Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . 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. The Unfolded Protein Response and Diabetic Retinopathy Wed, 29 Oct 2014 13:48:58 +0000 Diabetic retinopathy, a common complication of diabetes, is the leading cause of blindness in adults. Diabetes chronically damages retinal blood vessels and neurons likely through multiple pathogenic pathways such as oxidative stress, inflammation, and endoplasmic reticulum (ER) stress. To relieve ER stress, the cell activates an adaptive mechanism known as the unfolded protein response (UPR). The UPR coordinates the processes of protein synthesis, protein folding, and degradation to ensure proteostasis, which is vital for cell survival and activity. Emerging evidence suggests that diabetes can activate all three UPR branches in retinal cells, among which the PERK/ATF4 pathway is the most extensively studied in the development of diabetic retinopathy. X-box binding protein 1 (XBP1) is a major transcription factor in the core UPR pathway and also regulates a variety of genes involved in cellular metabolism, redox state, autophagy, inflammation, cell survival, and vascular function. The exact function and implication of XBP1 in the pathogenesis of diabetic retinopathy remain elusive. Focusing on this less studied pathway, we summarize recent progress in studies of the UPR pertaining to diabetic changes in retinal vasculature and neurons, highlighting the perspective of XBP1 as a potential therapeutic target in diabetic retinopathy. Jacey Hongjie Ma, Josh J. Wang, and Sarah X. Zhang Copyright © 2014 Jacey Hongjie Ma et al. All rights reserved. Comment on “Impact of Diabetic Foot on Selected Psychological or Social Characteristics” Tue, 28 Oct 2014 10:21:55 +0000 Vladimíra Fejfarová, Alexandra Jirkovská, Eva Dragomirecká, Frances Game, Robert Bém, Michal Dubský, Veronika Wosková, Marta Křížová, Jelena Skibová, and Stephanie Wu Copyright © 2014 Vladimíra Fejfarová et al. All rights reserved. A Modified Method of Insulin Producing Cells’ Generation from Bone Marrow-Derived Mesenchymal Stem Cells Wed, 22 Oct 2014 13:50:05 +0000 Type 1 diabetes mellitus is a result of autoimmune destruction of pancreatic insulin producing β-cells and so far it can be cured only by insulin injection, by pancreas transplantation, or by pancreatic islet cells’ transplantation. The methods are, however, imperfect and have a lot of disadvantages. Therefore new solutions are needed. The best one would be the use of differentiated mesenchymal stem cells (MSCs). In the present study, we investigated the potential of the bone marrow-derived MSCs line for in vitro differentiation into insulin producing cells (IPSs). We applied an 18-day protocol to differentiate MSCs. Differentiating cells formed cell clusters some of which resembled pancreatic islet-like cells. Using dithizone we confirmed the presence of insulin in the cells. What is more, the expression of proinsulin C-peptide in differentiated IPCs was analyzed by flow cytometry. For the first time, we investigated the influence of growth factors’ concentration on IPCs differentiation efficiency. We have found that an increase in the concentration of growth factors up to 60 ng/mL of β-FGF/EGF and 30 ng/mL of activin A/β-cellulin increases the percentage of IPCs. Further increase of growth factors does not show any increase of the percentage of differentiated cells. Our findings suggest that the presented protocol can be adapted for differentiation of insulin producing cells from stem cells. Paweł Czubak, Agnieszka Bojarska-Junak, Jacek Tabarkiewicz, and Lechosław Putowski Copyright © 2014 Paweł Czubak et al. All rights reserved. Impact of Diabetic Foot on Selected Psychological or Social Characteristics Tue, 21 Oct 2014 09:41:29 +0000 Ugur Cakir, Ertugrul Kargi, Hakan Sarman, and Cengiz Isik Copyright © 2014 Ugur Cakir et al. All rights reserved. Targets and Candidate Agents for Type 2 Diabetes Treatment with Computational Bioinformatics Approach Tue, 21 Oct 2014 07:55:57 +0000 We sought to explore the molecular mechanism of type 2 diabetes (T2D) and identify potential drug targets and candidate agents for T2D treatment. The differentially expressed genes (DEGs) were assessed between human pancreatic islets with T2D and normal islets. The dysfunctional pathways, the potential transcription factor, and microRNA targets were analyzed by bioinformatics methods. Moreover, a group of bioactive small molecules were identified based on the connectivity map database. The pathways of Eicosanoid Synthesis, TGF-beta signaling pathway, Prostaglandin Synthesis and Regulation, and Integrated Pancreatic Cancer Pathway were found to be significantly dysregulated in the progression of T2D. The genes of ZADH2 (zinc binding alcohol dehydrogenase domain containing 2), BTBD3 (BTB (POZ) domain containing 3), Cul3-based ligases,  LTBP1 (latent-transforming growth factor beta binding protein 1), PDGFRA (alpha-type platelet-derived growth factor receptor), and FST (follistatin) were determined to be significant nodes regulated by potential transcription factors and microRNAs. Besides, two small molecules (sanguinarine and DL-thiorphan) were identified to be capable of reverse T2D. In the present study, a systematic understanding for the mechanism underlying T2D development was provided with biological informatics methods. The significant nodes and bioactive small molecules may be drug targets and candidate agents for T2D treatment. Qiong Wang, Zhigang Zhao, Jing Shang, and Wei Xia Copyright © 2014 Qiong Wang et al. All rights reserved. BlockingαVβ3 Integrin Ligand Occupancy Inhibits the Progression of Albuminuria in Diabetic Rats Mon, 20 Oct 2014 11:42:20 +0000 This study determined if blocking ligand occupancy of the αVβ3 integrin could inhibit the pathophysiologic changes that occur in the early stages of diabetic nephropathy (DN). Diabetic rats were treated with either vehicle or a monoclonal antibody that binds the β3 subunit of the αVβ3 integrin. After 4 weeks of diabetes the urinary albumin to creatinine ratio (UACR) increased in both diabetic animals that subsequently received vehicle and in the animals that subsequently received the anti-β3 antibody compared with control nondiabetic rats. After 8 weeks of treatment the UACR continued to rise in the vehicle-treated rats; however it returned to levels comparable to control nondiabetic rats in rats treated with the anti-β3 antibody. Treatment with the antibody prevented the increase of several profibrotic proteins that have been implicated in the development of DN. Diabetes was associated with an increase in phosphorylation of the β3 subunit in kidney homogenates from diabetic animals, but this was prevented by the antibody treatment. This study demonstrates that, when administered after establishment of early pathophysiologic changes in renal function, the anti-β3 antibody reversed the effects of diabetes normalizing albuminuria and profibrotic proteins in the kidney to the levels observed in nondiabetic control animals. Laura A. Maile, Katherine Gollahon, Christine Wai, Paul Dunbar, Walker Busby, and David Clemmons Copyright © 2014 Laura A. Maile et al. All rights reserved. Nonhuman Primate Models of Type 1 Diabetes Mellitus for Islet Transplantation Mon, 20 Oct 2014 06:43:37 +0000 Islet transplantation is an attractive treatment of type 1 diabetes mellitus (T1DM). Animal models of diabetes mellitus (DM) contribute a lot to the experimental studies of islet transplantation and to evaluations of isolated islet grafts for future clinical applications. Diabetic nonhuman primates (NHPs) represent the suitable models of DMs to better evaluate the effectiveness of islet transplantation, to assess new strategies for controlling blood glucose (BG), relieving immune rejection, or prolonging islet survival, and eventually to translate the preclinical data into tangible clinical practice. This review introduces some NHP models of DM, clarifies why and how the models should be used, and elucidates the usefulness and limitations of the models in islet transplantation. Haitao Zhu, Liang Yu, Yayi He, and Bo Wang Copyright © 2014 Haitao Zhu et al. All rights reserved. Renal Protective Effect of Sirtuin 1 Thu, 16 Oct 2014 07:15:56 +0000 Silent information regulator 2 (Sir2) is a nicotinamide adenine dinucleotide- (NAD+-) dependent deacetylase. The homology of SIRT1 and Sir2 has been extensively studied. SIRT1 deacetylates target proteins using the coenzyme NAD+ and is therefore linked to cellular energy metabolism and the redox state through multiple signalling and survival pathways. During the past decade, investigators have reported that SIRT1 activity is essential in cancer, neurodegenerative diseases, diabetes, cardiovascular disease, and other age-related diseases. In the kidneys, SIRT1 may inhibit renal cell apoptosis, inflammation, and fibrosis. Therefore its activation may also become a new therapeutic target in the patients with chronic kidney disease including diabetic nephropathy. In this paper, we would like to review the protective functions of sirtuins and the role of SIRT1 in the onset of kidney disease based on previous studies, including diabetic nephropathy, acute renal injury, chronic kidney disease as well as lupus nephritis. Yi-jun Dong, Nian Liu, Zhi Xiao, Tao Sun, Shu-hui Wu, Wei-xia Sun, Zhong-gao Xu, and Hang Yuan Copyright © 2014 Yi-jun Dong et al. All rights reserved. Downregulation of Type II Diabetes Mellitus and Maturity Onset Diabetes of Young Pathways in Human Pancreatic Islets from Hyperglycemic Donors Tue, 14 Oct 2014 12:59:58 +0000 Although several molecular pathways have been linked to type 2 diabetes (T2D) pathogenesis, it is uncertain which pathway has the most implication on the disease. Changes in the expression of an entire pathway might be more important for disease pathogenesis than changes in the expression of individual genes. To identify the molecular alterations in T2D, DNA microarrays of human pancreatic islets from donors with hyperglycemia and normoglycemia were subjected to Gene Set Enrichment Analysis (GSEA). About 178 KEGG pathways were investigated for gene expression changes between hyperglycemic donors compared to normoglycemic. Pathway enrichment analysis showed that type II diabetes mellitus (T2DM) and maturity onset diabetes of the young (MODY) pathways are downregulated in hyperglycemic donors, while proteasome and spliceosome pathways are upregulated. The mean centroid of gene expression of T2DM and MODY pathways was shown to be associated positively with insulin secretion and negatively with HbA1c level. To conclude, downregulation of T2DM and MODY pathways is involved in islet function and might be involved in T2D. Also, the study demonstrates that gene expression profiles from pancreatic islets can reveal some of the biological processes related to regulation of glucose hemostats and diabetes pathogenesis. Jalal Taneera, Petter Storm, and Leif Groop Copyright © 2014 Jalal Taneera et al. All rights reserved. Vitamin D Status and Its Relationship with Metabolic Markers in Persons with Obesity and Type 2 Diabetes in the UAE: A Cross-Sectional Study Mon, 13 Oct 2014 11:34:19 +0000 Aim. To report vitamin D status and its impact on metabolic parameters in people in the United Arab Emirates with obesity and type 2 diabetes (T2D). Methodology. This cross-sectional study included 309 individuals with obesity and T2D who were randomly selected based on study criteria. Serum concentrations of 25-hydroxy vitamin D (s-25(OH)D), calcium, phosphorus, parathyroid hormone, alkaline phosphatase, glycemic profile, and cardiometabolic parameters were assessed in fasting blood samples, and anthropometric measurements were recorded. Results. Vitamin D deficiency (s-25(OH)D < 50 nmol/L) was observed in 83.2% of the participants, with a mean s-25(OH)D of 33.8 ± 20.3 nmol/L. Serum 25(OH)D correlated negatively () with body mass index, fat mass, waist circumference, parathyroid hormone, alkaline phosphatase, triglycerides, LDL-cholesterol, and apolipoprotein B and positively () with age and calcium concentration. Waist circumference was the main predictor of s-25(OH)D status. There was no significant association between serum 25(OH)D and glycemic profile. Conclusion. There is an overwhelming prevalence of vitamin D deficiency in our sample of the Emirati population with obesity and T2D. Association of s-25(OH)D with body mass index, waist circumference, fat mass, markers of calcium homeostasis and cardiometabolic parameters suggests a role of vitamin D in the development of cardiometabolic disease-related process. Amena Sadiya, Solafa M. Ahmed, Sijomol Skaria, and Salah Abusnana Copyright © 2014 Amena Sadiya et al. All rights reserved. Role of Endothelial Nitric Oxide Synthase in Diabetic Nephropathy: Lessons from Diabetic eNOS Knockout Mice Mon, 13 Oct 2014 11:28:27 +0000 Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in many countries. The animal models that recapitulate human DN undoubtedly facilitate our understanding of this disease and promote the development of new diagnostic markers and therapeutic interventions. Based on the clinical evidence showing the association of eNOS dysfunction with advanced DN, we and others have created diabetic mice that lack eNOS expression and shown that eNOS-deficient diabetic mice exhibit advanced nephropathic changes with distinct features of progressive DN, including pronounced albuminuria, nodular glomerulosclerosis, mesangiolysis, and arteriolar hyalinosis. These studies clearly defined a critical role of eNOS in DN and developed a robust animal model of this disease, which enables us to study the pathogenic mechanisms of progressive DN. Further, recent studies with this animal model have explored the novel mechanisms by which eNOS deficiency causes advanced DN and provided many new insights into the pathogenesis of DN. Therefore, here we summarize the findings obtained with this animal model and discuss the roles of eNOS in DN, unresolved issues, and future investigations of this animal model study. Takamune Takahashi and Raymond C. Harris Copyright © 2014 Takamune Takahashi and Raymond C. Harris. All rights reserved. Characterization of Diabetic Neuropathy in the Zucker Diabetic Sprague-Dawley Rat: A New Animal Model for Type 2 Diabetes Mon, 13 Oct 2014 08:40:52 +0000 Recently a new rat model for type 2 diabetes the Zucker diabetic Sprague-Dawley (ZDSD/Pco) was created. In this study we sought to characterize the development of diabetic neuropathy in ZDSD rats using age-matched Sprague-Dawley rats as a control. Rats were examined at 34 weeks of age 12 weeks after the onset of hyperglycemia in ZDSD rats. At this time ZDSD rats were severely insulin resistant with slowing of both motor and sensory nerve conduction velocities. ZDSD rats also had fatty livers, elevated serum free fatty acids, triglycerides, and cholesterol, and elevated sciatic nerve nitrotyrosine levels. The corneas of ZDSD rats exhibited a decrease in subbasal epithelial corneal nerves and sensitivity. ZDSD rats were hypoalgesic but intraepidermal nerve fibers in the skin of the hindpaw were normal compared to Sprague-Dawley rats. However, the number of Langerhans cells was decreased. Vascular reactivity of epineurial arterioles, blood vessels that provide circulation to the sciatic nerve, to acetylcholine and calcitonin gene-related peptide was impaired in ZDSD rats. These data indicate that ZDSD rats develop many of the neural complications associated with type 2 diabetes and are a good animal model for preclinical investigations of drug development for diabetic neuropathy. Eric P. Davidson, Lawrence J. Coppey, Amey Holmes, Sergey Lupachyk, Brian L. Dake, Christine L. Oltman, Richard G. Peterson, and Mark A. Yorek Copyright © 2014 Eric P. Davidson et al. All rights reserved. Chronic Treatment with Ang-(1-7) Reverses Abnormal Reactivity in the Corpus Cavernosum and Normalizes Diabetes-Induced Changes in the Protein Levels of ACE, ACE2, ROCK1, ROCK2 and Omega-Hydroxylase in a Rat Model of Type 1 Diabetes Tue, 16 Sep 2014 08:46:52 +0000 Angiotensin-(1-7) [Ang-(1-7)] may have beneficial effects in diabetes mellitus-induced erectile dysfunction (DMIED) but its molecular actions in the diabetic corpus cavernosum (CC) are not known. We characterized the effects of diabetes and/or chronic in vivo administration of Ang-(1-7) on vascular reactivity in the rat corpus cavernosum (CC) and on protein expression levels of potential downstream effectors of the renin-angiotensin-aldosterone system (RAAS) such as angiotensin-converting enzyme (ACE), ACE2, Rho kinases 1 and 2 (ROCK1 and ROCK2), and omega-hydroxylase, the cytochrome-P450 enzyme that metabolizes arachidonic acid to form the vasoconstrictor, 20-hydroxyeicosatetraenoic acid. Streptozotocin-treated rats were chronicically administered Ang-(1-7) with or without A779, a Mas receptor antagonist, during weeks 4 to 6 of diabetes. Ang-(1-7) reversed diabetes-induced abnormal reactivity to vasoactive agents (endothelin-1, phenylepherine, and carbachol) in the CC without correcting hyperglycemia. Six weeks of diabetes led to elevated ACE, ROCK1, ROCK 2, and omega-hydroxylase and a concomitant decrease in ACE2 protein expression levels that were normalized by Ang-(1-7) treatment but not upon coadministration of A779. These data are supportive of the notion that the beneficial effects of Ang-(1-7) in DMIED involve counterregulation of diabetes-induced changes in ACE, ACE2, Rho kinases, and omega-hydroxylase proteins in the diabetic CC via a Mas receptor-dependent mechanism. Mariam H. M. Yousif, Batoul Makki, Ahmed Z. El-Hashim, Saghir Akhtar, and Ibrahim F. Benter Copyright © 2014 Mariam H. M. Yousif et al. All rights reserved. Ocular Inflammation in Uveal Tract in Aged Obese Type 2 Diabetic Rats (Spontaneously Diabetic Torii Fatty Rats) Sun, 14 Sep 2014 13:05:14 +0000 We report uveitis observed in an obese type 2 diabetes rat model, Spontaneously Diabetic Torii Leprfa (SDT fatty) rats aged over 50 weeks. The eyes of SDT fatty rats (16 animals: 7 males and 9 females with 50 or 60 weeks of age) were examined histopathologically. Infiltration of inflammatory cells in the uveal tract was observed in 13 of 16 animals. One female showed severe inflammation affecting the entire uveal tract including the iris, ciliary body, and choroid with a variety of inflammatory cells (neutrophils, lymphocytes, and macrophages). Those changes clinically mimic the findings of diabetic iridocyclitis in diabetic patients. Uveitis associated with diabetes can occur in diabetic patients but the pathogenesis still remains unknown. Since increased extramedullary hematopoiesis in the spleen and abscess in the genital and lower urinary tracts were observed in some SDT fatty rats, increased susceptibility to infection, prolongation of inflammatory states, and disorders of the immune system were considered to be possible factors of the uveitis in aged SDT fatty rats. There have been few reports on how diabetes has influence on the development of uveitis associated with bacterial infection. The SDT fatty rat can be an animal model to investigate diabetes-associated uveitis. Yusuke Kemmochi, Katsuhiro Miyajima, Takeshi Ohta, Tomohiko Sasase, Yuzo Yasui, Kaoru Toyoda, Kochi Kakimoto, Toshiyuki Shoda, and Akihiro Kakehashi Copyright © 2014 Yusuke Kemmochi et al. All rights reserved. The Influence of Peripheral Neuropathy, Gender, and Obesity on the Postural Stability of Patients with Type 2 Diabetes Mellitus Tue, 02 Sep 2014 12:04:07 +0000 Aim. To assess the influence of peripheral neuropathy, gender, and obesity on the postural stability of patients with type 2 diabetes mellitus. Methods. 151 patients with no history of otology, neurology, or orthopaedic or balance disorders accepted to participate in the study. After a clinical interview and neuropathy assessment, postural stability was evaluated by static posturography (eyes open/closed on hard/soft surface) and the “Up & Go” test. Results. During static posturography, on hard surface, the length of sway was related to peripheral neuropathy, gender, age, and obesity; on soft surface, the length of sway was related to peripheral neuropathy, gender, and age, the influence of neuropathy was larger in males than in females, and closing the eyes increased further the difference between genders. The mean time to perform the “Up & Go” test was 11.6 ± 2.2 sec, with influence of peripheral neuropathy, gender, and age. Conclusion. In order to preserve the control of static upright posture during conditions with deficient sensory input, male patients with type 2 diabetes mellitus with no history of balance disorders may be more vulnerable than females, and obesity may decrease the static postural control in both males and females. Aline Herrera-Rangel, Catalina Aranda-Moreno, Teresa Mantilla-Ochoa, Lylia Zainos-Saucedo, and Kathrine Jáuregui-Renaud Copyright © 2014 Aline Herrera-Rangel et al. All rights reserved. The Role of MicroRNAs in Diabetic Nephropathy Mon, 01 Sep 2014 11:24:42 +0000 Diabetic nephropathy (DN), as one of the chronic complications of diabetes, is the major cause of end-stage renal disease. However, the pathogenesis of this disease is not fully understood. In recent years, research on microRNAs (miRNAs) has become a hotspot because of their critical role in regulating posttranscriptional levels of protein-coding genes that may serve as key pathogenic factors in diseases. Several miRNAs were found to participate in the pathogenesis of DN, while others showed renal protective effects. Therefore, targeting miRNAs that are involved in DN may have a good prospect in the treatment of the disease. The aim of this review is to summarize DN-related miRNAs and provide potential targets for diagnostic strategies and therapeutic intervention. Hao Wu, Lili Kong, Shanshan Zhou, Wenpeng Cui, Feng Xu, Manyu Luo, Xiangqi Li, Yi Tan, and Lining Miao Copyright © 2014 Hao Wu et al. All rights reserved. Characteristics and Determinants of Partial Remission in Children with Type 1 Diabetes Using the Insulin-Dose-Adjusted A1C Definition Sun, 31 Aug 2014 09:18:38 +0000 To evaluate the characteristics and determinants of partial remission (PR) in Belgian children with type 1 diabetes (T1D), we analyzed records of 242 children from our center. Clinical and biological features were collected at diagnosis and during follow-up. PR was defined using the insulin-dose-adjusted A1C definition. PR occurred in 56.2% of patients and lasted 9.2 months (0.5 to 56.6). 25.6% of patients entered T1D with DKA, which correlated with lower PR incidence (17.6% versus 82.3% when no DKA). In our population, lower A1C levels at diagnosis were associated with higher PR incidence and in young children (0–4 years) initial A1C levels negatively correlated with longer PR. Early A1C levels were predictive of PR duration since 34% of patients had long PRs (>1 year) when A1C levels were ≤6% after 3 months whereas incidence of long PR decreased with higher A1Cs. C-peptide levels were higher in patients entering PR and remained higher until 3 years after diagnosis. Initial antibody titers did not influence PR except for anti-IA2 titers that correlated with A1C levels after 2 years. Presence of 2 versus 1 anti-islet antibodies correlated with shorter PR. PR duration did not influence occurrence of severe hypoglycemia or diabetes-related complications but was associated with lower A1C levels after 18 months. We show that, at diagnosis of T1D, parameters associated with -cell mass reserve (A1C, C-peptide, and DKA) correlate with the occurrence of PR, which affects post-PR A1C levels. Further research is needed to determine the long-term significance of PR. Aurore Pecheur, Thierry Barrea, Valérie Vandooren, Véronique Beauloye, Annie Robert, and Philippe A. Lysy Copyright © 2014 Aurore Pecheur et al. All rights reserved. Continuous Electrical Current and Zinc Sulphate Administered by Transdermal Iontophoresis Improves Skin Healing in Diabetic Rats Induced by Alloxan: Morphological and Ultrastructural Analysis Thu, 28 Aug 2014 08:44:09 +0000 Purpose. Evaluated the effects of continuous electrical current (CEC) or zinc administrated by transdermal iontophoresis (Zn+TDI). Methods. 120 male Wistar rats were submitted to an incision surgery at the anterior region of abdomen and distributed into 6 experimental groups with 40 animals: 3 diabetic groups and 3 normal groups, untreated and treated with CEC alone or with Zn + TDI. Each group was further divided into 4 subgroups with 10 rats each to be evaluated on the 4th, 7th, 14th, and 21st day after surgery. In each period, clinical and laboratory parameters from the animals were analyzed. Results. The analysis by optical and scanning electron microscopy showed a delay in the phases of wound healing in diabetic rats without treatment in all periods of the experiment; breaking strength (BS) was significantly reduced in skin scars of untreated diabetic rats when compared to other groups. In contrast, BS in skin scars of nondiabetic groups and diabetic rats treated with Zn + TDI showed significant increase in those, besides not presenting delayed healing. Conclusion. Electrical stimulation of surgical wounds used alone or in association with zinc by TDI is able to consistently improve the morphological and ultrastructural changes observed in the healing of diabetic animals. Lucas Langoni Cassettari, Pedro Colli Rocha Dias, Amanda Natália Lucchesi, Maurício Ferraz de Arruda, Érika Veruska Paiva Ortolan, Mariângela Esther A. Marques, and César Tadeu Spadella Copyright © 2014 Lucas Langoni Cassettari et al. All rights reserved. Histone Lysine Methylation in Diabetic Nephropathy Mon, 25 Aug 2014 10:52:46 +0000 Diabetic nephropathy (DN) belongs to debilitating microvascular complications of diabetes and is the leading cause of end-stage renal diseases worldwide. Furthermore, outcomes from the DCCT/EDIC study showed that DN often persists and progresses despite intensive glucose control in many diabetes patients, possibly as a result of prior episode of hyperglycemia, which is called “metabolic memory.” The underlying mechanisms responsible for the development and progression of DN remain poorly understood. Activation of multiple signaling pathways and key transcription factors can lead to aberrant expression of DN-related pathologic genes in target renal cells. Increasing evidence suggests that epigenetic mechanisms in chromatin such as DNA methylation, histone acetylation, and methylation can influence the pathophysiology of DN and metabolic memory. Exciting researches from cell culture and experimental animals have shown that key histone methylation patterns and the related histone methyltransferases and histone demethylases can play important roles in the regulation of inflammatory and profibrotic genes in renal cells under diabetic conditions. Because histone methylation is dynamic and potentially reversible, it can provide a window of opportunity for the development of much-needed novel therapeutic potential for DN in the future. In this minireview, we discuss recent advances in the field of histone methylation and its roles in the pathogenesis and progression of DN. Guang-dong Sun, Wen-peng Cui, Qiao-yan Guo, and Li-ning Miao Copyright © 2014 Guang-dong Sun et al. All rights reserved. Effect of Ranirestat, a New Aldose Reductase Inhibitor, on Diabetic Retinopathy in SDT Rats Mon, 25 Aug 2014 07:51:42 +0000 Purpose. To evaluate the effect of ranirestat, a new aldose reductase inhibitor (ARI), on diabetic retinopathy (DR) in Spontaneously Diabetic Torii (SDT) rats. Methods. The animals were divided into six groups, normal Sprague-Dawley rats , untreated SDT rats , ranirestat-treated SDT rats (0.1, 1.0, and 10 mg/kg/day, , and , resp.), and epalrestat-treated SDT rats (100 mg/kg/day, . Treated rats received oral ranirestat or epalrestat once daily for 40 weeks after the onset of diabetes. After the eyes were enucleated, the retinal thickness and the area of stained glial fibrillary acidic protein (GFAP) were measured. Results. The retinas in the untreated group were significantly thicker than those in the normal and ranirestat-treated (0.1, 1.0, and 10 mg/kg/day) groups. The immunostained area of GFAP in the untreated group was significantly larger than that in the normal and ranirestat-treated (1.0 and 10 mg/kg/day) groups. There were no significant differences between the untreated group and epalrestat-treated group in the retinal thickness and the area of stained GFAP. Conclusion. Ranirestat reduced the retinal thickness and the area of stained GFAP in SDT rats and might suppress DR and have a neuroprotective effect on diabetic retinas. Fumihiko Toyoda, Yoshiaki Tanaka, Ayumi Ota, Machiko Shimmura, Nozomi Kinoshita, Hiroko Takano, Takafumi Matsumoto, Junichi Tsuji, and Akihiro Kakehashi Copyright © 2014 Fumihiko Toyoda et al. All rights reserved.