (200 mg/kg) rescued mitochondrial ultrastructure in skeletal muscle, as detected with transmission electron microscopy. The relative mRNA level of peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) ? was significantly decreased in muscle tissue of diabetic mice, while this effect was reversed by catalpol, resulting in a dose-dependent up-regulation. Taken together, we found that catalpol was capable of lowering FBG level via improving mitochondrial function in skeletal muscle of HFD/STZ-induced diabetic mice. PMID:25178463

Li, Xia; Xu, Zhimeng; Jiang, Zhenzhou; Sun, Lixin; Ji, Jinzi; Miao, Jingshan; Zhang, Xueji; Li, Xiaojie; Huang, Shan; Wang, Tao; Zhang, Luyong

2014-09-01

346

Anti-diabetic effect of purple corn extract on C57BL/KsJ db/db mice  

PubMed Central

BACKGROUND/OBJECTIVES Recently, anthocyanins have been reported to have various biological activities. Furthermore, anthocyanin-rich purple corn extract (PCE) ameliorated insulin resistance and reduced diabetes-associated mesanginal fibrosis and inflammation, suggesting that it may have benefits for the prevention of diabetes and diabetes complications. In this study, we determined the anthocyanins and non-anthocyanin component of PCE by HPLC-ESI-MS and investigated its anti-diabetic activity and mechanisms using C57BL/KsJ db/db mice. MATERIALS/METHODS The db/db mice were divided into four groups: diabetic control group (DC), 10 or 50 mg/kg PCE (PCE 10 or PCE 50), or 10 mg/kg pinitol (pinitol 10) and treated with drugs once per day for 8 weeks. During the experiment, body weight and blood glucose levels were measured every week. At the end of treatment, we measured several diabetic parameters. RESULTS Compared to the DC group, Fasting blood glucose levels were 68% lower in PCE 50 group and 51% lower in the pinitol 10 group. Furthermore, the PCE 50 group showed 2- fold increased C-peptide and adiponectin levels and 20% decreased HbA1c levels, than in the DC group. In pancreatic islets morphology, the PCE- or pinitol-treated mice showed significant prevention of pancreatic ?-cell damage and higher insulin content. Microarray analyses results indicating that gene and protein expressions associated with glycolysis and fatty acid metabolism in liver and fat tissues. In addition, purple corn extract increased the phosphorylation of AMP-activated protein kinase (AMPK) and decreased phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6pase) genes in liver, and also increased glucose transporter 4 (GLUT4) expressions in skeletal muscle. CONCLUSIONS Our results suggested that PCE exerted anti-diabetic effects through protection of pancreatic ?-cells, increase of insulin secretion and AMPK activation in the liver of C57BL/KsJ db/db mice. PMID:25671064

Huang, Bo; Wang, Zhiqiang; Park, Jong Hyuk; Ryu, Ok Hyun; Choi, Moon Ki; Lee, Jae-Yong; Kang, Young-Hee

2015-01-01

347

Wound Healing in Mice with High-Fat Diet- or ob Gene-Induced Diabetes-Obesity Syndromes: A Comparative Study  

PubMed Central

In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes-impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NF?B (I?B-?) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders. PMID:21318183

Seitz, Oliver; Schürmann, Christoph; Hermes, Nadine; Müller, Elke; Pfeilschifter, Josef; Frank, Stefan; Goren, Itamar

2010-01-01

348

Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice  

SciTech Connect

AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK ? subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. - Highlights: • C24 activates AMPK through antagonizing autoinhibition within ? subunit. • C24 activates AMPK in hepatocytes and decreases glucose output via AMPK. • C24 exerts beneficial effects on diabetic db/db mice. • C24 represents a novel therapeutic for treatment of metabolic syndrome.

Li, Yuan-Yuan; Yu, Li-Fang; Zhang, Li-Na; Qiu, Bei-Ying; Su, Ming-Bo; Wu, Fang; Chen, Da-Kai; Pang, Tao; Gu, Min; Zhang, Wei; Ma, Wei-Ping; Jiang, Hao-Wen; Li, Jing-Ya, E-mail: jyli@mail.shcnc.ac.cn; Nan, Fa-Jun, E-mail: fjnan@mail.shcnc.ac.cn; Li, Jia, E-mail: jli@mail.shcnc.ac.cn

2013-12-01

349

Differential IL-21 signaling in APCs leads to disparate Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice  

PubMed Central

Type 1 diabetes (T1D) is an autoimmune disease that shows familial aggregation in humans and likely has genetic determinants. Disease linkage studies have revealed many susceptibility loci for T1D in mice and humans. The mouse T1D susceptibility locus insulin-dependent diabetes susceptibility 3 (Idd3), which has a homologous genetic interval in humans, encodes cytokine genes Il2 and Il21 and regulates diabetes and other autoimmune diseases; however, the cellular and molecular mechanisms of this regulation are still being elucidated. Here we show that T cells from NOD mice produce more Il21 and less Il2 and exhibit enhanced Th17 cell generation compared with T cells from NOD.Idd3 congenic mice, which carry the protective Idd3 allele from a diabetes-resistant mouse strain. Further, APCs from NOD and NOD.Idd3 mice played a central role in this differential Th17 cell development, and IL-21 signaling in APCs was pivotal to this process. Specifically, NOD-derived APCs showed increased production of pro-Th17 mediators and dysregulation of the retinoic acid (RA) signaling pathway compared with APCs from NOD.Idd3 and NOD.Il21r-deficient mice. These data suggest that the protective effect of the Idd3 locus is due, in part, to differential RA signaling in APCs and that IL-21 likely plays a role in this process. Thus, we believe APCs provide a new candidate for therapeutic intervention in autoimmune diseases. PMID:22019586

Liu, Sue M.; Lee, David H.; Sullivan, Jenna M.; Chung, Denise; Jäger, Anneli; Shum, Bennett O.V.; Sarvetnick, Nora E.; Anderson, Ana C.; Kuchroo, Vijay K.

2011-01-01

350

Streptozotocin-induced diabetes partially attenuates the effects of a high-fat diet on liver and brain fatty acid composition in mice.  

PubMed

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 % kcal from fat) or high-fat (54 % kcal 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 partially attenuated by concomitant hyperglycemia with hypoinsulinemia. PMID:23893338

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

2013-09-01

351

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

352

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin.  

PubMed

This study tested the hypothesis that in diabetic arteries, cyclooxygenase (COX)-1 mediates endothelial prostacyclin (PGI2) synthesis, which evokes vasoconstrictor activity under the pathological condition. Non-insulin-dependent diabetes was induced to C57BL/6 mice and those with COX-1 deficiency (COX-1(-/-) mice) using a high-fat diet in combination with streptozotocin injection. In vitro analyses were performed 3 mo after. Results showed that in diabetic aortas, the endothelial muscarinic receptor agonist ACh evoked an endothelium-dependent production of the PGI2 metabolite 6-keto-PGF1?, which was abolished in COX-1(-/-) mice. Meanwhile, COX-1 deficiency or COX-1 inhibition prevented vasoconstrictor activity in diabetic abdominal aortas, resulting in enhanced relaxation evoked by ACh. In a similar manner, COX-1 deficiency increased the relaxation evoked by ACh in nitric oxide synthase-inhibited diabetic renal arteries. Also, in diabetic abdominal aortas and/or renal arteries, both PGI2 and the COX substrate arachidonic acid evoked contractions similar to those of nondiabetic mice. However, the contraction to arachidonic acid, but not that to PGI2, was abolished in vessels from COX-1(-/-) mice. Moreover, we found that 3 mo after streptozotocin injection, systemic blood pressure increased in diabetic C57BL/6 mice but not in diabetic COX-1(-/-) mice. These results explicitly demonstrate that in the given arteries from non-insulin-dependent diabetic mice, COX-1 remains a major contributor to the endothelial PGI2 synthesis that evokes vasoconstrictor activity under the pathological condition. Also, our data suggest that COX-1 deficiency prevents or attenuates diabetic hypertension in mice, although this could be related to the loss of COX-1-mediated activities derived from both vascular and nonvascular tissues. PMID:24878773

Zhu, Ningxia; Liu, Bin; Luo, Wenhong; Zhang, Yingzhan; Li, Hui; Li, Shasha; Zhou, Yingbi

2014-08-01

353

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

354

The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice.  

PubMed

Mucormycosis is a fungal infection of the sinuses, brain, or lungs that causes a mortality rate of at least 50% despite first-line therapy. Because angioinvasion is a hallmark of mucormycosis infections, we sought to define the endothelial cell receptor(s) for fungi of the order Mucorales (the fungi that cause mucormycosis). Furthermore, since patients with elevated available serum iron, including those with diabetic ketoacidosis (DKA), are uniquely susceptible to mucormycosis, we sought to define the role of iron and glucose in regulating the expression of such a receptor. Here, we have identified glucose-regulated protein 78 (GRP78) as what we believe to be a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae, the most common etiologic species of Mucorales, but not Candida albicans or Aspergillus fumigatus. Elevated concentrations of glucose and iron, consistent with those seen during DKA, enhanced GRP78 expression and the resulting R. oryzae invasion and damage of endothelial cells in a receptor-dependent manner. Mice with DKA, which have enhanced susceptibility to mucormycosis, exhibited increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. Finally, GRP78-specific immune serum protected mice with DKA from mucormycosis. These results suggest a