Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Beneficial Effects of Omega-3 Polyunsaturated Fatty Acids in Gestational Diabetes: Consequences in Macrosomia and Adulthood Obesity Thu, 16 Apr 2015 11:30:41 +0000 Omega-3 polyunsaturated fatty acids (PUFAs) are increasingly being used to prevent cardiovascular diseases, including diabetes and obesity. In this paper, we report data on the observed effects of omega-3 PUFA on major metabolic disorders and immune system disruption during gestational diabetes and their consequences on macrosomia. While controversies still exist about omega-3 PUFA effects on antioxidant status regarding the level of omega-3 PUFA in diet supplementation, their lipid-lowering effects are unanimously recognized by researchers. Animal studies have shown that omega-3 PUFA contributes to the maintenance of the immune defense system by promoting the differentiation of T helper (Th) cell to a Th2 phenotype in diabetic pregnancy and by shifting the Th1/Th2 ratio from a deleterious proinflammatory Th1 phenotype to a protective anti-inflammatory Th2 phenotype in macrosomia and in adulthood obesity that results from macrosomia at birth. Based on the available evidence, international nutritional and food agencies recommend administration of omega-3 PUFA as triglyceride-lowering agents, for the prevention of cardiovascular disease risk and during human pregnancy and lactation. Furthermore, studies targeting humans are still required to explore application of the fatty acids as supplement in the management of gestational diabetes and inflammatory and immune diseases. Akadiri Yessoufou, Magloire P. Nekoua, Adam Gbankoto, Yohana Mashalla, and Kabirou Moutairou Copyright © 2015 Akadiri Yessoufou et al. All rights reserved. Characterization of the ZDSD Rat: A Translational Model for the Study of Metabolic Syndrome and Type 2 Diabetes Thu, 16 Apr 2015 11:19:44 +0000 Metabolic syndrome and T2D produce significant health and economic issues. Many available animal models have monogenic leptin pathway mutations that are absent in the human population. Development of the ZDSD rat model was undertaken to produce a model that expresses polygenic obesity and diabetes with an intact leptin pathway. A lean ZDF rat with the propensity for beta-cell failure was crossed with a polygenetically obese Crl:CD (SD) rat. Offspring were selectively inbred for obesity and diabetes for >30 generations. In the current study, ZDSD rats were followed for 6 months; routine clinical metabolic endpoints were included throughout the study. In the prediabetic metabolic syndrome phase, ZDSD rats exhibited obesity with increased body fat, hyperglycemia, insulin resistance, dyslipidemia, glucose intolerance, and elevated HbA1c. As disease progressed to overt diabetes, ZDSD rats demonstrated elevated glucose levels, abnormal oral glucose tolerance, increases in HbA1c levels, reductions in body weight, increased insulin resistance with decreasing insulin levels, and dyslipidemia. The ZDSD rat develops prediabetic metabolic syndrome and T2D in a manner that mirrors the development of metabolic syndrome and T2D in humans. ZDSD rats will provide a novel, translational animal model for the study of human metabolic diseases and for the development of new therapies. Richard G. Peterson, Charles V. Jackson, Karen Zimmerman, Willem de Winter, Norman Huebert, and Michael K. Hansen Copyright © 2015 Richard G. Peterson et al. All rights reserved. Effectiveness of a Nurse-Managed Protocol to Prevent Hypoglycemia in Hospitalized Patients with Diabetes Thu, 16 Apr 2015 11:00:02 +0000 Background. Hypoglycemia due to inadequate carbohydrate intake is a frequent complication of insulin treatment of diabetic in-patients. Objective. To assess the effectiveness of a nurse-managed protocol to prevent hypoglycemia during subcutaneous insulin treatment. Design. Prospective pre-post-intervention study. Methods. In 350 consecutive diabetic in-patients the incidence of hypoglycemia (blood glucose < 70 mg/dL) during subcutaneous insulin treatment was assessed before (phase A) and after (phase B) the protocol was adopted to permit (1) the patient to opt for substitutive food to integrate incomplete carbohydrate intake in the meal; (2) in case of lack of appetite or repeatedly partial intake of the planned food, prandial insulin administered at the end of the meal to be related to the actual amount of carbohydrates eaten; (3) intravenous infusion of glucose during prolonged fasting. Results. Eighty-four patients in phase A and 266 in phase B received subcutaneous insulin for median periods of, respectively, 7 (Q1–Q3 6–12) and 6 days (Q1–Q3 4–9). Hypoglycemic events declined significantly from 0.34 ± 0.33 per day in phase A to 0.19 ± 0.30 in phase B . Conclusions. A nurse-managed protocol focusing on carbohydrate intake reduced the incidence of hypoglycemia in patients with diabetes receiving subcutaneous insulin in hospital. Giuseppe Marelli, Fausto Avanzini, Giuseppe Iacuitti, Enrico Planca, Ilaria Frigerio, Giovanna Busi, Liliana Carlino, Laura Cortesi, Maria Carla Roncaglioni, and Emma Riva Copyright © 2015 Giuseppe Marelli et al. All rights reserved. Characterization of the Prediabetic State in a Novel Rat Model of Type 2 Diabetes, the ZFDM Rat Thu, 16 Apr 2015 09:31:47 +0000 We recently established a novel animal model of obese type 2 diabetes (T2D), the Zucker fatty diabetes mellitus (ZFDM) rat strain harboring the fatty mutation (fa) in the leptin receptor gene. Here we performed a phenotypic characterization of the strain, focusing mainly on the prediabetic state. At 6–8 weeks of age, fa/fa male rats exhibited mild glucose intolerance and severe insulin resistance. Although basal insulin secretion was remarkably high in the isolated pancreatic islets, the responses to both glucose stimulation and the incretin GLP-1 were retained. At 10–12 weeks of age, fa/fa male rats exhibited marked glucose intolerance as well as severe insulin resistance similar to that at the earlier age. In the pancreatic islets, the insulin secretory response to glucose stimulation was maintained but the response to the incretin was diminished. In nondiabetic Zucker fatty (ZF) rats, the insulin secretory responses to both glucose stimulation and the incretin in the pancreatic islets were similar to those of ZFDM rats. As islet architecture was destroyed with age in ZFDM rats, a combination of severe insulin resistance, diminished insulin secretory response to incretin, and intrinsic fragility of the islets may cause the development of T2D in this strain. Ghupurjan Gheni, Norihide Yokoi, Masayuki Beppu, Takuro Yamaguchi, Shihomi Hidaka, Ayako Kawabata, Yoshikazu Hoshino, Masayuki Hoshino, and Susumu Seino Copyright © 2015 Ghupurjan Gheni et al. All rights reserved. The Association between Serum Cytokines and Damage to Large and Small Nerve Fibers in Diabetic Peripheral Neuropathy Thu, 16 Apr 2015 06:35:28 +0000 Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with neuropathic pain (NP). We recruited a group of 32 type 2 DM patients who underwent serum cytokines (TNF-α, IL-2, IL-4, IL-6, and IL-10) dosage as well as electrodiagnostic and quantitative sensory testing (QST) assessment to explore damage to large and small nerve fibers. Raised serum levels of IL-6 and IL-10 correlated with markers of large nerve fiber sensory and motor axonal damage. Raised IL-10 serum level was associated with signs of motor nerve demyelination. No differences were found in pain characteristics and electrodiagnostic and QST markers of small nerve fiber function in relation to cytokines serum levels. IL-6 and IL-10 serum levels were associated with large nerve fiber damage but not to small fibers function or NP. IL-6 and IL-10 cytokines might play a role in the pathogenesis of nerve fiber damage or represent a compensatory or neuroprotective mechanism. Francesca Magrinelli, Chiara Briani, Marcello Romano, Susanna Ruggero, Elisabetta Toffanin, Giuseppa Triolo, George Chummar Peter, Marialuigia Praitano, Matteo Francesco Lauriola, Giampietro Zanette, and Stefano Tamburin Copyright © 2015 Francesca Magrinelli et al. All rights reserved. Immunological Hypoglycemia Associated with Insulin Antibodies Induced by Exogenous Insulin in 11 Chinese Patients with Diabetes Wed, 15 Apr 2015 13:18:34 +0000 Aims. To investigate the characteristics of immunological hypoglycemia associated with insulin antibodies (IAbs) induced by exogenous insulin in Chinese patients with diabetes. Methods. The clinical data of patients with immunological hypoglycemia due to IAbs were retrospectively analyzed by screening patients with diabetes discharged from West China Hospital from 2007 to 2013. Results. A total of 11 patients (eight men and three women) were identified. Insulin-C-peptide separation was found in all patients via insulin and C-peptide release test. Previous insulin use was ceased after admission and was switched to oral hypoglycemic agents (OHAs) (8/11), lifestyle modification only (2/11), or regular human insulin (1/11). Hypoglycemia was ameliorated after a median of 20 days (interquartile range [IQR], 11–40), while IAbs turned negative after a median of 17 months (IQR, 4–19), and serum immunoreactive insulin (IRI) levels dropped substantially after a median of 22 months (IQR, 9–32) in these cases. Conclusions. In insulin-treated patients with unexpected and refractory hypoglycemia even after insulin therapy was gradually reduced or even withdrawn, IAbs induced by exogenous insulin should be considered, and insulin withdrawal might be promptly needed. The course of immunological hypoglycemia was benign and self-limited. Heng Quan, Huiwen Tan, Qianrui Li, Jianwei Li, and Sheyu Li Copyright © 2015 Heng Quan et al. All rights reserved. Ocular Rigidity and Outflow Facility in Nonproliferative Diabetic Retinopathy Tue, 14 Apr 2015 09:54:47 +0000 Purpose. To compare ocular rigidity (OR) and outflow facility (C) in patients with nonproliferative diabetic retinopathy (NPDR) and control subjects. Methods. Twenty-four patients with NPDR (NPDR group) and 24 controls (control group) undergoing cataract surgery were enrolled. NPDR group was further divided into patients with mild NPDR (NPDR1-group) and patients with moderate and/or severe NPDR (NPDR2-group). After cannulation of the anterior chamber, a computer-controlled device was used to infuse saline and increase the intraocular pressure (IOP) in a stepping procedure from 15 to 40 mmHg. Ocular rigidity and outflow facility coefficients were estimated from IOP and volume recordings. Results. Ocular rigidity was 0.0205 μL−1 in NPDR group and 0.0202 μL−1 in control group (). In NPDR1-group, OR was 0.017 μL−1 and in NPDR2-group it was 0.025 μL−1 (). Outflow facility was 0.120 μL/min/mmHg in NPDR-group compared to 0.153 μL/min/mmHg in the control group at an IOP of 35 mmHg (). There was no difference in C between NPDR1-group and NPDR2-group (). Conclusions. No statistically significant differences in ocular rigidity and outflow facility could be documented between diabetic patients and controls. No difference in OR and C was detected between mild NPDR and severe NPDR. Theonitsa Panagiotoglou, Miltiadis Tsilimbaris, Harilaos Ginis, Nikos Karyotakis, Vaggelis Georgiou, Pavlos Koutentakis, and Ioannis Pallikaris Copyright © 2015 Theonitsa Panagiotoglou et al. All rights reserved. Is Type 2 Diabetes Really Resolved after Laparoscopic Sleeve Gastrectomy? Glucose Variability Studied by Continuous Glucose Monitoring Tue, 14 Apr 2015 08:23:53 +0000 The study was carried out on type 2 diabetic obese patients who underwent laparoscopic sleeve gastrectomy (LSG). Patients underwent regular glycemic controls throughout 3 years and all patients were defined cured from diabetes according to conventional criteria defined as normalization of fasting glucose levels and glycated hemoglobin in absence of antidiabetic therapy. After 3 years of follow-up, Continuous Glucose Monitoring (CGM) was performed in each patient to better clarify the remission of diabetes. In this study, we found that the diabetes resolution after LSG occurred in 40% of patients; in the other 60%, even if they showed a normal fasting glycemia and A1c, patients spent a lot of time in hyperglycemia. During the oral glucose tolerance test (OGTT), we found that 2 h postload glucose determinations revealed overt diabetes only in a small group of patients and might be insufficient to exclude the diagnosis of diabetes in the other patients who spent a lot of time in hyperglycemia, even if they showed a normal glycemia (<140 mg/dL) at 120 minutes OGTT. These interesting data could help clinicians to better individualize patients in which diabetes is not resolved and who could need more attention in order to prevent chronic complications of diabetes. D. Capoccia, F. Coccia, A. Guida, M. Rizzello, F. De Angelis, G. Silecchia, and F. Leonetti Copyright © 2015 D. Capoccia et al. All rights reserved. Increased DNA Dicarbonyl Glycation and Oxidation Markers in Patients with Type 2 Diabetes and Link to Diabetic Nephropathy Thu, 09 Apr 2015 14:04:02 +0000 Aim. The aim of this study was to assess the changes of markers of DNA damage by glycation and oxidation in patients with type 2 diabetes and the association with diabetic nephropathy. Methodology. DNA oxidation and glycation adducts were analysed in plasma and urine by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. DNA markers analysed were as follows: the oxidation adduct 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-OxodG) and glycation adducts of glyoxal and methylglyoxal—imidazopurinones GdG, MGdG, and N2-(1,R/S-carboxyethyl)deoxyguanosine (CEdG). Results. Plasma 8-OxodG and GdG were increased 2-fold and 6-fold, respectively, in patients with type 2 diabetes, with respect to healthy volunteers. Median urinary excretion rates of 8-OxodG, GdG, MGdG, and CEdG were increased 28-fold, 10-fold, 2-fold, and 2-fold, respectively, in patients with type 2 diabetes with respect to healthy controls. In patients with type 2 diabetes, nephropathy was associated with increased plasma 8-OxodG and increased urinary GdG and CEdG. In a multiple logistic regression model for diabetic nephropathy, diabetic nephropathy was linked to systolic blood pressure and urinary CEdG. Conclusion. DNA oxidative and glycation damage-derived nucleoside adducts are increased in plasma and urine of patients with type 2 diabetes and further increased in patients with diabetic nephropathy. Sahar Waris, Brigitte M. Winklhofer-Roob, Johannes M. Roob, Sebastian Fuchs, Harald Sourij, Naila Rabbani, and Paul J. Thornalley Copyright © 2015 Sahar Waris et al. All rights reserved. Longitudinal Analysis of Adiponectin through 20-Year Type 1 Diabetes Duration Thu, 09 Apr 2015 12:58:22 +0000 Little information exists on the trajectory and determinants of adiponectin, a possible insulin sensitizer and marker for inflammation and endothelial function, across the duration of type 1 diabetes. The Wisconsin Diabetes Registry Study followed an incident cohort ≤30 years of age when diagnosed with type 1 diabetes during 1987–1992 up to 20-year duration. Adiponectin was concurrently and retrospectively (from samples frozen at −80°C) measured for those participating in a 20-year exam (), during 2007–2011. Adiponectin levels were higher in females, declined through adolescence, and increased with age thereafter. Lower levels were associated with greater body weight and waist circumference and with higher insulin dose, especially at longer diabetes durations. Higher levels were associated with higher HbA1c and, at longer durations, with higher albumin-creatinine ratio. Adiponectin levels showed consistency within individuals that was not explained by these factors. We conclude that markers for insulin resistance are associated with lower adiponectin, and markers for potential microvascular complications are associated with higher adiponectin. The previously reported relationship with HbA1c remains largely unexplained. Additional individual specific factors likely also influence adiponectin level. The relationship between adiponectin and urinary protein excretion may enable identification of those predisposed to kidney disease earlier in type 1 diabetes. Tamara J. LeCaire and Mari Palta Copyright © 2015 Tamara J. LeCaire and Mari Palta. All rights reserved. A Novel Multidisciplinary Intervention for Long-Term Weight Loss and Glycaemic Control in Obese Patients with Diabetes Wed, 08 Apr 2015 14:17:07 +0000 Introduction. Obesity and diabetes are difficult to treat in public clinics. We sought to determine the effectiveness of the Metabolic Rehabilitation Program (MRP) in achieving long-term weight loss and improving glycaemic control versus “best practice” diabetes clinic (DC) in obese patients using a retrospective cohort study. Methods. Patients with diabetes and BMI > 30 kg/m2 who attended the MRP, which consisted of supervised exercise and intense allied health integration, or the DC were selected. Primary outcomes were improvements in weight and glycaemia with secondary outcomes of improvements in blood pressure and lipid profile at 12 and 30 months. Results. Baseline characteristics of both cohorts (40 MRP and 40 DC patients) were similar at baseline other than age (63 in MRP versus 68 years in DC, ). At 12 months, MRP patients lost 7.65 ± 1.74 kg versus 1.76 ± 2.60 kg in the DC group () and 9.70 ± 2.13 kg versus 0.98 ± 2.65 kg at 30 months (). Similarly, MRP patients had significant absolute reductions in %HbA1c at 30 months versus the DC group (−0.86 ± 0.31% versus 0.12% ± 0.33%, ), with nonsignificant improvements in lipids and blood pressure in MRP patients. Conclusion. Further research is needed to establish the MRP as an effective strategy for achieving sustained weight loss and improving glycaemic control in obese patients with type 2 diabetes. Anna Lih, Lorraine Pereira, Ramy H. Bishay, Johnson Zang, Abdullah Omari, Evan Atlantis, and Nic Kormas Copyright © 2015 Anna Lih et al. All rights reserved. Aberrant Phenotype in Human Endothelial Cells of Diabetic Origin: Implications for Saphenous Vein Graft Failure? Wed, 08 Apr 2015 13:09:15 +0000 Type 2 diabetes (T2DM) confers increased risk of endothelial dysfunction, coronary heart disease, and vulnerability to vein graft failure after bypass grafting, despite glycaemic control. This study explored the concept that endothelial cells (EC) cultured from T2DM and nondiabetic (ND) patients are phenotypically and functionally distinct. Cultured human saphenous vein- (SV-) EC were compared between T2DM and ND patients in parallel. Proliferation, migration, and in vitro angiogenesis assays were performed; western blotting was used to quantify phosphorylation of Akt, ERK, and eNOS. The ability of diabetic stimuli (hyperglycaemia, TNF-α, and palmitate) to modulate angiogenic potential of ND-EC was also explored. T2DM-EC displayed reduced migration (~30%) and angiogenesis (~40%) compared with ND-EC and a modest, nonsignificant trend to reduced proliferation. Significant inhibition of Akt and eNOS, but not ERK phosphorylation, was observed in T2DM cells. Hyperglycaemia did not modify ND-EC function, but TNF-α and palmitate significantly reduced angiogenic capacity (by 27% and 43%, resp.), effects mimicked by Akt inhibition. Aberrancies of EC function may help to explain the increased risk of SV graft failure in T2DM patients. This study highlights the importance of other potentially contributing factors in addition to hyperglycaemia that may inflict injury and long-term dysfunction to the homeostatic capacity of the endothelium. Anna C. Roberts, Jai Gohil, Laura Hudson, Kyle Connolly, Philip Warburton, Rakesh Suman, Peter O’Toole, David J. O’Regan, Neil A. Turner, Kirsten Riches, and Karen E. Porter Copyright © 2015 Anna C. Roberts et al. All rights reserved. Present and Future in the Treatment of Diabetic Kidney Disease Tue, 07 Apr 2015 16:54:55 +0000 Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade. Borja Quiroga, David Arroyo, and Gabriel de Arriba Copyright © 2015 Borja Quiroga et al. All rights reserved. New-Onset Diabetes and Glucose Regulation Are Significant Determinants of Left Ventricular Hypertrophy in Renal Transplant Recipients Tue, 07 Apr 2015 12:02:57 +0000 Background. New-onset diabetes after transplantation (NODAT) is associated with decreased graft survival and an increased risk for cardiovascular disease. The objective of this study was to evaluate the risk factors for development of NODAT and its’ relationship with arterial stiffness and left ventricular mass index (LVMI) in kidney transplant recipients. Methods. 159 kidney transplant recipients were selected from our transplantation center who underwent renal transplantation between years 2007 and 2010. Results. Among 159 patients, 57 (32.2%) patients were with NODAT who were significantly older than patients without diabetes (: 0.0001). Patients with NODAT had significantly higher pulse wave velocity (PWv) (: 0.033) and left ventricular mass index LVMI (: 0.001) compared to patients without NODAT. Further analysis was done according to LVMI as follows: LVMI > 130 g/m2 (: 57) and LVMI ≤ 130 g/m2 (: 102). We observed higher office systolic and diastolic BP, serum trygliceride, glucose, creatinine, age, and HbA1c (: 0.0001) levels in patients with LVMI > 130 g/m2. Linear regression analysis revealed that HbA1c was the major determinant of LVMI (: 0.026, : 0.361). Conclusions. HbA1c is the major determinant of LVMI, so strict control of serum glucose levels is essential for preventing cardiovascular disease in patients with NODAT. Siren Sezer, Mehtap Erkmen Uyar, Emre Tutal, Zeynep Bal, Orhan Guliyev, Turan Colak, Efe Hasdemir, and Mehmet Haberal Copyright © 2015 Siren Sezer et al. All rights reserved. Therapeutic Benefit of Extended Thymosin β4 Treatment Is Independent of Blood Glucose Level in Mice with Diabetic Peripheral Neuropathy Tue, 07 Apr 2015 08:23:25 +0000 Peripheral neuropathy is a chronic complication of diabetes mellitus. To investigated the efficacy and safety of the extended treatment of diabetic peripheral neuropathy with thymosin β4 (Tβ4), male diabetic mice (db/db) at the age of 24 weeks were treated with Tβ4 or saline for 16 consecutive weeks. Treatment of diabetic mice with Tβ4 significantly improved motor (MCV) and sensory (SCV) conduction velocity in the sciatic nerve and the thermal and mechanical latency. However, Tβ4 treatment did not significantly alter blood glucose levels. Treatment with Tβ4 significantly increased intraepidermal nerve fiber density. Furthermore, Tβ4 counteracted the diabetes-induced axon diameter and myelin thickness reductions and the -ratio increase in sciatic nerve. In vitro, compared with dorsal root ganglia (DRG) neurons derived from nondiabetic mice, DRG neurons derived from diabetic mice exhibited significantly decreased neurite outgrowth, whereas Tβ4 promoted neurite growth in these diabetic DRG neurons. Blockage of the Ang1/Tie2 signaling pathway with a neutralized antibody against Tie2 abolished Tβ4-increased neurite outgrowth. Our data demonstrate that extended Tβ4 treatment ameliorates diabetic-induced axonal degeneration and demyelination, which likely contribute to therapeutic effect of Tβ4 on diabetic neuropathy. The Ang1/Tie2 pathway may mediate Tβ4-induced axonal remodeling. Lei Wang, Michael Chopp, Longfei Jia, Xuerong Lu, Alexandra Szalad, Yi Zhang, RuiLan Zhang, and Zheng Gang Zhang Copyright © 2015 Lei Wang et al. All rights reserved. A New Approach to Define and Diagnose Cardiometabolic Disorder in Children Mon, 06 Apr 2015 11:44:18 +0000 The aim of the study was to test the performance of a new definition of metabolic syndrome (MetS), which better describes metabolic dysfunction in children. Methods. 15,794 youths aged 6–18 years participated. Mean z-score for CVD risk factors was calculated. Sensitivity analyses were performed to evaluate which parameters best described the metabolic dysfunction by analysing the score against independent variables not included in the score. Results. More youth had clustering of CVD risk factors (>6.2%) compared to the number selected by existing MetS definitions (International Diabetes Federation (IDF) < 1%). Waist circumference and BMI were interchangeable, but using insulin resistance homeostasis model assessment (HOMA) instead of fasting glucose increased the score. The continuous MetS score was increased when cardiorespiratory fitness (CRF) and leptin were included. A mean z-score of 0.40–0.85 indicated borderline and above 0.85 indicated clustering of risk factors. A noninvasive risk score based on adiposity and CRF showed sensitivity and specificity of 0.85 and an area under the curve of 0.92 against IDF definition of MetS. Conclusions. Diagnosis for MetS in youth can be improved by using continuous variables for risk factors and by including CRF and leptin. Lars Bo Andersen, Jeppe Bo Lauersen, Jan Christian Brønd, Sigmund Alfred Anderssen, Luis B. Sardinha, Jostein Steene-Johannessen, Robert G. McMurray, Mauro V. G. Barros, Susi Kriemler, Niels Christian Møller, Anna Bugge, Peter Lund Kristensen, Mathias Ried-Larsen, Anders Grøntved, and Ulf Ekelund Copyright © 2015 Lars Bo Andersen et al. All rights reserved. Diabetic Retinopathy in Pregnancy: A Population-Based Study of Women with Pregestational Diabetes Mon, 06 Apr 2015 09:31:47 +0000 The aim of this observational study was to evaluate screening and progression of diabetic retinopathy during pregnancy in women with pregestational diabetes attending five antenatal centres along the Irish Atlantic seaboard. An adequate frequency of screening was defined as at least two retinal evaluations in separate trimesters. Progression was defined as at least one stage of deterioration of diabetic retinopathy and/or development of diabetic macular edema on at least one eye. Women with pregestational diabetes who delivered after 22 gestational weeks () were included. In total, 185 (60.3%) had an adequate number of retinal examinations. Attendance at prepregnancy care was associated with receiving adequate screening (odds ratio 6.23; CI 3.39–11.46 ()). Among those who received adequate evaluations (), 48 (25.9%) had retinopathy progression. Increasing booking systolic blood pressure (OR 1.03, CI 1.01–1.06, ) and greater drop in HbA1c between first and third trimesters of pregnancy (OR 2.05, CI 1.09–3.87, ) significantly increased the odds of progression. A significant proportion of women continue to demonstrate retinopathy progression during pregnancy. This study highlights the role of prepregnancy care and the importance of close monitoring during pregnancy and identifies those patients at the highest risk for retinopathy progression. Aoife M. Egan, Lyle McVicker, Adrienne Heerey, Louise Carmody, Fiona Harney, and Fidelma P. Dunne Copyright © 2015 Aoife M. Egan et al. All rights reserved. Sensitivity and Specificity Improvement in Abdominal Obesity Diagnosis Using Cluster Analysis during Waist Circumference Cut-Off Point Selection Sun, 05 Apr 2015 13:42:40 +0000 Introduction. The purpose of this study was to analyze the influence of metabolic phenotypes during the construction of ROC curves for waist circumference (WC) cutpoint selection. Materials and Methods. A total of 1,902 subjects of both genders were selected from the Maracaibo City Metabolic Syndrome Prevalence Study database. Two-Step Cluster Analysis (TSCA) was applied to select metabolically healthy and sick men and women. ROC curves were constructed to determine WC cutoff points by gender. Results. Through TSCA, metabolic phenotype predictive variables were selected: HOMA2-IR and HOMA2-βcell for women and HOMA2-IR, HOMA2-βcell, and TAG for men. Subjects were classified as healthy normal weight, metabolically obese normal weight, healthy and metabolically disturbed overweight, and healthy and metabolically disturbed obese. Final WC cutpoints were 91.50 cm for women (93.4% sensitivity, 93.7% specificity) and 98.15 cm for men (96% sensitivity, 99.5% specificity). Conclusions. TSCA in the selection of the groups used in ROC curves construction proved to be an important tool, aiding in the detection of MOWN and MHO which cannot be identified with WC alone. The resulting WC cutpoints were <91.00 cm for women and <98.00 cm for men. Furthermore, anthropometry is insufficient to determine healthiness, and, biochemical analysis is needed to properly filter subjects during classification. Valmore Bermúdez, Joselyn Rojas, Juan Salazar, Roberto Añez, Alexandra Toledo, Luis Bello, Vanessa Apruzzese, Robys González, Maricarmen Chacín, Mayela Cabrera, Clímaco Cano, Manuel Velasco, and José López-Miranda Copyright © 2015 Valmore Bermúdez et al. All rights reserved. Liraglutide, a Glucagon-Like Peptide-1 Analog, Increased Insulin Sensitivity Assessed by Hyperinsulinemic-Euglycemic Clamp Examination in Patients with Uncontrolled Type 2 Diabetes Mellitus Thu, 02 Apr 2015 18:22:15 +0000 Aims. Glucagon-like peptide-1 (GLP-1) analog promotes insulin secretion by acting on pancreatic β-cells. This antihyperglycemic treatment for type 2 diabetes mellitus (DM) has attracted increased clinical attention not only for its antihyperglycemic action but also for its potential extrapancreatic effects. We investigated whether liraglutide, a GLP-1 analog, could enhance insulin sensitivity as assessed by the hyperinsulinemic-euglycemic clamp in type 2 DM patients. Materials. We prospectively enrolled 31 uncontrolled type 2 DM patients who were hospitalized and equally managed by guided diet- and exercise-therapies and then introduced to either liraglutide- or intensive insulin-therapy for 4 weeks. Insulin sensitivity was assessed by the glucose infusion rate (GIR) using hyperinsulinemic-euglycemic clamp before and after the therapies. Results. Values of HbA1c, postprandial plasma glucose, and body mass index (BMI) were significantly decreased by hospitalized intensive insulin-therapy or liraglutide-therapy. GIR was significantly increased by liraglutide-therapy but not by insulin-therapy, indicating that liraglutide-therapy significantly enhanced insulin sensitivity. BMI decreased during liraglutide-therapy but was not significantly correlated with changes in GIR. Multivariate logistic regression analysis demonstrated that liraglutide-therapy significantly correlated with increased insulin sensitivity in uncontrolled DM patients. Conclusions. Liraglutide may exhibit favorable effects on diabetes control for type 2 DM patients by increasing insulin sensitivity as an extrapancreatic action. Clinical trial registration Unique Identifier is UMIN000015201. Hideaki Jinnouchi, Seigo Sugiyama, Akira Yoshida, Kunio Hieshima, Noboru Kurinami, Tomoko Suzuki, Fumio Miyamoto, Keizo Kajiwara, Kunihiko Matsui, and Tomio Jinnouchi Copyright © 2015 Hideaki Jinnouchi et al. All rights reserved. The Association of Soluble IGF2R and IGF2R Gene Polymorphism with Type 2 Diabetes Thu, 02 Apr 2015 09:29:09 +0000 The aim of this study is to investigate the insulin-like growth factor type 2 (IGF2R) gene and circulating soluble IGF2R in relation to type 2 diabetes (T2DM). Six hundred fifty-four subjects without history of diabetes were screened for diabetes by oral glucose tolerance test. In addition, 145 subjects with known diabetes were recruited from a local diabetes clinic. Circulating IGF2R levels were measured by ELISA method; plasma glucose was measured by colorimetric method; insulin levels were determined by chemiluminescent method; IGF2R gene rs416572 was genotyped using real-time PCR. The distributions of IGF2R genotypes were 69.2% CC, 27.8% CT, and 3.0% TT. The C allele was more commonly found in diabetes subjects, with a significant difference . In the presence of the T allele, circulating IGF2R levels were significantly lower . There was no significant difference in other potential confounders including age, sex, and BMI. Only circulating IGF2R, age, and BMI were independently associated with the degree of insulin resistance, as assessed by the HOMA model. It was found that age, sex, and BMI were associated with beta cell function. In conclusion, IGF2R gene polymorphism and circulating IGF2R are associated with T2DM. Suwannee Chanprasertyothin, Wallaya Jongjaroenprasert, and Boonsong Ongphiphadhanakul Copyright © 2015 Suwannee Chanprasertyothin et al. All rights reserved. Impaired Adipose Tissue Expandability and Lipogenic Capacities as Ones of the Main Causes of Metabolic Disorders Thu, 02 Apr 2015 08:39:05 +0000 Obesity is considered a major health problem. However, mechanisms involved and its comorbidities are not elucidated. Recent theories concerning the causes of obesity have focused on a limit to the functional capacity of adipose tissue, comparing it with other vital organs. This assumption has been the central point of interest in our laboratory. We proposed that the failure of adipose tissue is initiated by the difficulty of this tissue to increase its cellularity due to excess in fat contribution, owing to genetic or environmental factors. Nevertheless, why the adipose tissue reduces its capacity to make new adipocytes via mesenchymal cells of the stroma has not yet been elucidated. Thus, we suggest that this tissue ceases fulfilling its main function, the storage of excess fat, thereby affecting some of the key factors involved in lipogenesis, some of which are reviewed in this paper (PPARγ, ROR1, FASN, SCD1, Rab18, BrCa1, ZAG, and FABP4). On the other hand, mechanisms involved in adipose tissue expandability are also impaired, predominating hypertrophy via an increase in apoptosis and a decrease in adipogenesis and angiogenesis. However, adipose tissue failure is only part of this great orchestra, only a chapter of this nightmare. Isabel Moreno-Indias and Francisco José Tinahones Copyright © 2015 Isabel Moreno-Indias and Francisco José Tinahones. All rights reserved. Relationship between Serum 25-Hydroxyvitamin D and Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus Patients and the Analysis of the Intervention of Vitamin D Wed, 01 Apr 2015 14:59:59 +0000 The aim of this study was to explore the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and lower extremity arterial disease (LEAD) in type 2 diabetes mellitus (T2DM) patients and to investigate the intervention effect of vitamin D. 145 subjects were assigned to a control group (Group NC), T2DM group (Group DM1), and T2DM complicated with LEAD group (Group DM2); then Group DM2 were randomly divided into Group DM3 who received oral hypoglycemic agents and Group DM4 who received oral hypoglycemic drugs and vitamin D3 therapy. Compared to Group NC, 25(OH)D was significantly lower in Group DM2 and marginally lower in Group DM1. In contrast to baseline and Group DM3, 25(OH)D rose while low density lipoprotein (LDL), retinol binding protein 4 (RBP4), and HbA1c significantly lowered in Group DM4. Statistical analysis revealed that 25(OH)D had a negative correlation with RBP4, duration, HbA1c, homeostasis model assessment for insulin resistance (HOMA-IR), and fasting plasma glucose (FPG). LDL, systolic blood pressure (SBP), FPG, and smoking were risk factors of LEAD while high density lipoprotein (HDL) and 25(OH)D were protective ones. Therefore, we deduced that low level of 25(OH)D is significantly associated with the occurrence of T2DM complicated with LEAD. Wan Zhou and Shan-Dong Ye Copyright © 2015 Wan Zhou and Shan-Dong Ye. All rights reserved. Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice Tue, 31 Mar 2015 13:07:03 +0000 The pathogenesis of diabetic retinopathy (DR) remains unclear but hyperglycemia is an established risk factor. Endothelial dysfunction and changes in Ca2+ signaling have been shown to precede the onset of DR. We recently demonstrated that high extracellular glucose activates the Ca2+/calcineurin-dependent transcription factor NFAT in cerebral arteries and aorta, promoting the expression of inflammatory markers. Here we show, using confocal immunofluorescence, that NFAT is expressed in the endothelium of retinal microvessels and is readily activated by high glucose. This was inhibited by the NFAT blocker A-285222 as well as by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. Acute hyperglycemia induced by an IP-GTT (intraperitoneal glucose tolerance test) resulted in increased NFATc3 nuclear accumulation and NFAT-dependent transcriptional activity in retinal vessels of NFAT-luciferase reporter mice. In both Akita (Ins2+/−) and streptozotocin- (STZ-) induced diabetic mice, NFAT transcriptional activity was elevated in retinal vessels. In vivo inhibition of NFAT with A-285222 decreased the expression of OPN and ICAM-1 mRNA in retinal vessels, prevented a diabetes driven downregulation of anti-inflammatory IL-10 in retina, and abrogated the increased vascular permeability observed in diabetic mice. Results identify NFAT signaling as a putative target for treatment of microvascular complications in diabetes. Anna V. Zetterqvist, Fabiana Blanco, Jenny Öhman, Olga Kotova, Lisa M. Berglund, Sergio de Frutos Garcia, Raed Al-Naemi, Maria Wigren, Paul G. McGuire, Laura V. Gonzalez Bosc, and Maria F. Gomez Copyright © 2015 Anna V. Zetterqvist et al. All rights reserved. Adipokines as Drug Targets in Diabetes and Underlying Disturbances Tue, 31 Mar 2015 09:57:50 +0000 Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed “adipokines.” Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled “low-grade inflammatory state” of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases. Vinícius Andrade-Oliveira, Niels O.S. Câmara, and Pedro M. Moraes-Vieira Copyright © 2015 Vinícius Andrade-Oliveira et al. All rights reserved. Effect of Sulodexide on Urinary Biomarkers of Kidney Injury in Normoalbuminuric Type 2 Diabetes: A Randomized Controlled Trial Tue, 31 Mar 2015 08:04:00 +0000 Glycosaminoglycans or sulodexide has shown benefits in early experimental diabetic nephropathy (DN) models, but its efficacy in patients with early stage of DN is unknown. Methods. Twenty patients were randomly assigned to the placebo group and another 20 patients were randomly assigned to receive sulodexide 100 mg/day for 14 weeks. Primary outcome was a change of urinary TGF-beta1, albuminuria, and glomerular filtration rate (GFR). All patients had stable metabolic profiles for at least 90 days before randomization. Results. Urinary TGF-beta1 increased significantly in the placebo group but did not change significantly in the sulodexide group. Additionally, the mean change of urine TGF-beta1 in the placebo group was significantly higher than that in the sulodexide group ( versus  pg/mg Cr, ). Mean changes of urinary albumin were  μg/mg Cr () in the placebo group and  μg/mg Cr () in the sulodexide group. No consistent patterns of side effects were observed. Conclusion. In this 14-week trial, benefits of sulodexide in preventing the increase of urinary TGF-beta1 were observed in patients with normoalbuminuric type 2 diabetes. The study suggests that sulodexide treatment may provide additional renoprotection in early stage DN. This trial is registered with TCTR20140806001. Bancha Satirapoj, Wisit Kaewput, Ouppatham Supasyndh, and Prajej Ruangkanchanasetr Copyright © 2015 Bancha Satirapoj et al. All rights reserved. Cardiovascular Control during Exercise in Type 2 Diabetes Mellitus Mon, 30 Mar 2015 13:24:39 +0000 Controlled studies of male and female subjects with type 2 diabetes mellitus (DM) of short duration (~3–5 years) show that DM reduces peak (L·min−1 and mL·kg−1·min−1) by an average of 12–15% and induces a greater slowing of the dynamic response of pulmonary during submaximal exercise. These effects occur in individuals less than 60 years of age but are reduced or absent in older males and are consistently associated with significant increases in the exercise pressor response despite normal resting blood pressure. This exaggerated pressor response, evidence of exertional hypertension in DM, is manifest during moderate submaximal exercise and coincides with a more constrained vasodilation in contracting muscles. Maximum vasodilation during contractions involving single muscle groups is reduced by DM, and the dynamic response of vasodilation during submaximal contractions is slowed. Such vascular constraint most likely contributes to exertional hypertension, impairs dynamic and peak responses, and reduces exercise tolerance. There is a need to establish the effect of DM on dynamic aspects of vascular control in skeletal muscle during whole-body exercise and to clarify contributions of altered cardiovascular control and increased arterial stiffness to exertional hypertension. Simon Green, Mikel Egaña, J. Chris Baldi, Regis Lamberts, and Judith G. Regensteiner Copyright © 2015 Simon Green et al. All rights reserved. Renal Kallikrein Activation and Renoprotection after Dual Blockade of Renin-Angiotensin System in Diet-Induced Diabetic Nephropathy Mon, 30 Mar 2015 12:39:53 +0000 Purpose. The objective of this study is to investigate the effect of dual blockage of renin-angiotensin system (RAS) on renal kallikrein expression and inflammatory response in diabetic nephropathy (DN). Methods. Rats were randomly divided into 5 groups with 10 rats in each group: normal control; DN model induced by high fat and high sucrose diets; and DN treated with either benazepril 10 mg/kg/d, irbesartan 30 mg/kg/d, or both. After 8-week treatment, we examined changes in the kidney histopathology, function and immunohistochemical stain of kallikrein, macrophage marker CD68, and profibrotic markers transforming growth factor- (TGF-) and -smooth muscle action (SMA). Results. DN rats showed enlarged kidneys with glomerulosclerosis, interstitial chronic inflammation and fibrosis, and proteinuria. All the pathological damage and functional impairments were improved after the RAS blockades (all ). Compared with monotherapy, combined treatment further alleviated the kidney impairments in parallel to increased tubular immunoreactivity for kallikrein and decreased immunopositive cells for CD68, TGF-, and -SMA. Conclusion. The renoprotective effects of the dual RAS blockade in diabetic nephropathy may be attributed to improved tubular kallikrein expression and interstitial inflammatory response. Xia Zou, Xiao-xi Zhang, Xin-yu Liu, Rong Li, Min Wang, Wei-jie Wu, Yi Sui, and Hai-lu Zhao Copyright © 2015 Xia Zou et al. All rights reserved. Alteration of Mevalonate Pathway in Proliferated Vascular Smooth Muscle from Diabetic Mice: Possible Role in High-Glucose-Induced Atherogenic Process Mon, 30 Mar 2015 09:30:10 +0000 The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis induced by high glucose. Mevalonate pathway is an important metabolic pathway that plays a key role in multiple cellular processes. The aim of this study was to define whether the enzyme expression in mevalonate pathway is changed in proliferated VSMCs during atherogenic process in diabetic mice. Diabetes was induced in BALB/c mice with streptozotocin (STZ, 50 mg/kg/day for 5 days). Induction of diabetes with STZ was associated with an increase of lesion area and media thickness after 8 and 16 weeks of diabetes. In aorta, there were overexpressions of some enzymes, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), farnesyl pyrophosphate synthase (FPPS), geranylgeranyl pyrophosphate synthase (GGPPS), farnesyltransferase (FNT), and geranylgeranyltransferase-1 (GGT-1), and unchanged expression of squalene synthase (SQS) and phosphor-3-hydroxy-3-methylglutaryl-coenzyme A reductase (P-HMGR) in 8 and 16 weeks of diabetes. In vitro, VSMCs were cultured and treated with different glucose concentrations for 48 h. High glucose (22.2 mM) induced VSMC proliferation and upregulation of HMGR, FPPS, GGPPS, FNT, and GGT-1 but did not change the expressions of SQS and P-HMGR. In conclusion, altered expression of several key enzymes in the mevalonate pathway may play a potential pathophysiological role in atherogenic process of diabetes macrovascular complication. Guo-Ping Chen, Xiao-Qin Zhang, Tao Wu, Liang Li, Jie Han, and Chang-Qing Du Copyright © 2015 Guo-Ping Chen et al. All rights reserved. High-Intensity Interval Training as an Efficacious Alternative to Moderate-Intensity Continuous Training for Adults with Prediabetes Mon, 30 Mar 2015 08:08:19 +0000 Aims. High-intensity interval training (HIIT) leads to improvements in various markers of cardiometabolic health but adherence to HIIT following a supervised laboratory intervention has yet to be tested. We compared self-report and objective measures of physical activity after one month of independent exercise in individuals with prediabetes who were randomized to HIIT () or traditional moderate-intensity continuous training (MICT, ). Method. After completing 10 sessions of supervised training participants were asked to perform HIIT or MICT three times per week for four weeks. Results. Individuals in HIIT (89 ± 11%) adhered to their prescribed protocol to a greater extent than individuals in MICT (71 ± 31%) as determined by training logs completed over one-month follow-up ( = 0.05, Cohen’s d = 0.75). Minutes spent in vigorous physical activity per week measured by accelerometer were higher in HIIT (24 ± 18) as compared to MICT (11 ± 10) at one-month follow-up ( = 0.049, Cohen’s d = 0.92). Cardiorespiratory fitness and systolic blood pressure assessed at one-month follow-up were equally improved (’s < 0.05). Conclusions. This study provides preliminary evidence that individuals with prediabetes can adhere to HIIT over the short-term and do so at a level that is greater than MICT. Mary E. Jung, Jessica E. Bourne, Mark R. Beauchamp, Emily Robinson, and Jonathan P. Little Copyright © 2015 Mary E. Jung et al. All rights reserved. Time-Series Analysis of Continuously Monitored Blood Glucose: The Impacts of Geographic and Daily Lifestyle Factors Sun, 29 Mar 2015 12:30:45 +0000 Type 2 diabetes is known to be associated with environmental, behavioral, and lifestyle factors. However, the actual impacts of these factors on blood glucose (BG) variation throughout the day have remained relatively unexplored. Continuous blood glucose monitors combined with human activity tracking technologies afford new opportunities for exploration in a naturalistic setting. Data from a study of 40 patients with diabetes is utilized in this paper, including continuously monitored BG, food/medicine intake, and patient activity/location tracked using global positioning systems over a 4-day period. Standard linear regression and more disaggregated time-series analysis using autoregressive integrated moving average (ARIMA) are used to explore patient BG variation throughout the day and over space. The ARIMA models revealed a wide variety of BG correlating factors related to specific activity types, locations (especially those far from home), and travel modes, although the impacts were highly personal. Traditional variables related to food intake and medications were less often significant. Overall, the time-series analysis revealed considerable patient-by-patient variation in the effects of geographic and daily lifestyle factors. We would suggest that maps of BG spatial variation or an interactive messaging system could provide new tools to engage patients and highlight potential risk factors. Sean T. Doherty and Stephen P. Greaves Copyright © 2015 Sean T. Doherty and Stephen P. Greaves. All rights reserved.