http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . 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. Thu, 18 Apr 2013 15:24:08 +0000 http://www.hindawi.com/journals/jdr/2013/979702/ The involvement of the Notch signaling pathway in the cellular differentiation of the mammalian kidney is established. Recently, the dysregulation of Notch signaling molecules has been identified in acute and chronic renal injuries, fibrosis models, and diabetic kidney biopsies. The canonical Notch ligand , Jagged1, is upregulated in a transforming growth factor-beta- (TGF-β-) dependent manner during chronic kidney disease. TGF-β, a central mediator of renal fibrosis, also is a major contributor to the development of diabetic nephropathy. To explore the roles and possible mechanisms of Notch signaling molecules in the pathogenesis of diabetic nephropathy, we exposed cultured rat mesangial cells to a γ-secretase inhibitor (DAPT) or high glucose and measured the expression of Notch signaling molecules and the fibrosis index. Notch pathway-related molecules, TGF-β, and fibronectin increased with exposure to high glucose and decreased with DAPT treatment. Our results suggest that the Notch signaling pathway may precipitate diabetic nephropathy via TGF-β activation. Li Liu, Chenlin Gao, Guo Chen, Xia Li, Jia Li, Qin Wan, and Yong Xu Copyright © 2013 Li Liu et al. All rights reserved. Mon, 15 Apr 2013 18:43:05 +0000 http://www.hindawi.com/journals/jdr/2013/781360/ Objective. This study aimed to investigate the angiographic manifestations of lower extremity atherosclerotic steno-occlusive disease in patients with diabetes. Materials and Methods. A total of 162 patients with diabetes were enrolled in this study. The angiographic findings of lower extremity arterial lesions were evaluated according to location (iliac, femoral, popliteal, and crural artery), type (stenosis or occlusion), and length (<5 cm, 5–10 cm, and >5 cm). Results. A total of 131 of 162 (80.9%) diabetics showed multiple segmental lesions, and 19.1% (31/162) presented single segmental lesions in the lower extremity artery. Crural artery was the mainly involved location (39/162, 85.8%). Among the recorded 660 lesions of 162 cases, 437 (66.2%) were occlusion lesions, while 223 (33.8%) were stenosis lesions. Of 437 occlusion lesions, 308 lesions (70.5%) were in crural artery. More than 10 cm occlusion lesion (242/392, 61.7%) was the main manifestation in crural artery, especially in anterior (92/127, 67.2%) and posterior tibial arteries (91/124, 73.4%), which was higher than that in iliac artery (8/33, 24.2%), popliteal artery (53/157, 33.8%), and femoral artery (11/78, 14.1%). Conclusion. In diabetic subjects with lower limb artery ischemia, the vascular involvement is extremely diffuse and particularly severe in crural arteries, with high prevalence of more than 10 cm occlusion lesions. XiangJiang Guo, YaXue Shi, XiaoZhong Huang, Meng Ye, GuanHua Xue, and JiWei Zhang Copyright © 2013 XiangJiang Guo et al. All rights reserved. Sun, 14 Apr 2013 09:50:57 +0000 http://www.hindawi.com/journals/jdr/2013/848679/ Diabetic nephropathy (DN) is one of the most common causes of end-stage renal failure. This study was performed to determine the effect of Dantonic Pill (DP) treatment on β-catenin expression in a rat model of streptozotocin- (STZ-) induced early-stage DN, with irbesartan treatment as a positive control. Including an analysis of the general metabolic index and renal function, immunohistochemical staining and reverse transcription real-time PCR for β-catenin were performed in the renal cortex of the rat models every 4 weeks. After the treatments of DP and irbesartan, the albuminuria level, kidney weight/body weight, and thickness of the glomerular basement membrane were decreased, but the expression of β-catenin was not downregulated in the renal cortex. The effective drug target of DP to ameliorate albuminuria and renal hypertrophy should not inhibit the upregulated expression of β-catenin in rats with STZ-induced early-stage diabetic damage. Zhou Shuhong, Lv Hongjun, Cui Bo, Xu Li, and Shi Bingyin Copyright © 2013 Zhou Shuhong et al. All rights reserved. Thu, 11 Apr 2013 10:22:20 +0000 http://www.hindawi.com/journals/jdr/2013/906590/ More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics. Gabriela da Silva Xavier, Elisa A. Bellomo, James A. McGinty, Paul M. French, and Guy A. Rutter Copyright © 2013 Gabriela da Silva Xavier et al. All rights reserved. Wed, 10 Apr 2013 13:33:11 +0000 http://www.hindawi.com/journals/jdr/2013/658548/ This study was conducted to determine the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in a time-dependent manner and the effect of extracellular-signal-regulated kinases-1/2 (ERK1/2) inhibition on the expressions of MMP-9, TIMP-1, and inflammatory biomarkers in the retinas of diabetic rats. The expression of MMP-9 was quantified by zymography, and the mRNA level of MMP-9 and TIMP-1 was quantified by RT-PCR. The expression of inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) was examined by Western blot analysis. MMP-9 expression was significantly higher in diabetic rat retinas compared to controls at all time points.TIMP-1 expression was nonsignificantly upregulated at 1week of diabetes and was significantly downregulated at 4 and 12 weeks of diabetes. Intravitreal administration of the ERK1/2 inhibitor U0126 prior to induction of diabetes decreased ERK1/2 activation, attenuated diabetes-induced upregulation of MMP-9, iNOS, IL-6, and TNF-α and upregulated TIMP-1 expression. In MMP-9 knockout mice, diabetes had no effect on retinal iNOS expression and its level remained unchanged. These data provide evidence that ERK1/2 signaling pathway is involved in MMP-9, iNOS, IL-6, and TNF-α induction in diabetic retinas and suggest that ERK1/2 can be a novel therapeutic target in diabetic retinopathy. Ghulam Mohammad, Mohammad Mairaj Siddiquei, Mohammad Imtiaz Nawaz, and Ahmed M. Abu El-Asrar Copyright © 2013 Ghulam Mohammad et al. All rights reserved. Wed, 10 Apr 2013 09:06:58 +0000 http://www.hindawi.com/journals/jdr/2013/329596/ Diabetes mellitus (DM) is a group of metabolic diseases in which a person has high blood glucose levels resulting from defects in insulin secretion and insulin action. The chronic hyperglycemia damages the eyes, kidneys, nerves, heart, and blood vessels. Curative therapies mainly include diet, insulin, and oral hypoglycemic agents. However, these therapies fail to maintain blood glucose levels in the normal range all the time. Although pancreas or islet-cell transplantation achieves better glucose control, a major obstacle is the shortage of donor organs. Recently, research has focused on stem cells which can be classified into embryonic stem cells (ESCs) and tissue stem cells (TSCs) to generate functional β cells. TSCs include the bone-marrow-, liver-, and pancreas-derived stem cells. In this review, we focus on treatment using bone marrow stem cells for type 1 and 2 DM. Ming Li and Susumu Ikehara Copyright © 2013 Ming Li and Susumu Ikehara. All rights reserved. Tue, 09 Apr 2013 09:52:15 +0000 http://www.hindawi.com/journals/jdr/2013/647107/ In this paper, we established a delayed wound healing model on diabetic rat to mimic the pathophysiology of clinical patients who suffered from diabetic foot ulcers. We also evaluated if transplantation of allogeneic bone marrow-derived mesenchymal stem cells could promote the delayed wound healing and investigated the possible underlying biological mechanisms and stem cell behavior involved in this process. The results showed that bone marrow-derived mesenchymal stem cells had a positive effect on delayed wound healing in diabetic rats. Intramuscular transplantation demonstrated the best efficacy. This effect is associated with granulation tissue formation, angiogenesis, cellular proliferation, and high vascular endothelial growth factor expression in wound tissues. In addition, bone marrow-derived mesenchymal stem cells have been shown to mobilize and find home for ischemic and wounded tissues to participate in the process of wound healing. Intramuscular transplantation of exogenous isogeneic stem cells may be suitable for clinical application in the treatment of diabetic foot ulcers although the safety of this therapy should be considered. Jiangbo Wan, Liulu Xia, Wenjia Liang, Yi Liu, and Qian Cai Copyright © 2013 Jiangbo Wan et al. All rights reserved. Mon, 08 Apr 2013 15:37:26 +0000 http://www.hindawi.com/journals/jdr/2013/105780/ Endomorphins (EMs) have a very important bridge-function in cardiovascular, endocrinological, and neurological systems. This study is to investigate the effects of EMs on the synthesis and secretion of vasoactive substances induced by advanced glycation end products in primary cultured human umbilical vein endothelial cells (HUVECs). Firstly, HUVECs were stimulated with AGEs-bovine serum albumin (AGEs-BSA), bovine serum albumin (BSA), or both AGEs-BSA and EMs together, respectively. Then, HUVEC survival rate was calculated by MTT assay, the levels of NO, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) were detected by colorimetric analysis, and the contents of endothelin-1 (ET-1) were detected by ELISA. The mRNA levels of eNOS and ET-1 were measured by RT-PCR. The expression of p38 mitogen-activated protein kinase (p38 MAPK) was detected by immunofluorescence assay. The results showed that the mRNA expression and secretion of eNOS were significantly enhanced after incubation with EMs compared to those with AGEs-BSA, while the secretion of NO and iNOS, mRNA expression, and secretion of ET-1 had opposite changes. The fluorescence intensity of p38MAPK in nuclear was decreased after pretreatment with EMs compared to incubation with AGEs-BSA. Conclusion. The present study suggests that EMs have certain protection effect on AGEs-BSA-induced injury in HUVEC. Jing Liu, Liping Yan, Ruilan Niu, Limin Tian, Qi Zhang, Jinxing Quan, Hua Liu, Suhong Wei, and Qian Guo Copyright © 2013 Jing Liu et al. All rights reserved. Mon, 08 Apr 2013 08:58:45 +0000 http://www.hindawi.com/journals/jdr/2013/165327/ This review compares two novel polygenic mouse models of type 2 diabetes (T2D), TALLYHO/JngJ and NONcNZO10/LtJ, and contrasts both with the well-known C57BLKS/J-Leprdb (db/db) monogenic diabesity model. We posit that the new polygenic models are more representative of the “garden variety” obesity underlying human T2D in terms of their polygenetic rather than monogenic etiology. Moreover, the clinical phenotypes in these new models are less extreme, for example, more moderated development of obesity coupled with less extreme endocrine disturbances. The more progressive development of obesity produces a maturity-onset development of hyperglycemia in contrast to the juvenile-onset diabetes observed in the morbidly obese db/db model. Unlike the leptin receptor-deficient db/db models with central leptin resistance, the new models develop a progressive peripheral leptin resistance and are able to maintain reproductive function. Although the T2D pathophysiology in both TALLYHO/JngJ and NONcNZO10/LtJ is remarkably similar, their genetic etiologies are clearly different, underscoring the genetic heterogeneity underlying T2D in humans. Edward H. Leiter, Marjorie Strobel, Adam O'Neill, David Schultz, Andrew Schile, and Peter C. Reifsnyder Copyright © 2013 Edward H. Leiter et al. All rights reserved. Sun, 07 Apr 2013 16:35:09 +0000 http://www.hindawi.com/journals/jdr/2013/690650/ Background and Aims. Adipose tissue dysfunction results from many factors, including glycation-induced microvascular damages. We tested the usefulness of inhibiting methylglyoxal-induced glycation to adipose tissue microvasculature in this work, using the antioxidant and dicarbonyl scavenger drug pyridoxamine. Methods. A group of Wistar rats was treated daily with methylglyoxal (MG, 75 mg/Kg/day, 8 weeks). Half of this group was treated with pyridoxamine in the following 4 weeks (Pyr) (100 mg/Kg/day) and the other half did not have any further treatment (MG). A group of Wistar rats without MG treatment was used as control (C). Results. MG group showed decreased HDL cholesterol and increased plasma free fatty acids levels, what was reverted by pyridoxamine. MG also caused an increase of tissue CEL levels (glycation marker), as well as increased staining of PAS and Masson Trichrome-positive components. Pyridoxamine led to CEL and TGF-β levels similar to those observed in control rats and inhibited the accumulation of PAS and Masson Trichrome-positive components. MG caused a decrease of Bcl-2/Bax ratio (marker of apoptosis) and vWF staining (microvascular marker), what was partially reverted by the treatment with pyridoxamine. Conclusions. Preventing methylglyoxal-induced accumulation of glycated and fibrotic materials using pyridoxamine improves the microvascular lesions of the adipose tissue. Tiago Rodrigues, Paulo Matafome, Daniela Santos-Silva, Cristina Sena, and Raquel Seiça Copyright © 2013 Tiago Rodrigues et al. All rights reserved. Sun, 07 Apr 2013 12:12:16 +0000 http://www.hindawi.com/journals/jdr/2013/357630/ Type 2 diabetes and its chronic complications have become a worldwide epidemic nowadays. However, its molecular mechanism is still unknown. We have previously identified a novel variant rs12742393 of NOS1AP for type 2 diabetes susceptibility in the Chinese population. In this study, we analyzed the total serum profiling among three genotypes of rs12742393 to discover potential crosstalk under the variant and the disease through proteomic analyses for the first time. We used OFFGEL peptide fractionation, LC-MS/MS analysis, and label-free quantification to profile the fasting human serum samples of the genotypes in rs12742393 (, for CC, AC, and AA, resp.). Four proteins were identified, including apoA4, alpha1-ACT, HABP2, and keratin 10, with blood levels changed significantly between CC and AA homozygotes of rs12742393. Compared with AA group, the levels of apoA4 increased (), whereas the concentration of alpha1-ACT, HABP2, and keratin 10 decreased in CC group (, 0.021175, and 0.015661, resp.). Then we selected additional fasting serum samples for ELISA and western blot validation. However, no significant differences were identified by neither ELISA nor western blot (). The protein profiling changes between the genotypes of rs12742393 indicated that this SNP might play a role in the development of type 2 diabetes. Feng Jiang, Congrong Wang, Rongxia Li, Quanhu Sheng, Cheng Hu, Rong Zhang, Qichen Fang, Yuqian Bao, Kunsan Xiang, Rong Zeng, and Weiping Jia Copyright © 2013 Feng Jiang et al. All rights reserved. Sun, 07 Apr 2013 11:44:29 +0000 http://www.hindawi.com/journals/jdr/2013/849295/ We analysed endothelial function and oxidative stress in patients with abnormal glucose metabolism, the effect of glucose load, and the impact of nateglinide. 109 participants were grouped into newly diagnosed diabetes, prediabetes, and control. Fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycosylated haemoglobin (), and glycated albumin (GA) varied significantly among the study groups (). Nitric oxide (NO) and insulin resistance index (HOMA-IRI) levels were markedly different between the newly diagnosed diabetes and the control (). Glucose loading lowered flow-mediated endothelium-dependent dilation (FMEDD), NO, and superoxide dismutase (SOD) (). Fasting and glucose loading FMEDD, FPG, PPG, , and GA were negatively correlated (, −0.4602, −0.3895, −0.3897, and , −0.4803, −0.4494, −0.3885; ), whereas NO, SOD, and HOMA-β were positively correlated (, 0.3211, 0.311, and , 0.361, 0.2569; ). After the treatment with nateglinide, significant decreases in FPG, PPG, GA, HbA1C, endothelin-1(ET-1), malondialdehyde (MDA), and HOMA-IRI were observed, whereas FMEDD, NO, and SOD increased (). Thus, the study demonstrated the adverse effect of glucose load on endothelial function and oxidative stress. Nateglinide lowers blood glucose, reduces insulin resistance and oxidative stress, and improves endothelial function in newly diagnosed diabetes. Leilei Wang, Lixin Guo, Lina Zhang, Yan Zhou, Qinghua He, Zheng Zhang, and Meng Wang Copyright © 2013 Leilei Wang et al. All rights reserved. Thu, 04 Apr 2013 14:02:56 +0000 http://www.hindawi.com/journals/jdr/2013/390534/ Type 2 diabetes mellitus (T2DM) has an intersecting underlying pathology with thyroid dysfunction. The literature is punctuated with evidence indicating a contribution of abnormalities of thyroid hormones to type 2 DM. The most probable mechanism leading to T2DM in thyroid dysfunction could be attributed to perturbed genetic expression of a constellation of genes along with physiological aberrations leading to impaired glucose utilization and disposal in muscles, overproduction of hepatic glucose output, and enhanced absorption of splanchnic glucose. These factors contribute to insulin resistance. Insulin resistance is also associated with thyroid dysfunction. Hyper- and hypothyroidism have been associated with insulin resistance which has been reported to be the major cause of impaired glucose metabolism in T2DM. The state-of-art evidence suggests a pivotal role of insulin resistance in underlining the relation between T2DM and thyroid dysfunction. A plethora of preclinical, molecular, and clinical studies have evidenced an undeniable role of thyroid malfunctioning as a comorbid disorder of T2DM. It has been investigated that specifically designed thyroid hormone analogues can be looked upon as the potential therapeutic strategies to alleviate diabetes, obesity, and atherosclerosis. These molecules are in final stages of preclinical and clinical evaluation and may pave the way to unveil a distinct class of drugs to treat metabolic disorders. Chaoxun Wang Copyright © 2013 Chaoxun Wang. All rights reserved. Sun, 31 Mar 2013 15:17:39 +0000 http://www.hindawi.com/journals/jdr/2013/614908/ In the present study, we have decided to evaluate if serum transforming growth factor-beta 1 (TGF-β1) concentrations may have diagnostic value in predicting the occurrence of diabetic retinopathy (DR) in juvenile patients with type 1 diabetes mellitus (T1DM). The study included 81 children and adolescents with T1DM and 19 control subjects. All study participants had biochemical parameters examined, underwent an eye examination, and 24-hour blood pressure monitoring. Moreover, serum concentrations of TGF-β1 were measured. The group of patients with T1DM and nonproliferative diabetic retinopathy (NPDR) had statistically significant higher serum levels of TGF-β1 () as compared to T1DM patients without retinopathy as well as the healthy control subject. The threshold serum TGF-β1 concentrations which had a discriminative ability to predict the presence of DR were calculated using the receiver operating characteristic (ROC) curves analysis and amounted to 443 pg/ml. The area under the ROC curve () was 0.80, and its population value was in the range of 0.66 to 0.94. The sensitivity and specificity were calculated to be 72% and 88%, respectively. Our results suggest that TGF-β1 serum concentrations may be an additional parameter in predicting the occurrence of DR in juvenile patients with T1DM. Katarzyna Zorena, Ewa Malinowska, Dorota Raczyńska, Małgorzata Myśliwiec, and Krystyna Raczyńska Copyright © 2013 Katarzyna Zorena et al. All rights reserved. Sun, 31 Mar 2013 12:07:17 +0000 http://www.hindawi.com/journals/jdr/2013/575814/ Patients with chronic diabetic complications experience high morbidity and mortality. Sex disparities in modifiable factors such as processes of care or self-care activities have not been explored in detail, particularly in these high-risk patients. Sex differences in processes of care and self-care activities were assessed in a cross-sectional analysis of the Pathways Study, an observational cohort of primary care diabetic patients from a managed care organization (). Compared to men, women had decreased odds of dyslipidemia screening (adjusted odds ratio (AOR) 0.73, 95% CI 0.62–0.85), reaching low-density lipoprotein goal (AOR 0.70, 95% CI 0.58–0.86), and statin use (AOR 0.69, 95% CI 0.58–0.81); women had 19% greater odds of reaching hemoglobin A1c <7% (95% CI 1.02–1.41). There were no sex differences in hemoglobin A1c testing, microalbuminuria screening, or angiotensin-converting enzyme inhibitor use. Women were less likely to report regular exercise but had better adherence to healthy diet, glucose monitoring, and self-foot examination compared to men. Patterns of sex differences were consistent in subjects with diabetic complications. Significant sex disparities exist in diabetes process of care measures and self-care, even amongst patients known to have chronic diabetic complications. Margaret K. Yu, Courtney Rees Lyles, Luis A. Bent-Shaw, and Bessie A. Young Copyright © 2013 Margaret K. Yu et al. All rights reserved.