Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . 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. Risk Factors for Macro- and Microvascular Complications among Older Adults with Diagnosed Type 2 Diabetes: Findings from The Irish Longitudinal Study on Ageing Sun, 15 May 2016 10:06:05 +0000 Objective. To explore risk factors for macro- and microvascular complications in a nationally representative sample of adults aged 50 years and over with type 2 diabetes in Ireland. Methods. Data from the first wave of The Irish Longitudinal Study on Ageing (TILDA) (2009–2011) was used in cross-sectional analysis. The presence of doctor diagnosis of diabetes, risk factors, and macro- and microvascular complications were determined by self-report. Gender-specific differences in risk factor prevalence were assessed with the chi-squared test. Binomial regression analysis was conducted to explore independent associations between established risk factors and diabetes-related complications. Results. Among 8175 respondents, 655 were classified as having type 2 diabetes. Older age, being male, a history of smoking, a lower level of physical activity, and a diagnosis of high cholesterol were independent predictors of macrovascular complications. Diabetes diagnosis of 10 or more years, a history of smoking, and a diagnosis of hypertension were associated with an increased risk of microvascular complications. Older age, third-level education, and a high level of physical activity were protective factors (). Conclusions. Early intervention to target modifiable risk factors is urgently needed to reduce diabetes-related morbidity in the older population in Ireland. Marsha L. Tracey, Sheena M. McHugh, Anthony P. Fitzgerald, Claire M. Buckley, Ronan J. Canavan, and Patricia M. Kearney Copyright © 2016 Marsha L. Tracey et al. All rights reserved. A Narrative Review of Diabetes Intervention Studies to Explore Diabetes Care Opportunities for Pharmacists Tue, 10 May 2016 10:54:28 +0000 Background. We conducted a review of current diabetes intervention studies in type 2 diabetes and identified opportunities for pharmacists to deliver quality diabetes care. Methods. A search on randomised controlled trials (RCT) on diabetes management by healthcare professionals including pharmacists published between 2010 and 2015 was conducted. Results and Discussion. Diabetes management includes multifactorial intervention which includes seven factors as outlined in diabetes guidelines, namely, glycaemic, cholesterol and blood pressure control, medication, lifestyle, education, and cardiovascular risk factors. Most studies do not provide evidence that the intervention methods used included all seven factors with exception of three RCT which indicated HbA1c (glycated hemoglobin) reduction range of 0.5% to 1.8%. The varied HbA1C reduction suggests a lack of standardised and consistent approach to diabetes care. Furthermore, the duration of most studies was from one month to two years; therefore long term outcomes could not be established. Conclusion. Although pharmacists’ contribution towards improving clinical outcomes of diabetes patients was well documented, the methods used to deliver structured, consistent evidence-based care were not clearly stipulated. Therefore, approaches to achieving long term continuity of care are uncertain. An intervention strategy that encompass all seven evidence-based factors will be useful. Shamala Ayadurai, H. Laetitia Hattingh, Lisa B. G. Tee, and Siti Norlina Md Said Copyright © 2016 Shamala Ayadurai et al. All rights reserved. Sex Differences in the Renal Function Decline of Patients with Type 2 Diabetes Mon, 09 May 2016 11:42:44 +0000 Aims. We aimed to investigate the sex differences in the renal function decline among patients with type 2 diabetic mellitus (T2DM), focusing on the differences in the risk factors at early stage of renal dysfunction. Methods. A clinic-based retrospective longitudinal study (follow-up duration: years) was conducted to assess the sex differences in the annual estimated glomerular filtration rate (eGFR) change in 344 (247 male and 97 female) Japanese T2DM patients. The sex differences in the risk factors of annual eGFR decline were subjected to linear regression analyses. Results. The mean annual eGFR change was %/year in females and %/year in males (). Baseline retinopathy and proteinuria were significantly associated with a larger eGFR decline, irrespective of sex, while HbA1c and LDL-cholesterol levels were significantly associated with an eGFR decline in females only. Interactive effects were observed between sex and the HbA1c, LDL-cholesterol, retinopathy, or proteinuria levels on the annual eGFR decline. Conclusions. The increased susceptibility to poor metabolic control seemed to contribute to a higher risk of renal dysfunction in females with T2DM. Our study highlights the importance of aggressive therapeutic intervention to improve metabolic profiles at early stage, especially in females. Ayami Kajiwara, Ayana Kita, Junji Saruwatari, Hiroko Miyazaki, Yuki Kawata, Kazunori Morita, Kentaro Oniki, Akira Yoshida, Hideaki Jinnouchi, and Kazuko Nakagawa Copyright © 2016 Ayami Kajiwara et al. All rights reserved. Physiological and Pharmacological Roles of FGF21 in Cardiovascular Diseases Mon, 09 May 2016 11:38:44 +0000 Cardiovascular disease (CVD) is one of the most severe diseases in clinics. Fibroblast growth factor 21 (FGF21) is regarded as an important metabolic regulator playing a therapeutic role in diabetes and its complications. The heart is a key target as well as a source of FGF21 which is involved in heart development and also induces beneficial effects in CVDs. Our review is to clarify the roles of FGF21 in CVDs. Strong evidence showed that the development of CVDs including atherosclerosis, coronary heart disease, myocardial ischemia, cardiac hypertrophy, and diabetic cardiomyopathy is associated with serum FGF21 levels increase which was regarded as a compensatory response to induced cardiac protection. Furthermore, administration of FGF21 suppressed the above CVDs. Mechanistic studies revealed that FGF21 induced cardiac protection likely by preventing cardiac lipotoxicity and the associated oxidative stress, inflammation, and apoptosis. Normally, FGF21 induced therapeutic effects against CVDs via activation of the above kinases-mediated pathways by directly binding to the FGF receptors of the heart in the presence of β-klotho. However, recently, growing evidence showed that FGF21 induced beneficial effects on peripheral organs through an indirect way mediated by adiponectin. Therefore whether adiponectin is also involved in FGF21-induced cardiac protection still needs further investigation. Peng Cheng, Fangfang Zhang, Lechu Yu, Xiufei Lin, Luqing He, Xiaokun Li, Xuemian Lu, Xiaoqing Yan, Yi Tan, and Chi Zhang Copyright © 2016 Peng Cheng et al. All rights reserved. A Molecular and Whole Body Insight of the Mechanisms Surrounding Glucose Disposal and Insulin Resistance with Hypoxic Treatment in Skeletal Muscle Thu, 05 May 2016 12:27:01 +0000 Although the mechanisms are largely unidentified, the chronic or intermittent hypoxic patterns occurring with respiratory diseases, such as chronic pulmonary disease or obstructive sleep apnea (OSA) and obesity, are commonly associated with glucose intolerance. Indeed, hypoxia has been widely implicated in the development of insulin resistance either via the direct action on insulin receptor substrate (IRS) and protein kinase B (PKB/Akt) or indirectly through adipose tissue expansion and systemic inflammation. Yet hypoxia is also known to encourage glucose transport using insulin-dependent mechanisms, largely reliant on the metabolic master switch, 5′ AMP-activated protein kinase (AMPK). In addition, hypoxic exposure has been shown to improve glucose control in type 2 diabetics. The literature surrounding hypoxia-induced changes to glycemic control appears to be confusing and conflicting. How is it that the same stress can seemingly cause insulin resistance while increasing glucose uptake? There is little doubt that acute hypoxia increases glucose metabolism in skeletal muscle and does so using the same pathway as muscle contraction. The purpose of this review paper is to provide an insight into the mechanisms underpinning the observed effects and to open up discussions around the conflicting data surrounding hypoxia and glucose control. R. W. A. Mackenzie and P. Watt Copyright © 2016 R. W. A. Mackenzie and P. Watt. All rights reserved. The Relationships between Anabolic Hormones and Body Composition in Middle-Aged and Elderly Men with Prediabetes: A Cross-Sectional Study Tue, 03 May 2016 15:06:36 +0000 The influence of anabolic hormones and body composition in men with prediabetes (PD) is unknown. In a cross-sectional study we investigated the relationships between total testosterone (TT), calculated free testosterone (cFT), dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF-1) and body composition assessed using dual-energy X-ray absorptiometry (DXA) method in 84 patients with PD (40–80 years) and 56 men in control group. Patients with PD had lower TT, cFT, and DHEAS levels but similar IGF-1 levels in both groups. Patients with PD presented the higher total and abdominal fat as well as the lower total and abdominal lean than control (, , and , resp.). We observed negative relationship between TT and total fat () and positive with abdominal lean mass (), while cFT was negatively associated with abdominal (), trunk (), and leg fat () and positively associated with total () and trunk lean (). DHEAS were negatively associated with total fat (), and IGF-1 were positively associated with abdominal () and leg lean (). In conclusion, the lowered anabolic hormones are involved in body composition rearrangement in men with PD. Further studies are needed to establish whether the androgen replacement therapy would be beneficial in men with PD. Michał Rabijewski, Lucyna Papierska, and Paweł Piątkiewicz Copyright © 2016 Michał Rabijewski et al. All rights reserved. Modeling and Measurement of Correlation between Blood and Interstitial Glucose Changes Wed, 27 Apr 2016 11:27:39 +0000 One of the most effective methods for continuous blood glucose monitoring is to continuously measure glucose in the interstitial fluid (ISF). However, multiple physiological factors can modulate glucose concentrations and affect the lag phase between blood and ISF glucose changes. This study aims to develop a compensatory tool for measuring the delay in ISF glucose variations in reference to blood glucose changes. A theoretical model was developed based on biophysics and physiology of glucose transport in the microcirculation system. Blood and interstitial fluid glucose changes were measured in mice and rats by fluorescent and isotope methods, respectively. Computer simulation mimicked curves were fitted with data resulting from fluorescent measurements of mice and isotope measurements of rats, indicating that there were lag times for ISF glucose changes. It also showed that there was a required diffusion distance for glucose to travel from center of capillaries to interstitial space in both mouse and rat models. We conclude that it is feasible with the developed model to continuously monitor dynamic changes of blood glucose concentration through measuring glucose changes in ISF with high accuracy, which requires correct parameters for determining and compensating for the delay time of glucose changes in ISF. Ting Shi, Dachao Li, Guoqing Li, Yiming Zhang, Kexin Xu, and Luo Lu Copyright © 2016 Ting Shi et al. All rights reserved. Influence of Age at Diagnosis and Time-Dependent Risk Factors on the Development of Diabetic Retinopathy in Patients with Type 1 Diabetes Tue, 26 Apr 2016 17:33:38 +0000 Aim. To determine the influence of age at onset of type 1 diabetes and of traditional vascular risk factors on the development of diabetic retinopathy, in a cohort of patients who have been followed up after onset. Methods. Observational, retrospective study. The cohort consists of 989 patients who were followed up after diagnosis for a mean of 10.1 (SD: 6.8) years. The influence of age at diagnosis, glycemic control, duration of diabetes, sex, blood pressure, lipids, BMI, and smoking is analyzed using Cox univariate and multivariate models with fixed and time-dependent variables. Results. 135 patients (13.7%) developed diabetic retinopathy. The cumulative incidence was 0.7, 5.9, and 21.8% at 5-, 10-, and 15-year follow-up, respectively. Compared to the group with onset at age <10 years, the risk of retinopathy increased 2.5-, 3-, 3.3-, and 3.7-fold in the groups with onset at 10–14, 15–29, 30–44, and >44 years, respectively. During follow-up we also observed an association between diabetic retinopathy and HbA1c levels, HDL-cholesterol, and diastolic blood pressure. Conclusion. The rate of diabetic retinopathy is higher in patients who were older at type 1 diabetes diagnosis. In addition, we confirmed the influence of glycemic control, HDL-cholesterol, and diastolic blood pressure on the occurrence of retinopathy. Luis Forga, María José Goñi, Berta Ibáñez, Koldo Cambra, Marta García-Mouriz, and Ana Iriarte Copyright © 2016 Luis Forga et al. All rights reserved. Increased Mortality in Diabetic Foot Ulcer Patients: The Significance of Ulcer Type Sun, 24 Apr 2016 12:48:49 +0000 Diabetic foot ulcer (DFU) patients have a greater than twofold increase in mortality compared with nonulcerated diabetic patients. We investigated (a) cause of death in DFU patients, (b) age at death, and (c) relationship between cause of death and ulcer type. This was an eleven-year retrospective study on DFU patients who attended King’s College Hospital Foot Clinic and subsequently died. A control group of nonulcerated diabetic patients was matched for age and type of diabetes mellitus. The cause of death was identified from death certificates (DC) and postmortem (PM) examinations. There were 243 DFU patient deaths during this period. Ischaemic heart disease (IHD) was the major cause of death in 62.5% on PM compared to 45.7% on DC. Mean age at death from IHD on PM was 5 years lower in DFU patients compared to controls (68.2 ± 8.7 years versus 73.1 ± 8.0 years, ). IHD as a cause of death at PM was significantly linked to neuropathic foot ulcers (OR 3.064, 95% CI 1.003–9.366, and ). Conclusions. IHD is the major cause of premature mortality in DFU patients with the neuropathic foot ulcer patients being at a greater risk. N. K. Chammas, R. L. R. Hill, and M. E. Edmonds Copyright © 2016 N. K. Chammas et al. All rights reserved. Lower Hemoglobin Concentration Is Associated with Retinal Ischemia and the Severity of Diabetic Retinopathy in Type 2 Diabetes Wed, 20 Apr 2016 13:00:03 +0000 Aims. To assess the association of blood oxygen-transport capacity variables with the prevalence of diabetic retinopathy (DR), retinal ischemia, and macular oedema in patients with type 2 diabetes mellitus (T2DM). Methods. Cross-sectional, case-control study () with T2DM: 153 individuals with DR and 159 individuals with no DR. Participants were classified according to the severity of DR and the presence of retinal ischemia or macular oedema. Hematological variables were collected by standardized methods. Three logistic models were adjusted to ascertain the association between hematologic variables with the severity of DR and the presence of retinal ischemia or macular oedema. Results. Individuals with severe DR showed significantly lower hemoglobin, hematocrit, and erythrocyte levels compared with those with mild disease and in individuals with retinal ischemia and macular oedema compared with those without these disorders. Hemoglobin was the only factor that showed a significant inverse association with the severity of DR [beta-coefficient = −0.52,  value = 0.003] and retinal ischemia [beta-coefficient = −0.49,  value = 0.001]. Lower erythrocyte level showed a marginally significant association with macular oedema [beta-coefficient = −0.86,  value = 0.055]. Conclusions. In patients with DR, low blood oxygen-transport capacity was associated with more severe DR and the presence of retinal ischemia. Low hemoglobin levels may have a key role in the development and progression of DR. Alicia Traveset, Esther Rubinat, Emilio Ortega, Nuria Alcubierre, Beatriz Vazquez, Marta Hernández, Carmen Jurjo, Ramon Espinet, Juan Antonio Ezpeleta, and Didac Mauricio Copyright © 2016 Alicia Traveset et al. All rights reserved. Variations in the Obesity Gene “LEPR” Contribute to Risk of Type 2 Diabetes Mellitus: Evidence from a Meta-Analysis Mon, 18 Apr 2016 14:21:17 +0000 Leptin is a hormone protein regulating food intake and energy expenditure. A number of studies have evaluated the genetic effect of leptin (LEP) and leptin receptor (LEPR) genes on T2DM. This study aimed to investigate the association between these gene polymorphisms and T2DM by a systematic review and meta-analysis. Published studies were identified through extensive search in PubMed and EMBASE. A total of 5143 T2DM cases and 5021 controls from 14 articles were included in this study. Five functional variants in LEPR were well evaluated. Meta-analysis showed that rs1137101 (p.R223Q) was significantly associated with T2DM in all genetic models: allele model (OR = 1.27, 95% confidence interval (CI) = 1.13–1.42), dominant model (OR = 1.19, 95% CI = 1.05–1.35), homozygote model (OR = 1.82, 95% CI = 1.38–2.39), and recessive model (OR = 1.75, 95% CI = 1.35–2.28), with minimal heterogeneity and no indication of publication bias. Similar associations with T2DM were also found for rs62589000 (p.P1019P) and 3′UTR ins/del, although the data was obtained from a small number of studies. For the other two polymorphisms rs1137100 (p.R109K) and rs8179183 (p.K656N), they were not significantly associated with T2DM. Our results provide robust evidences for the genetic association of rs1137101 (p.R223Q) in LEPR with T2DM susceptibility. Ming Ming Yang, Jun Wang, Jiao Jie Fan, Tsz Kin Ng, Dian Jun Sun, Xin Guo, Yan Teng, and Yan-Bo Li Copyright © 2016 Ming Ming Yang et al. All rights reserved. Collagen V Is a Potential Substrate for Clostridial Collagenase G in Pancreatic Islet Isolation Mon, 18 Apr 2016 12:12:18 +0000 The clostridial collagenases, H and G, play key roles in pancreatic islet isolation. Collagenases digest the peptide bond between Yaa and the subsequent Gly in Gly-Xaa-Yaa repeats. To fully understand the pancreatic islet isolation process, identification of the collagenase substrates in the tissue is very important. Although collagen types I and III were reported as possible substrates for collagenase H, the substrate for collagenase G remains unknown. In this study, collagen type V was focused upon as the target for collagenases. In vitro digestion experiments for collagen type V were performed and analyzed by SDS-PAGE and mass spectrometry. Porcine pancreatic tissues were digested in vitro under three conditions and observed during digestion. The results revealed that collagen type V was only digested by collagenase G and that the digestion was initiated from the N-terminal part. Tissue degradation during porcine islet isolation was only observed in the presence of both collagenases H and G. These findings suggest that collagen type V is one of the substrates for collagenase G. The enzymatic activity of collagenase G appears to be more important for pancreatic islet isolation in large mammals such as pigs and humans. Hiroki Shima, Akiko Inagaki, Takehiro Imura, Youhei Yamagata, Kimiko Watanabe, Kazuhiko Igarashi, Masafumi Goto, and Kazutaka Murayama Copyright © 2016 Hiroki Shima et al. All rights reserved. Heart Rate Variability as Early Biomarker for the Evaluation of Diabetes Mellitus Progress Thu, 14 Apr 2016 13:20:44 +0000 According to the American Diabetes Association (ADA), the side effects of diabetes mellitus have recently increased the global health expenditure each year. Of these, the early diagnostic can contribute to the decrease on renal, cardiovascular, and nervous systems complications. However, the diagnostic criteria, which are commonly used, do not suggest the diabetes progress in the patient. In this study, the streptozotocin model in mice (cDM) was used as early diagnostic criterion to reduce the side effects related to the illness. The results showed some clinical signs similarly to five-year diabetes progress without renal injury, neuropathies, and cardiac neuropathy autonomic in the cDM-model. On the other hand, the electrocardiogram was used to determine alterations in heart rate and heart rate variability (HRV), using the Poincaré plot to quantify the HRV decrease in the cDM-model. Additionally, the SD1/SD2 ratio and ventricular arrhythmias showed increase without side effects of diabetes. Therefore, the use of HRV as an early biomarker contributes to evaluating diabetes mellitus complications from the diagnostic. Rosa Elena Arroyo-Carmona, Ana Laura López-Serrano, Alondra Albarado-Ibañez, Francisca María Fabiola Mendoza-Lucero, David Medel-Cajica, Ruth Mery López-Mayorga, and Julián Torres-Jácome Copyright © 2016 Rosa Elena Arroyo-Carmona et al. All rights reserved. Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy Wed, 13 Apr 2016 10:27:40 +0000 Prostaglandin E2 (PGE2) is an endogenous lipid mediator, produced from the metabolism of arachidonic acids, upon the sequential actions of phospholipase A2, cyclooxygenases, and prostaglandin E synthases. The various biological functions governed by PGE2 are mediated through its four distinct prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4, among which the EP4 receptor is the one most widely distributed in the heart. The availability of global or cardiac-specific EP4 knockout mice and the development of selective EP4 agonists/antagonists have provided substantial evidence to support the role of EP4 receptor in the heart. However, like any good drama, activation of PGE2-EP4 signaling exerts both protective and detrimental effects in the ischemic heart disease. Thus, the primary object of this review is to provide a comprehensive overview of the current progress of the PGE2-EP4 signaling in ischemic heart diseases, including cardiac hypertrophy and myocardial ischemia/reperfusion injury. A better understanding of PGE2-EP4 signaling should promote the development of more effective therapeutic approaches to treat the ischemic heart diseases without triggering unwanted side effects. Lei Pang, Yin Cai, Eva Hoi Ching Tang, Michael G. Irwin, Haichun Ma, and Zhengyuan Xia Copyright © 2016 Lei Pang et al. All rights reserved. A Novel Chemically Modified Curcumin “Normalizes” Wound-Healing in Rats with Experimentally Induced Type I Diabetes: Initial Studies Wed, 13 Apr 2016 07:57:04 +0000 Introduction. Impaired wound-healing in diabetics can lead to life-threatening complications, such as limb amputation, associated in part with excessive matrix metalloproteinase- (MMP-) mediated degradation of collagen and other matrix constituents. In the current study, a novel triketonic chemically modified curcumin, CMC2.24, was tested for efficacy in healing of standardized skin wounds in streptozotocin-induced diabetic rats. Initially, CMC2.24 was daily applied topically at 1% or 3% concentrations or administered systemically (oral intubation; 30 mg/kg); controls received vehicle treatment only. Over 7 days, the diabetics exhibited impaired wound closure, assessed by gross and histologic measurements, compared to the nondiabetic controls. All drug treatments significantly improved wound closure with efficacy ratings as follows: 1% 2.24 > systemic 2.24 > 3% 2.24 with no effect on the severe hyperglycemia. In subsequent experiments, 1% CMC2.24 “normalized” wound-healing in the diabetics, whereas 1% curcumin was no more effective than 0.25% CMC2.24, and the latter remained 34% worse than normal. MMP-8 was increased 10-fold in the diabetic wounds and topically applied 1% (but not 0.25%) CMC2.24 significantly reduced this excessive collagenase-2; MMP-13/collagenase-3 did not show significant changes. Additional studies indicated efficacy of 1% CMC2.24 over more prolonged periods of time up to 30 days. Yazhou Zhang, Steve A. McClain, Hsi-Ming Lee, Muna S. Elburki, Huiwen Yu, Ying Gu, Yu Zhang, Mark Wolff, Francis Johnson, and Lorne M. Golub Copyright © 2016 Yazhou Zhang et al. All rights reserved. Fiber in Diet Is Associated with Improvement of Glycated Hemoglobin and Lipid Profile in Mexican Patients with Type 2 Diabetes Sun, 10 Apr 2016 08:22:01 +0000 Objective. To assess the association of dietary fiber on current everyday diet and other dietary components with glycated hemoglobin levels (HbA1c), glucose, lipids profile, and body weight body weight, in patients with type 2 diabetes. Methods. A cross-sectional survey of 395 patients with type 2 diabetes was performed. HbA1c, fasting glucose, triglycerides, and lipids profile were measured. Weight, waist circumference, blood pressure, and body composition were measured. Everyday diet with a semiquantitative food frequency questionnaire was evaluated. ANOVA, Kruskal-Wallis, chi-square tests and multivariate logistic regression were used in statistical analysis. Results. Higher fiber intake was associated with a low HbA1c, high HDL-c levels, low weight, and waist circumference. The highest tertile of calories consumption was associated with a higher fasting glucose level and weight. The highest tertile of carbohydrate consumption was associated with a lower weight. The lowest tertile of total fat and saturated fat was associated with the highest tertile of HDL-c levels, and lower saturated fat intake was associated with lower weight . Conclusions. A higher content of fiber in the diet reduces HbA1c and triglycerides, while improving HDL-c levels. Increasing fiber consumption while lowering calorie consumption seems to be an appropriate strategy to reduce body weight and promote blood glucose control. Lubia Velázquez-López, Abril Violeta Muñoz-Torres, Carmen García-Peña, Mardia López-Alarcón, Sergio Islas-Andrade, and Jorge Escobedo-de la Peña Copyright © 2016 Lubia Velázquez-López et al. All rights reserved. Impaired Thermogenesis and a Molecular Signature for Brown Adipose Tissue in Id2 Null Mice Sun, 10 Apr 2016 06:29:20 +0000 Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our previous studies have demonstrated that Id2 null mice have sex-specific elevated glucose uptake in brown adipose tissue (BAT). Here we further explored the role of Id2 in the regulation of core body temperature over the circadian cycle and the impact of Id2 deficiency on genes involved in insulin signaling and adipogenesis in BAT. We discovered a reduced core body temperature in Id2−/− mice. Moreover, in Id2−/− BAT, 30 genes including Irs1, PPARs, and PGC-1s were identified as differentially expressed in a sex-specific pattern. These data provide valuable insights into the impact of Id2 deficiency on energy homeostasis of mice in a sex-specific manner. Peng Zhou, Maricela Robles-Murguia, Deepa Mathew, and Giles E. Duffield Copyright © 2016 Peng Zhou et al. All rights reserved. Central Administration of Galanin Receptor 1 Agonist Boosted Insulin Sensitivity in Adipose Cells of Diabetic Rats Tue, 05 Apr 2016 09:50:00 +0000 Our previous studies testified the beneficial effect of central galanin on insulin sensitivity of type 2 diabetic rats. The aim of the study was further to investigate whether central M617, a galanin receptor 1 agonist, can benefit insulin sensitivity. The effects of intracerebroventricular administration of M617 on insulin sensitivity and insulin signaling were evaluated in adipose tissues of type 2 diabetic rats. The results showed that central injection of M617 significantly increased plasma adiponectin contents, glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, GLUT4 mRNA expression levels, GLUT4 contents in plasma membranes, and total cell membranes of the adipose cells but reduced the plasma C-reactive protein concentration in nondiabetic and diabetic rats. The ratios of GLUT4 contents were higher in plasma membranes to total cell membranes in both nondiabetic and diabetic M617 groups than each control. In addition, the central administration of M617 enhanced the ratios of pAkt/Akt and pAS160/AS160, but not phosphorylative cAMP response element-binding protein (pCREB)/CREB in the adipose cells of nondiabetic and diabetic rats. These results suggest that excitation of central galanin receptor 1 facilitates insulin sensitivity via activation of the Akt/AS160 signaling pathway in the fat cells of type 2 diabetic rats. Zhenwen Zhang, Penghua Fang, Biao He, Lili Guo, Johan Runesson, Ülo Langel, Mingyi Shi, Yan Zhu, and Ping Bo Copyright © 2016 Zhenwen Zhang et al. All rights reserved. Anti-Thyroid Peroxidase Antibodies and Male Gender Are Associated with Diabetes Occurrence in Patients with Beta-Thalassemia Major Thu, 31 Mar 2016 17:24:17 +0000 Background. Intensive transfusion schedule and iron-chelating therapy prolonged and improved quality of life in patients with β-thalassemia (β-T) major. However, this led to an increased risk of developing impaired glucose tolerance or diabetes. In this study we analyzed variables associated with the occurrence of impaired glucose tolerance or diabetes in patients with β-T major. Methods. 388 Sardinian patients were included. Age, gender, duration of chelation therapy, body mass index, and markers of pancreatic and extrapancreatic autoimmunity were analyzed. Results. Multiple logistic regression analysis showed that anti-thyroid peroxidase (TPO) antibodies (Ab) (OR = 3.36; ) and male gender (OR = 1.98; ) were significantly associated with glucose impairment, while the other variables were not. Ferritin levels were significantly higher in TPOAb positive compared to TPOAb negative patients (4870 ± 1665 μg/L versus 2922 ± 2773 μg/L; ). Conclusions. In patients with β-T major a progressive damage of insulin-producing cells due to secondary hemosiderosis appears to be the most reasonable mechanism associated with glucose metabolism disorders. The findings need to be confirmed with additional well designed studies to address the question of whether TPOAb may have a role in the management of these patients. Giovanni M. Pes, Francesco Tolu, and Maria P. Dore Copyright © 2016 Giovanni M. Pes et al. All rights reserved. Calpain-Calcineurin-Nuclear Factor Signaling and the Development of Atrial Fibrillation in Patients with Valvular Heart Disease and Diabetes Thu, 31 Mar 2016 09:50:24 +0000 Calpain, calcineurin (CaN), and nuclear factor of activated T cell (NFAT) play a key role in the development of atrial fibrillation. Patients with valvular heart disease (VHD) are prone to develop atrial fibrillation (AF). Thus, our current study was aimed at investigating whether activation of calpain-CaN-NFAT pathway is associated with the incidence of AF in the patients with VHD and diabetes. The expressions of calpain 2 and alpha- and beta-isoforms of CaN catalytic subunit (CnA) as well as NFAT-c3 and NFAT-c4 were quantified by quantitative reverse transcription-polymerase chain reaction in atrial tissues from 77 hospitalized patients with VHD and diabetes. The relevant protein content was measured by Western blot and calpain 2 in human atrium was localized by immunohistochemistry. We found that the expressions of calpain 2, CnA alpha and CnA beta, and NFAT-c3 but not NFAT-c4 were significantly elevated in the samples from patients with AF compared to those with sinus rhythm (SR). Elevated protein levels of calpain 2 and CnA were observed in patients with AF, and so was the enhanced localization of calpain 2. We thereby concluded that CaN together with its upstream molecule, calpain 2, and its downstream effector, NFAT-c3, might contribute to the development of AF in patients with VHD and diabetes. Yong Zhao, Guo-ming Cui, Nan-nan Zhou, Cong Li, Qing Zhang, Hui Sun, Bo Han, Cheng-wei Zou, Li-juan Wang, Xiao-dong Li, and Jian-chun Wang Copyright © 2016 Yong Zhao et al. All rights reserved.