Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Exendin-4 Promotes Survival of Mouse Pancreatic β-Cell Line in Lipotoxic Conditions, through the Extracellular Signal-Related Kinase 1/2 Pathway Tue, 30 Aug 2016 14:16:37 +0000 Type 2 diabetes is a heterogeneous disorder that develops as a result of relatively inappropriate insulin secretion and insulin resistance. Increased levels of free fatty acids (FFAs) are one of the important factors for the pathogenesis of type 2 diabetes and contribute to defective β-cell proliferation and increased β-cell apoptosis. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have been shown to possess an antiapoptotic effect, by increasing β-cell mass and improving β-cell function. However, their effects on β-cells in vitro against lipotoxicity have not been elucidated completely. In this study, we investigated whether the GLP-1 receptor agonist exendin-4 displays prosurvival effects in pancreatic β-cells exposed to chronic elevated FFAs. Results showed that exendin-4 inhibited apoptosis induced by palmitate in MIN6 cells. After 24 h of incubation, exendin-4 caused rapid activation of extracellular signal-related kinase 1/2 (ERK1/2) under lipotoxic conditions. The ERK1/2 inhibitor PD98059 blocked the antilipotoxic effect of exendin-4 on MIN6 cells. Exendin-4 also inhibited the mitochondrial pathway of apoptosis. This inhibition is associated with upregulation of BCL-2. Our findings suggested that exendin-4 may exert cytoprotective effects through activation of ERK1/2 and inhibition of the mitochondrial apoptosis pathway. Jianqiu Gu, Qian Wei, Hongzhi Zheng, Xin Meng, Jin Zhang, and Difei Wang Copyright © 2016 Jianqiu Gu et al. All rights reserved. Charcot Neuropathic Arthropathy of the Foot: A Literature Review and Single-Center Experience Tue, 30 Aug 2016 10:21:04 +0000 Charcot neuropathic osteoarthropathy of the foot is a relatively common complication of diabetic neuropathy. Incorrect diagnosis and improper treatment often result in the extremity having to be amputated. This paper summarises the current view on the etiology, diagnostics, and treatment of diabetic Charcot neuropathic osteoarthropathy, with particular focus on preserving the extremity through surgical intervention from our own experiences. Tomas Kucera, Haroun Hassan Shaikh, and Pavel Sponer Copyright © 2016 Tomas Kucera et al. All rights reserved. The Influence of Diabetes Mellitus in Myocardial Ischemic Preconditioning Tue, 30 Aug 2016 09:59:25 +0000 Ischemic preconditioning (IP) is a powerful mechanism of protection discovered in the heart in which ischemia paradoxically protects the myocardium against other ischemic insults. Many factors such as diseases and medications may influence IP expression. Although diabetes poses higher cardiovascular risk, the physiopathology underlying this condition is uncertain. Moreover, although diabetes is believed to alter intracellular pathways related to myocardial protective mechanisms, it is still controversial whether diabetes may interfere with ischemic preconditioning and whether this might influence clinical outcomes. This review article looks at published reports with animal models and humans that tried to evaluate the possible influence of diabetes in myocardial ischemic preconditioning. Paulo Cury Rezende, Rosa Maria Rahmi, and Whady Hueb Copyright © 2016 Paulo Cury Rezende et al. All rights reserved. Patient Activation in Type 2 Diabetes: Does It Differ between Men and Women? Tue, 30 Aug 2016 06:43:18 +0000 Background. Aim was to investigate whether the degree of patient activation of patients with type 2 diabetes (T2D) is different between men and women. Furthermore, we investigated which factors are associated with patient activation in men and women. Methods. This cross-sectional study included 1615 patients with T2D from general practices. Patient activation was measured with the Patient Activation Measure (PAM) questionnaire. Multivariate linear regression analyses were used to investigate the association between gender and patient activation. Stratified analyses according to gender were performed to investigate which factors are associated with patient activation. Results. No association between gender and PAM score was found after adjustment for all selected confounders (). In men, lower age (), a higher WHO-5 score (), and a lower BMI () were associated with a higher PAM score. In women, a higher WHO-5 score () and the absence of macrovascular complications () were associated with a higher PAM score. Conclusion. There is no difference in the degree of patient activation of men and women with T2D. Age, well-being, and BMI were found to be associated with patient activation in men, whereas well-being and macrovascular complications were found to be associated with patient activation in women. Steven H. Hendriks, Laura C. Hartog, Klaas H. Groenier, Angela H. E. M. Maas, Kornelis J. J. van Hateren, Nanne Kleefstra, and Henk J. G. Bilo Copyright © 2016 Steven H. Hendriks et al. All rights reserved. Update on RAAS Modulation for the Treatment of Diabetic Cardiovascular Disease Mon, 29 Aug 2016 13:15:37 +0000 Since the advent of insulin, the improvements in diabetes detection and the therapies to treat hyperglycemia have reduced the mortality of acute metabolic emergencies, such that today chronic complications are the major cause of morbidity and mortality among diabetic patients. More than half of the mortality that is seen in the diabetic population can be ascribed to cardiovascular disease (CVD), which includes not only myocardial infarction due to premature atherosclerosis but also diabetic cardiomyopathy. The importance of renin-angiotensin-aldosterone system (RAAS) antagonism in the prevention of diabetic CVD has demonstrated the key role that the RAAS plays in diabetic CVD onset and development. Today, ACE inhibitors and angiotensin II receptor blockers represent the first line therapy for primary and secondary CVD prevention in patients with diabetes. Recent research has uncovered new dimensions of the RAAS and, therefore, new potential therapeutic targets against diabetic CVD. Here we describe the timeline of paradigm shifts in RAAS understanding, how diabetes modifies the RAAS, and what new parts of the RAAS pathway could be targeted in order to achieve RAAS modulation against diabetic CVD. Stella Bernardi, Andrea Michelli, Giulia Zuolo, Riccardo Candido, and Bruno Fabris Copyright © 2016 Stella Bernardi et al. All rights reserved. Involvement of Histone Lysine Methylation in p21 Gene Expression in Rat Kidney In Vivo and Rat Mesangial Cells In Vitro under Diabetic Conditions Mon, 29 Aug 2016 09:51:56 +0000 Diabetic nephropathy (DN), a common complication associated with type 1 and type 2 diabetes mellitus (DM), characterized by glomerular mesangial expansion, inflammation, accumulation of extracellular matrix (ECM) protein, and hypertrophy, is the major cause of end-stage renal disease (ESRD). Increasing evidence suggested that p21-dependent glomerular and mesangial cell (MC) hypertrophy play key roles in the pathogenesis of DN. Recently, posttranscriptional modifications (PTMs) have uncovered novel molecular mechanisms involved in DN. However, precise regulatory mechanism of histone lysine methylation (HKme) mediating p21 related hypertrophy associated with DN is not clear. We evaluated the roles of HKme and histone methyltransferase (HMT) SET7/9 in p21 gene expression in glomeruli of diabetic rats and in high glucose- (HG-) treated rat mesangial cells (RMCs). p21 gene expression was upregulated in diabetic rats glomeruli; chromatin immunoprecipitation (ChIP) assays showed decreased histone H3-lysine9-dimethylation (H3K9me2) accompanied with enhanced histone H3-lysine4-methylation (H3K4me1/3) and SET7/9 occupancies at the p21 promoter. HG-treated RMCs exhibited increased p21 mRNA, H3K4me level, SET7/9 recruitment, and inverse H3K9me, which were reversed by TGF-β1 antibody. These data uncovered key roles of H3Kme and SET7/9 responsible for p21 gene expression in vivo and in vitro under diabetic conditions and confirmed preventive effect of TGF-β1 antibody on DN. Xiangjun Li, Chaoyuan Li, Xiaoxia Li, Peihe Cui, Qifeng Li, Qiaoyan Guo, Hongbo Han, Shujun Liu, and Guangdong Sun Copyright © 2016 Xiangjun Li et al. All rights reserved. Teneligliptin Decreases Uric Acid Levels by Reducing Xanthine Dehydrogenase Expression in White Adipose Tissue of Male Wistar Rats Mon, 29 Aug 2016 06:48:04 +0000 We investigated the effects of teneligliptin on uric acid metabolism in male Wistar rats and 3T3-L1 adipocytes. The rats were fed with a normal chow diet (NCD) or a 60% high-fat diet (HFD) with or without teneligliptin for 4 weeks. The plasma uric acid level was not significantly different between the control and teneligliptin groups under the NCD condition. However, the plasma uric acid level was significantly decreased in the HFD-fed teneligliptin treated rats compared to the HFD-fed control rats. The expression levels of xanthine dehydrogenase (Xdh) mRNA in liver and epididymal adipose tissue of NCD-fed rats were not altered by teneligliptin treatment. On the other hand, Xdh expression was reduced significantly in the epididymal adipose tissue of the HFD-fed teneligliptin treated rats compared with that of HFD-fed control rats, whereas Xdh expression in liver did not change significantly in either group. Furthermore, teneligliptin significantly decreased Xdh expression in 3T3-L1 adipocytes. DPP-4 treatment significantly increased Xdh expression in 3T3-L1 adipocytes. With DPP-4 pretreatment, teneligliptin significantly decreased Xdh mRNA expression compared to the DPP-4-treated 3T3-L1 adipocytes. In conclusion, our studies suggest that teneligliptin reduces uric acid levels by suppressing Xdh expression in epididymal adipose tissue of obese subjects. Chihiro Moriya and Hiroaki Satoh Copyright © 2016 Chihiro Moriya and Hiroaki Satoh. All rights reserved. The Relationship between Branched-Chain Amino Acid Related Metabolomic Signature and Insulin Resistance: A Systematic Review Thu, 25 Aug 2016 16:06:51 +0000 Recent studies have shown the positive association between increased circulating BCAAs (valine, leucine, and isoleucine) and insulin resistance (IR) in obese or diabetic patients. However, results seem to be controversial in different races, diets, and distinct tissues. Our aims were to evaluate the relationship between BCAA and IR as well as later diabetes risk and explore the phenotypic and genetic factors influencing BCAA level based on available studies. We performed systematic review, searching MEDLINE, EMASE,, the Cochrane Library, and Web of Science from inception to March 2016. After selection, 23 studies including 20,091 participants were included. Based on current evidence, we found that BCAA is a useful biomarker for early detection of IR and later diabetic risk. Factors influencing BCAA level can be divided into four parts: race, gender, dietary patterns, and gene variants. These factors might not only contribute to the elevated BCAA level but also show obvious associations with insulin resistance. Genes related to BCAA catabolism might serve as potential targets for the treatment of IR associated metabolic disorders. Moreover, these factors should be controlled properly during study design and data analysis. In the future, more large-scale studies with elaborate design addressing BCAA and IR are required. Xue Zhao, Qing Han, Yujia Liu, Chenglin Sun, Xiaokun Gang, and Guixia Wang Copyright © 2016 Xue Zhao et al. All rights reserved. Gluten-Free Diet Only during Pregnancy Efficiently Prevents Diabetes in NOD Mouse Offspring Thu, 25 Aug 2016 11:15:58 +0000 Studies have documented that the pathogenesis of autoimmune diabetes is influenced by the intake of gluten. Aims. To investigate the importance of gluten exposure during pregnancy and the subsequent development of autoimmune diabetes in offspring. Methods. Nonobese diabetic mice were divided into 7 groups to receive combinations of gluten-free and standard diet before, during, or after pregnancy. Diabetes incidence in offspring was followed in each group () for 310 days. Insulitis score and intestinal expression of T-cell transcription factors (RT-QPCR) were evaluated in animals from the different diet groups. Results. If mothers were fed a gluten-free diet only during pregnancy, the development of autoimmune diabetes in offspring was almost completely prevented with an incidence reduction from 62.5% in gluten-consuming mice to 8.3% () in the gluten-free group. The islets of Langerhans were less infiltrated () and the intestinal expression of RORγt (Th17) () reduced in mice whose mothers were Gluten-free during pregnancy. Conclusion. A gluten-free diet exclusively during pregnancy efficiently prevents autoimmune diabetes development in offspring and reduces insulitis and intestinal expression of RORγt (Th17). Julie C. Antvorskov, Knud Josefsen, Martin Haupt-Jorgensen, Petra Fundova, David P. Funda, and Karsten Buschard Copyright © 2016 Julie C. Antvorskov et al. All rights reserved. GDF-15 and Hepcidin Levels in Nonanemic Patients with Impaired Glucose Tolerance Thu, 25 Aug 2016 09:58:34 +0000 Aims. Growth Differentiation Factor-15 (GDF-15) has been suggested as one of the regulators of hepcidin, an important regulatory peptide for iron deposition. Current data is conflicting about the relationship between hepcidin and disorders of glucose metabolism. We aimed to investigate serum hepcidin and GDF-15 concentrations and their associations with each other, in nonanemic subjects with impaired glucose tolerance (IGT) in comparison with the nonanemic subjects with normal glucose tolerance (NGT). Methods. Thirty-seven subjects with IGT and 32 control subjects with NGT, who were age-, gender-, and body mass index- (BMI-) matched, were included in the study. Results. Serum GDF-15 levels were significantly higher in IGT compared to NGT. There were no differences in hepcidin, interleukin-6, and high sensitive C-reactive protein levels between the groups. We found a positive correlation between GDF-15 and hepcidin levels. There were also positive correlations between GDF-15 and age, uric acid, creatinine, and area under the curve for glucose (AUC-G). Hepcidin was correlated positively with ferritin levels. In the multiple regression analysis, GDF-15 concentrations were independently associated with age, uric acid, and AUC-G. Conclusions. Impaired glucose tolerance is associated with increased GDF-15 levels even in the absence of anemia, but the levels of hepcidin are not significantly altered in prediabetic state. Mehmet Muhittin Yalcin, Alev Eroglu Altinova, Mujde Akturk, Ozlem Gulbahar, Emre Arslan, Damla Ors Sendogan, Ilhan Yetkin, and Fusun Balos Toruner Copyright © 2016 Mehmet Muhittin Yalcin et al. All rights reserved. Effectiveness and Safety of Newer Antidiabetic Medications for Ramadan Fasting Diabetic Patients Wed, 24 Aug 2016 17:52:31 +0000 Hypoglycemia is the most common side effects for most glucose-lowering therapies. It constitutes a serious risk that faces diabetic patients who fast during Ramadan (the 9th month in the Islamic calendar). New glucose-lowering classes like dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 receptor agonist (GLP-1 RA), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are efficacious in controlling blood glucose level with less tendency to induce hypoglycemia and thus may constitute a good choice for diabetic patients during Ramadan. This study reviews the safety and efficacy of newer glucose-lowering therapies during Ramadan. This study was accomplished through a careful literature search about studies that assess the benefit and side effects of these new glucose-lowering therapies during Ramadan during September 2015. Vildagliptin, sitagliptin, liraglutide, exenatide, and dapagliflozin were the only studied glucose-lowering therapies. All of the studied newer glucose-lowering therapies except dapagliflozin were associated with reduced risk to induce hypoglycemia. Gastrointestinal upset was common with the usage of liraglutide while increased thirst sensation was common with dapagliflozin. In conclusion DPP-4 inhibitors such as vildagliptin and sitagliptin may form a suitable glucose-lowering therapy option for Ramadan fasting patients. Ehab Mudher Mikhael Copyright © 2016 Ehab Mudher Mikhael. All rights reserved. Comment on “Puerarin Improves Diabetic Aorta Injury by Inhibiting NADPH Oxidase-Derived Oxidative Stress in STZ-Induced Diabetic Rats” Tue, 23 Aug 2016 13:16:58 +0000 Qiang Xie, Jian Zhong, and Jun Li Copyright © 2016 Qiang Xie et al. All rights reserved. Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus Tue, 23 Aug 2016 11:54:46 +0000 Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population. Gary Tse, Eric Tsz Him Lai, Vivian Tse, and Jie Ming Yeo Copyright © 2016 Gary Tse et al. All rights reserved. High Glucose-Induced Oxidative Stress Mediates Apoptosis and Extracellular Matrix Metabolic Imbalances Possibly via p38 MAPK Activation in Rat Nucleus Pulposus Cells Mon, 22 Aug 2016 14:28:25 +0000 Objectives. To investigate whether high glucose-induced oxidative stress is implicated in apoptosis of rat nucleus pulposus cells (NPCs) and abnormal expression of critical genes involved in the metabolic balance of extracellular matrix (ECM). Methods. NPCs were cultured with various concentrations of glucose to detect cell viability and apoptosis. Cells cultured with high glucose (25 mM) were untreated or pretreated with N-acetylcysteine or a p38 MAPK inhibitor SB 202190. Reactive oxygen species (ROS) production was evaluated. Activation of p38 MAPK was measured by Western blot. The expression of ECM metabolism-related genes, including type II collagen, aggrecan, SRY-related high-mobility-group box 9 (Sox-9), matrix metalloproteinase 3 (MMP-3), and tissue inhibitor of metalloproteinase 1 (TIMP-1), was analyzed by semiquantitative RT-PCR. Results. High glucose reduced viability of NPCs and induced apoptosis. High glucose resulted in increased ROS generation and p38 MAPK activation. In addition, it negatively regulated the expression of type II collagen, aggrecan, Sox-9, and TIMP-1 and positively regulated MMP-3 expression. These results were changed by pretreatment with N-acetylcysteine or SB 202190. Conclusions. High glucose might promote apoptosis of NPCs, trigger ECM catabolic pathways, and inhibit its anabolic activities, possibly through a p38 MAPK-dependent oxidative stress mechanism. Xiaofei Cheng, Bin Ni, Feng Zhang, Ying Hu, and Jie Zhao Copyright © 2016 Xiaofei Cheng et al. All rights reserved. Advanced Glycation End Products Impair Glucose-Stimulated Insulin Secretion of a Pancreatic β-Cell Line INS-1-3 by Disturbance of Microtubule Cytoskeleton via p38/MAPK Activation Mon, 22 Aug 2016 14:02:23 +0000 Advanced glycation end products (AGEs) are believed to be involved in diverse complications of diabetes mellitus. Overexposure to AGEs of pancreatic β-cells leads to decreased insulin secretion and cell apoptosis. Here, to understand the cytotoxicity of AGEs to pancreatic β-cells, we used INS-1-3 cells as a β-cell model to address this question, which was a subclone of INS-1 cells and exhibited high level of insulin expression and high sensitivity to glucose stimulation. Exposed to large dose of AGEs, even though more insulin was synthesized, its secretion was significantly reduced from INS-1-3 cells. Further, AGEs treatment led to a time-dependent increase of depolymerized microtubules, which was accompanied by an increase of activated p38/MAPK in INS-1-3 cells. Pharmacological inhibition of p38/MAPK by SB202190 reversed microtubule depolymerization to a stabilized polymerization status but could not rescue the reduction of insulin release caused by AGEs. Taken together, these results suggest a novel role of AGEs-induced impairment of insulin secretion, which is partially due to a disturbance of microtubule dynamics that resulted from an activation of the p38/MAPK pathway. Jia You, Zai Wang, Shiqing Xu, Wenjian Zhang, Qing Fang, Honglin Liu, Liang Peng, Tingting Deng, and Jinning Lou Copyright © 2016 Jia You et al. All rights reserved. Microflora Disturbance during Progression of Glucose Intolerance and Effect of Sitagliptin: An Animal Study Thu, 18 Aug 2016 15:29:57 +0000 Background. Emerging evidences have shown a close interplay between obesity, diabetes, and intestinal flora disturbance. Dipeptidyl peptidase-4 inhibitor, exemplified by sitagliptin, is highly efficacious in treating type 2 diabetes (T2DM), yet little is known if sitagliptin exerts beneficial effects on microbiota associated with obesity and T2DM. We evaluated changes of gut microbiota following the induction of obesity and T2DM in a streptozotocin treated high fat/high carbohydrate fed (HF/HC-STZ) rat model and explored the effect of sitagliptin on gut microbiota for HF/HC-STZ rats. Methods. Sitagliptin was administered via oral gavage to diabetic rats. Fecal DNA extraction and 454 pyrosequencing based on analysis of 16S rRNA genes was utilized to determine the overall structure of microbiota in fecal DNA samples. Results. Results showed that, at the level of phylum, there was higher abundance of Firmicutes and Tenericutes and less abundance of Bacteroidetes in obese rats compared to their lean counterparts. At the level of genus, short-chain fatty acid- (SCFA-) producing bacteria, Blautia, Roseburia, and Clostridium, and probiotics Lactobacillus, Bifidobacterium, and so forth were identified significantly different from each other among conditions. Conclusion. Marked shifts of the gut microbiota structure were observed in the rats during development of glucose intolerance. Intestinal flora changed in the process of glucose intolerance, and treatment of sitagliptin moderately corrected the dysbiosis of microbiota in T2DM. Xinfeng Yan, Bo Feng, Peicheng Li, Zhaosheng Tang, and Lin Wang Copyright © 2016 Xinfeng Yan et al. All rights reserved. Noninvasive Tracking of Encapsulated Insulin Producing Cells Labelled with Magnetic Microspheres by Magnetic Resonance Imaging Thu, 18 Aug 2016 09:33:52 +0000 Microencapsulated islets are usually injected free-floating into the peritoneal cavity, so the position of the grafts remains elusive after transplantation. This study aims to assess magnetic resonance imaging (MRI) as a noninvasive means to track microencapsulated insulin producing cells following transplantation. Encapsulated insulin producing cells (MIN6 and human islets) were labelled with magnetic microspheres (MM), assessed for viability and insulin secretion, and imaged in vitro using a clinical grade 3 T MRI and in vivo using both clinical grade 3 T and research grade 11.7 T MRI. Fluorescent imaging demonstrated the uptake of MM by both MIN6 and human islets with no changes in cell morphology and viability. MM labelling did not affect the glucose responsiveness of encapsulated MIN6 and islets in vitro. In vivo encapsulated MM-labelled MIN6 normalized sugar levels when transplanted into diabetic mice. In vitro MRI demonstrated that single microcapsules as well as clusters of encapsulated MM-labelled cells could be visualised clearly in agarose gel phantoms. In vivo encapsulated MM-labelled MIN6 could be visualised more clearly within the peritoneal cavity as discrete hypointensities using the high power 11.7 T but not the clinical grade 3 T MRI. This study demonstrates a method to noninvasively track encapsulated insulin producing cells by MM labelling and MRI. Vijayaganapathy Vaithilingam, Mandy M. W. Yim, Jayne L. Foster, Timothy Stait-Gardner, Jose Oberholzer, and Bernard E. Tuch Copyright © 2016 Vijayaganapathy Vaithilingam et al. All rights reserved. Pilot Study of a Web-Delivered Multicomponent Intervention for Rural Teens with Poorly Controlled Type 1 Diabetes Wed, 17 Aug 2016 09:20:22 +0000 Objective. The purpose of this study was to examine the feasibility and effectiveness of a web-delivered multicomponent behavioral and family-based intervention targeting self-regulation and self-monitoring of blood glucose levels (SMBG) and glycemic control (HbA1c) in teens with type 1 diabetes (T1DM) living in rural US. Methods. 15 teens with poorly controlled T1DM participated in a 25-week web-delivered intervention with two phases, active treatment (weekly treatment sessions and working memory training program) and maintenance treatment (fading of treatment sessions). Results. Almost all (13 of 15) participants completed at least 14 of 15 treatment sessions and at least 20 of 25 working memory training sessions. SMBG was increased significantly at end of active and maintenance treatment, and HbA1c was decreased at end of active treatment (’s ≤ 0.05). Executive functioning improved at end of maintenance treatment: performance on working memory and inhibitory control tasks significantly improved (’s ≤ 0.02) and parents reported fewer problems with executive functioning (). Improvement in inhibitory control was correlated with increases in SMBG and decreases in HbA1c. Conclusions. An innovative web-delivered and multicomponent intervention was feasible for teens with poorly controlled T1DM and their families living in rural US and associated with significant improvements in SMBG and HbA1c. Amy Hughes Lansing, Catherine Stanger, Alan Budney, Ann S. Christiano, and Samuel J. Casella Copyright © 2016 Amy Hughes Lansing et al. All rights reserved. Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses Tue, 16 Aug 2016 11:53:48 +0000 Globally, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation, which plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. This review summarises the current concepts on the role played by both innate and adaptive immune responses in setting up metainflammation in DM-CAD. More specifically, the role played by innate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), NOD1-like receptors (NLRs), Rig-1-like receptors (RLRs), and C-type lectin like receptors (CLRs) and metabolic endotoxemia in fuelling metainflammation in DM-CAD would be discussed. Further, the role played by adaptive immune cells (Th1, Th2, Th17, and Th9 cells) in fuelling metainflammation in DM-CAD will also be discussed. Vivekanandhan Aravindhan and Haridoss Madhumitha Copyright © 2016 Vivekanandhan Aravindhan and Haridoss Madhumitha. All rights reserved. The Relationship of Metabolic Syndrome Traits with Beta-Cell Function and Insulin Sensitivity by Oral Minimal Model Assessment in South Asian and European Families Residing in the Netherlands Thu, 11 Aug 2016 07:59:59 +0000 Background. There are different metabolic syndrome traits among patients with different ethnicities. Methods. We investigated this by studying 44 South Asians and 54 Europeans and classified them in three groups according to the occurrence of metabolic syndrome (MetS) and Type 2 Diabetes (T2D). Insulin sensitivity index (ISI), static, dynamic, and total beta-cell responsivity indices (), and disposition indices (DIs) were calculated with the use of oral minimal model (OMM). Results. In both ethnicities, ISI was lower in the subgroup with MetS and T2D as compared to the subgroup without MetS nor T2D (). South Asians without MetS were more insulin resistant than Europeans without MetS (). In the South Asians, ISI, dynamic DI, and static DI were associated significantly () with high-density lipoprotein cholesterol and triglycerides. In the Europeans, ISI was associated with waist-to-hip ratio () and systolic and diastolic blood pressure (), while static DI was related to the systolic blood pressure (). Conclusions. MetS was linked with insulin resistance and reduced capacity to handle glucose regardless of ethnicity. ISI and DIs were associated with lipid traits in South Asians and with blood pressure in Europeans suggesting that insulin resistance enhances different metabolic syndrome traits among different ethnicities. Thekla Geragotou, Sjaam Jainandunsing, Behiye Özcan, Felix W. M. de Rooij, Alexander Kokkinos, Nicholas Tentolouris, and Eric J. G. Sijbrands Copyright © 2016 Thekla Geragotou et al. All rights reserved. Comparison of the Current Diagnostic Criterion of HbA1c with Fasting and 2-Hour Plasma Glucose Concentration Thu, 11 Aug 2016 07:26:32 +0000 To determine the effectiveness of hemoglobin A1c (HbA1c) ≥ 6.5% in diagnosing diabetes compared to fasting plasma glucose (FPG) ≥ 126 mg/dL and 2-hour plasma glucose (2hPG) ≥ 200 mg/dL in a previously undiagnosed diabetic cohort, we included 5,764 adult subjects without established diabetes for whom HbA1c, FPG, 2hPG, and BMI measurements were collected. Compared to the FPG criterion, the sensitivity of HbA1c ≥ 6.5% was only 43.3% (106 subjects). Compared to the 2hPG criterion, the sensitivity of HbA1c ≥ 6.5% was only 28.1% (110 subjects). Patients who were diabetic using 2hPG criterion but had HbA1c < 6.5% were more likely to be older ( versus years old, , mean ± STD), female (53.2% versus 38.2%, ), leaner ( versus  kg/m2, ), and less likely to be current smokers (18.1% versus 29.1%, ) as compared to those with HbA1c ≥ 6.5%. The diagnostic agreement in the clinical setting revealed the current HbA1c ≥ 6.5% is less likely to detect diabetes than those defined by FPG and 2hPG. HbA1c ≥ 6.5% detects less than 50% of diabetic patients defined by FPG and less than 30% of diabetic patients defined by 2hPG. When the diagnosis of diabetes is in doubt by HbA1c, FPG and/or 2hPG should be obtained. Rudruidee Karnchanasorn, Jean Huang, Horng-Yih Ou, Wei Feng, Lee-Ming Chuang, Ken C. Chiu, and Raynald Samoa Copyright © 2016 Rudruidee Karnchanasorn et al. All rights reserved. The Influence of Health Literacy and Depression on Diabetes Self-Management: A Cross-Sectional Study Wed, 10 Aug 2016 10:45:04 +0000 Despite an increasing focus on health literacy in the clinical setting and in the literature, there is still ongoing debate about its influence on diabetes self-management. The aim of the study was to examine the relationships of sociodemographic, clinical, and psychological factors on health literacy and diabetes self-management. A cross-sectional survey was undertaken on 224 patients with type 2 diabetes at two diabetes centres in Sydney, Australia. Findings showed that people with low health literacy were more likely to (a) have lower educational attainment; (b) be migrants; and (c) have depressed mood. Unexpectedly, those who met threshold of good glucose control were more likely to have low health literacy. Predictors of low diabetes self-management included (a) younger age group (AOR: 2.58, 95% CI: 1.24–4.64); (b) having postsecondary education (AOR: 2.30, 95% CI: 1.05–5.01); (c) low knowledge of diabetes management (AOR: 2.29, 95% CI: 1.25–4.20); and (d) having depressed mood (AOR: 2.30, 95% CI: 1.30–4.06). The finding that depressed mood predicted both low health literacy and low diabetes self-management stresses the importance of screening for depression. Increasing people’s understanding of diabetes self-management and supporting those with depression are crucial to enhance participation in diabetes self-management. D. Maneze, B. Everett, C. Astorga, D. Yogendran, and Y. Salamonson Copyright © 2016 D. Maneze et al. All rights reserved. Experimental Diabetes Mellitus in Different Animal Models Tue, 09 Aug 2016 15:26:52 +0000 Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. Diabetes mellitus disease, commonly known as diabetes, is a group of metabolic disorders characterized by high blood glucose levels for a prolonged time. To avoid late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic symptoms, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty (ZDF) rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. The advantages and disadvantages that these models comprise were also addressed in this review. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. Amin Al-awar, Krisztina Kupai, Médea Veszelka, Gergő Szűcs, Zouhair Attieh, Zsolt Murlasits, Szilvia Török, Anikó Pósa, and Csaba Varga Copyright © 2016 Amin Al-awar et al. All rights reserved. Acute Thermotherapy Prevents Impairments in Cutaneous Microvascular Function Induced by a High Fat Meal Tue, 09 Aug 2016 08:01:42 +0000 We tested the hypothesis that a high fat meal (HFM) would impair cutaneous vasodilation, while thermotherapy (TT) would reverse the detrimental effects. Eight participants were instrumented with skin heaters and laser-Doppler (LD) probes and tested in three trials: control, HFM, and HFM + TT. Participants wore a water-perfused suit perfused with 33°C (control and HFM) or 50°C (HFM + TT) water. Participants consumed 1 g fat/kg body weight. Blood samples were taken at baseline and two hours post-HFM. Blood pressure was measured every 5–10 minutes. Microvascular function was assessed via skin local heating from 33°C to 39°C two hours after HFM. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%). HFM had no effect on initial peak (48 ± 4 %) compared to control (49 ± 4 %) but attenuated the plateau (51 ± 4 %) compared to control (63 ± 4 %, P < 0.001). Initial peak was augmented in HFM + TT (66 ± 4 %) compared to control and HFM (P < 0.05), while plateau (73 ± 3 % ) was augmented only compared to the HFM trial (P < 0.001). These data suggest that HFM negatively affects cutaneous vasodilation but can be minimized by TT. Jennifer C. Harvey, Bruno T. Roseguini, Benjamin M. Goerger, Elizabeth A. Fallon, and Brett J. Wong Copyright © 2016 Jennifer C. Harvey et al. All rights reserved. Coronary Plaque Characteristics Assessed by 256-Slice Coronary CT Angiography and Association with High-Sensitivity C-Reactive Protein in Symptomatic Patients with Type 2 Diabetes Mon, 08 Aug 2016 12:02:20 +0000 Little is known regarding plaque distribution, composition, and the association with inflammation in type 2 diabetes mellitus (DM2). This study aimed to assess the relationship between coronary plaque subtypes and high-sensitivity C-reactive protein levels. Coronary CTA were performed in 98 symptomatic DM2 patients and 107 non-DM2 patients using a 256-slice CT. The extent and types of plaque as well as luminal narrowing were evaluated. Patients with DM2 were more likely to have significant stenosis (>50%) with calcified plaques in at least one coronary segment (); the prevalence rates of diffuse calcified plaques in the DM2 and non-DM2 groups were 31.6% and 4.7%, respectively (). Plasma hs-CRP levels in DM2 with calcified plaques were higher compared with values obtained for the non-DM2 group (). In conclusion, combination of coronary CTA and hs-CRP might improve risk stratification in symptomatic DM2 patients. Jinling Zhang, Zhehao Lv, Deli Zhao, Lili Liu, Yong Wan, Tingting Fan, Huimin Li, Ying Guan, Bailu Liu, and Qi Yang Copyright © 2016 Jinling Zhang et al. All rights reserved. Potential of IL-33 for Preventing the Kidney Injury via Regulating the Lipid Metabolism in Gout Patients Sun, 07 Aug 2016 13:31:52 +0000 Interleukin-33 (IL-33), the most recently discovered member of the IL-1 superfamily, has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2. However, there is little information regarding the role of IL-33 in gout. In this study, we investigated the potential role of IL-33 in gout patients. The serum level of IL-33 was measured by ELISA, and the clinical and laboratory parameters, serum creatinine, urea, and lipid, were extracted from medical record system. The serum IL-33 expression was predominantly increased in gout patients compared to healthy controls, and the IL-33 levels were higher in patients without kidney injury. Furthermore, IL-33 showed a negative correlation with biomarkers of kidney injury, such as CRE and urea. The lipid metabolism dysfunction, tophi, and hypertension are the common reasons for kidney injury in gout. Interestingly, inverse and positive correlation of IL-33 expression was observed in LDL and HDL, respectively. However, there was no significant alteration in the gout patients with hypertension and tophi. These data suggested that IL-33 might act as a protective role in kidney injury through regulating the lipid metabolism in gout. Lihua Duan, Yan Huang, Qun Su, Qingyan Lin, Wen Liu, Jiao Luo, Bing Yu, Yan He, Hongyan Qian, Yuan Liu, Jie Chen, and Guixiu Shi Copyright © 2016 Lihua Duan et al. All rights reserved. The Change in HbA1c Associated with Initial Adherence and Subsequent Change in Adherence among Diabetes Patients Newly Initiating Metformin Therapy Sun, 07 Aug 2016 09:47:24 +0000 Introduction. Whether changes in adherence are associated with changes in HbA1c is assumed but not known. Methods. We conducted a observational study of 2,844 type 2 diabetes patients who initiated metformin as their first antihyperglycemic drug. Using HbA1c measures before, 6–12 months after, and up to 3 years after metformin initiation, we analyzed HbA1c change as a function of initial adherence and change in adherence. Results. Compared with no adherence, initial adherence of 50–79% was associated with an adjusted reduction in HbA1c of 0.45% while adherence ≥80% was associated with HbA1c reduction of 0.73%. Change from some initial adherence (1–79%) to total nonadherence was associated with 0.25% increase in HbA1c. Change from some to full adherence was associated with an HbA1c decrease of 0.15%. Those associations were accentuated among patients not in glycemic control: change from some to no adherence was associated with an HbA1c increase of 0.63% and change from some to full adherence was associated with an HbA1c decrease of 0.40%. Conclusions. Initial adherence to newly prescribed metformin therapy produces substantial HbA1c reduction. Among those with modest adherence but suboptimal glycemic control, the difference between moving to full adherence versus nonadherence results in lower HbA1c of one percentage point. Gregory A. Nichols, A. Gabriela Rosales, Teresa M. Kimes, Kaan Tunceli, Karen Kurtyka, and Panagiotis Mavros Copyright © 2016 Gregory A. Nichols et al. All rights reserved. Effect of Endomorphins on HUVECs Treated by ox-LDL and Its Related Mechanisms Thu, 04 Aug 2016 09:06:15 +0000 We found in the present study that treatment with ox-LDL decreased the cell viability and the content of nitric oxide (NO) and the activity of nitric oxide synthase (NOS) as well as eNOS mRNA expression, while increasing the mRNA expression and content of endothelin-1 (ET-1) in human umbilical vein endothelial cells (HUVECs). However, endomorphins EM1/EM2 increased the cell viability and the content of NO and the activity of NOS as well as eNOS mRNA expression, while decreasing the mRNA expression and content of ET-1 compared with ox-LDL alone. Meanwhile, the expressions of JNK and p-JNK were enhanced by ox-LDL while being suppressed by EM1/EM2. The results suggested that EM1 and EM2 can correct the endothelial cell dysfunction induced by ox-LDL and the protective effect may be achieved by affecting the JNK pathway. Juan Zhao, Qi Zhang, Jing Liu, Liming Tian, Wenhui Huang, Jinxing Quan, Jinyang Wang, Yanjia Xu, Yunfang Wang, and Ruilan Niu Copyright © 2016 Juan Zhao et al. All rights reserved. Social Support Groups in the Maintenance of Glycemic Control after Community-Based Intervention Wed, 03 Aug 2016 14:34:49 +0000 Native Hawaiians and other Pacific Islanders (NH/PI; e.g., Samoan and Chuukese) have higher type 2 diabetes prevalence compared to other groups in Hawai‘i. Partners in Care (PIC), a culturally tailored, community-based, diabetes self-management education intervention (DSME), is effective at improving participants’ glycemic control and self-care behaviors. Maintenance of improvements is challenging. Diabetes-related social support groups (SSG) are a promising maintenance component for DSME. This study examined the effects of a diabetes-specific SSG component relative to a control group, after the receipt of the 3-month PIC intervention, which was delivered to 47 adult NH/PI with type 2 diabetes. Participants were then randomized to either a 3-month, 6-session SSG or a control group. Hemoglobin A1c (HbA1c), blood pressure, triglycerides, cholesterol, and diabetes self-management knowledge and behaviors were assessed at baseline, 3 months, and 6 months. Results indicated significant improvements in HbA1c, diabetes-related self-management knowledge, and behaviors from baseline to 3-month assessment. However, no differences between the SSG and control group from 3-month to 6-month assessment suggest that all participants were able to maintain initial improvements. The SSG group had a significant decrease in systolic blood pressure from 3-month to 6-month assessment while the control group did not. Study limitations and future directions are discussed. Claire Townsend Ing, Guangxing Zhang, Adrienne Dillard, Sheryl R. Yoshimura, Claire Hughes, Donna-Marie Palakiko, Bridget Puni Kehauoha, Ka‘imi A. Sinclair, and Joseph Keawe‘aimoku Kaholokula Copyright © 2016 Claire Townsend Ing et al. All rights reserved. The Expanded Bead Size of Corneal C-Nerve Fibers Visualized by Corneal Confocal Microscopy Is Associated with Slow Conduction Velocity of the Peripheral Nerves in Patients with Type 2 Diabetes Mellitus Wed, 03 Aug 2016 14:27:41 +0000 This study aims to establish the corneal nerve fiber (CNF) morphological alterations in a large cohort of type 2 diabetic patients and to investigate the association between the bead size, a novel parameter representing composite of accumulated mitochondria, glycogen particles, and vesicles in CNF, and the neurophysiological dysfunctions of the peripheral nerves. 162 type 2 diabetic patients and 45 healthy control subjects were studied in detail with a battery of clinical and neurological examinations and corneal confocal microscopy. Compared with controls, patients had abnormal CNF parameters. In particular the patients had reduced density and length of CNF and beading frequency and increased bead size. Alterations in CNF parameters were significant even in patients without neuropathy. The HbA1c levels were tightly associated with the bead size, which was inversely related to the motor and sensory nerve conduction velocity (NCV) and to the distal latency period of the median nerve positively. The CNF density and length positively correlated with the NCV and amplitude. The hyperglycemia-induced expansion of beads in CNF might be a predictor of slow NCV in peripheral nerves in type 2 diabetic patients. Fukashi Ishibashi, Rie Kojima, Miki Taniguchi, Aiko Kosaka, Harumi Uetake, and Mitra Tavakoli Copyright © 2016 Fukashi Ishibashi et al. All rights reserved.