Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Diabetes-Resistant NOR Mice Are More Severely Affected by Streptozotocin Compared to the Diabetes-Prone NOD Mice: Correlations with Liver and Kidney GLUT2 Expressions Wed, 28 Jan 2015 15:08:03 +0000 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. S. Kahraman, C. Aydin, G. O. Elpek, E. Dirice, and A. D. Sanlioglu Copyright © 2015 S. Kahraman et al. All rights reserved. The PI3K/Akt Signaling Pathway Mediates the High Glucose-Induced Expression of Extracellular Matrix Molecules in Human Retinal Pigment Epithelial Cells Wed, 28 Jan 2015 08:09:27 +0000 Prolonged hyperglycemia is an important risk factor of the pathogenesis of diabetic retinopathy (DR). Extracellular matrix molecules, such as fibronectin, collagen IV, and laminin, are associated with fibrotic membranes. In this study, we investigated the expression of fibronectin, collagen IV, and laminin in RPE cells under high glucose conditions. Furthermore, we also detected the phosphorylation of protein kinase B (Akt) under high glucose conditions in RPE cells. Our results showed that high glucose upregulated fibronectin, collagen IV, and laminin expression, and activated Akt in RPE cells. We also found that pretreatment with LY294002 (an inhibitor of phosphatidylinositol 3-kinase) abolished high glucose-induced expression of fibronectin, collagen IV, and laminin in RPE cells. Thus, high glucose induced the expression of fibronectin, collagen IV, and laminin through PI3K/Akt signaling pathway in RPE cells, and the PI3K/Akt signaling pathway may contribute to the formation of fibrotic membrane during the development of DR. Dong Qin, Guo-ming Zhang, Xun Xu, and Li-ya Wang Copyright © 2015 Dong Qin et al. All rights reserved. Retracted: Prognostic Utility of Coronary Computed Tomographic Angiography: A 5-Year Follow-Up in Type 2 Diabetes Patients with Suspected Coronary Artery Disease Tue, 27 Jan 2015 07:39:09 +0000 Journal of Diabetes Research Copyright © 2015 Journal of Diabetes Research. All rights reserved. Lower Extremity Function following Partial Calcanectomy in High-Risk Limb Salvage Patients Thu, 22 Jan 2015 14:21:00 +0000 Partial calcanectomy (PC) is an established limb salvage procedure for treatment of deep heel ulceration with concomitant calcaneal osteomyelitis. The purpose of this study is to determine if a relationship exists between the amount of calcaneus removed during PC and the resulting lower extremity function and limb salvage outcomes. Consecutive PC patients were retrospectively divided into two cohorts defined by the amount of calcaneus resected before wound closure: patients in cohort 1 retained = 50% of calcaneus, while patients in cohort 2 underwent resection of >50% of the calcaneus. The Lower Extremity Function Scale (LEFS) was used to assess postoperative lower extremity function. The average amount of calcaneus resected was 13% ± 9.2 (1–39%) and 74% ± 19.5 (51–100) in cohorts 1 and 2, respectively (). Below knee amputation was performed in 7 (28%) and 5 (29%) of subjects in cohorts 1 and 2, respectively (). The average LEFS score was 33.9 ± 15.0 for subjects in cohort 1 and 36.2 ± 19.9 for the subjects cohort 2 () which correlates to “moderate to quite a bit of difficulty.” Our study suggests that regardless of the amount of calcaneus resected, PC provides a viable treatment option for high-risk patients with calcaneal osteomyelitis. Noah G. Oliver, John S. Steinberg, Kelly Powers, Karen K. Evans, Paul J. Kim, and Christopher E. Attinger Copyright © 2015 Noah G. Oliver et al. All rights reserved. Determining Predictors of Early Response to Exenatide in Patients with Type 2 Diabetes Mellitus Tue, 20 Jan 2015 13:52:03 +0000 Exenatide is a GLP-1 analogue used in the management of T2DM yet within a subset of patients fails due to adverse side effects or from failure to attain the end goal. This retrospective observational study aimed to determine whether we could predict response to exenatide in patients with T2DM. 112 patients on exenatide were included with patient age, gender, duration of T2DM, medications alongside exenatide and weight, BMI, and HbA1c at baseline and 3 and 6 months of exenatide use being recorded. 63 responded with 11 mmol/mol reduction from baseline HbA1c after six months and 49 did not respond to exenatide. HbA1c solely differed significantly between cohorts at baseline, 3 months, and 6 months (P < 0.05). Regression analyses identified a negative linear relationship with higher baseline HbA1c correlating to greater reductions in HbA1c by 6 months (P < 0.0001). HbA1c was the sole predictor of exenatide response with higher baseline HbA1c increasing the odds of response by 5% (P = 0.004). Patients with HbA1c reductions ≥15–20% by 3 months were more likely to be responders by 6 months (P = 0.033). Our study identified that baseline HbA1c acted as the sole predictor of exenatide response and that response may be determined after 3 months of exenatide administration. Muhammad Khan, Jing Ouyang, Karen Perkins, Sunil Nair, and Franklin Joseph Copyright © 2015 Muhammad Khan et al. All rights reserved. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis Tue, 20 Jan 2015 06:52:55 +0000 To evaluate the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on weight reduction in patients with Type 2 diabetes mellitus (Type 2 DM), a network meta-analysis was conducted. MEDLINE, EMBASE, Cochrane Library, and were searched from 1950 to October 2013. Randomized controlled trials (RCTs) involving GLP-1 RAs were included if they provided information on body weight. A total of 51 RCTs were included and 17521 participants were enrolled. The mean duration of 51 RCTs was 31 weeks. Exenatide 10 μg twice daily (EX10BID) reduced weight compared with exenatide 5 μg twice daily (EX5BID), liraglutide 0.6 mg once daily (LIR0.6QD), liraglutide—1.2 mg once daily (LIR1.2QD), and placebo treatment, with mean differences of −1.07 kg (95% CI: −2.41, −0.02), −2.38 kg (95% CI: −3.71, −1.06), −1.62 kg (95% CI: −2.79, −0.43), and −1.92 kg (95% CI: −2.61, −1.24), respectively. Reductions of weight treated with liraglutide—1.8 mg once daily (LIR1.8QD) reach statistical significance (−1.43 kg (95% CI: −2.73, −0.15)) versus LIR1.2QD and (−0.98 kg (95% CI: −1.94, −0.02)) versus placebo. Network meta-analysis found that EX10BID, LIR1.8QD, and EX2QW obtained a higher proportion of patients with weight loss than other traditional hypoglycemic agents. Our results suggest GLP-1 RAs are promising candidates for weight control in comparison with traditional hypoglycemic drugs, and EX10BID, LIR1.8QD, and EX2QW rank the top three drugs. Feng Sun, Sanbao Chai, Lishi Li, Kai Yu, Zhirong Yang, Shanshan Wu, Yuan Zhang, Linong Ji, and Siyan Zhan Copyright © 2015 Feng Sun et al. All rights reserved. Differential Effects of Leptin and Adiponectin in Endothelial Angiogenesis Thu, 15 Jan 2015 06:32:45 +0000 Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality. Endothelial dysfunction is pivotal to the development of cardiovascular disease (CVD). In relation to this, adipose tissue secreted factors termed “adipokines” have been reported to modulate endothelial dysfunction. In this review, we focus on two of the most abundant circulating adipokines, that is, leptin and adiponectin, in the development of endothelial dysfunction. Leptin has been documented to influence a multitude of organ systems, that is, central nervous system (appetite regulation, satiety factor) and cardiovascular system (endothelial dysfunction leading to atherosclerosis). Adiponectin, circulating at a much higher concentration, exists in different molecular weight forms, essentially made up of the collagenous fraction and a globular domain, the latter being investigated minimally for its involvement in proinflammatory processes including activation of NF-κβ and endothelial adhesion molecules. The opposing actions of the two forms of adiponectin in endothelial cells have been recently demonstrated. Additionally, a local and systemic change to multimeric forms of adiponectin has gained importance. Thus detailed investigations on the potential interplay between these adipokines would likely result in better understanding of the missing links connecting CVD, adipokines, and obesity. Raghu Adya, Bee K. Tan, and Harpal S. Randeva Copyright © 2015 Raghu Adya et al. All rights reserved. Suppressive Effect of Insulin on the Gene Expression and Plasma Concentrations of Mediators of Asthmatic Inflammation Tue, 06 Jan 2015 12:52:36 +0000 Background and Hypothesis. Following our recent demonstration that the chronic inflammatory and insulin resistant state of obesity is associated with an increase in the expression of mediators known to contribute to the pathogenesis of asthma and that weight loss after gastric bypass surgery results in the reduction of these genes, we have now hypothesized that insulin suppresses the cellular expression and plasma concentrations of these mediators. Methods. The expression of IL-4, LIGHT, LTBR, ADAM-33, and TSLP in MNC and plasma concentrations of LIGHT, TGF-β1, MMP-9, MCP-1, TSLP, and NOM in obese patients with T2DM were measured before, during, and after the infusion of a low dose (2 U/h) infusion of insulin for 4 hours. The patients were also infused with dextrose or saline for 4 hours on two separate visits and served as controls. Results. Following insulin infusion, the mRNA expression of IL-4, ADAM-33, LIGHT, and LTBR mRNA expression fell significantly ( for all). There was also a concomitant reduction in plasma NOM, LIGHT, TGF-β1, MCP-1, and MMP-9 concentrations. Conclusions. Insulin suppresses the expression of these genes and mediators related to asthma and may, therefore, have a potential role in the treatment of asthma. Husam Ghanim, Kelly Green, Sanaa Abuaysheh, Manav Batra, Nitesh D. Kuhadiya, Reema Patel, Antoine Makdissi, Sandeep Dhindsa, Ajay Chaudhuri, and Paresh Dandona Copyright © 2015 Husam Ghanim et al. All rights reserved. An Altered Pattern of Myocardial Histopathological and Molecular Changes Underlies the Different Characteristics of Type-1 and Type-2 Diabetic Cardiac Dysfunction Mon, 05 Jan 2015 13:46:47 +0000 Increasing evidence suggests that both types of diabetes mellitus (DM) lead to cardiac structural and functional changes. In this study we investigated and compared functional characteristics and underlying subcellular pathological features in rat models of type-1 and type-2 diabetic cardiomyopathy. Type-1 DM was induced by streptozotocin. For type-2 DM, Zucker Diabetic Fatty (ZDF) rats were used. Left ventricular pressure-volume analysis was performed to assess cardiac function. Myocardial nitrotyrosine immunohistochemistry, TUNEL assay, hematoxylin-eosin, and Masson’s trichrome staining were performed. mRNA and protein expression were quantified by qRT-PCR and Western blot. Marked systolic dysfunction in type-1 DM was associated with severe nitrooxidative stress, apoptosis, and fibrosis. These pathological features were less pronounced or absent, while cardiomyocyte hypertrophy was comparable in type-2 DM, which was associated with unaltered systolic function and increased diastolic stiffness. mRNA-expression of hypertrophy markers c-fos, c-jun, and β-MHC, as well as pro-apoptotic caspase-12, was elevated in type-1, while it remained unaltered or only slightly increased in type-2 DM. Expression of the profibrotic TGF-β1 was upregulated in type-1 and showed a decrease in type-2 DM. We compared type-1 and type-2 diabetic cardiomyopathy in standard rat models and described an altered pattern of key pathophysiological features in the diabetic heart and corresponding functional consequences. Tamás Radovits, Sevil Korkmaz, Csaba Mátyás, Attila Oláh, Balázs Tamás Németh, Szabolcs Páli, Kristóf Hirschberg, Alina Zubarevich, Patricia Neh Gwanmesia, Shiliang Li, Sivakkanan Loganathan, Enikő Barnucz, Béla Merkely, and Gábor Szabó Copyright © 2015 Tamás Radovits et al. All rights reserved. Dendrobium chrysotoxum Lindl. Alleviates Diabetic Retinopathy by Preventing Retinal Inflammation and Tight Junction Protein Decrease Thu, 01 Jan 2015 14:10:12 +0000 Diabetic retinopathy (DR) is a serious complication of diabetes mellitus. This study aimed to observe the alleviation of the ethanol extract of Dendrobium chrysotoxum Lindl. (DC), a traditional Chinese herbal medicine, on DR and its engaged mechanism. After DC (30 or 300 mg/kg) was orally administrated, the breakdown of blood retinal barrier (BRB) in streptozotocin- (STZ-) induced diabetic rats was attenuated by DC. Decreased retinal mRNA expression of tight junction proteins (including occludin and claudin-1) in diabetic rats was also reversed by DC. Western blot analysis and retinal immunofluorescence staining results further confirmed that DC reversed the decreased expression of occludin and claudin-1 proteins in diabetic rats. DC reduced the increased retinal mRNA expressions of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor α (TNFα), interleukin- (IL-) 6, and IL-1β in diabetic rats. In addition, DC alleviated the increased 1 and phosphorylated p65, IκB, and IκB kinase (IKK) in diabetic rats. DC also reduced the increased serum levels of TNFα, interferon-γ (IFN-γ), IL-6, IL-1β, IL-8, IL-12, IL-2, IL-3, and IL-10 in diabetic rats. Therefore, DC can alleviate DR by inhibiting retinal inflammation and preventing the decrease of tight junction proteins, such as occludin and claudin-1. Zengyang Yu, Chenyuan Gong, Bin Lu, Li Yang, Yuchen Sheng, Lili Ji, and Zhengtao Wang Copyright © 2015 Zengyang Yu et al. All rights reserved. Novel KIF6 Polymorphism Increases Susceptibility to Type 2 Diabetes Mellitus and Coronary Heart Disease in Han Chinese Men Wed, 31 Dec 2014 12:47:34 +0000 Objectives. The effect of the KIF6 polymorphism Trp719Arg on the risk of T2DM and T2DM with CHD remains unclear. Methods. 946 unrelated subjects of Han Chinese origin were recruited, comprising 346 controls, 312 T2DM, and 288 T2DM + CHD patients. Genotyping was performed by high-resolution melting curve analysis using real-time qPCR. The impact of the variant on T2DM/T2DM + CHD and gene-sex interaction were evaluated by stepwise multiple regression analysis. Results. The frequencies of the Trp719 allele in T2DM and T2DM + CHD patients were similar to the control group, whereas significantly increased 719Arg allele frequencies were observed in male T2DM and T2DM + CHD patients compared with the corresponding control group. Further sex partition analysis revealed that only male 719Arg allele carriers had approximately 3-fold and 5-fold higher risk of T2DM and T2DM + CHD, respectively, than noncarriers. There was also a significant association between carriers and higher TG and lower HDL-C levels. Conclusion. The KIF6 719Arg allele may increase the risk of T2DM and T2DM + CHD only in Han Chinese men by modulating lipid metabolism, especially with regard to TG and HDL. Ge Wu, Gui-Bin Li, Bin Dai, and Dong-Qing Zhang Copyright © 2014 Ge Wu et al. All rights reserved. The Class I Histone Deacetylase Inhibitor MS-275 Prevents Pancreatic Beta Cell Death Induced by Palmitate Wed, 31 Dec 2014 08:32:57 +0000 Elevation of the dietary saturated fatty acid palmitate contributes to the reduction of functional beta cell mass in the pathogenesis of type 2 diabetes. The diabetogenic effect of palmitate is achieved by increasing beta cell death through induction of the endoplasmic reticulum (ER) stress markers including activating transcription factor 3 (Atf3) and CAAT/enhancer-binding protein homologous protein-10 (Chop). In this study, we investigated whether treatment of beta cells with the MS-275, a HDAC1 and HDAC3 activity inhibitor which prevents beta cell death elicited by cytokines, is beneficial for combating beta cell dysfunction caused by palmitate. We show that culture of isolated human islets and MIN6 cells with MS-275 reduced apoptosis evoked by palmitate. The protective effect of MS-275 was associated with the attenuation of the expression of Atf3 and Chop. Silencing of HDAC3, but not of HDAC1, mimicked the effects of MS-275 on the expression of the two ER stress markers and apoptosis. These data point to HDAC3 as a potential drug target for preserving beta cells against lipotoxicity in diabetes. Valérie Plaisance, Laure Rolland, Valéry Gmyr, Jean-Sébastien Annicotte, Julie Kerr-Conte, François Pattou, and Amar Abderrahmani Copyright © 2014 Valérie Plaisance et al. All rights reserved. Hyperglycemia Inhibits Complement-Mediated Immunological Control of S. aureus in a Rat Model of Peritonitis Wed, 31 Dec 2014 00:10:47 +0000 Hyperglycemia from diabetes is associated with increased risk of infection from S. aureus and increased severity of illness. Previous work in our laboratory demonstrated that elevated glucose (>6 mM) dramatically inhibited S. aureus-initiated complement-mediated immune effectors. Here we report in vivo studies evaluating the extent to which a hyperglycemic environment alters complement-mediated control of S. aureus infection in a rat peritonitis model. Rats were treated with streptozocin to induce diabetes or sham-treated and then inoculated i.p. with S. aureus. Rats were euthanized and had peritoneal lavage at 2 or 24 hours after infection to evaluate early and late complement-mediated effects. Hyperglycemia decreased the influx of IgG and complement components into the peritoneum in response to S. aureus infection and decreased anaphylatoxin generation. Hyperglycemia decreased C4-fragment and C3-fragment opsonization of S. aureus recovered in peritoneal fluids, compared with euglycemic or insulin-rescued rats. Hyperglycemic rats showed decreased phagocytosis efficiency compared with euglycemic rats, which correlated inversely with bacterial survival. These results suggest that hyperglycemia inhibited humoral effector recruitment, anaphylatoxin generation, and complement-mediated opsonization of S. aureus, suggesting that hyperglycemic inhibition of complement effectors may contribute to the increased risk and severity of S. aureus infections in diabetic patients. Clifford T. Mauriello, Pamela S. Hair, Reuben D. Rohn, Nicholas S. Rister, Neel K. Krishna, and Kenji M. Cunnion Copyright © 2014 Clifford T. Mauriello et al. All rights reserved. Hyperglycemia Induces Toll-Like Receptor-2 and -4 Expression and Activity in Human Microvascular Retinal Endothelial Cells: Implications for Diabetic Retinopathy Wed, 31 Dec 2014 00:10:46 +0000 Diabetic retinopathy (DR) causes visual impairment in working age adults and hyperglycemia-mediated inflammation is central in DR. Toll-like receptors (TLRs) play a key role in innate immune responses and inflammation. However, scanty data is available on their role in DR. Hence, in this study, we examined TLR2 and TLR4 mRNA and protein expression and activity in hyperglycemic human retinal endothelial cells (HMVRECs). HMVRECs were treated with hyperglycemia (HG) or euglycemia and mRNA and protein levels of TLR-2, TLR-4, MyD88, IRF3, and TRIF as well as NF-κB p65 activation were measured. IL-8, IL-1β, TNF-α and MCP-1, ICAM-1, and VCAM-1 as well as monocyte adhesion to HMVRECs were also assayed. HG (25 mM) significantly induced TLR2 and TLR4 mRNA and protein in HMVRECs. It also increased both MyD88 and non-MyD88 pathways, nuclear factor-κB (NF-κB), biomediators, and monocyte adhesion. This inflammation was attenuated by TLR-4 or TLR-2 inhibition, and dual inhibition by a TLR inhibitory peptide as well as TLR2 and 4 siRNA. Additionally, antioxidant treatment reduced TLR-2 and TLR4 expression and downstream inflammatory markers. Collectively, our novel data suggest that hyperglycemia induces TLR-2 and TLR-4 activation and downstream signaling mediating increased inflammation possibly via reactive oxygen species (ROS) and could contribute to DR. Uthra Rajamani and Ishwarlal Jialal Copyright © 2014 Uthra Rajamani and Ishwarlal Jialal. All rights reserved. Sodium Meta-Arsenite Ameliorates Hyperglycemia in Obese Diabetic db/db Mice by Inhibition of Hepatic Gluconeogenesis Wed, 24 Dec 2014 00:10:11 +0000 Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10 mg kg−1 body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1. Young-Sun Lee, Eun-Kyu Lee, Hyun-Hee Oh, Cheol Soo Choi, Sujong Kim, and Hee-Sook Jun Copyright © 2014 Young-Sun Lee et al. All rights reserved. Generating and Reversing Chronic Wounds in Diabetic Mice by Manipulating Wound Redox Parameters Tue, 23 Dec 2014 09:22:07 +0000 By 2025, more than 500 M people worldwide will suffer from diabetes; 125 M will develop foot ulcer(s) and 20 M will undergo an amputation, creating a major health problem. Understanding how these wounds become chronic will provide insights to reverse chronicity. We hypothesized that oxidative stress (OS) in wounds is a critical component for generation of chronicity. We used the db/db mouse model of impaired healing and inhibited, at time of injury, two major antioxidant enzymes, catalase and glutathione peroxidase, creating high OS in the wounds. This was necessary and sufficient to trigger wounds to become chronic. The wounds initially contained a polymicrobial community that with time selected for specific biofilm-forming bacteria. To reverse chronicity we treated the wounds with the antioxidants α-tocopherol and N-acetylcysteine and found that OS was highly reduced, biofilms had increased sensitivity to antibiotics, and granulation tissue was formed with proper collagen deposition and remodeling. We show for the first time generation of chronic wounds in which biofilm develops spontaneously, illustrating importance of early and continued redox imbalance coupled with the presence of biofilm in development of wound chronicity. This model will help decipher additional mechanisms and potentially better diagnosis of chronicity and treatment of human chronic wounds. Sandeep Dhall, Danh C. Do, Monika Garcia, Jane Kim, Seyed H. Mirebrahim, Julia Lyubovitsky, Stefano Lonardi, Eugene A. Nothnagel, Neal Schiller, and Manuela Martins-Green Copyright © 2014 Sandeep Dhall et al. All rights reserved. ACE Insertion/Deletion Polymorphism and Diabetic Nephropathy: Clinical Implications of Genetic Information Tue, 23 Dec 2014 07:39:12 +0000 Approximately 20–40% of diabetic patients develop nephropathy which is the leading cause of ESRD in developed countries. The ACE I/D polymorphism is thought to be a marker for functional polymorphism which regulates circulating and tissue ACE activity. While the initial study found a protective effect of the II genotype on the development of nephropathy in IDDM patients, subsequent studies have addressed the role of ACE I/D polymorphism in the development and progression of diabetic nephropathy. RAAS blockers are the first line drugs for the treatment hypertension associated with diabetes and have been widely used in everyday clinical practice for the purpose of reducing proteinuria in patients with various renal diseases. However, the antiproteinuric effect of RAAS blockers is variable and the percentage of reducing proteinuria is in the range of 20–80%. The antiproteinuric effect of RAAS blockers may be related to a number of factors: the type or the dose of RAAS blockers, the duration of therapy, the level of sodium intake, and the type of patient’s ACE I/D genotype. Besides the nongenetic factors, drug responses, can be influenced by ACE gene polymorphism. In this review, we discuss the relationship between ACE I/D polymorphism and diabetic nephropathy and therapeutic response of RAAS blockers. Sung-Kyu Ha Copyright © 2014 Sung-Kyu Ha. All rights reserved. T-Cell Cytokine Gene Polymorphisms and Vitamin D Pathway Gene Polymorphisms in End-Stage Renal Disease due to Type 2 Diabetes Mellitus Nephropathy: Comparisons with Health Status and Other Main Causes of End-Stage Renal Disease Mon, 22 Dec 2014 11:34:21 +0000 Background. T-cell cytokine gene polymorphisms and vitamin D pathway gene polymorphisms were evaluated as possibly associated with end-stage renal disease (ESRD) resulting from type 2 diabetes mellitus (DM) nephropathy. Methods. Studies were conducted among hemodialysis (HD) patients with ESRD due to type 2 DM nephropathy, chronic glomerulonephritis, chronic infective tubulointerstitial nephritis, and hypertensive nephropathy as well as in healthy subjects. A frequency distribution of T-cell-related interleukin (IL) genes (IL18 rs360719, IL12A rs568408, IL12B rs3212227, IL4R rs1805015, IL13 rs20541, IL28B rs8099917, IL28B, and rs12979860) and vitamin D pathway genes (GC genes: rs2298849, rs7041, and rs1155563; VDR genes: rs2228570, rs1544410; and RXRA genes: rs10776909, rs10881578, and rs749759) was compared between groups. Results. No significant differences in a frequency distribution of tested polymorphisms were shown between type 2 DM nephropathy patients and controls. A difference was found in IL18 rs360719 polymorphic distribution between the former group and chronic infective tubulointerstitial nephritic patients (), which also differed in this polymorphism from controls (). Conclusion. T-cell cytokine and vitamin D pathway gene polymorphisms are not associated with ESRD due to type 2 DM nephropathy in Polish HD patients. IL18 rs360719 is probably associated with the pathogenesis of chronic infective tubulointerstitial nephritis. Alicja E. Grzegorzewska, Grzegorz Ostromecki, Paulina Zielińska, Adrianna Mostowska, and Paweł P. Jagodziński Copyright © 2014 Alicja E. Grzegorzewska et al. All rights reserved. TNF-α and Microalbuminuria in Patients with Type 2 Diabetes Mellitus Mon, 22 Dec 2014 10:56:25 +0000 Aim. Recent evidence suggests that chronic subclinical inflammation plays a key role in the pathogenesis and progression of diabetic nephropathy. Aim of the present study was to investigate possible correlation between the presence and degree of microalbuminuria and markers of inflammation in patients with type 2 diabetes mellitus (DM). Patients-Methods. Eighty patients were enrolled and clinical and laboratory data were recorded. Albumin-creatinine ratio (ACR) was calculated in first-morning urine samples. Serum and urinary tumor necrosis factor- (TNF-) levels were determined by ELISA. Results. Forty-five patients had normoalbuminuria, 33 microalbuminuria, and 2 macroalbuminuria. Patients with microalbuminuria were older, with higher glycosylated hemoglobin levels (HbA1c) and they more frequently had diabetic retinopathy, neuropathy, and cardiovascular disease and were on treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). ACR was significantly correlated with the presence of cardiovascular disease, hypertension, and HbA1c levels and the administration of clopidogrel and ACEi or ARBs. ACR was not correlated with C-reactive protein, fibrinogen, or serum TNF- levels but had a strong correlation with urinary TNF- levels. Conclusions. In patients with type 2 DM, urinary, but not serum, TNF- levels are associated with the presence and severity of microalbuminuria. I.-Th. Lampropoulou, M. Stangou, A. Papagianni, T. Didangelos, F. Iliadis, and G. Efstratiadis Copyright © 2014 I.-Th. Lampropoulou et al. All rights reserved. Relationship between Levels of Brain-Derived Neurotrophic Factor and Metabolic Parameters in Patients with Type 2 Diabetes Mellitus Mon, 22 Dec 2014 08:24:37 +0000 Background and Aim. Studies have suggested that brain-derived neurotrophic factor (BDNF) plays a role in glucose and lipid metabolism and inflammation. The aim of this study was to evaluate the relationship between serum BDNF levels and various metabolic parameters and inflammatory markers in patients with type 2 diabetes mellitus (T2DM). Materials and Methods. The study included 88 T2DM patients and 33 healthy controls. Fasting blood samples were obtained from the patients and the control group. The serum levels of BDNF were measured with an ELISA kit. The current paper introduces a receiver-operating characteristic (ROC) generalization curve to identify cut-off for the BDNF values in type 2 diabetes patients. Results. The serum levels of BDNF were significantly higher in T2DM patients than in the healthy controls (206.81 ± 107.32 pg/mL versus 130.84 ± 59.81 pg/mL; ). They showed a positive correlation with the homeostasis model assessment of insulin resistance (HOMA-IR) (; ), the triglyceride level (; ), and white blood cell (WBC) count (; ). In logistic regression analysis, age (), body mass index (BMI) (), C-reactive protein (CRP) (), and BDNF () were independently associated with T2DM. In ROC curve analysis, BDNF cut-off was 137. Conclusion. The serum BDNF level was higher in patients with T2DM. The BDNF had a cut-off value of 137. The findings suggest that BDNF may contribute to glucose and lipid metabolism and inflammation. Banu Boyuk, Serife Degirmencioglu, Hande Atalay, Savas Guzel, Ayse Acar, Aslan Celebi, Ismail Ekizoglu, and Caglar Simsek Copyright © 2014 Banu Boyuk et al. All rights reserved. Nonadherence and Contributing Factors among Ambulatory Patients with Antidiabetic Medications in Adama Referral Hospital Wed, 03 Dec 2014 09:58:21 +0000 The objective of this study was to determine the magnitude of nonadherence and its contributing factors among diabetic patients attending the diabetic clinic in Adama Hospital. Methods. This descriptive cross-sectional study was carried out among patients with diabetes mellitus attending the diabetes mellitus clinic of Adama Referral Hospital. Every other patient was selected and data regarding their medication adherence was collected using a structured interview. Data analysis was carried out using SPSS-16. Result. The response rate from this study was 98.3%. A total of 270 patients were interviewed; 51.5% were males. A total of 68.1% of the patients included in the study were married. 14% were younger than 40 years, and 50% were between 40 and 60 years. 21.8% of the participants ascribed their nonadherence to forgetting to take their medications. Patients with duration of diabetes 5 years (82.07%) were more compliant to their medication than those with 5 years (60.8%), which was found to be statistically significant . Insulin, 47%, and glibenclamide plus metformin, 43.7%, were the most commonly prescribed mono- and combination therapies, respectively. Common comorbid conditions include hypertension, 148 (54.82%), and visual impairment, 89 (32.96%). The proportion of male patients adherent to their antidiabetic medications was found to be lower than 69.78% compared to the female patients (74.81%), but the difference was not statistically significant . Conclusion. Most diabetic patients are currently being managed with the most effective available drugs. However the result from this study indicates that the desired blood sugar level could not be controlled and maintained adequately. This was because of poor adherence to the prescribed drug regimen and poor knowledge and practice of successful self-management. Belayneh Kefale Gelaw, Abdela Mohammed, Gobezie Temesgen Tegegne, Amsalu Degu Defersha, Muluneh Fromsa, Esayas Tadesse, Thrumurgan Gunasekaran, and Mustefa Ahmed Copyright © 2014 Belayneh Kefale Gelaw et al. All rights reserved. Effects of Fenofibrate on Adiponectin Expression in Retinas of Streptozotocin-Induced Diabetic Rats Mon, 01 Dec 2014 10:08:20 +0000 Adiponectin has been associated with increased risks of microvascular complications in diabetes; however, its role in the development of diabetic retinopathy (DR) is unknown. Fenofibrate is a lipid-lowering agent that has been shown to be capable of preventing DR progression. We investigated the expression of adiponectin and its receptors in DR and evaluated the effects of fenofibrate on their expression. The mRNA and protein levels of adiponectin and its receptors were elevated in retinas of streptozotocin-induced diabetic rats and were suppressed following fenofibrate treatment. Immunofluorescence staining demonstrated that adiponectin and adipoR1 were expressed in cells located within blood vessels, the retinal ganglion, and the inner nuclear layer. AdipoR1 was strongly expressed whereas adipoR2 was only weekly expressed in vascular endothelial cells. The in vitro experiments showed that adiponectin expression was induced by high glucose concentrations in RGC-5 and RAW264.7 cells and was suppressed following fenofibrate treatment. AdipoR1 and adipoR2 levels in RGC-5 cells were elevated in high glucose concentrations and suppressed by fenofibrate. Our results demonstrated that adiponectin may be a proinflammatory mediator in diabetic retinas and fenofibrate appears to modulate the expression of adiponectin and its receptors in diabetic retinas, effectively reducing DR progression. Ying-Jung Hsu, Lu-Chun Wang, Wei-Shiung Yang, Chung-May Yang, and Chang-Hao Yang Copyright © 2014 Ying-Jung Hsu et al. All rights reserved. Low Molecular Weight Fucoidan Alleviates Cardiac Dysfunction in Diabetic Goto-Kakizaki Rats by Reducing Oxidative Stress and Cardiomyocyte Apoptosis Sun, 30 Nov 2014 07:54:51 +0000 Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and cardiomyocyte apoptosis. Oxidative stress is suggested to be the major contributor to the development of DCM. This study was intended to evaluate the protective effect of low molecular weight fucoidan (LMWF) against cardiac dysfunction in diabetic rats. Type 2 diabetic goto-kakizaki rats were untreated or treated with LMWF (50 and 100 mg/kg/day) for three months. The establishment of DCM model and the effects of LMWF on cardiac function were evaluated by echocardiography and isolated heart perfusion. Ventricle staining with H-E or Sirius Red was performed to investigate the structural changes in myocardium. Functional evaluation demonstrated that LMWF has a beneficial effect on DCM by enhancing myocardial contractility and mitigating cardiac fibrosis. Additionally, LMWF exerted significant inhibitory effects on the reactive oxygen species production and myocyte apoptosis in diabetic hearts. The depressed activity of superoxide dismutase in diabetic heart was also improved by intervention with LMWF. Moreover, LMWF robustly inhibited the enhanced expression of protein kinase C β, an important contributor to oxidative stress, in diabetic heart and high glucose-treated cardiomyocytes. In conclusion, LMWF possesses a protective effect against DCM through ameliorations of PKCβ-mediated oxidative stress and subsequent cardiomyocyte apoptosis in diabetes. Xinfeng Yu, Quanbin Zhang, Wentong Cui, Zheng Zeng, Wenzhe Yang, Chao Zhang, Hongwei Zhao, Weidong Gao, Xiaomin Wang, and Dali Luo Copyright © 2014 Xinfeng Yu et al. All rights reserved. Glyoxylate, a New Marker Metabolite of Type 2 Diabetes Thu, 27 Nov 2014 08:36:26 +0000 Type 2 diabetes (T2D) is characterized by a variety of metabolic impairments that are closely linked to nonenzymatic glycation reactions of proteins and peptides resulting in advanced glycation end-products (AGEs). Reactive aldehydes derived from sugars play an important role in the generation of AGEs. Using metabolite profiling to characterize human plasma from diabetic versus nondiabetic subjects we observed in a recent study that the reactive aldehyde glyoxylate was increased before high levels of plasma glucose, typical for a diabetic condition, could be measured. Following this observation, we explored the relevance of increased glyoxylate in diabetic subjects and in diabetic C57BLKS/J- mice in the pathophysiology of diabetes. A retrospective study using samples of long-term blood donors revealed that glyoxylate levels unlike glucose levels became significantly elevated up to 3 years prior to diabetes diagnosis (difference to control ). Elevated glyoxylate levels impact on newly identified mechanisms linking hyperglycemia and AGE production with diabetes-associated complications such as diabetic nephropathy. Glyoxylate in its metabolic network may serve as an early marker in diabetes diagnosis with predictive qualities for associated complications and as potential to guide the development of new antidiabetic therapies. Victoria J. Nikiforova, Pieter Giesbertz, Jan Wiemer, Bianca Bethan, Ralf Looser, Volker Liebenberg, Patricia Ruiz Noppinger, Hannelore Daniel, and Dietrich Rein Copyright © 2014 Victoria J. Nikiforova et al. All rights reserved. The GLP-1 Analogue Exenatide Improves Hepatic and Muscle Insulin Sensitivity in Diabetic Rats: Tracer Studies in the Basal State and during Hyperinsulinemic-Euglycemic Clamp Sun, 16 Nov 2014 00:00:00 +0000 Objective. Glucagon-like peptide-1 (GLP-1) analogues (e.g., exenatide) increase insulin secretion in diabetes but less is known about their effects on glucose production or insulin-stimulated glucose uptake in peripheral tissues. Methods. Four groups of Sprague-Dawley rats were studied: nondiabetic (control, C); nondiabetic + exenatide (C + E); diabetic (D); diabetic + exenatide (D + E) with diabetes induced by streptozotocin and high fat diet. Infusion of 3-3H-glucose and U-13C-glycerol was used to measure basal rates of appearance () of glucose and glycerol and gluconeogenesis from glycerol (GNG). During hyperinsulinemic-euglycemic clamp, glucose uptake into gastrocnemius muscles was measured with 2-deoxy-D-14C-glucose. Results. In the diabetic rats, exenatide reduced the basal of glucose () and glycerol () and GNG (). During the clamp, of glucose was also reduced, whereas the rate of disappearance of glucose increased and there was increased glucose uptake into muscle () during the clamp. In the nondiabetic rats, exenatide had no effect. Conclusion. In addition to its known effects on insulin secretion, administration of the GLP-1 analogue, exenatide, is associated with increased inhibition of gluconeogenesis and improved glucose uptake into muscle in diabetic rats, implying improved hepatic and peripheral insulin sensitivity. Hui Wu, Chunhua Sui, Hui Xu, Fangzhen Xia, Hualing Zhai, Huixin Zhang, Pan Weng, Bing Han, Sichun Du, and Yingli Lu Copyright © 2014 Hui Wu et al. All rights reserved. The Efficacy of Jing Wan Hong Ointment for Nerve Injury Diabetic Foot Ulcer and Its Mechanisms Sun, 16 Nov 2014 00:00:00 +0000 Jing Wan Hong ointment contains 30 kinds of Chinese herbs, with functions of activating blood circulation to disperse blood stasis, clearing heat, eliminating dampness, and reducing swelling by detoxification. Therefore, Jing Wan Hong ointment may facilitate the healing of ulcers. The aim of this study was to evaluate the efficacy and mechanisms of Jing Wan Hong ointment for healing diabetic foot ulceration in Wistar rats induced by streptozotocin and sciatic nerve damage. The results showed that Jing Wan Hong ointment had a marked effect on foot ulcers in diabetic rats induced by initial nerve injury. These effects were manifested by reducing the foot ulcer size and Wagner grade after seven days of treatment. The diabetic rats with foot ulcers were almost healed after 21 days of treatment. Moreover, the mechanisms of this effect seem to be dependent on increased expression of PDGF mRNA, but there was no influence on the expression of TGF-β, VEGF, and FLT-1 mRNA. Shumei Jin, Mixia Zhang, Yan Gao, Xuebin Zhang, Guangzhi Cui, and Yanjun Zhang Copyright © 2014 Shumei Jin et al. All rights reserved. Plasma Gelsolin Levels Decrease in Diabetic State and Increase upon Treatment with F-Actin Depolymerizing Versions of Gelsolin Wed, 12 Nov 2014 12:04:22 +0000 The study aims to map plasma gelsolin (pGSN) levels in diabetic humans and mice models of type II diabetes and to evaluate the efficacy of gelsolin therapy in improvement of diabetes in mice. We report that pGSN values decrease by a factor of 0.45 to 0.5 in the blood of type II diabetic humans and mice models. Oral glucose tolerance test in mice models showed that subcutaneous administration of recombinant pGSN and its F-actin depolymerizing competent versions brought down blood sugar levels comparable to Sitagliptin, a drug used to manage hyperglycemic condition. Further, daily dose of pGSN or its truncated versions to diabetic mice for a week kept sugar levels close to normal values. Also, diabetic mice treated with Sitagliptin for 7 days, showed increase in their pGSN values with the decrease in blood glucose as compared to their levels at the start of treatment. Gelsolin helped in improving glycemic control in diabetic mice. We propose that gelsolin level monitoring and replacement of F-actin severing capable gelsolin(s) should be considered in diabetic care. Neeraj Khatri, Amin Sagar, Nagesh Peddada, Vikas Choudhary, Bhupinder Singh Chopra, Veena Garg, Renu Garg, and Ashish Copyright © 2014 Neeraj Khatri et al. All rights reserved. Mild Cognitive Impairment and Depressive Symptoms in Elderly Patients with Diabetes: Prevalence, Risk Factors, and Comorbidity Sun, 09 Nov 2014 14:10:33 +0000 The aim of the study was to estimate the prevalence of mild cognitive impairment (MCI), depressive syndrome cases, and its comorbidity, and to identify predictors of these conditions. Methods. 276 diabetics elders were screened for MCI and depressive symptoms. Detailed information of history of diabetes, and data of BMI, HbA1c, and blood lipids were collected. Results. The prevalence of MCI was 31.5%, depressive syndrome was 29.7%, and MCI with coexisting depressive mood was 9.1%. The logistic regression analysis revealed that variables which increased the likelihood of having been diagnosed with MCI were: higher HbA1c level, previous CVD, hypertension, retinopathy, increased number of comorbidities, and less years of formal education. Significant predictors of having a depressive mood included female gender, single marital status, current and past smoking status, lack of physical activity, higher BMI and total cholesterol level, increased number of comorbidities, history of hypoglycemia, and insulin treatment. Factors associated with both MCI and depressive syndrome were female gender, single marital status, past smoking status, retinopathy, previous CVD or stroke, increased number of comorbidities, and insulin treatment. Conclusions. Depressive symptoms, MCI, and its comorbidity are common in elderly subjects with type 2 diabetes. Systematic screening could result in the identification of high-risk patients. Malgorzata Gorska-Ciebiada, Malgorzata Saryusz-Wolska, Maciej Ciebiada, and Jerzy Loba Copyright © 2014 Malgorzata Gorska-Ciebiada et al. All rights reserved. Evaluation of Hypoglycemic Efficacy of Tangningtongluo Formula, a Traditional Chinese Miao Medicine, in Two Rodent Animal Models Wed, 05 Nov 2014 11:01:06 +0000 Traditional Chinese medicines largely lack adequate and scientifically rigorous evidence regarding efficacy and functional mechanisms. The present study was aimed to confirm the hypoglycemic effect of Tangningtongluo (TNTL) formula, a traditional Chinese Miao medicine, in two animal models: high-fat diet and streptozotocin- (STZ-) induced diabetic rats and C57BL/KsJ-db/db diabetic mice. After 4 weeks, TNTL intervention in STZ-induced diabetic rats yielded in significant improvement on the glucose tolerance test. Moreover, the islet histopathology showed that oral TNTL reduced the severity of islet necrosis in pancreases tissue. Compared with diabetic controls, a 12-week TNTL treatment regimen (dosages = 0.9, 1.8, and 3.6 g/kg) in db/db mice significantly decreased fasting glucose and HbA1c. Additionally, oral glucose tolerance in TNTL-treated mice improved significantly, compared with diabetic mice receiving metformin. Finally, tissue histopathology and biochemical index evaluations revealed significant improvement in TNTL-treated mice. Taken together, our results show that TNTL exerted a strong hypoglycemic effect in two diabetic rodent animal models, preserving -cells in the pancreas islet and reducing the risk of diabetic retinopathy and nephropathy. Long Cheng, Xiang-bao Meng, Shan Lu, Ting-ting Wang, Yue Liu, Gui-bo Sun, and Xiao-bo Sun Copyright © 2014 Long Cheng et al. All rights reserved. Comparative MicroRNA Expression Profiles of Cynomolgus Monkeys, Rat, and Human Reveal that miR-182 Is Involved in T2D Pathogenic Processes Tue, 04 Nov 2014 00:00:00 +0000 Type 2 diabetes (T2D) is a prevalent disease that happens around the world and usually happens with insulin resistance. MicroRNAs (miRNAs) represented important roles in the suppression of gene expression and were proven to be related to human diseases. In this study, we used cynomolgus monkey fed with normal and high fatty diet (HFD), respectively, to analyze the miRNA expression profile in whole blood by deep sequencing. Finally in total 24 miRNAs with differential expression were filtered. Among them, miR-182 related to the insulin resistance by modulating FOXO1 and PI3K/AKT cascade and had the greatest copy number in the whole blood. Decrease of miR-182 in T2D cynomolgus individuals is completely consistent with the previous studies in human and rat. Integrating miR-182 tissue expression profile, target genes, and copy number in blood reveals that miR-182 plays a key role in crucial genes modulation, such as FOXO1 and BHLHE22, which leads to potential hyperglycemia and modulates the insulin secretion. In addition, miR-182 might regulate the processes of both cell proliferation and apoptosis that play crucial role in determining the cells’ fate. Therefore, miR-182 can be a biomarker in diagnosis of the potential T2D that has benefits for medical purpose. Jinghui Zhou, Yuhuan Meng, Shuai Tian, Junhui Chen, Mingyu Liu, Min Zhuo, Yu Zhang, Hongli Du, and Xiaoning Wang Copyright © 2014 Jinghui Zhou et al. All rights reserved.