http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Tue, 18 Jun 2013 16:36:24 +0000 http://www.hindawi.com/journals/jdr/2013/716219/ Brahma-related gene 1 (Brg1) is a key gene in inducing the expression of important endogenous antioxidant enzymes, including heme oxygenase-1 (HO-1) which is central to cardioprotection, while cardiac HO-1 expression is reduced in diabetes. It is unknown whether or not cardiac Brg1 expression is reduced in diabetes. We hypothesize that cardiac Brg1 expression is reduced in diabetes which can be restored by antioxidant treatment with N-acetylcysteine (NAC). Control (C) and streptozotocin-induced diabetic (D) rats were treated with NAC in drinking water or placebo for 4 weeks. Plasma and cardiac free15-F2t-isoprostane in diabetic rats were increased, accompanied with increased plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), while cardiac Brg1, p-STAT3 and HO-1 protein expression levels were significantly decreased. Left ventricle weight/body weight ratio was higher, while the peak velocities of early (E) and late (A) flow ratio was lower in diabetic than in C rats. NAC normalized tissue and plasma levels of 15-F2t-isoprostane, significantly increased cardiac Brg1, HO-1 and p-STAT3 protein expression levels and reduced TNF-alpha and IL-6, resulting in improved cardiac function. In conclusion, myocardial Brg1 is reduced in diabetes and enhancement of cardiac Brg1 expression may represent a novel mechanism whereby NAC confers cardioprotection. Jinjin Xu, Shaoqing Lei, Yanan Liu, Xia Gao, Michael G. Irwin, Zhong-yuan Xia, Ziqing Hei, Xiaoliang Gan, Tingting Wang, and Zhengyuan Xia Copyright © 2013 Jinjin Xu et al. All rights reserved. Tue, 18 Jun 2013 14:36:29 +0000 http://www.hindawi.com/journals/jdr/2013/590456/ The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, since these drugs not only improve glycemia with minimal risk of hypoglycemia, but also have other extraglycemic beneficial effects. These agents, which are effective in improving glucose control, could also have positive effects on the incidence of cardiovascular events. The aim of this review is to summarize the present literature about the role of dipeptidyl peptidase 4 (DPP4) in cardiovascular districts, not only strictly correlated to its effect on glucagon-like peptide-1 (GLP-1) circulating levels, but also to what is known about possible cardiovascular actions. Actually, DPP4 is known to be present in many cells and tissues and its effects go beyond purely metabolic aspects. Almost always the inhibition of DPP4 activity is associated with improved cardiovascular profile, but it has shown to possess antithrombotic properties and these different effects could be connected with a site and/or species specificity of DPP4. Certainly, DPP4 seems to exert many functions, both directly and indirectly, on cardiovascular districts, opening new possibilities of prevention and treatment of complications at this level, not only in patients affected by diabetes mellitus. L. Pala and C. M. Rotella Copyright © 2013 L. Pala and C. M. Rotella. All rights reserved. Mon, 17 Jun 2013 13:22:12 +0000 http://www.hindawi.com/journals/jdr/2013/290671/ D. R. Webb, K. Herbert, Melanie J. Davies, K. Khunti, N. Sattar, and C. D. A. Stehouwer Copyright © 2013 D. R. Webb et al. All rights reserved. Mon, 17 Jun 2013 09:04:22 +0000 http://www.hindawi.com/journals/jdr/2013/689841/ Researchers have proposed that amyloid precursor protein 17 peptide (APP17 peptide), an active fragment of amyloid precursor protein (APP) in the nervous system, has therapeutic effects on neurodegeneration. Diabetic encephalopathy (DE) is a neurological disease caused by diabetes. Here we use multiple experimental approaches to investigate the effect of APP17 peptide on changes in learning behavior and glycol metabolism in rats. It was found that rats with DE treated by APP17 peptide showed reversed behavioral alternation. The [18F]-FDG-PET images and other results all showed that the APP17 peptide could promote glucose metabolism in the brain of the DE rat model. Meanwhile, the insulin signaling was markedly increased as shown by increased phosphorylation of Akt and enhanced GLUT4 activation. Compared with the DE group, the activities of SOD, GSH-Px, and CAT in the rat hippocampal gyrus were increased, while MDA decreased markedly in the DE + APP17 peptide group. No amyloid plaques in the cortex and the hippocampus were detected in either group, indicating that the experimental animals in the current study were not suffering from Alzheimer’s disease. These results indicate that APP17 peptide could be used to treat DE effectively. Heng Meng, Duo Zhang, and Haishan Yang Copyright © 2013 Heng Meng et al. All rights reserved. Thu, 13 Jun 2013 15:27:14 +0000 http://www.hindawi.com/journals/jdr/2013/797548/ Diabetic nephropathy (DN) is one of the microvascular complications of both type 1 and type 2 diabetes, which is also associated with a poor life expectancy of diabetic patients. However, the pathogenesis of DN is still unclear. Thus, it is of great use to establish appropriate animal models of DN for doing research on pathogenesis and developing novel therapeutic strategies. Although a large number of murine models of DN including artificially induced, spontaneous, and genetically engineered (knockout and transgenic) animal models have been developed, none of them develops renal changes sufficiently reflecting those seen in humans. Here we review the identified murine models of DN from the aspects of genetic background, type of diabetes, method of induction, gene deficiency, animal age and gender, kidney histopathology, and phenotypic alterations in the hope of enhancing our comprehension of genetic susceptibility and molecular mechanisms responsible for this disease and providing new clues as to how to choose appropriate animal models of DN. Li-li Kong, Hao Wu, Wen-peng Cui, Wen-hua Zhou, Ping Luo, Jing Sun, Hang Yuan, and Li-ning Miao Copyright © 2013 Li-li Kong et al. All rights reserved. Thu, 13 Jun 2013 09:11:08 +0000 http://www.hindawi.com/journals/jdr/2013/761415/ Animal models of atherosclerosis have proven to be an invaluable asset in understanding the pathogenesis of the disease. However, large animal models may be needed in order to assess novel therapeutic approaches to the treatment of atherosclerosis. Porcine models of coronary and peripheral atherosclerosis offer several advantages over rodent models, including similar anatomical size to humans, as well as genetic expression and development of high-risk atherosclerotic lesions which are similar to humans. Here we review the four models of porcine atherosclerosis, including the diabetic/hypercholesterolemic model, Rapacz-familial hypercholesterolemia pig, the (PCSK9) gain-of-function mutant pig model, and the Ossabaw miniature pig model of metabolic syndrome. All four models reliably represent features of human vascular disease. Damir Hamamdzic and Robert L. Wilensky Copyright © 2013 Damir Hamamdzic and Robert L. Wilensky. All rights reserved. Wed, 12 Jun 2013 13:35:14 +0000 http://www.hindawi.com/journals/jdr/2013/589451/ Type 1 Diabetes (T1D) is considered to be a T-helper- (Th-) 1 autoimmune disease; however, T1D pathogenesis likely involves many factors, and sufficient tools for autoreactive T cell detection for the study of this disease are currently lacking. In this study, using gene expression microarrays, we analysed the effect of diabetes-associated autoantigens on peripheral blood mononuclear cells (PBMCs) with the purpose of identifying (pre)diabetes-associated cell processes. Twelve patients with recent onset T1D, 18 first-degree relatives of the TD1 patients (DRL; 9/18 autoantibody positive), and 13 healthy controls (DV) were tested. PBMCs from these individuals were stimulated with a cocktail of diabetes-associated autoantigens (proinsulin, IA-2, and GAD65-derived peptides). After 72 hours, gene expression was evaluated by high-density gene microarray. The greatest number of functional differences was observed between relatives and controls (69 pathways), from which 15% of the pathways belonged to “immune response-related” processes. In the T1D versus controls comparison, more pathways (24%) were classified as “immune response-related.” Important pathways that were identified using data from the T1D versus controls comparison were pathways involving antigen presentation by MHCII, the activation of Th17 and Th22 responses, and cytoskeleton rearrangement-related processes. Genes involved in Th17 and TGF-beta cascades may represent novel, promising (pre)diabetes biomarkers. Jana Vcelakova, Radek Blatny, Zbynek Halbhuber, Michal Kolar, Ales Neuwirth, Lenka Petruzelkova, Tereza Ulmannova, Stanislava Kolouskova, Zdenek Sumnik, Pavlina Pithova, Maria Krivjanska, Dominik Filipp, and Katerina Stechova Copyright © 2013 Jana Vcelakova et al. All rights reserved. Wed, 12 Jun 2013 11:04:58 +0000 http://www.hindawi.com/journals/jdr/2013/905058/ Purpose. To evaluate the changes in thickness of individual inner and outer macular and peripapillary retinal layers in diabetes. Methods. 124 subjects (124 eyes) were enrolled: 74 diabetics and 50 controls. Macular edema, proliferative diabetic retinopathy (DR), any intraocular treatment and refractive error diopters were the main exclusion criteria. Full ophthalmic examination, stereoscopic fundus photography, and spectral domain-OCT were performed. After automatic retinal segmentation (layering) in 5 layers, the thickness of each layer was calculated, and values compared among groups. Results. Thirty patients had no DR, 44 patients had non proliferative DR. A significant increase of inner plexiform and nuclear layers was found in DR eyes versus controls (). A significant decrease () of retinal nerve fiber layer (RNFL) and at specific sites of retinal ganglion cell layer () was documented in the macula. In the peripapillary area there were no differences between diabetics and controls. Conclusions. Decreased RNFL thickness and increased INL/OPL thickness in diabetics without DR or with initial DR suggest early alterations in the inner retina. On the contrary, the outer retina seems not to be affected at early stages of DM. Automatic intraretinal layering by SD-OCT may be a useful tool to diagnose and monitor early intraretinal changes in DR. Stela Vujosevic and Edoardo Midena Copyright © 2013 Stela Vujosevic and Edoardo Midena. All rights reserved. Thu, 06 Jun 2013 17:34:20 +0000 http://www.hindawi.com/journals/jdr/2013/370212/ Thrombosis is a life-threatening complication of diabetes. Platelet reactivity is crucial to thrombus formation, particularly in arterial vessels and in thrombotic complications causing myocardial infarction or ischaemic stroke, but diabetic patients often respond poorly to current antiplatelet medication. In this study, we used a nonhuman primate model of Type 1 diabetes to measure early downstream signalling events following engagement of the major platelet collagen receptor, glycoprotein (GP)VI. Diabetic monkeys were given enough insulin to maintain their blood glucose levels either at ~8 mM (well-controlled diabetes) or ~15 mM (poorly controlled diabetes). Flow cytometric analysis was used to measure platelet reactive oxygen species (ROS) generation, calcium mobilisation, receptor surface expression, and immature platelet fraction. We observed exacerbated intracellular ROS and calcium flux associated with engagement of GPVI in monkeys with poorly controlled diabetes. GPVI surface levels did not differ between healthy monkeys or the two diabetic groups. Treatment of platelets with the specific Syk inhibitor BAY61-3606 inhibited GPVI-dependent ROS and, importantly, reduced ROS generation in the poorly controlled diabetes group to that observed in healthy monkeys. These data indicate that glycaemic control is important in reducing GPVI-dependent platelet hyperreactivity and point to a potential antithrombotic therapeutic benefit of Syk inhibition in hyperglycaemic diabetes. J. F. Arthur, Y. Shen, Y. Chen, J. Qiao, R. Ni, Y. Lu, R. K. Andrews, E. E. Gardiner, and J. Cheng Copyright © 2013 J. F. Arthur et al. All rights reserved. Wed, 05 Jun 2013 17:51:06 +0000 http://www.hindawi.com/journals/jdr/2013/712092/ Plants have always been a source of drugs for humans since time immemorial. The Indian traditional system of medicine is replete with the use of plants for the management of diabetic conditions. According to the World Health Organization, up to 90% of population in developing countries use plants and its products as traditional medicine for primary health care. There are about 800 plants which have been reported to show antidiabetic potential. The present review is aimed at providing in-depth information about the antidiabetic potential and bioactive compounds present in Ficus religiosa, Pterocarpus marsupium, Gymnema sylvestre, Allium sativum, Eugenia jambolana, Momordica charantia, and Trigonella foenum-graecum. The review provides a starting point for future studies aimed at isolation, purification, and characterization of bioactive antidiabetic compounds present in these plants. Syed Ibrahim Rizvi and Neetu Mishra Copyright © 2013 Syed Ibrahim Rizvi and Neetu Mishra. All rights reserved. Wed, 05 Jun 2013 11:45:06 +0000 http://www.hindawi.com/journals/jdr/2013/585897/ Uncoupling proteins (UCPs) are anion carriers expressed in the mitochondrial inner membrane that uncouple oxygen consumption by the respiratory chain from ATP synthesis. The physiological functions of UCPs have long been debated since the new UCPs (UCP2 to 5) were discovered, and the role of UCPs in the pathogeneses of diabetes mellitus is one of the hottest topics. UCPs are thought to be activated by superoxide and then decrease mitochondrial free radicals generation; this may provide a protective effect on diabetes mellitus that is under the oxidative stress conditions. UCP1 is considered to be a candidate gene for diabetes because of its role in thermogenesis and energy expenditure. UCP2 is expressed in several tissues and acts in the negative regulation of insulin secretion by β-cells and in fatty acid metabolism. UCP3 plays a role in fatty acid metabolism and energy homeostasis and modulates insulin sensitivity. Several gene polymorphisms of UCP1, UCP2, and UCP3 were reported to be associated with diabetes. The progress in the role of UCP1, UCP2, and UCP3 on diabetes mellitus is summarized in this review. Jing Liu, Ji Li, Wen-Jian Li, and Chun-Ming Wang Copyright © 2013 Jing Liu et al. All rights reserved. Mon, 03 Jun 2013 13:08:28 +0000 http://www.hindawi.com/journals/jdr/2013/248563/ Diabetes and insulin resistance can greatly increase microvascular complications of diabetes including diabetic nephropathy (DN). Hyperglycemic control in diabetes is key to preventing the development and progression of DN. However, it is clinically very difficult to achieve normal glucose control in individual diabetic patients. Many factors are known to contribute to the development of DN. These include diet, age, lifestyle, or obesity. Further, inflammatory- or oxidative-stress-induced basis for DN has been gaining interest. Although anti-inflammatory or antioxidant drugs can show benefits in rodent models of DN, negative evidence from large clinical studies indicates that more effective anti-inflammatory and antioxidant drugs need to be studied to clear this question. In addition, our recent report showed that potential endogenous protective factors could decrease inflammation and oxidative stress, showing great promise for the treatment of DN. Akira Mima Copyright © 2013 Akira Mima. All rights reserved. Sat, 01 Jun 2013 13:42:55 +0000 http://www.hindawi.com/journals/jdr/2013/218102/ Alcohol is a potential risk factor of type 2 diabetes, but its underlying mechanism is unclear. To explore this issue, Wistar rats and mouse hepatoma cells (Hepa 1–6) were exposed to ethanol, 8 g·kg−1·d−1 for 3 months and 100 mM for 48 h, respectively. Glucose and insulin tolerance tests in vivo were performed, and protein levels of 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) and glucocorticoid receptor (GR) in liver and Hepa 1–6 cells were measured. Alterations of key enzymes of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase), as well as glycogen synthase kinase 3a (GSK3α), were also examined. The results revealed that glucose levels were increased, and insulin sensitivity was impaired accompanied with liver injury in rats exposed to ethanol compared with controls. The 11-HSD1, GR, PEPCK, G6Pase, and GSK3α proteins were increased in the liver of rats treated with ethanol compared with controls. Ethanol-exposed Hepa 1–6 cells also showed higher expression of 11-HSD1, GR, PEPCK, G6Pase, and GSK3α proteins than control cells. After treatment of Hepa 1–6 cells exposed to ethanol with the GR inhibitor RU486, the expression of 11-HSD1 and GR was significantly decreased. At the same time the increases in PEPCK, G6Pase, and GSK3α levels induced by ethanol in Hepa 1–6 cells were also attenuated by RU486. The results indicate that ethanol causes glucose intolerance by increasing hepatic expression of 11-HSD1 and GR, which leads to increased expression of gluconeogenic and glycogenolytic enzymes. Zhaojie Meng, Xueying Bao, Ming Zhang, Shengnan Wei, Wenguang Chang, Jing Li, Li Chen, and B. L. Grégoire Nyomba Copyright © 2013 Zhaojie Meng et al. All rights reserved. Thu, 30 May 2013 14:02:13 +0000 http://www.hindawi.com/journals/jdr/2013/738485/ Aim. The present population-based study aimed to assess prevalence of metabolic syndrome and itsrelated components in Iranian youth in the different sex, age, and residential subgroups. Method. Overall, 1039 junior high school and 953 high school students were selected using multistage random sampling. Fasting blood sugar, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were determined. Trained individuals measured waist circumference and blood pressure. Subjects with MetS were selected according to two definitions provided by the IDF and de Ferranti. Results. Among girls in intervention area, hypertriglyceridemia was more prevalent in rural than in urban areas using IDF definition. Significant differences were observed between boys in rural and urban areas regarding some components of metabolic syndrome including hypertriglyceridemia and high waist circumference. Besides, boys who are residents in urban areas had higher blood pressure, as well as higher waist circumference, than boys in rural areas. Conclusion. Our youth population is at significant risk of developing metabolic syndrome, and the pattern of this phenomenon seems to be discrepant in boys as well as in rural and urban areas probably due to the different lifestyle aspects, genetic factors, and racial differences. Alireza Ahmadi, Mojgan Gharipour, Fatemeh Nouri, and Nizal Sarrafzadegan Copyright © 2013 Alireza Ahmadi et al. All rights reserved. Wed, 29 May 2013 09:16:22 +0000 http://www.hindawi.com/journals/jdr/2013/382670/ Background/Aims. Gestational diabetes mellitus (GDM) and milder gestational impaired glucose tolerance (GIGT) identify women who are at risk of developing cardiovascular disease. Endothelial dysfunction, as indicated by impaired flow-mediated dilatation (FMD) on brachial artery ultrasound, is an early marker of vascular disease. Thus, we sought to evaluate endothelial function in women with and without recent glucose intolerance in pregnancy. Methods. One-hundred and seventeen women underwent oral glucose tolerance testing (OGTT) in pregnancy, enabling stratification into those with normal gestational glucose tolerance () and those with GDM or GIGT (). 6 years postpartum, they underwent a repeat of OGTT and brachial artery FMD studies, enabling assessment of FMD and 4 secondary vascular measures: FMD after 60 seconds (FMD60), baseline arterial diameter, peak shear rate, and reactive hyperemia. Results. There were no differences between the normal gestational glucose tolerance and GDM/GIGT groups in FMD (mean 8.5 versus 9.3%, ), FMD60 (4.1 versus 5.1%, ), baseline diameter (3.4 versus 3.4 mm, ), peak shear rate (262.6 versus 274.8 s−1, ), and reactive hyperemia (576.6 versus 496.7%, ). After covariate adjustment, there were still no differences between the groups. Conclusion. Despite their long-term cardiovascular risk, women with glucose intolerance in pregnancy do not display endothelial dysfunction 6 years postpartum. Shireen Brewster, John Floras, Bernard Zinman, and Ravi Retnakaran Copyright © 2013 Shireen Brewster et al. All rights reserved. Thu, 23 May 2013 17:26:10 +0000 http://www.hindawi.com/journals/jdr/2013/432695/ Diabetic retinopathy is a complex condition where inflammation and oxidative stress represent crucial pathways in the pathogenesis of the disease. Aim of the study was to investigate the effects of a fortified extract of red berries, Ginkgo biloba and white willow bark containing carnosine and -lipoic acid in early retinal and plasma changes of streptozotocin-induced diabetic rats. Diabetes was induced by a single streptozotocin injection in Sprague Dawley rats. Diabetics and nondiabetic (control) rats were treated daily with the fortified extract for the ten days. Retina samples were collected and analyzed for their TNF- and VEGF content. Moreover, plasma oxidative stress was evaluated by thiobarbituric acid reacting substances (TBARS). Increased TNF- and VEGF levels were observed in the retina of diabetic rats. Treatment with the fortified extract significantly lowered retinal cytokine levels and suppressed diabetes-related lipid peroxidation. These data demonstrate that the fortified extract attenuates the degree of retinal inflammation and plasma lipid peroxidation preserving the retina in early diabetic rats. Claudio Bucolo, Giuseppina Marrazzo, Chiara Bianca Maria Platania, Filippo Drago, Gian Marco Leggio, and Salvatore Salomone Copyright © 2013 Claudio Bucolo et al. All rights reserved. Thu, 23 May 2013 08:32:17 +0000 http://www.hindawi.com/journals/jdr/2013/184258/ Diabetes mellitus (DM) is a pandemics that affects more than 170 million people worldwide, associated with increased mortality and morbidity due to coronary artery disease (CAD). In type 1 (T1) DM, the main pathogenic mechanism seems to be the destruction of pancreatic β-cells mediated by autoreactive T-cells resulting in chronic insulitis, while in type 2 (T2) DM primary insulin resistance, rather than defective insulin production due to β-cell destruction, seems to be the triggering alteration. In our study, we investigated the role of systemic inflammation and T-cell subsets in T1- and T2DM and the possible mechanisms underlying the increased cardiovascular risk associated with these diseases. Daniela Pedicino, Giovanna Liuzzo, Francesco Trotta, Ada Francesca Giglio, Simona Giubilato, Francesca Martini, Francesco Zaccardi, Giuseppe Scavone, Marco Previtero, Gianluca Massaro, Pio Cialdella, Maria Teresa Cardillo, Dario Pitocco, Giovanni Ghirlanda, and Filippo Crea Copyright © 2013 Daniela Pedicino et al. All rights reserved. Wed, 22 May 2013 16:41:35 +0000 http://www.hindawi.com/journals/jdr/2013/787084/ We have previously shown that dental caries may be produced in diabetic rodent models fed with noncariogenic standard diets; however, many studies usually add large amounts of sugar to the diet to induce dental caries. Moreover, the physical properties of cariogenic diets have been reported as an important factor in the formation of caries. The aim of this study was to clarify the effect of the hardness of non-cariogenic diets on the development of dental caries in diabetic rodents. Seven-week-old female F344 rats were divided into 4 groups: intact rats fed with a standard pelletized or powdered diet and alloxan-induced diabetic rats fed with a standard pelletized or powdered diet. All of the rats were sacrificed at 52 weeks of age for morphological examinations on their dental tissue. Dental caries had developed and extended to all the molars in the diabetic rats that were fed with both the pelletized and powdered diets. Moreover, the lesion was significantly enhanced in the powdered diet group compared to that in the pelletized diet group. In conclusion, food hardness is an important factor influencing the development of dental caries in diabetic rats. Yutaka Nakahara, Tomoya Sano, Yasushi Kodama, Kiyokazu Ozaki, and Tetsuro Matsuura Copyright © 2013 Yutaka Nakahara et al. All rights reserved. Tue, 21 May 2013 16:10:21 +0000 http://www.hindawi.com/journals/jdr/2013/193461/ Diabetes mellitus (DM) is a chronic metabolic disease, and its incidence is growing worldwide. The endoplasmic reticulum (ER) is a central component of cellular functions and is involved in protein folding and trafficking, lipid synthesis, and maintenance of calcium homeostasis. The ER is also a sensor of both intra- and extracellular stress and thus participates in monitoring and maintaining cellular homeostasis. Therefore, the ER is one site of interaction between environmental signals and a cell’s biological function. The ER is tightly linked to autophagy, inflammation, and apoptosis, and recent evidence suggests that these processes are related to the pathogenesis of DM and its complications. Thus, the ER has been considered an intersection integrating multiple stress responses and playing an important role in metabolism-related diseases including DM. Here, we review the relationship between the ER and autophagy, inflammation, and apoptosis in DM to better understand the molecular mechanisms of this disease. Jing Su, Lei Zhou, Xiaoxia Kong, Xiaochun Yang, Xiyan Xiang, Yu Zhang, Xiaoning Li, and Liankun Sun Copyright © 2013 Jing Su et al. All rights reserved. Tue, 21 May 2013 10:39:00 +0000 http://www.hindawi.com/journals/jdr/2013/986906/ The development of new therapies for the treatment of type 2 diabetes requires robust, reproducible and well validated in vivo experimental systems. Mice provide the most ideal animal model for studies of potential therapies. Unlike larger animals, mice have a short gestational period, are genetically similar, often give birth to many offspring at once and can be housed as multiple groups in a single cage. The mouse model has been extensively metabolically characterized using different tests. This report summarizes how these tests can be executed and how arising data are analyzed to confidently determine changes in insulin resistance and insulin secretion with high reproducibility. The main tests for metabolic assessment in the mouse reviewed here are the glucose clamp, the intravenous and the oral glucose tolerance tests. For all these experiments, including some commonly adopted variants, we describe: (i) their performance; (ii) their advantages and limitations; (iii) the empirical formulas and mathematical models implemented for the analysis of the data arising from the experimental procedures to obtain reliable measurements of peripheral insulin sensitivity and beta cell function. Finally, a list of previous applications of these methods and analytical techniques is provided to better comprehend their use and the evidences that these studies yielded. G. Pacini, B. Omar, and B. Ahrén Copyright © 2013 G. Pacini et al. All rights reserved. Thu, 16 May 2013 09:38:33 +0000 http://www.hindawi.com/journals/jdr/2013/170532/ Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipose tissue is now considered to be an active endocrine organ that secretes various adipokines such as adiponectin, leptin, resistin, tumour necrosis factor-, and interleukin-6. Recent studies have shown that these factors might provide a molecular link between increased adiposity and impaired insulin sensitivity. Since hepatic insulin resistance plays the key role in the whole body insulin resistance, clarification of the regulatory processes about hepatic insulin resistance by adipokines in rodents and human would seem essential in order to understand the mechanism of type 2 diabetes and for developing novel therapeutic strategies to treat it. Yu Li, Lin Ding, Waseem Hassan, Daoud Abdelkader, and Jing Shang Copyright © 2013 Yu Li et al. All rights reserved. Mon, 13 May 2013 10:52:57 +0000 http://www.hindawi.com/journals/jdr/2013/965832/ Type 1 diabetes (T1D) is characterized by hyperglycemia due to lost or damaged islet insulin-producing β-cells. Rodent models of T1D result in hyperglycemia, but with different forms of islet deterioration. This study focused on 1 toxin-induced and 2 autoimmune rodent models of T1D: BioBreeding Diabetes Resistant rats, nonobese diabetic mice, and Dark Agouti rats treated with streptozotocin. Immunochemistry was used to evaluate the insulin levels in the β-cells, cell composition, and insulitis. T1D caused complete or significant loss of β-cells in all animal models, while increasing numbers of α-cells. Lymphocytic infiltration was noted in and around islets early in the progression of autoimmune diabetes. The loss of lymphocytic infiltration coincided with the absence of β-cells. In all models, the remaining α- and δ-cells regrouped by relocating to the islet center. The resulting islets were smaller in size and irregularly shaped. Insulin injections subsequent to induction of toxin-induced diabetes significantly preserved β-cells and islet morphology. Diabetes in animal models is anatomically heterogeneous and involves important changes in numbers and location of the remaining α- and δ-cells. Comparisons with human pancreatic sections from healthy and diabetic donors showed similar morphological changes to the diabetic BBDR rat model. Lesya Novikova, Irina V. Smirnova, Sonia Rawal, Abby L. Dotson, Stephen H. Benedict, and Lisa Stehno-Bittel Copyright © 2013 Lesya Novikova et al. All rights reserved. Sun, 12 May 2013 16:38:21 +0000 http://www.hindawi.com/journals/jdr/2013/852754/ Aim. To investigate the role of AMPK activation and autophagy in mediating the beneficial effects of exercise and caloric restriction in obesity. Methods. Dietary-induced obesity mice were made and divided into 5 groups; one additional group of normal mice serves as control. Mice in each group received different combinations of interventions including low fat diet, caloric restriction, and exercise. Then their metabolic conditions were assessed by measuring serum glucose and insulin, serum lipids, and liver function. AMPK phosphorylation and autophagy activity were detected by western blotting. Results. Obese mice models were successfully induced by high fat diet. Caloric restriction consistently improved the metabolic conditions of the obese mice, and the effects are more prominent than the mice that received only exercise. Also, caloric restriction, exercise, and low fat diet showed a synergistic effect in the improvement of metabolic conditions. Western blotting results showed that this improvement was not related with the activation of AMPK in liver, skeletal muscle, or heart but correlates well with the autophagy activity. Conclusion. Caloric restriction has more prominent beneficial effects than exercise in dietary-induced obese mice. These effects are correlated with the autophagy activity and may be independent of AMPK activation. Mingxia Cui, Han Yu, Jinli Wang, Junjie Gao, and Ji Li Copyright © 2013 Mingxia Cui et al. All rights reserved. Wed, 08 May 2013 09:22:26 +0000 http://www.hindawi.com/journals/jdr/2013/763125/ The aim of the present study was to evaluate the potential antidiabetic effects of two-component drug Subetta and its components (release-active dilutions of antibodies to β-subunit insulin receptor (RAD of Abs to β-InsR) and to endothelial nitric oxide synthase (RAD of Abs to eNOS)) in Goto-Kakizaki (Paris colony) (GK/Par) diabetic rats. Subetta was administered orally for 28 days once daily (5 mL/kg) and compared to its two components (2.5 mL/kg), Rosiglitazone (5 mg/kg), and vehicle (5 mL water/kg). At day 28, fasting plasma glucose levels were significantly decreased only in Subetta and Rosiglitazone groups as compared to vehicle ():  mg/dL and  mg/dL and  mg/dL, respectively. The data of glucose tolerance test showed that Subetta and RAD of Abs to β-InsR (similar to Rosiglitazone) prevented significantly () the age-related spontaneous deterioration of glucose tolerance as seen in the control group. Subetta and RAD of Abs to β-InsR did not significantly modify the glucose-induced insulin secretion. Chronic administration of Subetta and RAD of Abs to β-InsR improves glucose control, to an extent similar to that of Rosiglitazone. We hypothesize that Subetta and RAD of Abs to β-InsR mostly act via an insulin-sensitizing effect upon target tissues. Danielle Bailbé, Erwann Philippe, Evgeniy Gorbunov, Sergey Tarasov, Oleg Epstein, and Bernard Portha Copyright © 2013 Danielle Bailbé et al. All rights reserved. Tue, 30 Apr 2013 15:14:36 +0000 http://www.hindawi.com/journals/jdr/2013/589474/ Background. Hyperglycemia plays a pivotal role in the development of diabetic nephropathy (DN) and may be related to epigenetic metabolic memory. One of the most crucial epigenetic mechanisms is histone modification, which is associated with the expression of a fibrosis factor in vascular injury. Aim .In this study, we investigated the ubiquitination of histones H2A and H2B to explore the epigenetic mechanisms of DN. Materials and Methods. The GMCs were cultured as follows: normal group, high glucose group, mannitol group, and intervention group. After 12 hr, 24 hr, and 48 hr, histones ubiquitination, transforming growth factor- (TGF-), and fibronectin (FN) were measured using WB, RT-PCR, and IF. Result. High glucose can induce the upregulation of FN. H2A ubiquitination in GMCs increased in high glucose group , whereas it decreased significantly in intervention group . In contrast, H2B ubiquitination decreased with an increasing concentration of glucose, but it was recovered in the intervention group . Expression of TGF- changed in response to abnormal histone ubiquitination. Conclusions. The high glucose may induce H2A ubiquitination and reduce H2B ubiquitination in GMCs. The changes of histone ubiquitination may be due in part to DN by activating TGF- signaling pathway. Chenlin Gao, Guo Chen, Li Liu, Xia Li, Jianhua He, Lan Jiang, Jianhua Zhu, and Yong Xu Copyright © 2013 Chenlin Gao et al. All rights reserved. Wed, 24 Apr 2013 18:08:21 +0000 http://www.hindawi.com/journals/jdr/2013/498925/ The KK.Cg-/J (KK-) mouse strain is a previously described model of type 2 diabetes with renal impairment. In the present study, female KK- mice received an elevated fat content diet (24% of calories), and a cohort was uninephrectomized (Unx) to drive renal disease severity. Compared to KK- controls, 26-week-old KK- mice had elevated HbA1c, insulin, leptin, triglycerides, and cholesterol, and Unx further elevated these markers of metabolic dysregulation. Unx KK- mice also exhibited elevated serum BUN and reduced glomerular filtration, indicating that reduction in renal mass leads to more severe impairment in renal function. Glomerular hypertrophy and hypercellularity, mesangial matrix expansion, podocyte effacement, and basement membrane thickening were present in both binephric and uninephrectomized cohorts. Glomerular size was increased in both groups, but podocyte density was reduced only in the Unx animals. Consistent with functional and histological evidence of increased injury, fibrotic (fibronectin 1, MMP9, and TGFβ1) and inflammatory (IL-6, CD68) genes were markedly upregulated in Unx KK- mice, while podocyte markers (nephrin and podocin) were significantly decreased. These data suggest podocyte injury developing into glomerulopathy in KK- mice. The addition of uninephrectomy enhances renal injury in this model, resulting in a disease which more closely resembles human diabetic nephropathy. Stephen P. O'Brien, Mandy Smith, Hong Ling, Lucy Phillips, William Weber, John Lydon, Colleen Maloney, Steven Ledbetter, Cynthia Arbeeny, and Stefan Wawersik Copyright © 2013 Stephen P. O'Brien et al. All rights reserved. Tue, 23 Apr 2013 13:15:49 +0000 http://www.hindawi.com/journals/jdr/2013/621693/ HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called “Tregitopes”) have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4+ T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. In ex vivo studies of human T cells, peripheral blood mononuclear cells’ (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopes ex vivo by Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management. Leslie P. Cousens, Yan Su, Elizabeth McClaine, Xin Li, Frances Terry, Robert Smith, Jinhee Lee, William Martin, David W. Scott, and Anne S. De Groot Copyright © 2013 Leslie P. Cousens et al. All rights reserved. Mon, 22 Apr 2013 17:03:32 +0000 http://www.hindawi.com/journals/jdr/2013/459821/ Objective. To review the current literature investigating the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on the risk factors of cardiovascular disease (CVD). Methods. We conducted a search of PubMed and MEDLINE database, using the term DPP-4 inhibitor in combination with the following terms: metabolic syndrome, hypertension, dyslipidemia, insulin resistance, obesity, and CVD. We reviewed 100 relevant studies out of 227 articles, excluding single case reports, studies using animal models, and reports not written in English. We included 38 references in this review article. Results. The majority of the recent clinical studies have demonstrated that DPP-4 inhibitors have beneficial effects on cardiovascular (CV) system. These agents may have the potential to lower blood pressure, improve lipid profile and endothelial dysfunction, decrease the macrophage-mediated inflammatory response, and prevent myocardial injury. Conclusion. DPP-4 inhibitors have some CV protective effects in type 2 diabetes mellitus (T2DM) in addition to their antidiabetic actions. Long-term outcome clinical trials are under way to investigate the effects of the DPP-4 inhibitors on the elevated CV risks in patients with T2DM. Further investigation in a large cohort is warranted to assess the exact mechanisms of CV protective effects of DPP-4 inhibitors. Pegah Yousefzadeh and Xiangbing Wang Copyright © 2013 Pegah Yousefzadeh and Xiangbing Wang. All rights reserved. Mon, 22 Apr 2013 11:40:52 +0000 http://www.hindawi.com/journals/jdr/2013/416451/ Background. Lipoprotein(a) [Lp(a)] is a known risk factor for cardiovascular disease, yet its influence on metabolic syndrome (MS) is still controversial. The purpose of this study was to assess the impact generated by this diagnosis in serum Lp(a) concentrations. Materials and Methods. A total of 1807 subjects of both genders (55.3% women and 44.7% men) belonging to the Maracaibo City Metabolic Syndrome Prevalence Study were evaluated. Results were expressed as Mean ± SD, determining differences through Student’s t-test and One-Way ANOVA test. Multiple logistic regression models were utilized for analyzing factors associated with elevated serum Lp(a) levels and MS. Total cholesterol and LDL-C were corrected according to Lp(a)-Cholesterol when necessary. Results. No differences were found in Lp(a) values between genders; . The association between MS and the classification of Lp(a) was statistically significant (; ), with greater levels in subjects with this diagnosis. In the univariate analysis, subjects with each of the separate diagnostic criteria showed higher serum Lp(a) concentrations, except for hyperglycemia. Conclusions. Lp(a) values exhibit important variations regarding MS and each of its components. Impaired fasting glucose appeared as a protecting factor against elevated Lp(a) concentrations, whereas its association with LDL-C and hs-CRP suggests a potential pro-inflammatory role. Valmore Bermúdez, Joselyn Rojas, Juan Salazar, Luis Bello, Roberto Áñez, Alexandra Toledo, Maricarmen Chacín, Miguel Aguirre, Marjorie Villalobos, Mervin Chávez, María Sofía Martínez, Wheeler Torres, Yaquelin Torres, José Mejías, Edgardo Mengual, Liliana Rojas, Milagro Sánchez de Rosales, Ana Quevedo, Raquel Cano, Mayela Cabrera, Rafael París, Adonías Lubo, María Montiel, and Climaco Cano Copyright © 2013 Valmore Bermúdez et al. All rights reserved. Thu, 18 Apr 2013 17:06:23 +0000 http://www.hindawi.com/journals/jdr/2013/620313/ 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. Erin E. Hillhouse, Roxanne Collin, Geneviève Chabot-Roy, Marie-Josée Guyon, Nathalie Tessier, Maryse Boulay, Patricia Liscourt, and Sylvie Lesage Copyright © 2013 Erin E. Hillhouse et al. All rights reserved.