Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice Wed, 28 Sep 2016 07:50:44 +0000 Aim. Models combining diabetes and atherosclerosis are important in evaluating the cardiovascular (CV) effects and safety of antidiabetes drugs in the development of treatments targeting CV complications. Our aim was to evaluate if crossing the heterozygous glucokinase knockout mouse (GK+/−) and hyperlipidemic mouse deficient in apolipoprotein E (ApoE−/−) will generate a disease model exhibiting a diabetic and macrovascular phenotype. Methods. The effects of defective glucokinase on the glucose metabolism and on the progression and regression of atherosclerosis on high-fat diets were studied in both genders of GK+/−ApoE−/− and ApoE−/− mice. Coronary vascular function of the female GK+/−ApoE−/− and ApoE−/− mice was also investigated. Results. GK+/−ApoE−/− mice show a stable hyperglycemia which was increased on Western diet. In oral glucose tolerance test, GK+/−ApoE−/− mice showed significant glucose intolerance and impaired glucose-stimulated insulin secretion. Plasma lipids were comparable with ApoE−/− mice; nevertheless the GK+/−ApoE−/− mice showed slightly increased atherosclerosis development. Conclusions. The GK+/−ApoE−/− mice showed a stable and reproducible hyperglycemia, accelerated atherosclerotic lesion progression, and no lesion regression after lipid lowering. This novel model provides a promising tool for drug discovery, enabling the evaluation of compound effects against both diabetic and cardiovascular endpoints simultaneously in one animal model. Damilola D. Adingupu, Suvi E. Heinonen, Anne-Christine Andréasson, Mikael Brusberg, Andrea Ahnmark, Margareta Behrendt, Brendan Leighton, and Ann-Cathrine Jönsson-Rylander Copyright © 2016 Damilola D. Adingupu et al. All rights reserved. Knowledge and Self-Reported Practice of Insulin Injection Device Disposal among Diabetes Patients in Gondar Town, Ethiopia: A Cross-Sectional Study Sun, 25 Sep 2016 14:17:01 +0000 Background. Incorrect sharp disposal practices may expose the public to needle-stick injuries. The present study aimed at assessing the knowledge and practice of diabetic patients towards insulin injection device disposal in Gondar town, Ethiopia. Methods. A cross-sectional study was employed on insulin requiring diabetes patients who visited the diabetes clinic at Gondar University Referral Hospital (GURH) from February 1 to March 28, 2016. Frequencies, percentages, and ANOVA (analysis of variance) and Student’s t-test were used to analyze variables. Results. About half of the participants (49.5%) had poor knowledge towards safe insulin injection waste disposal. More than two-thirds (80.7%) of respondents had poor practice and 64.3% of respondents did not put insulin needle and lancets into the household garbage. 31% of respondents threw sharps on street when they travel outside. Respondents living in urban areas had a higher mean of knowledge and practice score than those who live in rural area. Conclusions. This study revealed that knowledge and practice of diabetic patients were low towards safe insulin injection waste disposal in study area. Healthcare providers should also be aware of safe disposing system and counsel patients on appropriate disposal of used syringes. Abebe Basazn Mekuria, Begashaw Melaku Gebresillassie, Daniel Asfaw Erku, Kaleab Taye Haile, and Eshetie Melese Birru Copyright © 2016 Abebe Basazn Mekuria et al. All rights reserved. The Safety and Tolerability of 5-Aminolevulinic Acid Phosphate with Sodium Ferrous Citrate in Patients with Type 2 Diabetes Mellitus in Bahrain Thu, 22 Sep 2016 11:51:43 +0000 Type 2 diabetes mellitus is prevalent especially in Gulf countries and poses serious long-term risks to patients. A multifaceted treatment approach can include nutritional supplements with antioxidant properties such as 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC). This prospective, randomized, single-blind, placebo-controlled, dose escalating pilot clinical trial assessed the safety of 5-ALA with SFC at doses up to 200 mg 5-ALA/229.42 mg SFC per day in patients living in Bahrain with type 2 diabetes mellitus that was uncontrolled despite the use of one or more antidiabetic drugs. Fifty-three patients () from 3 sites at one center were enrolled by Dr. Feryal (Site #01), Dr. Hesham (Site #02), and Dr. Waleed (Site #03) (, 5-ALA-SFC; , placebo). There was no significant difference in incidence of adverse events reported, and the most frequent events reported were gastrointestinal in nature, consistent with the known safety profile of 5-ALA in patients with diabetes. No significant changes in laboratory values and no difference in hypoglycemia between patients receiving 5-ALA and placebo were noted. Overall, the current results support that use of 5-ALA-SFC up to 200 mg per day taken as 2 divided doses is safe in patients taking concomitant oral antidiabetic medications and may offer benefits in the diabetic population. This trial is registered with NCT02481141. Feryal Al-Saber, Waleed Aldosari, Mariam Alselaiti, Hesham Khalfan, Ahmed Kaladari, Ghulam Khan, George Harb, Riyadh Rehani, Sizuka Kudo, Aya Koda, Tohru Tanaka, Motowo Nakajima, and Abdulla Darwish Copyright © 2016 Feryal Al-Saber et al. All rights reserved. Validity of the Finnish Diabetes Risk Score for Detecting Undiagnosed Type 2 Diabetes among General Medical Outpatients in Botswana Thu, 22 Sep 2016 09:35:18 +0000 This was a cross-sectional study designed to assess the validity of the Finnish Diabetes Risk Score for detecting undiagnosed type 2 diabetes among general medical outpatients in Botswana. Participants aged ≥20 years without previously diagnosed diabetes were screened by (1) an 8-item Finnish diabetes risk assessment questionnaire and (2) Haemoglobin A1c test. Data from 291 participants were analyzed (74.2% were females). The mean age of the participants was 50.1 (SD = ±11) years, and the prevalence of undiagnosed diabetes was 42 (14.4%) with no significant differences between the gender (20% versus 12.5%, ). The area under curve for detecting undiagnosed diabetes was 0.63 (95% CI 0.55–0.72) for the total population, 0.65 (95% CI: 0.56–0.75) for women, and 0.67 (95% CI: 0.52–0.83) for men. The optimal cut-off point for detecting undiagnosed diabetes was 17 (sensitivity = 48% and specificity = 73%) for the total population, 17 (sensitivity = 56% and specificity = 66%) for females, and 13 (sensitivity = 53% and specificity = 77%) for males. The positive predictive value and negative predictive value were 20% and 89.5%, respectively. The findings indicate that the Finnish questionnaire was only modestly effective in predicting undiagnosed diabetes among outpatients in Botswana. Bernard Omech, Julius Chacha Mwita, Jose-Gaby Tshikuka, Billy Tsima, Oathokwa Nkomazna, and Kennedy Amone-P’Olak Copyright © 2016 Bernard Omech et al. All rights reserved. Plasma C1q/TNF-Related Protein-3 (CTRP-3) and High-Mobility Group Box-1 (HMGB-1) Concentrations in Subjects with Prediabetes and Type 2 Diabetes Thu, 22 Sep 2016 07:47:47 +0000 Aims. To detect the association of C1q/TNF-related protein-3 (CTRP-3) and high-mobility group box-1 (HMGB-1) in subjects with prediabetes (pre-DM) and newly diagnosed type 2 diabetes (nT2DM). Methods. 224 eligible participants were included. The 75 g oral glucose tolerance test (OGTT) and several clinical parameters of metabolic disorders and cytokines were measured. All participants were divided into three groups: normal glucose tolerance (NGT, ), pre-DM (), and nT2DM group (). Results. Plasma CTRP-3 concentrations were significantly lower in subjects with pre-DM and nT2DM than that of the NGT group, while plasma HMGB-1 levels were higher in pre-DM and nT2DM group compared with the NGT group (). A multiple linear regression analysis showed both plasma CTRP-3 and HMGB-1 concentrations were independently associated with homeostasis model assessment for insulin resistance (HOMA-IR) and interleukin-6 (IL-6) ( for all). Further multiple logistical regression analyses revealed that both plasma CTRP-3 and HMGB-1 levels were significantly associated with pre-DM and nT2DM after adjusting for several confounders ( for all). Conclusions. Circulating CTRP-3 and HMGB-1 concentrations might be promising biomarkers to predict prediabetes and type 2 diabetes. Huili Wei, Hua Qu, Hang Wang, and Huacong Deng Copyright © 2016 Huili Wei et al. All rights reserved. Influence of Dapagliflozin on Glycemic Variations in Patients with Newly Diagnosed Type 2 Diabetes Mellitus Wed, 21 Sep 2016 14:29:40 +0000 Objectives. To observe changes in blood glycemic variations and oxidative stress level before and after dapagliflozin treatment in patients with newly diagnosed T2DM. Methods. This was a randomized, double-blind, placebo-controlled, phase 3 trial. A total of 28 patients with newly diagnosed T2DM with levels of 7.5–10.5% were randomly selected to receive dapagliflozin or placebo treatment for 24 weeks. After baseline data were collected, we analyzed glycemic variations and plasma 8-iso PGF2α level at baseline and at the endpoint. Primary outcome was the changes of mean amplitude glycemic excursion (MAGE) within groups. Results. After 24-week dapagliflozin therapy, our data showed the significant improvement of MAGE with dapagliflozin therapy (). Compared with control group, patients in dapagliflozin group exhibited reduction in 24-hour MBG () and lower mean plasma glucose concentrations, especially during periods from 2400 to 0200 and 1300 to 1800 (, resp.). In addition, plasma 8-iso PGF2α level was notably decreased in the treatment group compared to the control group (). Conclusions. In conclusion, this study shows the ability of dapagliflozin to improve glycemic variations and associate with reduction of oxidative stress in patients with T2DM, which may benefit the cardiovascular system. Feng-fei Li, Gu Gao, Qian Li, Hong-hong Zhu, Xiao-fei Su, Jin-dan Wu, Lei Ye, and Jian-hua Ma Copyright © 2016 Feng-fei Li et al. All rights reserved. Reversal of Early Diabetic Nephropathy by Islet Transplantation under the Kidney Capsule in a Rat Model Tue, 20 Sep 2016 12:07:16 +0000 Objective. Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus, and insulin therapy has many side effects in the treatment of DN. Islet transplantation has emerged as a promising therapy for diabetic patients. This study was established to investigate its advantageous effects in a rat model of early DN. Methods. Streptozotocin was administered to the rats to induce diabetes. Twelve weeks later, the diabetic rats were divided into 3 groups: the islet-transplanted group (IT group), the insulin-treated group (IN group), and the untreated group (DN group). Renal injury and kidney structure were assessed by urinalysis and transmission electron microscopy (TEM) detection. Immunohistochemical staining and western blotting were performed to assess renal fibrosis levels. Results. The early DN features were reversed and the glomerular filtration barrier and basement membrane structures were improved at 4 weeks after islet transplantation. The urine microalbumin-to-creatinine ratio (ACR), protein-to-creatinine ratio, and mean thickness of the glomerular basement membrane (GBM) were significantly decreased in the IT group. The expression of renal fibrotic factors was also significantly decreased. Conclusions. These data suggest that early DN can be reversed after islet transplantation, and they may facilitate the development of a clinical therapeutic strategy for human diabetes mellitus. Yunqiang He, Ziqiang Xu, Mingshi Zhou, Minmin Wu, Xuehai Chen, Silu Wang, Kaiyan Qiu, Yong Cai, Hongxing Fu, Bicheng Chen, and Mengtao Zhou Copyright © 2016 Yunqiang He et al. All rights reserved. Developing a Conceptually Equivalent Type 2 Diabetes Risk Score for Indian Gujaratis in the UK Thu, 15 Sep 2016 07:43:14 +0000 Aims. To apply and assess the suitability of a model consisting of commonly used cross-cultural translation methods to achieve a conceptually equivalent Gujarati language version of the Leicester self-assessment type 2 diabetes risk score. Methods. Implementation of the model involved multiple stages, including pretesting of the translated risk score by conducting semistructured interviews with a purposive sample of volunteers. Interviews were conducted on an iterative basis to enable findings to inform translation revisions and to elicit volunteers’ ability to self-complete and understand the risk score. Results. The pretest stage was an essential component involving recruitment of a diverse sample of 18 Gujarati volunteers, many of whom gave detailed suggestions for improving the instructions for the calculation of the risk score and BMI table. Volunteers found the standard and level of Gujarati accessible and helpful in understanding the concept of risk, although many of the volunteers struggled to calculate their BMI. Conclusions. This is the first time that a multicomponent translation model has been applied to the translation of a type 2 diabetes risk score into another language. This project provides an invaluable opportunity to share learning about the transferability of this model for translation of self-completed risk scores in other health conditions. Naina Patel, Andrew Willis, Margaret Stone, Shaun Barber, Laura Gray, Melanie Davies, and Kamlesh Khunti Copyright © 2016 Naina Patel et al. All rights reserved. The Yin and Yang of the Opioid Growth Regulatory System: Focus on Diabetes—The Lorenz E. Zimmerman Tribute Lecture Wed, 14 Sep 2016 11:08:38 +0000 The Opioid Growth Regulatory System consists of opioid growth factor (OGF), [Met5]-enkephalin, and its unique receptor (OGFr). OGF inhibits cell division when bound to OGFr. Conversely, blockade of the interaction of OGF and OGFr, using the potent, long-acting opioid receptor antagonist, naltrexone (NTX), results in increased DNA synthesis and cell division. The authors have demonstrated both in vitro and in vivo that the addition of exogenous OGF or an increase in available OGFr decreases corneal epithelial cell division and wound healing. Conversely, blockade of the OGF-OGFr interaction by NTX or a decrease in the production of the OGFr increases corneal epithelial cell division and facilitates corneal epithelial wound healing. The authors also have demonstrated that depressed corneal and cutaneous wound healing, dry eye, and abnormal corneal sensitivity in type 1 and type 2 diabetes in animals can be reversed by OGF-OGFr blockade by NTX. Thus, the function of the Opioid Growth Regulatory System appears to be disordered in diabetic animals, and its function can be restored with NTX treatment. These studies suggest a fundamental role for the Opioid Growth Regulatory System in the pathobiology of diabetic complications and a need for studies to elucidate this role further. Joseph W. Sassani, Patricia J. Mc Laughlin, and Ian S. Zagon Copyright © 2016 Joseph W. Sassani et al. All rights reserved. Novel Tubular Biomarkers Predict Renal Progression in Type 2 Diabetes Mellitus: A Prospective Cohort Study Thu, 08 Sep 2016 17:37:57 +0000 Background. Tubulointerstitial injury is both a key feature of diabetic nephropathy and an important predictor of renal dysfunction. Novel tubular biomarkers related to renal injury in diabetic nephropathy could improve risk stratification and prediction. Methods. A total of 303 type 2 diabetic patients were followed up. The baseline urine values of cystatin-C to creatinine ratio (UCCR), angiotensinogen to creatinine ratio (UANG), NGAL to creatinine ratio (UNGAL), and KIM-1 to creatinine ratio (UKIM-1) were measured. The primary outcome was a decline in estimated GFR of ≥25% yearly from baseline. Results. Urine tubular biomarkers of UCCR, UANG, UNGAL, and UKIM-1 were significantly higher according to the degree of albuminuria and all were significantly higher among patients with rapid decline in estimated GFR of ≥25% yearly from baseline. All biomarkers predicted primary outcomes with ROC for UCCR of 0.72; 95% CI 0.64–0.79, for UANG of 0.71; 95% CI 0.63–0.79, for UNGAL of 0.64; 95% CI 0.56–0.72, and for UKIM-1 of 0.71; 95% CI 0.63–0.79. Using multivariate Cox regression analysis, the number of patients with rapid renal progression was higher among those in the upper quartiles of all biomarkers than in those in the lower quartiles. Conclusions. Type 2 diabetic patients with high levels of urine tubular biomarkers had a more rapid decline in renal function. Bancha Satirapoj, Kasemsan Aramsaowapak, Theerasak Tangwonglert, and Ouppatham Supasyndh Copyright © 2016 Bancha Satirapoj et al. All rights reserved. The Rise and the Fall of Betatrophin/ANGPTL8 as an Inducer of β-Cell Proliferation Thu, 08 Sep 2016 12:49:05 +0000 Diabetes is a global health problem that is caused by impaired insulin production from pancreatic β-cells. Efforts to regenerate β-cells have been advancing rapidly in the past two decades with progress made towards identifying new agents that induce β-cells regeneration. ANGPTL8, also named betatrophin, has been recently identified as a hormone capable of inducing β-cells proliferation and increasing β-cells mass in rodents. Its discovery has been cherished as a breakthrough and a game changer in the field of β-cells regeneration. Initially, ANGPTL8 has been identified as atypical member of the angiopoietin-like protein family as a regulator of triglyceride in plasma through its interaction with ANGPTL3 and its regulation of lipoprotein lipase activity. In this review, we will review literature on the proposed role of ANGPTL8 in β-cells proliferation, the controversy regarding this role, and the emerging data questioning its involvement in β-cells proliferation. Additionally we will discuss new clinical data that describes its role in diabetes and the putative therapeutic targeting of this protein. Mohamed Abu-Farha, Ashraf Al Madhoun, and Jehad Abubaker Copyright © 2016 Mohamed Abu-Farha et al. All rights reserved. Association between Serum Cystatin C and Diabetic Foot Ulceration in Patients with Type 2 Diabetes: A Cross-Sectional Study Wed, 07 Sep 2016 07:41:11 +0000 Serum cystatin C (CysC) has been identified as a possible potential biomarker in a variety of diabetic complications, including diabetic peripheral neuropathy and peripheral artery disease. We aimed to examine the association between CysC and diabetic foot ulceration (DFU) in patients with type 2 diabetes (T2D). 411 patients with T2D were enrolled in this cross-sectional study at a university hospital. Clinical manifestations and biochemical parameters were compared between DFU group and non-DFU group. The association between serum CysC and DFU was explored by binary logistic regression analysis. The cut point of CysC for DFU was also evaluated by receiver operating characteristic (ROC) curve. The prevalence of coronary artery disease, diabetic nephropathy (DN), and DFU dramatically increased with CysC () in CysC quartiles. Multivariate logistic regression analysis indicated that the significant risk factors for DFU were serum CysC, coronary artery disease, hypertension, insulin use, the differences between supine and sitting TcPO2, and hypertension. ROC curve analysis revealed that the cut point of CysC for DFU was 0.735 mg/L. Serum CysC levels correlated with DFU and severity of tissue loss. Our study results indicated that serum CysC was associated with a high prevalence of DFU in Chinese T2D subjects. Jie Zhao, Wuquan Deng, Yuping Zhang, Yanling Zheng, Lina Zhou, Johnson Boey, David G. Armstrong, Gangyi Yang, Ziwen Liang, and Bing Chen Copyright © 2016 Jie Zhao et al. All rights reserved. Optimising Health Literacy and Access of Service Provision to Community Dwelling Older People with Diabetes Receiving Home Nursing Support Wed, 07 Sep 2016 06:11:16 +0000 Background. Health literacy is the ability to access, understand, and use information and services for good health. Among people with chronic conditions, health literacy requirements for effective self-management are high. The Optimising Health Literacy and Access (Ophelia) study engaged diverse organisations in the codesign of interventions involving the Health Literacy Questionnaire (HLQ) needs assessment, followed by development and evaluation of interventions addressing identified needs. This study reports the process and outcomes of one of the nine organisations, the Royal District Nursing Service (RDNS). Methods. Participants were home nursing clients with diabetes. The intervention included tailored diabetes self-management education according to preferred learning style, a standardised diabetes education tool, resources, and teach-back method. Results. Needs analysis of 113 quota-sampled clients showed difficulties managing health and finding and appraising health information. The service-wide diabetes education intervention was applied to 24 clients. The intervention was well received by clients and nurses. Positive impacts on clients’ diabetes knowledge and behaviour were seen and nurses reported clear benefits to their practice. Conclusion. A structured method that supports healthcare services to codesign interventions that respond to the health literacy needs of their clients can lead to evidence-informed, sustainable practice changes that support clients to better understand effective diabetes self-management. Dianne Goeman, Sue Conway, Ralph Norman, Jo Morley, Rona Weerasuriya, Richard H. Osborne, and Alison Beauchamp Copyright © 2016 Dianne Goeman et al. All rights reserved. Altered Macrophage and Dendritic Cell Response in Mif−/− Mice Reveals a Role of Mif for Inflammatory-Th1 Response in Type 1 Diabetes Tue, 06 Sep 2016 14:11:14 +0000 Macrophage migration inhibitory factor (Mif) is highly expressed in type 1 diabetes mellitus (T1DM). However, there is limited information about how Mif influences the activation of macrophages (Mφ) and dendritic cells (DC) in T1DM. To address this issue, we induced T1DM by administering multiple low doses of streptozotocin (STZ) to Mif−/− or wild-type (Wt) BALB/c mice. We found that Mif−/− mice treated with STZ (Mif−/−STZ) developed lower levels of hyperglycemia, inflammatory cytokines, and specific pancreatic islet antigen- (PIAg-) IgG and displayed reduced cellular infiltration into the pancreatic islets compared to Wt mice treated with STZ (WtSTZ). Moreover, Mφ and DC from Mif−/−STZ displayed lower expression of MHC-II, costimulatory molecules CD80, CD86, and CD40, Toll-like receptor- (TLR-) 2, and TLR-4 than WtSTZ. These changes were associated with a reduced capacity of Mφ and DC from Mif−/−STZ to induce proliferation in ovalbumin-specific T cells. All the deficiencies observed in Mif−/−STZ were recovered by exogenous administration of recombinant Mif. These findings suggest that Mif plays a role in the molecular mechanisms of Mφ and DC activation and drives T cell responses involved in the pathology of T1DM. Therefore, Mif is a potential therapeutic target to reduce the pathology of T1DM. Yuriko Itzel Sánchez-Zamora, Imelda Juarez-Avelar, Alicia Vazquez-Mendoza, Marcia Hiriart, and Miriam Rodriguez-Sosa Copyright © 2016 Yuriko Itzel Sánchez-Zamora et al. All rights reserved. Effects of a Patient-Provider, Collaborative, Medication-Planning Tool: A Randomized, Controlled Trial Tue, 06 Sep 2016 08:14:11 +0000 Among patients with various levels of health literacy, the effects of collaborative, patient-provider, medication-planning tools on outcomes relevant to self-management are uncertain. Objective. Among adult patients with type II diabetes mellitus, we tested the effectiveness of a medication-planning tool (Medtable™) implemented via an electronic medical record to improve patients’ medication knowledge, adherence, and glycemic control compared to usual care. Design. A multicenter, randomized controlled trial in outpatient primary care clinics. 674 patients received either the Medtable tool or usual care and were followed up for up to 12 months. Results. Patients who received Medtable had greater knowledge about indications for medications in their regimens and were more satisfied with the information about their medications. Patients’ knowledge of drug indication improved with Medtable regardless of their literacy status. However, Medtable did not improve patients’ demonstrated medication use, regimen adherence, or glycemic control (HbA1c). Conclusion. The Medtable tool supported provider/patient collaboration related to medication use, as reflected in patient satisfaction with communication, but had limited impact on patient medication knowledge, adherence, and HbA1c outcomes. This trial is registered with NCT01296633. James F. Graumlich, Huaping Wang, Anna Madison, Michael S. Wolf, Darren Kaiser, Kumud Dahal, and Daniel G. Morrow Copyright © 2016 James F. Graumlich et al. All rights reserved. Development and Validation of a Simple Risk Score for Undiagnosed Type 2 Diabetes in a Resource-Constrained Setting Sun, 04 Sep 2016 11:08:24 +0000 Objective. To develop and validate a risk score for detecting cases of undiagnosed diabetes in a resource-constrained country. Methods. Two population-based studies in Peruvian population aged ≥35 years were used in the analysis: the ENINBSC survey () and the CRONICAS Cohort Study (). Fasting plasma glucose ≥7.0 mmol/L was used to diagnose diabetes in both studies. Coefficients for risk score were derived from the ENINBSC data and then the performance was validated using both baseline and follow-up data of the CRONICAS Cohort Study. Results. The prevalence of undiagnosed diabetes was 2.0% in the ENINBSC survey and 2.9% in the CRONICAS Cohort Study. Predictors of undiagnosed diabetes were age, diabetes in first-degree relatives, and waist circumference. Score values ranged from 0 to 4, with an optimal cutoff ≥2 and had a moderate performance when applied in the CRONICAS baseline data (AUC = 0.68; 95% CI: 0.62–0.73; sensitivity 70%; specificity 59%). When predicting incident cases, the AUC was 0.66 (95% CI: 0.61–0.71), with a sensitivity of 69% and specificity of 59%. Conclusions. A simple nonblood based risk score based on age, diabetes in first-degree relatives, and waist circumference can be used as a simple screening tool for undiagnosed and incident cases of diabetes in Peru. Antonio Bernabe-Ortiz, Liam Smeeth, Robert H. Gilman, Jose R. Sanchez-Abanto, William Checkley, J. Jaime Miranda, and CRONICAS Cohort Study Group Copyright © 2016 Antonio Bernabe-Ortiz et al. 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.