Journal of Diabetes Research The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Oxidative Stress, Epigenetics, Environment, and Epidemiology of Diabetic Retinopathy Wed, 22 Feb 2017 10:09:51 +0000 Goran Petrovski, Kai Kaarniranta, and Daniel Petrovič Copyright © 2017 Goran Petrovski et al. All rights reserved. Classification and Differential Diagnosis of Diabetic Nephropathy Mon, 20 Feb 2017 00:00:00 +0000 Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world in both developed and developing countries. This review briefly introduces the characteristic pathological changes of DN and Tervaert pathological classification, which divides DN into four classifications according to glomerular lesions, along with a separate scoring system for tubular, interstitial, and vascular lesions. Given the heterogeneity of the renal lesions and the complex mechanism underlying diabetic nephropathy, Tervaert classification has both significance and controversies in the guidance of diagnosis and prognosis. Applications and evaluations using Tervaert classification and indications for renal biopsy are summarized in this review according to recent studies. Meanwhile, differential diagnosis with another nodular glomerulopathy and the situation that a typical DN superimposed with a nondiabetic renal disease (NDRD) are discussed and concluded in this review. Chenyang Qi, Xing Mao, Zhigang Zhang, and Huijuan Wu Copyright © 2017 Chenyang Qi et al. All rights reserved. Relationship between Immunological Abnormalities in Rat Models of Diabetes Mellitus and the Amplification Circuits for Diabetes Sun, 19 Feb 2017 07:14:41 +0000 A better understanding of pathogenic mechanisms is required in order to treat diseases. However, the mechanisms of diabetes mellitus and diabetic complications are extremely complex. Immune reactions are involved in the pathogenesis of diabetes and its complications, while diabetes influences immune reactions. Furthermore, both diabetes and immune reactions are influenced by genetic and environmental factors. To address these issues, animal models are useful tools. So far, various animal models of diabetes have been developed in rats, which have advantages over mice models in terms of the larger volume of tissue samples and the variety of type 2 diabetes models. In this review, we introduce rat models of diabetes and summarize the immune reactions in diabetic rat models. Finally, we speculate on the relationship between immune reactions and diabetic episodes. For example, diabetes-prone Biobreeding rats, type 1 diabetes model rats, exhibit increased autoreactive cellular and inflammatory immune reactions, while Goto-Kakizaki rats, type 2 diabetes model rats, exhibit increased Th2 reactions and attenuation of phagocytic activity. Investigation of immunological abnormalities in various diabetic rat models is useful for elucidating complicated mechanisms in the pathophysiology of diabetes. Studying immunological alterations, such as predominance of Th1/17 or Th2 cells, humoral immunity, and innate immune reactions, may improve understanding the structure of amplification circuits for diabetes in future studies. Yuji Takeda, Tomoko Shimomura, Hironobu Asao, and Ichiro Wakabayashi Copyright © 2017 Yuji Takeda et al. All rights reserved. Hepatic Cholesterol-25-Hydroxylase Overexpression Improves Systemic Insulin Sensitivity in Mice Sun, 19 Feb 2017 00:00:00 +0000 Obesity is a major risk factor for several diseases including diabetes, heart disease, and some forms of cancer and due to its rapidly increasing prevalence it has become one of the biggest problems medicine is facing today. All the more surprising, a substantial percentage of obese patients are metabolically healthy when classified based on insulin resistance and systemic inflammation. Oxysterols are naturally occurring molecules that play important role in various metabolic and inflammatory processes and their levels are elevated in patients suffering from obesity and diabetes. 25-Hydroxycholesterol (25-OHC) is produced in cells from cholesterol by the enzyme cholesterol 25-hydroxylase (Ch25h) and is involved in lipid metabolism, inflammatory processes, and cell proliferation. Here, we investigated the role of hepatic Ch25h in the transition from metabolically healthy obesity to insulin resistance and diabetes. Using several different experimental approaches, we demonstrated the significance of Ch25h on the border of “healthy” and “diseased” states of obesity. Adenovirus-mediated Ch25h overexpression in mice improved glucose tolerance and insulin sensitivity and lowered HOMA-IR. Our data suggest that low hepatic Ch25h levels could be considered a risk marker for unhealthy obesity. Britta Noebauer, Alexander Jais, Jelena Todoric, Klaus Gossens, Hedwig Sutterlüty-Fall, and Elisa Einwallner Copyright © 2017 Britta Noebauer et al. All rights reserved. Neutrophils Infiltrate the Spinal Cord Parenchyma of Rats with Experimental Diabetic Neuropathy Wed, 15 Feb 2017 09:27:28 +0000 Spinal glial cell activation and cytokine secretion have been implicated in the etiology of neuropathic pain in a number of experimental models, including diabetic neuropathy. In this study, streptozotocin- (STZ-) induced diabetic rats were either untreated or treated with gabapentin (50 mg/kg/day by gavage for 2 weeks, from 6 weeks after STZ). At 8 weeks after STZ, hypersensitivity was confirmed in the untreated diabetic rats as a reduced response threshold to touch, whilst mechanical thresholds in gabapentin-treated diabetic rats were no different from controls. Diabetes-associated thermal hypersensitivity was also ameliorated by gabapentin. We performed a cytokine profiling array in lumbar spinal cord samples from control and diabetic rats. This revealed an increase in L-selectin, an adhesion molecule important for neutrophil transmigration, in the spinal cord of diabetic rats but not diabetic rats treated with gabapentin. Furthermore, we found an increase in the number of neutrophils present in the parenchyma of the spinal cord, which was again ameliorated in gabapentin-treated diabetic rats. Therefore, we suggest that dysregulated spinal L-selectin and neutrophil infiltration into the spinal cord could contribute to the pathogenesis of painful diabetic neuropathy. Victoria L. Newton, Jonathan D. Guck, Mary A. Cotter, Norman E. Cameron, and Natalie J. Gardiner Copyright © 2017 Victoria L. Newton et al. All rights reserved. Effect of Human Myotubes-Derived Media on Glucose-Stimulated Insulin Secretion Tue, 14 Feb 2017 13:35:37 +0000 Fasting to postprandial transition requires a tight adjustment of insulin secretion to its demand, so tissue (e.g., skeletal muscle) glucose supply is assured while hypo-/hyperglycemia are prevented. High muscle glucose disposal after meals is pivotal for adapting to increased glycemia and might drive insulin secretion through muscle-released factors (e.g., myokines). We hypothesized that insulin influences myokine secretion and then increases glucose-stimulated insulin secretion (GSIS). In conditioned media from human myotubes incubated with/without insulin (100 nmol/L) for 24 h, myokines were qualitatively and quantitatively characterized using an antibody-based array and ELISA-based technology, respectively. C57BL6/J mice islets and Wistar rat beta cells were incubated for 24 h with control and conditioned media from noninsulin- and insulin-treated myotubes prior to GSIS determination. Conditioned media from insulin-treated versus nontreated myotubes had higher RANTES but lower IL6, IL8, and MCP1 concentration. Qualitative analyses revealed that conditioned media from noninsulin- and insulin-treated myotubes expressed 32 and 23 out of 80 myokines, respectively. Islets incubated with conditioned media from noninsulin-treated myotubes had higher GSIS versus control islets . Meanwhile, conditioned media from insulin-treated myotubes did not influence GSIS. In beta cells, GSIS was similar across conditions. In conclusion, factors being present in noninsulin-stimulated muscle cell-derived media appear to influence GSIS in mice islets. Maria L. Mizgier, Luis R. Cataldo, Juan Gutierrez, José L. Santos, Mariana Casas, Paola Llanos, Ariel E. Contreras-Ferrat, Cedric Moro, Karim Bouzakri, and Jose E. Galgani Copyright © 2017 Maria L. Mizgier et al. All rights reserved. Adipokines: Potential Therapeutic Targets for Vascular Dysfunction in Type II Diabetes Mellitus and Obesity Mon, 13 Feb 2017 00:00:00 +0000 Adipokines are bioactive molecules that regulate several physiological functions such as energy balance, insulin sensitization, appetite regulation, inflammatory response, and vascular homeostasis. They include proinflammatory cytokines such as adipocyte fatty acid binding protein (A-FABP) and anti-inflammatory cytokines such as adiponectin, as well as vasodilator and vasoconstrictor molecules. In obesity and type II diabetes mellitus (DM), insulin resistance causes impairment of the endocrine function of the perivascular adipose tissue, an imbalance in the secretion of vasoconstrictor and vasodilator molecules, and an increased production of reactive oxygen species. Recent studies have shown that targeting plasma levels of adipokines or the expression of their receptors can increase insulin sensitivity, improve vascular function, and reduce the risk of cardiovascular morbidity and mortality. Several reviews have discussed the potential of adipokines as therapeutic targets for type II DM and obesity; however, this review is the first to focus on their therapeutic potential for vascular dysfunction in type II DM and obesity. Mostafa Wanees Ahmed El husseny, Mediana Mamdouh, Sara Shaban, Abdelrahman Ibrahim Abushouk, Marwa Mostafa Mohamed Zaki, Osama M. Ahmed, and Mohamed M. Abdel-Daim Copyright © 2017 Mostafa Wanees Ahmed El husseny et al. All rights reserved. Prognostic Relevance and Function of MSX2 in Colorectal Cancer Sun, 12 Feb 2017 00:00:00 +0000 Colorectal cancer patients with diabetes had the high risks of total mortality. High expression of MSX2 is related to development of diabetes. There are few reports about the clinical implications and function of MSX2 in colorectal cancer (CRC). The purpose of this study is to investigate the relationship between the expression of MSX2 and clinical relevance and discover the possible mechanism of MSX2 in the development of CRC. Compared with adjacent tissues, the expression of MSX2 was higher in tumor tissues in both mRNA and protein levels (). Kaplan-Meier survival analysis showed that high mRNA expression of MSX2 was associated with short survival time (). Chi-squared test analysis indicated that MSX2 expression was related to tumor size (), tumor locus (), clinical stage (), tumor invasion (), lymphatic metastasis (), and distant metastasis (). In vitro experiments demonstrated that knockdown of MSX2 expression attenuated cell proliferation and invasion, promoted cell cycle arrest and apoptosis, and inactivated Akt phosphorylation. In conclusion, MSX2 played a crucial role in the progression of CRC and may be a potential novel prognostic factor and therapeutic target for CRC therapy. Our work may provide certain enlightenment for investigating the mechanism of MSX2 in the process of diabetes. Jiancheng Liu, Huaying An, Wei Yuan, Qiang Feng, Lianzhen Chen, and Jie Ma Copyright © 2017 Jiancheng Liu et al. All rights reserved. Medication Adherence Mediates the Association between Type D Personality and High HbA1c Level in Chinese Patients with Type 2 Diabetes Mellitus: A Six-Month Follow-Up Study Thu, 09 Feb 2017 09:02:59 +0000 Aims. To examine the association between Type D personality and HbA1c level and to explore the mediating role of medication adherence between them in patients with type 2 diabetes mellitus (T2DM). Methods. 330 patients went on to complete a self-report measure of medication adherence and the HbA1c tests. Chi-square test, test, Ordinary Least Square Regression (OLS), and Recentered Influence Function Regression (RIF) were employed. Results. Patients with Type D personality had significantly higher HbA1c value (). When Type D personality was operationalized as a categorical variable, SI was associated with HbA1c (). When NA, SI, and their interaction term were entered into regression, all of them were no longer associated with HbA1c level (). On the other hand, when Type D personality was operationalized as a continuous variable, only SI trait was associated with HbA1c level (). When NA, SI, and term together were entered into regression, only SI was not related to HbA1c level. Furthermore, medication adherence had a significant mediation effect between Type D personality and HbA1c, accounting for 54.43% of the total effect. Conclusion. Type D personality was associated with HbA1c in direct and indirect ways, and medication adherence acted as a mediator role. Xuemei Li, Min Gao, Shengfa Zhang, Huiwen Xu, Huixuan Zhou, Xiaohua Wang, Zhiyong Qu, Jing Guo, Weijun Zhang, and Donghua Tian Copyright © 2017 Xuemei Li et al. All rights reserved. Electrochemical Skin Conductance May Be Used to Screen for Diabetic Cardiac Autonomic Neuropathy in a Chinese Population with Diabetes Thu, 09 Feb 2017 00:00:00 +0000 Aims. This study aimed to assess whether the electrochemical skin conductance (ESC) could be used to screen for diabetic cardiac autonomic neuropathy (DCAN) in a Chinese population with diabetes. Methods. We recruited 75 patients with type 2 diabetes mellitus (T2DM) and 45 controls without diabetes. DCAN was diagnosed by the cardiovascular autonomic reflex tests (CARTs) as gold standard. In all subjects ESCs of hands and feet were also detected by SUDOSCAN™ as a new screening method. The efficacy was assessed by receiver operating characteristic (ROC) curve analysis. Results. The ESCs of both hands and feet were significantly lower in T2DM patients with DCAN than those without DCAN ( versus , , and versus , ). The ROC curve analysis showed the areas under the ROC curve were both 0.75 for ESCs of hands and feet in screening DCAN. And the optimal cut-off values of ESCs, sensitivities, and specificities were 76 μS, 76.7%, and 75.6% for hands and 75 μS, 80.0%, and 60.0% for feet, respectively. Conclusions. ESC measurement is a reliable and feasible method to screen DCAN in the Chinese population with diabetes before further diagnosis with CARTs. Tianyi He, Chuan Wang, Anju Zuo, Pan Liu, Ruxing Zhao, Wenjuan Li, Li Chen, and Xinguo Hou Copyright © 2017 Tianyi He et al. All rights reserved. Continuous Glucose Monitoring in Newly Diagnosed Type 2 Diabetes Patients Reveals a Potential Risk of Hypoglycemia in Older Men Wed, 08 Feb 2017 12:38:07 +0000 Objectives. We performed continuous glucose monitoring (CGM) to define the features of patients with newly diagnosed type 2 diabetes (T2D) before and after Continuous Subcutaneous Insulin Infusion (CSII) therapy. Methods. This was a retrospective analysis. Newly diagnosed T2D patients (106) were admitted from eight centers in China. They were divided into a younger patient group (<60 years) and an older patient group (≥60 years). Each group was further divided into male and female patients. CSII therapy was maintained for 3 weeks after the glycemic target was reached. CGM was performed 2 times before and after completion of insulin treatment. Results. CGM data showed the expected significant improvement of mean amplitude glycemic excursion (MAGE) with CSII therapy. The older patients had lower hourly glucose concentrations from 0200 to 0700 o’clock compared to the younger patients at baseline. Surprisingly, in the older patient group, the male patients had a potential risk of hypoglycemia after CSII therapy, especially during periods from 2300 to 2400 and 0400 to 0600. Conclusions. Our data suggested that older male patients with newly diagnosed T2D may have lower nocturnal glucose concentrations. This may potentially increase the risk of nocturnal hypoglycemia during CSII therapy. This study was registered with Chinese Clinical Trial Registry, number CliCTR-TRC-11001218. Feng-fei Li, Bing-li Liu, Hong-hong Zhu, Ting Li, Wen-li Zhang, Xiao-fei Su, Jin-dan Wu, Xue-qin Wang, Ning Xu, Wei-Nan Yu, Qun Yuan, Guan-cheng Qi, Lei Ye, Kok-Onn Lee, and Jian-hua Ma Copyright © 2017 Feng-fei Li et al. All rights reserved. Glycemic Excursions in Type 1 Diabetes in Pregnancy: A Semiparametric Statistical Approach to Identify Sensitive Time Points during Gestation Wed, 08 Feb 2017 00:00:00 +0000 Aim. To examine the gestational glycemic profile and identify specific times during pregnancy that variability in glucose levels, measured by change in velocity and acceleration/deceleration of blood glucose fluctuations, is associated with delivery of a large-for-gestational-age (LGA) baby, in women with type 1 diabetes. Methods. Retrospective analysis of capillary blood glucose levels measured multiple times daily throughout gestation in women with type 1 diabetes was performed using semiparametric mixed models. Results. Velocity and acceleration/deceleration in glucose levels varied across gestation regardless of delivery outcome. Compared to women delivering LGA babies, those delivering babies appropriate for gestational age exhibited significantly smaller rates of change and less variation in glucose levels between 180 days of gestation and birth. Conclusions. Use of innovative statistical methods enabled detection of gestational intervals in which blood glucose fluctuation parameters might influence the likelihood of delivering LGA baby in mothers with type 1 diabetes. Understanding dynamics and being able to visualize gestational changes in blood glucose are a potentially useful tool to assist care providers in determining the optimal timing to initiate continuous glucose monitoring. Resmi Gupta, Jane Khoury, Mekibib Altaye, Lawrence Dolan, and Rhonda D. Szczesniak Copyright © 2017 Resmi Gupta et al. All rights reserved. Metformin Improves Overall Survival of Colorectal Cancer Patients with Diabetes: A Meta-Analysis Wed, 08 Feb 2017 00:00:00 +0000 Introduction. Diabetic population has a higher risk of colorectal cancer (CRC) incidence and mortality than nondiabetics. The role of metformin in CRC prognosis is still controversial. The meta-analysis aims to investigate whether metformin improves the survival of diabetic CRC patients. Methods. PubMed, EMBASE, and Cochrane Library were searched till July 1, 2016. Cohort studies were included. All articles were evaluated by Newcastle-Ottawa Scale. Hazard Ratios (HRs) with 95% confidence intervals (CIs) for each study were calculated and pooled HRs with corresponding 95% CIs were generated using the random-effects model. Heterogeneity and publication bias were assessed. Results. We included seven cohort studies with a medium heterogeneity ( = 56.1% and ) in our meta-analysis. An improved overall survival (OS) for metformin users over nonusers among colorectal cancers with diabetes was noted (HR 0.75; 95% CI 0.65 to 0.87). However, metformin reveals no benefits for cancer-specific survival (HR 0.79, 95%, CI 0.58 to 1.08). Conclusions. Metformin prolongs the OS of diabetic CRC patients, but it does not affect the CRC-specific survival. Metformin may be a good choice in treating CRC patients with diabetes mellitus in clinical settings. Fanqiang Meng, Li Song, and Wenyue Wang Copyright © 2017 Fanqiang Meng et al. All rights reserved. The Next Frontier in Communication and the ECLIPPSE Study: Bridging the Linguistic Divide in Secure Messaging Tue, 07 Feb 2017 08:32:58 +0000 Health systems are heavily promoting patient portals. However, limited health literacy (HL) can restrict online communication via secure messaging (SM) because patients’ literacy skills must be sufficient to convey and comprehend content while clinicians must encourage and elicit communication from patients and match patients’ literacy level. This paper describes the Employing Computational Linguistics to Improve Patient-Provider Secure Email (ECLIPPSE) study, an interdisciplinary effort bringing together scientists in communication, computational linguistics, and health services to employ computational linguistic methods to (1) create a novel Linguistic Complexity Profile (LCP) to characterize communications of patients and clinicians and demonstrate its validity and (2) examine whether providers accommodate communication needs of patients with limited HL by tailoring their SM responses. We will study >5 million SMs generated by >150,000 ethnically diverse type 2 diabetes patients and >9000 clinicians from two settings: an integrated delivery system and a public (safety net) system. Finally, we will then create an LCP-based automated aid that delivers real-time feedback to clinicians to reduce the linguistic complexity of their SMs. This research will support health systems’ journeys to become health literate healthcare organizations and reduce HL-related disparities in diabetes care. Dean Schillinger, Danielle McNamara, Scott Crossley, Courtney Lyles, Howard H. Moffet, Urmimala Sarkar, Nicholas Duran, Jill Allen, Jennifer Liu, Danielle Oryn, Neda Ratanawongsa, and Andrew J. Karter Copyright © 2017 Dean Schillinger et al. All rights reserved. Investigating Factors Associated with Depressive Symptoms of Chronic Kidney Diseases in China with Type 2 Diabetes Thu, 02 Feb 2017 06:22:03 +0000 Aim. To assess the depressive symptoms status of chronic kidney diseases in Nantong, China, with type 2 diabetes and to identify factors associated with depressive symptoms. Methods. In this cross-sectional analytic study, 210 type 2 diabetic patients were recruited from the Second Affiliated Hospital of Nantong University. Depressive symptoms were assessed with the depression subscale of the Hospital Anxiety and Depression Scale (HAD-D). The quality of life was measured with the RAND 36-Item Health Survey (SF-36). And the independent risk factors of depressive symptoms were assessed by using a stepwise forward model of logistic regression analysis. Results. The mean age of the study subjects was 57.66 years (SD: 11.68). Approximately 21.4% of subjects reported depressive symptoms (). Forward stepwise logistic regression analysis showed that female gender (), hypertension (), Stage IV (), and Stage V () were significant risk factors for depressive symptoms. The quality of life of individuals with HAD-D score <11 was significantly better compared with individuals with HAD-D score ≥ 11. Conclusions. These results indicate that clinicians should be aware that female patients with chronic kidney diseases with T2DM in their late stage with hypertension are at a marked increased risk of depressive symptoms. Providing optimal care for the psychological health of this population is vital. Xu Wang, Biyu Shen, Xun Zhuang, Xueqin Wang, and Weiqun Weng Copyright © 2017 Xu Wang et al. All rights reserved. Urinary Sodium Concentration Is an Independent Predictor of All-Cause and Cardiovascular Mortality in a Type 2 Diabetes Cohort Population Wed, 01 Feb 2017 09:12:19 +0000 Objective. Sodium intake is associated with cardiovascular outcomes. However, no study has specifically reported an association between cardiovascular mortality and urinary sodium concentration (). We examined the association of with mortality in a cohort of type 2 diabetes (T2D) patients. Methods. Patients were followed for all-cause death and cardiovascular death. Baseline was measured from second morning spot urinary sample. We used Cox proportional hazard models to identify independent predictors of mortality. Improvement in prediction of mortality by the addition of to a model including known risk factors was assessed by the relative integrated discrimination improvement (rIDI) index. Results. Participants (,439) were followed for a median of 5.7 years, during which 254 cardiovascular deaths and 429 all-cause deaths were recorded. independently predicted all-cause and cardiovascular mortality. An increase of one standard deviation of was associated with a decrease of 21% of all-cause mortality and 22% of cardiovascular mortality. improved all-cause and cardiovascular mortality prediction beyond identified risk factors (rIDI = 2.8%, and rIDI = 4.6%, , resp.). Conclusions. In T2D, was an independent predictor of mortality (low concentration is associated with increased risk) and improved modestly its prediction in addition to traditional risk factors. Pierre-Jean Saulnier, Elise Gand, Stéphanie Ragot, Lise Bankir, Xavier Piguel, Frédéric Fumeron, Vincent Rigalleau, Jean-Michel Halimi, Richard Marechaud, Ronan Roussel, Samy Hadjadj, and SURDIAGENE Study group Copyright © 2017 Pierre-Jean Saulnier et al. All rights reserved. Role of T Lymphocytes in Type 2 Diabetes and Diabetes-Associated Inflammation Tue, 31 Jan 2017 00:00:00 +0000 Although a critical role of adaptive immune system has been confirmed in driving local and systemic inflammation in type 2 diabetes and promoting insulin resistance, the underlying mechanism is not completely understood. Inflammatory regulation has been focused on innate immunity especially macrophage for a long time, while increasing evidence suggests T cells are crucial for the development of metabolic inflammation and insulin resistance since 2009. There was growing evidence supporting the critical implication of T cells in the pathogenesis of type 2 diabetes. We will discuss the available effect of T cells subsets in adaptive immune system associated with the procession of T2DM, which may unveil several potential strategies that could provide successful therapies in the future. Chang Xia, Xiaoquan Rao, and Jixin Zhong Copyright © 2017 Chang Xia et al. All rights reserved. TNF-Alpha in Peripheral Neuropathy Patients with Impaired Glucose Regulation Mon, 30 Jan 2017 07:46:30 +0000 Impaired glucose regulation (IGR) is the prestate of diabetes; about 1/3 of IGR patients will develop to diabetes finally. In this study, we investigated the serum tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels in peripheral neuropathy impaired patients with impaired glucose regulation (IGR). A total of 70 IGR patients received the conventional nerve conduction test, including 30 patients with peripheral neuropathy (PN) and 40 patients without peripheral neuropathy (NPN). The other 40 healthy individuals were recruited as controls. The serum TNF-α and IL-6 in IGR patients were higher than in control group, and serum TNF-α and IL-6 levels in IGR-PN group were higher than in IGR-NPN group ( versus  pg/mL and versus  pg/mL, resp., both ). Multifactors logistic regression analysis showed that TNF-α (OR = 0.893; ) was an independent factor affecting whether IGR could combine with peripheral neuropathy. TNF-α and IL-6 could aggregate peripheral neuropathy in impaired glucose regulation patients; TNF-α might be independent risk factor for peripheral neuropathy in glucose regulation impaired patients. Xia Li, Ju Zhu, Na Liu, Jie Liu, and Zhecheng Zhang Copyright © 2017 Xia Li et al. All rights reserved. Urinary Excretion of Kidney Aquaporins as Possible Diagnostic Biomarker of Diabetic Nephropathy Thu, 26 Jan 2017 11:15:54 +0000 Diabetic nephropathy (DN) is a microangiopathic complication of diabetes mellitus (DM) affecting one-third of diabetic patients. The large variability in the clinical presentation of renal involvement in patients with DM makes kidney biopsy a prerequisite for a correct diagnosis. However, renal biopsy is an invasive procedure associated with risk of major complications. Numerous studies aimed to identify a noninvasive biomarker of DN but, so far, none of these is considered to be sufficiently specific and sensitive. Water channel aquaporins (AQPs), expressed at the plasma membrane of epithelial tubular cells, are often dysregulated during DN. In this work, we analyzed the urine excretion of AQP5 and AQP2 (uAQP5 and uAQP2), via exosomes, in 35 diabetic patients: 12 normoalbuminuric with normal renal function (DM), 11 with proteinuric nondiabetic nephropathy (NDN), and 12 with histological diagnosis and classification of DN. ELISA and WB analysis independently showed that uAQP5 was significantly increased in DN patients. Interestingly, linear regression analysis showed a positive correlation between uAQP5 and the histological class of DN. The same analysis, focusing on uAQP2, showed comparable results. Taken together, these data suggest a possible use of AQP5 and AQP2 as novel noninvasive biomarkers to help in classifying the clinical stage of DN. Luigi Rossi, Maria Celeste Nicoletti, Monica Carmosino, Lisa Mastrofrancesco, Antonella Di Franco, Francesca Indrio, Rossella Lella, Luigi Laviola, Francesco Giorgino, Maria Svelto, Loreto Gesualdo, and Giuseppe Procino Copyright © 2017 Luigi Rossi et al. All rights reserved. Visual Acuity, Retinal Sensitivity, and Macular Thickness Changes in Diabetic Patients without Diabetic Retinopathy after Cataract Surgery Tue, 24 Jan 2017 10:05:35 +0000 Aim. Functional and morphological macular study after cataract surgery in a group of diabetics without diabetic retinopathy compared to nondiabetics to evaluate the effect of surgical oxidative stress on diabetic retina. Methods. Prospective, comparative study. Preoperative eye exam, best corrected visual acuity (BCVA) measured by ETDRS letters, and optical coherence tomography (OCT) were followed by standard cataract surgery. The follow-up visits at 1, 3, and 6 months postoperatively included BCVA, OCT, and microperimetry, to analyze changes within and between the groups. Results. The BCVA improved significantly in diabetics and controls: 64.2 to 81.0 and 61.9 to 82.1 ETDRS at 6 months, respectively. The central macula at OCT significantly thickened in both groups, while the central 5 fields, corresponding to the microperimetry area, subclinically thickened from 284.20 to 291.18 μm at 6 months only in diabetics (). A matching slight decrease in the microperimetry sensitivity from 1 to 6 months was found also only in diabetics, with mean average difference −0.75 dB (). Conclusion. Underlying diabetes does not influence the surgical outcome in diabetics without diabetic retinopathy. However, slight thickening of wider macula and corresponding decrease in retinal sensitivity observed in diabetics 6 months postoperatively might influence visual function on long term. Spela Stunf Pukl, Nataša Vidović Valentinčič, Mojca Urbančič, Irena Irman Grčar, Rok Grčar, Vladimir Pfeifer, and Mojca Globočnik Petrovič Copyright © 2017 Spela Stunf Pukl et al. All rights reserved. Impact of ELKa, the Electronic Device for Prandial Insulin Dose Calculation, on Metabolic Control in Children and Adolescents with Type 1 Diabetes Mellitus: A Randomized Controlled Trial Mon, 23 Jan 2017 14:03:04 +0000 Background. The ELKa system is composed of computer software, with a database of nutrients, and a dedicated USB kitchen scale. It was designed to automatize the everyday calculations of food exchanges and prandial insulin doses. Aim. To investigate the influence of the ELKa on metabolic control in children with type 1 diabetes mellitus (T1DM). Methods. A randomized, parallel, open-label clinical trial involved 106 patients aged <18 years with T1DM, , undergoing intensive insulin therapy, allocated to the intervention group, who used the ELKa (), or the control group (), who used conventional calculation methods. Results. After the 26-week follow-up, the intention-to-treat analysis showed no differences to all endpoints. In per protocol analysis, 22/53 (41.5%) patients reporting ELKa usage for >50% of meals achieved lower levels (), lower basal insulin amounts (), and lower intrasubject standard deviation of blood glucose levels () in comparison with the control. Moreover, in the intervention group, significant reduction of level, by 0.55% point (), was noted. No intergroup differences were found in the hypoglycemic episodes, BMI-SDS, bolus insulin dosage, and total daily insulin dosage. Conclusions. The ELKa system improves metabolic control in children with T1DM under regular usage. The trial is registered at, number NCT02194517. Agnieszka Kowalska, Katarzyna Piechowiak, Anna Ramotowska, and Agnieszka Szypowska Copyright © 2017 Agnieszka Kowalska et al. All rights reserved. Transcriptional Profile of Kidney from Type 2 Diabetic db/db Mice Mon, 23 Jan 2017 06:02:48 +0000 Diabetic nephropathy (DN), a common diabetic microvascular complication, is characterized by progressive glomerular sclerosis and tubulointerstitial fibrosis. However, the underlying mechanisms involved in DN remain to be elucidated. We explored changes in the transcriptional profile in spontaneous type 2 diabetic db/db mice by using the cDNA microarray. Compared with control db/m mice, the db/db mice exhibited marked increases in body weight, kidney weight, and urinary albumin excretion. Renal histological analysis revealed mesangial expansion and thickness of the basement membrane in the kidney of the db/db mice. A total of 355 differentially expressed genes (DEGs) were identified by microarray analysis. Pathway enrichment analysis suggested that biological oxidation, bile acid metabolism, and steroid hormone synthesis were the 3 major significant pathways. The top 10 hub genes were selected from the constructed PPI network of DEGs, including Ccnb2 and Nr1i2, which remained largely unclear in DN. We believe that our study can help elucidate the molecular mechanisms underlying DN. Haojun Zhang, Tingting Zhao, Zhiguo Li, Meihua Yan, Hailing Zhao, Bin Zhu, and Ping Li Copyright © 2017 Haojun Zhang et al. All rights reserved. The Challenges of Electronic Health Records and Diabetes Electronic Prescribing: Implications for Safety Net Care for Diverse Populations Wed, 18 Jan 2017 14:16:27 +0000 Widespread electronic health record (EHR) implementation creates new challenges in the diabetes care of complex and diverse populations, including safe medication prescribing for patients with limited health literacy and limited English proficiency. This review highlights how the EHR electronic prescribing transformation has affected diabetes care for vulnerable patients and offers recommendations for improving patient safety through EHR electronic prescribing design, implementation, policy, and research. Specifically, we present evidence for (1) the adoption of RxNorm; (2) standardized naming and picklist options for high alert medications such as insulin; (3) the widespread implementation of universal medication schedule and language-concordant labels, with the expansion of electronic prescription 140-character limit; (4) enhanced bidirectional communication with pharmacy partners; and (5) informatics and implementation research in safety net healthcare systems to examine how EHR tools and practices affect diverse vulnerable populations. Neda Ratanawongsa, Lenny L. S. Chan, Michelle M. Fouts, and Elizabeth J. Murphy Copyright © 2017 Neda Ratanawongsa et al. All rights reserved. Lipids: A Suitable Therapeutic Target in Diabetic Neuropathy? Mon, 16 Jan 2017 09:39:25 +0000 Diabetic polyneuropathy (DPN) encompasses multiple syndromes with a common pathogenesis. Glycemic control shows a limited correlation with DPN, arguing in favor of major involvement of other factors, one of which is alterations of lipid and lipoprotein metabolism. Consistent associations have been found between plasma triglycerides/remnant lipoproteins and the risk of DPN. Studies in cultured nerve tissue or in murine models of diabetes have unveiled mechanisms linking lipid metabolism to DPN. Deficient insulin action increases fatty acids flux to nerve cells, inducing mitochondrial dysfunction, anomalous protein kinase C signaling, and perturbations in the physicochemical properties of the plasma membrane. Oxidized low-density lipoproteins bind to cellular receptors and promote generation of reactive oxygen species, worsening mitochondrial function and altering the electrical properties of neurons. Supplementation with specific fatty acids has led to prevention or reversal of different modalities of DPN in animal models. Post hoc and secondary analyses of clinical trials have found benefits of cholesterol reducing (statins and ezetimibe), triglyceride-reducing (fibrates), or lipid antioxidant (thioctic acid) therapies over the progression and severity of DPN. However, these findings are mostly hypothesis-generating. Randomized trials are warranted in which the impact of intensive plasma lipids normalization on DPN outcomes is specifically evaluated. M. C. Perez-Matos, M. C. Morales-Alvarez, and C. O. Mendivil Copyright © 2017 M. C. Perez-Matos et al. All rights reserved. Suppression of Excessive Histone Deacetylases Activity in Diabetic Hearts Attenuates Myocardial Ischemia/Reperfusion Injury via Mitochondria Apoptosis Pathway Mon, 16 Jan 2017 09:03:52 +0000 Background. Histone deacetylases (HDACs) play a pivotal role in signaling modification and gene transcriptional regulation that are essential for cardiovascular pathophysiology. Diabetic hearts with higher HDACs activity were more vulnerable to myocardial ischemia/reperfusion (MI/R) injury compared with nondiabetic hearts. We are curious about whether suppression of excessive HDACs activity in diabetic heart protects against MI/R injury. Methods. Diabetic rats were subjected to 45 min of ischemia, followed by 3 h of reperfusion. H9C2 cardiomyocytes were exposed to high glucose for 24 h, followed by 4 h of hypoxia and 2 h of reoxygenation (H/R). Results. Both MI/R injury and diabetes mellitus elevated myocardium HDACs activity. MI/R induced apoptotic cell death was significantly decreased in diabetic rats treated with HDACs inhibitor trichostatin A (TSA). TSA administration markedly moderated dissipation of mitochondrial membrane potential, protected the integrity of mitochondrial permeability transition pore (mPTP), and decreased cell apoptosis. Notably, cotreatment with Akt inhibitor partly or absolutely inhibited the protective effect of TSA in vivo and in vitro. Furthermore, TSA administration activated Akt/Foxo3a pathway, leading to Foxo3a cytoplasm translocation and attenuation proapoptosis protein Bim expression. Conclusions. Both diabetes mellitus and MI/R injury increased cardiac HDACs activity. Suppression of HDACs activity triggered protective effects against MI/R and H/R injury under hyperglycemia conditions through Akt-modulated mitochondrial apoptotic pathways via Foxo3a/Bim. Yang Wu, Yan Leng, Qingtao Meng, Rui Xue, Bo Zhao, Liying Zhan, and Zhongyuan Xia Copyright © 2017 Yang Wu et al. All rights reserved. Effects of a Novel Glucokinase Activator, HMS5552, on Glucose Metabolism in a Rat Model of Type 2 Diabetes Mellitus Mon, 16 Jan 2017 06:16:17 +0000 Glucokinase (GK) plays a critical role in the control of whole-body glucose homeostasis. We investigated the possible effects of a novel glucokinase activator (GKA), HMS5552, to the GK in rats with type 2 diabetes mellitus (T2DM). Male Sprague-Dawley (SD) rats were divided into four groups: control group, diabetic group, low-dose (10 mg/kg) HMS5552-treated diabetic group (HMS-L), and high-dose (30 mg/kg) HMS5552-treated diabetic group (HMS-H). HMS5552 was administered intragastrically to the T2DM rats for one month. The levels of total cholesterol, triglyceride, fasting plasma insulin (FINS), and glucagon (FG) were determined, and an oral glucose tolerance test was performed. The expression patterns of proteins and genes associated with insulin resistance and GK activity were assayed. Compared with diabetic rats, the FINS level was significantly decreased in the HMS5552-treated diabetic rats. HMS5552 treatment significantly lowered the blood glucose levels and improved GK activity and insulin resistance. The immunohistochemistry, western blot, and semiquantitative RT-PCR results further demonstrated the effects of HMS5552 on the liver and pancreas. Our data suggest that the novel GKA, HMS5552, exerts antidiabetic effects on the liver and pancreas by improving GK activity and insulin resistance, which holds promise as a novel drug for the treatment of T2DM patients. Ping Wang, Huili Liu, Li Chen, Yingli Duan, Qunli Chen, and Shoumin Xi Copyright © 2017 Ping Wang et al. All rights reserved. Metabolic Mechanisms and Potential Therapies of Diabetic Cardiac Complications Sun, 15 Jan 2017 07:56:32 +0000 Dake Qi, Zhengyuan Xia, and Zhenwu Zhuang Copyright © 2017 Dake Qi et al. All rights reserved. Urinary Microvesicle-Bound Uromodulin: A Potential Molecular Biomarker in Diabetic Kidney Disease Sun, 15 Jan 2017 00:00:00 +0000 This study was designed to investigate the changes of urinary microvesicle-bound uromodulin and total urinary uromodulin levels in human urine and the correlations with the severity of diabetic kidney disease (DKD). 31 healthy subjects without diabetes and 100 patients with type 2 diabetes mellitus (T2DM) were included in this study. The patients with T2DM were divided into three groups based on the urinary albumin/creatinine ratio (UACR): normoalbuminuria group (DM, ); microalbuminuria group (DN1, ); and macroalbuminuria group (DN2, ). We use a specific monoclonal antibody AD-1 to capture the urinary microvesicles. Urinary microvesicle-bound uromodulin and total urinary uromodulin levels were determined by enzyme-linked immunosorbent assay (ELISA). Our results showed that the levels of urinary microvesicle-bound uromodulin in DN1 and DN2 groups were significantly higher than those in control group and DM group (). Multiple stepwise linear regression analysis showed that UACR was independent determinant for urinary microvesicle-bound uromodulin () but not for total urinary uromodulin. These findings suggest that the levels of urinary microvesicle-bound uromodulin are associated with the severity of DKD. The uromodulin in urinary microvesicles may be a specific marker of DKD and potentially may be used to predict the onset and/or monitor the progression of DKD. Neng-jun Lou, Yi-hong Ni, Hong-ying Jia, Jing-ti Deng, Lu Jiang, Feng-jie Zheng, and Ai-li Sun Copyright © 2017 Neng-jun Lou et al. All rights reserved. Rationale, Design, and Baseline Characteristics of Beijing Prediabetes Reversion Program: A Randomized Controlled Clinical Trial to Evaluate the Efficacy of Lifestyle Intervention and/or Pioglitazone in Reversion to Normal Glucose Tolerance in Prediabetes Thu, 12 Jan 2017 11:26:32 +0000 Background. Patients with prediabetes are at high risk for diabetes and cardiovascular disease (CVD). No study has explored whether intervention could revert prediabetes to normal glycemic status as the primary outcome. Beijing Prediabetes Reversion Program (BPRP) would evaluate whether intensive lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia and improve the risk factors of CVD as well. Methods. BPRP is a randomized, multicenter, 2 × 2 factorial design study. Participants diagnosed as prediabetes were randomized into four groups (conventional/intensive lifestyle intervention and 30 mg pioglitazone/placebo) with a three-year follow-up. The primary endpoint was conversion into normal glucose tolerance. The trial would recruit 2000 participants (500 in each arm). Results. Between March 2007 and March 2011, 1945 participants were randomized. At baseline, the individuals were years old, with median BMI 26.0 (23.9, 28.2) kg/m2 and HbA1c 5.8 (5.6, 6.1)%. 85% of the participants had IGT and 15% had IFG. Parameters relevant to glucose, lipids, blood pressure, lifestyle, and other metabolic markers were similar between conventional and intensive lifestyle intervention group at baseline. Conclusion. BPRP was the first study to determine if lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia in Chinese population. Major baseline parameters were balanced between two lifestyle intervention groups. This trial is registered with ChiCTR-PRC-06000005. Yingying Luo, Sanjoy K. Paul, Xianghai Zhou, Cuiqing Chang, Wei Chen, Xiaohui Guo, Jinkui Yang, Linong Ji, and Hongyuan Wang Copyright © 2017 Yingying Luo et al. All rights reserved. Interorgan Crosstalk Contributing to β-Cell Dysfunction Thu, 12 Jan 2017 06:09:33 +0000 Type 2 diabetes mellitus (T2DM) results from pancreatic β-cell failure in the setting of insulin resistance. In the early stages of this disease, pancreatic β-cells meet increased insulin demand by both enhancing insulin-secretory capacity and increasing β-cell mass. As the disease progresses, β-cells fail to maintain these compensatory responses. This involves both extrinsic signals and mediators intrinsic to β-cells, which adversely affect β-cells by impairing insulin secretion, decreasing proliferative capacities, and ultimately causing apoptosis. In recent years, it has increasingly been recognized that changes in circulating levels of various factors from other organs play roles in β-cell dysfunction and cellular loss. In this review, we discuss current knowledge of interorgan communications underlying β-cell failure during the progression of T2DM. Katsuya Tanabe, Kikuko Amo-Shiinoki, Masayuki Hatanaka, and Yukio Tanizawa Copyright © 2017 Katsuya Tanabe et al. All rights reserved.