Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Assessment of Left Ventricular Structural Remodelling in Patients with Diabetic Cardiomyopathy by Cardiovascular Magnetic Resonance Wed, 22 Jun 2016 14:32:54 +0000 Background. Diabetic cardiomyopathy (DCM) is always accompanied with alteration of left ventricular structure and function. The aims of this study were to assess the structural remodelling in patients with DCM by cardiovascular magnetic resonance (CMR) and correlation of structural remodelling with severity of DCM. Methods. Twenty-five patients ( years, 52.0% males) with DCM and thirty-one normal healthy controls ( years, 45.2% males) were scanned by CMR cine to assess function and structure of left ventricular. Length of diabetic history and results of cardiac echocardiography (E′, A′, and E′/A′) were also measured. Results. Compared with normal controls group, DCM group was associated with significantly increased ratio of left ventricular mass at end diastole to end-diastolic volume (MVR) () and no significant difference was in mass at end diastole (). The ratio correlated with both length of diabetic history and echocardiographic Doppler tissue imaging E′ (all ). Conclusions. CMR can be a powerful technique to assess LV remodelling, and MVR may be considered as an imaging marker to evaluate the severity of LV remodelling in patients with DCM. Yongning Shang, Xiaochun Zhang, Liu Chen, Weiling Leng, Xiaotian Lei, Qi Yang, Ziwen Liang, and Jian Wang Copyright © 2016 Yongning Shang et al. All rights reserved. Role of Tissue and Systemic Hypoxia in Obesity and Type 2 Diabetes Tue, 21 Jun 2016 13:45:17 +0000 Lei Xi, Chin-Moi Chow, and Xingxing Kong Copyright © 2016 Lei Xi et al. All rights reserved. Urinary Biomarkers in the Assessment of Early Diabetic Nephropathy Thu, 16 Jun 2016 14:20:35 +0000 Diabetic nephropathy (DN) is a frequent and severe complication of diabetes mellitus (DM). Its diagnosis in incipient stages may allow prompt interventions and an improved prognosis. Towards this aim, biomarkers for detecting early DN can be used. Microalbuminuria has been proven a remarkably useful biomarker, being used for diagnosis of DN, for assessing its associated condition—mainly cardiovascular ones—and for monitoring its progression. New researches are pointing that some of these biomarkers (i.e., glomerular, tubular, inflammation markers, and biomarkers of oxidative stress) precede albuminuria in some patients. However, their usefulness is widely debated in the literature and has not yet led to the validation of a new “gold standard” biomarker for the early diagnosis of DN. Currently, microalbuminuria is an important biomarker for both glomerular and tubular injury. Other glomerular biomarkers (transferrin and ceruloplasmin) are under evaluation. Tubular biomarkers in DN seem to be of a paramount importance in the early diagnosis of DN since tubular lesions occur early. Additionally, biomarkers of inflammation, oxidative stress, podocyte biomarkers, and vascular biomarkers have been employed for assessing early DN. The purpose of this review is to provide an overview of the current biomarkers used for the diagnosis of early DN. Cristina Gluhovschi, Gheorghe Gluhovschi, Ligia Petrica, Romulus Timar, Silvia Velciov, Ioana Ionita, Adriana Kaycsa, and Bogdan Timar Copyright © 2016 Cristina Gluhovschi et al. All rights reserved. Activation of GPR119 Stimulates Human β-Cell Replication and Neogenesis in Humanized Mice with Functional Human Islets Thu, 16 Jun 2016 10:20:45 +0000 Using humanized mice with functional human islets, we investigated whether activating GPR119 by PSN632408, a small molecular agonist, can stimulate human β-cell regeneration in vivo. Human islets were transplanted under the left kidney capsule of immunodeficient mice with streptozotocin- (STZ-) induced diabetes. The recipient mice were treated with PSN632408 or vehicle and BrdU daily. Human islet graft function in the mice was evaluated by nonfasting glucose levels, oral glucose tolerance, and removal of the grafts. Immunostaining for insulin, glucagon, and BrdU or Ki67 was performed in islet grafts to evaluate α- and β-cell replication. Insulin and CK19 immunostaining was performed to evaluate β-cell neogenesis. Four weeks after human islet transplantation, 71% of PSN632408-treated mice achieved normoglycaemia compared with 24% of vehicle-treated mice. Also, oral glucose tolerance was significantly improved in the PSN632408-treated mice. PSN632408 treatment significantly increased both human α- and β-cell areas in islet grafts and stimulated α- and β-cell replication. In addition, β-cell neogenesis was induced from pancreatic duct cells in the islet grafts. Our results demonstrated that activation of GPR119 increases β-cell mass by stimulating human β-cell replication and neogenesis. Therefore, GPR119 activators may qualify as therapeutic agents to increase human β-cell mass in patients with diabetes. Ansarullah, Colette Free, Jenica Christopherson, Quanhai Chen, Jie Gao, Chengyang Liu, Ali Naji, Alex Rabinovitch, and Zhiguang Guo Copyright © 2016 Ansarullah et al. All rights reserved. Screening of Undiagnosed Hypothyroidism in Elderly Persons with Diabetes according to Age-Specific Reference Intervals for Serum Thyroid Stimulating Hormone and the Impact of Antidiabetes Drugs Wed, 15 Jun 2016 11:57:27 +0000 Background. Studies have suggested that hypothyroidism is more frequent in the elderly with diabetes mellitus. However, an adaptation of TSH levels to age should be considered in this assessment. Some antidiabetes drugs reportedly interfere with TSH levels. The objectives of this study were to evaluate the prevalence of undiagnosed hypothyroidism in patients with diabetes and the influence of antidiabetes drugs. Material and Methods. 1160 subjects, 60 years and older (751 with diabetes), were studied; results were compared according to diabetes treatment and with persons without diabetes. TSH, FT4, antithyroperoxidase, fasting glucose, and HbA1c were measured. Results and Discussion. 6.4% of patients with diabetes had hypothyroidism, a higher prevalence compared with persons without diabetes (5.1%), but lower than observed in many studies. The use of age-specific TSH reference interval (RI) could explain this difference. Patients taking metformin (MTF) had TSH (showed in medians) slightly lower (2.8 mU/L) than those not on MTF (3.3 mU/L), . MTF doses influenced TSH levels. Conclusions. The use of specific TSH RI could avoid the misdiagnosis of hypothyroidism in elderly with diabetes. Patients in use of MTF as single drug had lower TSH than those using other medications and persons without diabetes. Rosita Fontes, Patricia de Fatima dos Santos Teixeira, and Mario Vaisman Copyright © 2016 Rosita Fontes et al. All rights reserved. The Hospitalization Costs of Diabetes and Hypertension Complications in Zimbabwe: Estimations and Correlations Wed, 15 Jun 2016 06:38:17 +0000 Objective. Treating complications associated with diabetes and hypertension imposes significant costs on health care systems. This study estimated the hospitalization costs for inpatients in a public hospital in Zimbabwe. Methods. The study was retrospective and utilized secondary data from medical records. Total hospitalization costs were estimated using generalized linear models. Results. The median cost and interquartile range (IQR) for patients with diabetes, $994 (385–1553) mean $1319 (95% CI: 981–1657), was higher than patients with hypertension, $759 (494–1147) mean $914 (95% CI: 825–1003). Female patients aged below 65 years with diabetes had the highest estimated mean costs ($1467 (95% CI: 1177–1828)). Wound care had the highest estimated mean cost of all procedures, $2884 (95% CI: 2004–4149) for patients with diabetes and $2239 (95% CI: 1589–3156) for patients with hypertension. Age below 65 years, medical procedures (amputation, wound care, dialysis, and physiotherapy), the presence of two or more comorbidities, and being prescribed two or more drugs were associated with significantly higher hospitalization costs. Conclusion. Our estimated costs could be used to evaluate and improve current inpatient treatment and management of patients with diabetes and hypertension and determine the most cost-effective interventions to prevent complications and comorbidities. Mutsa P. Mutowo, Paula K. Lorgelly, Michael Laxy, Andre M. N. Renzaho, John C. Mangwiro, and Alice J. Owen Copyright © 2016 Mutsa P. Mutowo et al. All rights reserved. The Relation between Serum Uric Acid and HbA1c Is Dependent upon Hyperinsulinemia in Patients with Newly Diagnosed Type 2 Diabetes Mellitus Tue, 14 Jun 2016 07:42:45 +0000 Objective. The aim of our study was to explore the dependent condition of the relationship between uric acid and blood glucose in type 2 diabetes. Research Design and Methods. We measured the HbA1c, serum uric acid, creatinine, lipids profiles, and so forth of 605 newly diagnosed type 2 diabetes patients, and oral glucose tolerance tests (OGTTs) were performed on each patient. The population was divided into high and low insulin groups. Multiple linear regression analyses were conducted to assess the relationship between uric acid and HbA1c. Results. Serum uric acid and HbA1c levels were low in newly diagnosed type 2 diabetes patients. However, we found no significant relationship between uric acid and HbA1c by regression analysis after adjusting total insulin. The concentration of uric acid was inversely correlated with HbA1c in the high insulin group, regardless of patient sex. However, no associations were found in low insulin group. Conclusions. The negative correlation between uric acid and HbA1c is conditional in newly diagnosed type 2 diabetes patients and is related to hyperinsulinemia. Therefore, uric acid is likely only useful as a biomarker of blood glucose in patients exhibiting hyperinsulinemia. Yuliang Cui, Hemei Bu, Xianghua Ma, Sha Zhao, Xiaona Li, and Shan Lu Copyright © 2016 Yuliang Cui et al. All rights reserved. Interaction between Mean Arterial Pressure and HbA1c in Prediction of Cardiovascular Disease Hospitalisation: A Population-Based Case-Control Study Mon, 13 Jun 2016 10:42:02 +0000 Objective. To explore the relationship between mean arterial pressure (MAP), HbA1c, and cardiovascular (CV) hospitalisation risk in type 2 diabetes. Design. Population-based case-control study. Settings. Primary and secondary care level in Cambridgeshire, United Kingdom. Participants. 588 patients with type 2 diabetes from 18 English general practices recording a CV hospitalisation in 2009–2011 were included. Risk-set sampling was used to select 2920 gender, age, and practice matched control type 2 diabetes patients. Main Outcome Measure. Conditional logistic regression was used to explore further dose-response relationships between MAP, HbA1c, and CV hospitalisation risk. Results. The relationship between MAP and CV hospitalisation was nonlinear ( for linearity test). The MAP associated with the lowest CV hospitalisation risk was 97 (95% CI: 93–101) mmHg. An interaction between MAP and HbA1c for increased risk of cardiovascular hospitalisation was observed among those with HbA1c < 7% (53 mmol/mol) and MAP < 97 mmHg. Conclusions. In type 2 diabetes, MAP is a good predictor of CV hospitalisation risk. CV hospitalisation is lowest with a MAP between 93 and 101 mmHg. CV hospitalisation was particularly high among those with both a low MAP and a lower HbA1c. Dahai Yu, Zhanzheng Zhao, and David Simmons Copyright © 2016 Dahai Yu et al. All rights reserved. Increasing GLP-1 Circulating Levels by Bariatric Surgery or by GLP-1 Receptor Agonists Therapy: Why Are the Clinical Consequences so Different? Sun, 12 Jun 2016 07:32:45 +0000 The “incretin effect” is used to describe the observation that more insulin is secreted after the oral administration of glucose compared to that after the intravenous administration of the same amount of glucose. During the absorption of meals, the gut is thought to regulate insulin secretion by secreting a specific factor that targets pancreatic beta cells. Additional research confirmed this hypothesis with the discovery of two hormones called incretins: gastric inhibitory peptide (GIP) and glucagon-like peptide 1 (GLP-1). During meals, specific cells in the gut (L and K enteroendocrine cells) secrete incretins, causing an increase in the blood concentrations of, respectively, GLP-1 and GIP. Bariatric surgery is now proposed during the therapeutic management of type 2 diabetes in obese or overweight populations. It has been hypothesized that restoration of endogenous GLP-1 secretion after the surgery may contribute to the postsurgical resolution of diabetes. In 2005, the commercialization of GLP-1 receptor agonists gave the possibility to test this hypothesis. A few years later, it is now accepted that GLP-1 receptor agonists and bariatric surgery differently improve type 2 diabetes. These differences between endogenous and exogenous GLP-1 on glucose homeostasis emphasized the dual properties of GLP-1 as a peptide hormone and as a neurotransmitter. Chloé Amouyal and Fabrizio Andreelli Copyright © 2016 Chloé Amouyal and Fabrizio Andreelli. All rights reserved. Sex-Specific Association between Serum Uric Acid and Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Patients Sun, 12 Jun 2016 06:55:11 +0000 Across-sectional study was performed in 541 type 2 diabetic patients to determine the relationship between serum uric acid (SUA) and NAFLD in type 2 diabetic patients. Clinical parameters including SUA were determined and NAFLD was diagnosed by ultrasonography. SUA was significantly higher in type 2 diabetic subjects with NAFLD than in those without NAFLD in men, but not in women. Furthermore, the prevalence rate of NAFLD increased progressively across the sex-specific SUA tertiles only in men (37.9%, 58.6%, and 72.6%, resp., for trend < 0.001). After adjusting for confounding factors, the odd ratios (95% CI) for NAFLD were 1 (reference), 2.93 (95%CI 1.25–6.88), and 3.93 (95% CI 1.55–9.98), respectively, across the tertiles of SUA in men. Contrastingly, SUA levels in women were not independently associated with the risk of NAFLD. Our data suggests that SUA is specifically associated with NAFLD in male type 2 diabetic subjects, independent of insulin resistance and other metabolic factors. Nengguang Fan, Lijuan Zhang, Zhenhua Xia, Liang Peng, Yufan Wang, and Yongde Peng Copyright © 2016 Nengguang Fan et al. All rights reserved. Histone Acetylation and Its Modifiers in the Pathogenesis of Diabetic Nephropathy Thu, 09 Jun 2016 09:19:16 +0000 Diabetic nephropathy (DN) remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors contributing to DN is required to develop more effective therapeutic options. It is becoming more evident that histone acetylation (HAc), as one of the epigenetic mechanisms, is thought to be associated with the etiology of diabetic vascular complications such as diabetic retinopathy (DR), diabetic cardiomyopathy (DCM), and DN. Histone acetylases (HATs) and histone deacetylases (HDACs) are the well-known regulators of reversible acetylation in the amino-terminal domains of histone and nonhistone proteins. In DN, however, the roles of histone acetylation (HAc) and these enzymes are still controversial. Some new evidence has revealed that HATs and HDACs inhibitors are renoprotective in cellular and animal models of DN, while, on the other hand, upregulation of HAc has been implicated in the pathogenesis of DN. In this review, we focus on the recent advances on the roles of HAc and their covalent enzymes in the development and progression of DN in certain cellular processes including fibrosis, inflammation, hypertrophy, and oxidative stress and discuss how targeting these enzymes and their inhibitors can ultimately lead to the therapeutic approaches for treating DN. Xiaoxia Li, Chaoyuan Li, and Guangdong Sun Copyright © 2016 Xiaoxia Li et al. All rights reserved. The Role of Hyperglycemia and Insulin Resistance in the Development and Progression of Pulmonary Arterial Hypertension Wed, 08 Jun 2016 12:22:07 +0000 Pulmonary hypertension is a progressive disorder which often leads to right ventricular failure and death. While the existing classification system for pulmonary hypertension does not account for the impact of diabetes mellitus, evidence is emerging that suggests that diabetes is associated with pulmonary hypertension and that diabetes modifies the course of pulmonary hypertension. There is also growing radiographic, hemodynamic, biochemical, and pathologic data supporting an association between diabetes and pulmonary hypertension. More robust epidemiologic studies are needed to confirm an association between diabetes and pulmonary hypertension and to show that diabetes is a disease modifier in pulmonary hypertension. In addition, evaluating the effects of glucose control in animals with pulmonary hypertension and diabetes (as well as in humans) is warranted. Daniel Grinnan, Grant Farr, Adam Fox, and Lori Sweeney Copyright © 2016 Daniel Grinnan et al. All rights reserved. Circulating Biomarkers of Diabetic Retinopathy: An Overview Based on Physiopathology Wed, 08 Jun 2016 07:55:46 +0000 Diabetic retinopathy (DR) is the main cause of working-age adult-onset blindness. The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR. Therefore, new pharmacological treatments for these early stages of the disease are required. In order to develop therapeutic strategies for early stages of DR new diagnostic tools are urgently needed. In this regard, circulating biomarkers could be useful to detect early disease, to identify those diabetic patients most prone to progressive worsening who ought to be followed up more often and who could obtain the most benefit from these therapies, and to monitor the effectiveness of new drugs for DR before more advanced DR stages have been reached. Research of biomarkers for DR has been mainly based on the pathogenic mechanism involved in the development of DR (i.e., AGEs, oxidative stress, endothelial dysfunction, inflammation, and proangiogenic factors). This review focuses on circulating biomarkers at both early and advanced stages that could be relevant for the prediction or detection of DR. Olga Simó-Servat, Rafael Simó, and Cristina Hernández Copyright © 2016 Olga Simó-Servat et al. All rights reserved. Diabetic Foot: Current Status and Future Prospects Sun, 05 Jun 2016 14:02:10 +0000 Didac Mauricio, Edward Jude, Alberto Piaggesi, and Robert Frykberg Copyright © 2016 Didac Mauricio et al. All rights reserved. Serotonin- and Dopamine-Related Gene Expression in db/db Mice Islets and in MIN6 β-Cells Treated with Palmitate and Oleate Sun, 05 Jun 2016 07:33:01 +0000 High circulating nonesterified fatty acids (NEFAs) concentration, often reported in diabetes, leads to impaired glucose-stimulated insulin secretion (GSIS) through not yet well-defined mechanisms. Serotonin and dopamine might contribute to NEFA-dependent β-cell dysfunction, since extracellular signal of these monoamines decreases GSIS. Moreover, palmitate-treated β-cells may enhance the expression of the serotonin receptor Htr2c, affecting insulin secretion. Additionally, the expression of monoamine-oxidase type B (Maob) seems to be lower in islets from humans and mice with diabetes compared to nondiabetic islets, which may lead to increased monoamine concentrations. We assessed the expression of serotonin- and dopamine-related genes in islets from db/db and wild-type (WT) mice. In addition, the effect of palmitate and oleate on the expression of such genes, 5HT content, and GSIS in MIN6 β-cell was determined. Lower Maob expression was found in islets from db/db versus WT mice and in MIN6 β-cells in response to palmitate and oleate treatment compared to vehicle. Reduced 5HT content and impaired GSIS in response to palmitate (−25%; ) and oleate (−43%; ) were detected in MIN6 β-cells. In conclusion, known defects of GSIS in islets from db/db mice and MIN6 β-cells treated with NEFAs are accompanied by reduced Maob expression and reduced 5HT content. L. R. Cataldo, M. L. Mizgier, D. Busso, P. Olmos, J. E. Galgani, R. Valenzuela, D. Mezzano, E. Aranda, V. A. Cortés, and J. L. Santos Copyright © 2016 L. R. Cataldo et al. All rights reserved. Silymarin in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Wed, 01 Jun 2016 12:11:13 +0000 Type 2 diabetes mellitus (T2DM) is associated with increased risk of cardiovascular disease and nephropathy—now the leading cause of end-stage renal disease and dialysis in Europe and the United States. Inflammation and oxidative stress play a pivotal role in the development of diabetic complications. Silymarin, an herbal drug with antioxidant and anti-inflammatory properties, may improve glycemic control and prevent the progression of the complications. In a systematic review and meta-analysis including five randomized controlled trials and 270 patients, routine silymarin administration determines a significant reduction in fasting blood glucose levels (−26.86 mg/dL; 95% CI −35.42–18.30) and HbA1c levels (−1.07; 95% CI −1.73–0.40) and has no effect on lipid profile. Benefits for silymarin on proteinuria and CKD progressions are reported in only one small study and are uncertain. However, being aware of the low quality of the available evidence and elevated heterogeneity of these studies, no recommendation can be made and further studies are needed. Luminita Voroneanu, Ionut Nistor, Raluca Dumea, Mugurel Apetrii, and Adrian Covic Copyright © 2016 Luminita Voroneanu et al. All rights reserved. Upregulation of α3β1-Integrin in Podocytes in Early-Stage Diabetic Nephropathy Wed, 01 Jun 2016 08:36:28 +0000 Background. Podocyte injury plays an important role in the onset and progression of diabetic nephropathy (DN). Downregulation of α3β1-integrin expression in podocytes is thought to be associated with podocyte detachment from the glomerular basement membrane, although the mechanisms remain obscure. To determine the mechanism of podocyte detachment, we analyzed the expression levels of α3β1-integrin in podocytes in early and advanced stages of DN. Methods. Surgical specimens from DN patients were examined by in situ hybridization, and the expression levels of α3- and β1-integrin subunits in glomeruli of early () and advanced () stages were compared with those of normal glomeruli (). Heat-sensitive mouse podocytes (HSMP) were cultured with TGF-β1 to reproduce the microenvironment of glomeruli of DN, and the expression levels of integrin subunits and the properties of migration and attachment were examined. Results. Podocytes of early-stage DN showed upregulation of α3- and β1-integrin expression while those of advanced stage showed downregulation. Real-time PCR indicated a tendency for upregulation of α3- and β1-integrin in HSMP cultured with TGF-β1. TGF-β1-stimulated HSMP also showed enhanced in vitro migration and attachment on collagen substrate. Conclusions. The results suggested that podocyte detachment during early stage of DN is mediated through upregulation of α3β1-integrin. Kaichiro Sawada, Masao Toyoda, Noriko Kaneyama, Sawako Shiraiwa, Hitomi Moriya, Han Miyatake, Eitaro Tanaka, Naoyuki Yamamoto, Masaaki Miyauchi, Moritsugu Kimura, Takehiko Wada, and Masafumi Fukagawa Copyright © 2016 Kaichiro Sawada et al. All rights reserved. Par-4/NF-κB Mediates the Apoptosis of Islet β Cells Induced by Glucolipotoxicity Tue, 31 May 2016 13:38:42 +0000 Apoptosis of islet β cells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4)/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER) stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces islet β cell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro. We demonstrated that the high glucose/palmitate intervention induced the expression and secretion of Par-4. It also causes increased expression and activation of NF-κB, which induced NIT-1 cell apoptosis and dysfunction. Overexpression of Par-4 potentiates these effects, whereas downregulation of Par-4 attenuates them. Inhibition of NF-κB inhibited the Par-4-induced apoptosis. Furthermore, these effects occurred through the ER stress cell membrane and mitochondrial pathway of apoptosis. Our findings reveal a novel role for Par-4/NF-κB in islet β cell apoptosis and type 2 diabetes. Wu QiNan, Gan XiaGuang, Lei XiaoTian, Deng WuQuan, Zhang Ling, and Chen Bing Copyright © 2016 Wu QiNan et al. All rights reserved. Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia Sun, 29 May 2016 11:52:04 +0000 With-no-lysine (K) Kinase-4 (WNK4) consisted of unique serine and threonine protein kinases, genetically associated with an autosomal dominant form of hypertension. Argumentative consequences have lately arisen on the association of specific single nucleotide polymorphisms of WNK4 gene and essential hypertension (EHT). The aim of this study was to determine the association of Ala589Ser polymorphism of WNK4 gene with essential hypertensive patients in Malaysia. WNK4 gene polymorphism was specified utilizing mutagenically separated polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method in 320 subjects including 163 cases and 157 controls. Close relation between Ala589Ser polymorphism and elevated systolic and diastolic blood pressure (SBP and DBP) was recognized. Sociodemographic factors including body mass index (BMI), age, the level of fasting blood sugar (FBS), low density lipoprotein (LDL), and triglyceride (TG) in the cases and healthy subjects exhibited strong differences (). The distribution of allele frequency and genotype of WNK4 gene Ala589Ser polymorphism showed significant differences () between EHT subjects with or without type 2 diabetes mellitus (T2DM) and normotensive subjects, statistically. The WNK4 gene variation influences significantly blood pressure increase. Ala589Ser probably has effects on the enzymic activity leading to enhanced predisposition to the disorder. Nooshin Ghodsian, Patimah Ismail, Salma Ahmadloo, Farzad Heidari, Polin Haghvirdizadeh, Sima Ataollahi Eshkoor, and Ali Etemad Copyright © 2016 Nooshin Ghodsian et al. All rights reserved. Brain Activation during Memory Encoding in Type 2 Diabetes Mellitus: A Discordant Twin Pair Study Sun, 29 May 2016 09:18:29 +0000 Type 2 diabetes mellitus increases the risk of dementia and neuronal dysfunction may occur years before perceptible cognitive decline. We aimed to study the impact of type 2 diabetes on brain activation during memory encoding in middle-aged people, controlling for age, sex, genes, and early-shared environment. Twenty-two twin pairs discordant for type 2 diabetes mellitus (mean age 60.9 years) without neurological disease were recruited from the Australian Twin Registry (ATR) and underwent functional magnetic resonance imaging (fMRI) during a memory encoding task, cognitive tests, and structural MRI. Type 2 diabetes was associated with significantly reduced activation in left hemisphere temporoparietal regions including angular gyrus, supramarginal gyrus, and middle temporal gyrus and significantly increased activation in bilateral posteriorly distributed regions. These findings were present in the absence of within-pair differences in standard cognitive test scores, brain volumes, or vascular lesion load. Differences in activation were more pronounced among monozygotic (MZ) pairs, with MZ individuals with diabetes also displaying greater frontal activation. These results provide evidence for preclinical memory-related neuronal dysfunction in type 2 diabetes. They support the search for modifiable later-life environmental factors or epigenetic mechanisms linking type 2 diabetes and cognitive decline. Amanda G. Wood, Jian Chen, Christopher Moran, Thanh Phan, Richard Beare, Kimberley Cooper, Stacey Litras, and Velandai Srikanth Copyright © 2016 Amanda G. Wood et al. All rights reserved. Genomics and Metabolomics in Obesity and Type 2 Diabetes Wed, 25 May 2016 08:37:36 +0000 Adam Kretowski, Francisco J. Ruperez, and Michal Ciborowski Copyright © 2016 Adam Kretowski et al. All rights reserved. Diabetes Risk by Length of Residence among Somali Women in Oslo Area Wed, 25 May 2016 07:20:04 +0000 Type 2 diabetes represents a major health problem worldwide, with immigrants strongly contributing to the increase in diabetes in many countries. Norway is not immune to the process, and immigrants in the country are experiencing an increase in the prevalence of diabetes after arrival. However, the dynamics of these transitions in relation to the duration of residence in the new environment in Norway are not clearly understood. From this background, a cross-sectional quantitative study using a respondent-driven sampling method was conducted among 302 Somali women living in Oslo area. The results show that 41% of the study participants will be at risk for developing diabetes in the coming 10 years, which coincides with 85% of the study participants being abdominally obese. Significant associations were found between years of stay in Norway and the risk for diabetes with those who lived in Norway >10 years, having twofold higher odds of being at risk for developing diabetes compared to those who lived in Norway ≤5 years (OR: 2.16, CI: 1.08–4.32). Understanding the mechanisms through which exposure to the Norwegian environment leads to higher obesity and diabetes risk may aid in prevention efforts for the rapidly growing African immigrant population. Abdi A. Gele, Kjell Sverre Pettersen, Bernadette Kumar, and Liv Elin Torheim Copyright © 2016 Abdi A. Gele et al. All rights reserved. The Association of Type 2 Diabetes Mellitus with Cerebral Gray Matter Volume Is Independent of Retinal Vascular Architecture and Retinopathy Wed, 25 May 2016 06:32:26 +0000 It is uncertain whether small vessel disease underlies the relationship between Type 2 Diabetes Mellitus (T2DM) and brain atrophy. We aimed to study whether retinal vascular architecture, as a proxy for cerebral small vessel disease, may modify or mediate the associations of T2DM with brain volumes. In this cross-sectional study using Magnetic Resonance Imaging (MRI) scans and retinal photographs in 451 people with and without T2DM, we measured brain volumes, geometric measures of retinal vascular architecture, clinical retinopathy, and MRI cerebrovascular lesions. There were 270 people with (mean age 67.3 years) and 181 without T2DM (mean age 72.9 years). T2DM was associated with lower gray matter volume (). T2DM was associated with greater arteriolar diameter () and optimality ratio (), but these associations were attenuated by adjustments for age and sex. Only optimality ratio was associated with lower gray matter volume (). The inclusion of retinal measures in regression models did not attenuate the association of T2DM with gray matter volume. The association of T2DM with lower gray matter volume was independent of retinal vascular architecture and clinical retinopathy. Retinal vascular measures or retinopathy may not be sufficiently sensitive to confirm a microvascular basis for T2DM-related brain atrophy. C. Moran, R. J. Tapp, A. D. Hughes, C. G. Magnussen, L. Blizzard, T. G. Phan, R. Beare, N. Witt, A. Venn, G. Münch, B. C. Amaratunge, and V. Srikanth Copyright © 2016 C. Moran et al. All rights reserved. miRNA-375 a Sensor of Glucotoxicity Is Altered in the Serum of Children with Newly Diagnosed Type 1 Diabetes Tue, 24 May 2016 06:13:09 +0000 Background. The use of miRNAs as biomarkers for Type 1 Diabetes (T1D) risk is attractive as T1D is usually diagnosed in front of acute symptoms. As miR-375 is highly expressed in the endocrine pancreas, we postulated that its circulating level might reflect beta cell alterations and might be altered in the blood of T1D patients recently diagnosed. Methods. Sera were obtained from 22 T1D children at onset of the disease, before subcutaneous insulin treatment, and from 10 nondiabetic pediatric controls. MiR-375 seric level was quantified by stem-loop RT-PCR-based assay. MiRNAs regulations in isolated human islets in response to high glucose concentrations were determined by TaqMan Low-Density Array. Results. The abundance of miR-375, among the 410 miRNAs detected in human islets, mirrored its well-established role in rodent islet biology. Upregulated miRNAs targeted genes involved in islet homeostasis and regulation of beta cell mass. Downregulated miRNAs, including miR-375, were involved in pancreas secretion and protein turnover. Seric level of miR-375 was lower in T1D children versus age-matched controls, without any correlations with HbA1c, glycaemia, and number of autoantibodies. Conclusion. Altered circulating level of miR-375 at onset of T1D might be a general biomarker of metabolic alterations and inflammation associated with the disease. Lucien Marchand, Audrey Jalabert, Emmanuelle Meugnier, Kathleen Van den Hende, Nicole Fabien, Marc Nicolino, Anne-Marie Madec, Charles Thivolet, and Sophie Rome Copyright © 2016 Lucien Marchand et al. All rights reserved. The Role of Matrix Metalloproteinases in Diabetic Wound Healing in relation to Photobiomodulation Mon, 23 May 2016 14:03:22 +0000 The integration of several cellular responses initiates the process of wound healing. Matrix Metalloproteinases (MMPs) play an integral role in wound healing. Their main function is degradation, by removal of damaged extracellular matrix (ECM) during the inflammatory phase, breakdown of the capillary basement membrane for angiogenesis and cell migration during the proliferation phase, and contraction and remodelling of tissue in the remodelling phase. For effective healing to occur, all wounds require a certain amount of these enzymes, which on the contrary could be very damaging at high concentrations causing excessive degradation and impaired wound healing. The imbalance in MMPs may increase the chronicity of a wound, a familiar problem seen in diabetic patients. The association of diabetes with impaired wound healing and other vascular complications is a serious public health issue. These may eventually lead to chronic foot ulcers and amputation. Low intensity laser irradiation (LILI) or photobiomodulation (PBM) is known to stimulate several wound healing processes; however, its role in matrix proteins and diabetic wound healing has not been fully investigated. This review focuses on the role of MMPs in diabetic wound healing and their interaction in PBM. Sandra Matabi Ayuk, Heidi Abrahamse, and Nicolette Nadene Houreld Copyright © 2016 Sandra Matabi Ayuk et al. All rights reserved. Implementation of a Diabetes Educator Care Model to Reduce Paediatric Admission for Diabetic Ketoacidosis Tue, 17 May 2016 09:45:05 +0000 Introduction. Diabetic Ketoacidosis (DKA) is a serious complication that can be life-threatening. Management of DKA needs admission in a specialized center and imposes major constraints on hospital resources. Aim. We plan to study the impact of adapting a diabetes-educator care model on reducing the frequency of hospital admission of children and adolescents presenting with DKA. Method. We have proposed a model of care led by diabetes educators for children and adolescents with diabetes. The team consisted of highly trained nurses. The model effectiveness is measured by comparing the rate of hospital admission for DKA over 4-year period to the baseline year prior to implementing the model. Results. There were 158 admissions for DKA over a 5-year period. Number of patients followed up in the outpatient diabetes clinics increased from 37 to 331 patients at the start and the end of the study years. Admission rate showed a downward trend over the five-year period. Percentage of admission for DKA is reduced from 210% to 1.8% ( 0.001). Conclusion. Diabetes educator care model is an effective and a sustainable measure to reduce hospital admission for DKA in children and adolescents. Asma Deeb, Hana Yousef, Layla Abdelrahman, Mary Tomy, Shaker Suliman, Salima Attia, and Hana Al Suwaidi Copyright © 2016 Asma Deeb et al. All rights reserved. Nanoparticle Delivered Human Biliverdin Reductase-Based Peptide Increases Glucose Uptake by Activating IRK/Akt/GSK3 Axis: The Peptide Is Effective in the Cell and Wild-Type and Diabetic Ob/Ob Mice Tue, 17 May 2016 06:35:46 +0000 Insulin’s stimulation of glucose uptake by binding to the IRK extracellular domain is compromised in diabetes. We have recently described an unprecedented approach to stimulating glucose uptake. KYCCSRK (P2) peptide, corresponding to the C-terminal segment of hBVR, was effective in binding to and inducing conformational change in the IRK intracellular kinase domain. Although myristoylated P2, made of L-amino acids, was effective in cell culture, its use for animal studies was unsuitable. We developed a peptidase-resistant formulation of the peptide that was efficient in both mice and cell culture systems. The peptide was constructed of D-amino acids, in reverse order, and blocked at both termini. Delivery of the encapsulated peptide to HepG2 and HSKM cells was confirmed by its prolonged effect on stimulation of glucose uptake (>6 h). The peptide improved glucose clearance in both wild-type and Ob/Ob mice; it lowered blood glucose levels and suppressed glucose-stimulated insulin secretion. IRK activity was stimulated in the liver of treated mice and in cultured cells. The peptide potentiated function of IRK’s downstream effector, Akt-GSK3- axis. Thus, P2-based approach can be used for improving glucose uptake by cells. Also, it allows for screening peptides in vitro and in animal models for treatment of diabetes. Peter E. M. Gibbs, Tihomir Miralem, Nicole Lerner-Marmarosh, and Mahin D. Maines Copyright © 2016 Peter E. M. Gibbs et al. All rights reserved. Delay in the Detrended Fluctuation Analysis Crossover Point as a Risk Factor for Type 2 Diabetes Mellitus Mon, 16 May 2016 14:25:08 +0000 Detrended Fluctuation Analysis (DFA) measures the complexity of a glucose time series obtained by means of a Continuous Glucose Monitoring System (CGMS) and has proven to be a sensitive marker of glucoregulatory dysfunction. Furthermore, some authors have observed a crossover point in the DFA, signalling a change of dynamics, arguably dependent on the beta-insular function. We investigate whether the characteristics of this crossover point have any influence on the risk of developing type 2 diabetes mellitus (T2DM). To this end we recruited 206 patients at increased risk of T2DM (because of obesity, essential hypertension, or a first-degree relative with T2DM). A CGMS time series was obtained, from which the DFA and the crossover point were calculated. Patients were then followed up every 6 months for a mean of 17.5 months, controlling for the appearance of T2DM diagnostic criteria. The time to crossover point was a significant predictor risk of developing T2DM, even after adjusting for other variables. The angle of the crossover was not predictive by itself but became significantly protective when the model also considered the crossover point. In summary, both a delay and a blunting of the crossover point predict the development of T2DM. Manuel Varela, Luis Vigil, Carmen Rodriguez, Borja Vargas, and Rafael García-Carretero Copyright © 2016 Manuel Varela et al. All rights reserved. Antidiabetic Effect of Young and Old Ethanolic Leaf Extracts of Vernonia amygdalina: A Comparative Study Mon, 16 May 2016 11:25:02 +0000 The young leaves of Vernonia amygdalina are often utilized as vegetable and for medicinal purpose compared to the old leaves. This study was designed to evaluate and compare the antidiabetic effects between ethanolic leaf extracts of old and young V. amygdalina on streptozotocin (STZ) induced diabetic rat for four weeks. Preliminary screening of both young and old ethanolic extracts revealed the presence of the same phytochemicals except flavonoids which was only present in the old V. amygdalina. Difference in antioxidant power between the young and old leaf extracts was statistically significant (). Both leaf extracts produced a significant () antihyperglycaemic effect. Also results from treated rats revealed increasing effect in some haematological parameters. Similarly, the higher dose (300 mg/kg) of both extracts significantly () reduced serum ALT, AST, and ALP levels as compared to the diabetic control rats. Results also showed significant () decrease in LDL-C and VLDL-C in the extract-treated rats with a corresponding increase in HDL-C, as compared to the diabetic control rats. Moreover histopathological analysis revealed ameliorative effect of pathological insults induced by the STZ in the pancreas, liver, and spleen, most significantly the regeneration of the beta cells of the islets of Langerhans in treated rats. Du-Bois Asante, Emmanuel Effah-Yeboah, Precious Barnes, Heckel Amoabeng Abban, Elvis Ofori Ameyaw, Johnson Nyarko Boampong, Eric Gyamerah Ofori, and Joseph Budu Dadzie Copyright © 2016 Du-Bois Asante et al. All rights reserved. Metformin Protects H9C2 Cardiomyocytes from High-Glucose and Hypoxia/Reoxygenation Injury via Inhibition of Reactive Oxygen Species Generation and Inflammatory Responses: Role of AMPK and JNK Mon, 16 May 2016 08:00:39 +0000 Metformin is a first-line drug for the management of type 2 diabetes. Recent studies suggested cardioprotective effects of metformin against ischemia/reperfusion injury. However, it remains elusive whether metformin provides direct protection against hypoxia/reoxygenation (H/R) injury in cardiomyocytes under normal or hyperglycemic conditions. This study in H9C2 rat cardiomyoblasts was designed to determine cell viability under H/R and high-glucose (HG, 33 mM) conditions and the effects of cotreatment with various concentrations of metformin (0, 1, 5, and 10 mM). We further elucidated molecular mechanisms underlying metformin-induced cytoprotection, especially the possible involvement of AMP-activated protein kinase (AMPK) and Jun NH(2)-terminal kinase (JNK). Results indicated that 5 mM metformin improved cell viability, mitochondrial integrity, and respiratory chain activity under HG and/or H/R (). The beneficial effects were associated with reduced levels of reactive oxygen species generation and proinflammatory cytokines (TNF-, IL-1, and IL-6) (). Metformin enhanced phosphorylation level of AMPK and suppressed HG + H/R induced JNK activation. Inhibitor of AMPK (compound C) or activator of JNK (anisomycin) abolished the cytoprotective effects of metformin. In conclusion, our study demonstrated for the first time that metformin possessed direct cytoprotective effects against HG and H/R injury in cardiac cells via signaling mechanisms involving activation of AMPK and concomitant inhibition of JNK. Mingyan Hu, Ping Ye, Hua Liao, Manhua Chen, and Feiyan Yang Copyright © 2016 Mingyan Hu et al. All rights reserved.