Journal of Diabetes Research The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. High Plasma Glucagon Levels Correlate with Waist-to-Hip Ratio, Suprailiac Skinfold Thickness, and Deep Subcutaneous Abdominal and Intraperitoneal Adipose Tissue Depots in Nonobese Asian Indian Males with Type 2 Diabetes in North India Sun, 28 May 2017 00:00:00 +0000 We aimed to correlate plasma glucagon levels with anthropometric measures and abdominal adipose tissue depots. Nonobese males (; BMI < 25 kg/m2) with T2DM of less than one-year duration and nonobese males without diabetes () were evaluated for the following: anthropometry (BMI, waist circumference, W-HR, and truncal skinfolds), whole-body DEXA (for body fat and fat-free mass), and MRI scan (for volumes of subcutaneous abdominal adipose tissue (SCAT) including superficial and deep, intra-abdominal visceral adipose tissue (including intraperitoneal adipose tissue (IPAT), retroperitoneal adipose tissue, liver span and fatty liver, and pancreatic volume)). Plasma glucose and glucagon, serum insulin, hepatic transaminases, and lipid profile were measured. Significantly higher levels of fasting and postprandial glucagon () and fasting and postprandial insulin () were seen in patients with T2DM. The mean values of fasting and postprandial plasma glucagon levels were higher in T2DM patients with NAFLD () as compared to T2DM patients without NAFLD (). Four independent predictors were derived for fasting glucagon levels in patients with T2DM, namely, W-HR, suprailiac skinfold thickness, IPAT, and deep SCAT (; ). These observations in Asian Indians may have significance for diabetes therapies which impact glucagon levels. Shajith Anoop, Anoop Misra, Surya Prakash Bhatt, Seema Gulati, Harsh Mahajan, and Gokulraj Prabakaran Copyright © 2017 Shajith Anoop et al. All rights reserved. Leptin/Adiponectin Ratios Using Either Total Or High-Molecular-Weight Adiponectin as Biomarkers of Systemic Insulin Sensitivity in Normoglycemic Women Thu, 25 May 2017 09:00:37 +0000 Plasma leptin/adiponectin ratio (LAR) is negatively associated with insulin sensitivity indexes. High-molecular-weight adiponectin (HMWA) was proposed as the most biologically active form of this insulin-sensitizing adipokine. There are no studies assessing the relative merits of leptin/HMWA ratio over LAR as a biomarker of systemic insulin sensitivity. A standard 2-hour oral glucose tolerance test (OGTT; 75 g of glucose) and a short minimal-model intravenous glucose tolerance test (IVGTT; 0.3 g/kg body weight) were performed in 58 Chilean normoglycemic women (age: 27 ± 6.3 years, BMI 23.6 ± 3.2 kg/m2). LAR was negatively associated with HOMA-S (; ), Matsuda-ISICOMP (; ), and the calculated sensitivity index (CSi) derived from IVGTT (; ). In comparison to LAR, leptin/HMWA ratio did not increase neither the linear fit () nor the magnitude of association with insulin sensitivity indexes (slope of multiple linear regression). The discriminatory capacity of both ratios to classify insulin-resistant versus insulin-sensitive subjects was similar for HOMA-S (), Matsuda-ISICOMP (), or CSi (). In conclusion, LAR showed consistent negative associations with different systemic insulin sensitivity indexes. The use of HMWA to generate leptin/HMWA ratio did not show any advantage over LAR as a biomarker of systemic insulin sensitivity in normoglycemic women. Carolina Bravo, Luis Rodrigo Cataldo, José Galgani, Javier Parada, and José Luis Santos Copyright © 2017 Carolina Bravo et al. All rights reserved. The Effect of Social Support on Glycemic Control in Patients with Type 2 Diabetes Mellitus: The Mediating Roles of Self-Efficacy and Adherence Thu, 25 May 2017 00:00:00 +0000 Ample evidence suggests that social support, self-efficacy, and adherence significantly, independently, and together affect glycemic control in patients with type 2 diabetes mellitus (T2DM), but the pathway from social support to glycemic control remains unclear. This study hypothesized that the effect of social support on glycemic control was mediated sequentially by self-efficacy and adherence. Patients with T2DM were recruited from two hospitals in Guangzhou, China, from January 1 to July 31, 2014, and their sociodemographic clinical data and their assessments on social support, self-efficacy, and adherence were obtained from medical records and self-completed questionnaires. Of the 532 patients who participated, 35% achieved glycemic control (i.e., HbA1c < 7%). Social support, self-efficacy, and adherence had significant correlations with each other and with glycemic control (). Regression analyses and structural equation modeling showed that better social support was associated to better patient self-efficacy, which, in turn, was associated with better medical adherence, which was associated with improved glycemic control, and the relationship between social support and glycemic control was sequentially and completely mediated by self-efficacy and adherence. The five goodness-of-fit indices confirmed that our data fitted the hypothesized pathway model strongly. Yechang Shao, Lu Liang, Linjing Shi, Chengsong Wan, and Shouyi Yu Copyright © 2017 Yechang Shao et al. All rights reserved. Inadequate Triglyceride Management Worsens the Durability of Dipeptidyl Peptidase-4 Inhibitor in Subjects with Type 2 Diabetes Mellitus Thu, 25 May 2017 00:00:00 +0000 Dipeptidyl peptidase-4 (DPP-4) inhibitors are often used all over the world and exert various beneficial effects including glucose-lowering effect in many subjects with type 2 diabetes. It is poorly understood, however, which factors are closely related with the durability of glucose-lowering effect by DPP-4 inhibitor. In this study, we examined retrospectively which factors could mainly influence the durability of DPP-4 inhibitor. We enrolled 212 participants with type 2 diabetes to whom DPP-4 inhibitor was administered for over 1 year without an addition or increase of other hypoglycemic agents. Age and baseline HbA1c level were significantly higher in the effective group than those in the ineffective group. The effective group had a tendency of smaller amounts of weight change, average total cholesterol, and average triglyceride compared with the ineffective group. Multiple logistic regression analysis showed that average triglyceride and baseline HbA1c were independent predictors associated with the durability of DPP-4 inhibitor. Moreover, an average triglyceride level contributed to the durability of DPP-4 inhibitor in the obese group (BMI ≥ 25 kg/m2) but not in the nonobese group (BMI < 25 kg/m2). These results suggest the importance of strict triglyceride management to maintain the durability of glucose-lowering effect by DPP-4 inhibitor, especially in obese subjects with type 2 diabetes. Masashi Shimoda, Maiko Miyoshi-Takai, Shintaro Irie, Akihito Tanabe, Atsushi Obata, Seizo Okauchi, Hidenori Hirukawa, Tomohiko Kimura, Kenji Kohara, Shinji Kamei, Tomoatsu Mune, Kohei Kaku, and Hideaki Kaneto Copyright © 2017 Masashi Shimoda et al. All rights reserved. Upregulation of Tumor Necrosis Factor-α-Induced Protein 8-Like 2 mRNA Is Negatively Correlated with Serum Concentrations of Tumor Necrosis Factor-α and Interleukin 6 in Type 2 Diabetes Mellitus Wed, 24 May 2017 04:07:40 +0000 Background. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2 or TNFAIP8L2) is a negative regulator of natural and adaptive immunity. The role of TIPE2 in type 2 diabetes mellitus (T2DM) remains unknown, although TIPE2 plays key roles in preserving inflammatory homeostasis. Methods. TIPE2 expression was measured by Western blotting and real-time polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMCs) isolated from T2DM patients and healthy controls, and tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and other related biometabolic parameters were detected using a nephelometer or by ELISA. Differentiated THP-1 cells were exposed to siTIPE2 and TIPE2 adenovirus. Results. TIPE2 was significantly increased in PBMCs from T2DM patients compared with those from healthy controls and was negatively correlated with serum TNF-α, IL-6, and hsCRP concentrations but positively correlated with HbA1c and LDL-C in T2DM patients. High glucose treatment (50 mmol/L) can upregulate the expression of TIPE2 and cytokine secretion in differentiated THP-1 cells. siTIPE2 infection exacerbated the increased TNF-α and IL-6 concentrations in differentiated THP-1 cells under high glucose conditions (50 mmol/L), while infection with TIPE2 adenovirus reversed the increased TNF-α concentration. Conclusions. The present study indicates that TIPE2 may participate in T2DM by regulating TNF-α production. Yongliang Liu, Xinmei Wang, Yan Zhao, Peiqing Zhao, Lianqing Wang, Qiaoli Zhai, Xiaowei Zhang, Wenxiu Tian, Xinxin Xiang, and Tao Li Copyright © 2017 Yongliang Liu et al. All rights reserved. NGAL as an Early Predictive Marker of Diabetic Nephropathy in Children and Young Adults with Type 1 Diabetes Mellitus Tue, 23 May 2017 00:00:00 +0000 Aims. Type 1 diabetes (T1D) is often associated with early microvascular complications. Previous studies demonstrated that increased systolic (SAP) and diastolic arterial blood pressures (DAP) are linked to microvascular morbidity in T1D. The aim of the study was to investigate the predictive role of neutrophil gelatinase-associated lipocalin (NGAL) in unravelling early cardio-renal dysfunction in T1D. Methods. Two T1D patient groups participating in two-centre prospective cohorts were studied. Group A consisted of 57 participants aged 13.9 years (SD: 3.1) and group B consisted of 59 patients aged 28.0 years (SD: 4.4). Forty-nine healthy children [age: 10.5 years (SD: 6.6)] and 18 healthy adults [age 27.7 years (SD: 4.2)] served as controls. Serum concentrations of NGAL (ELISA) were determined, and SAP and DAP were examined (SAP and DAP also expressed as z-scores in the younger group). Results. NGAL correlated positively with SAP in both patient groups ( and , resp.) and SAP z-score () (group A) and negatively with eGFR in both groups ( and , resp.). Conclusions. NGAL may be proposed as a biomarker of early renal dysfunction even in nonalbuminuric T1D patients, since it was strongly associated with renal function decline and increasing systolic arterial pressure even at prehypertensive range in people with T1D, in a broad age range. Nektaria Papadopoulou-Marketou, Alexandra Margeli, Ioannis Papassotiriou, George P. Chrousos, Christina Kanaka-Gantenbein, and Jeanette Wahlberg Copyright © 2017 Nektaria Papadopoulou-Marketou et al. All rights reserved. Type 2 Diabetes in Young Females Results in Increased Serum Amyloid A and Changes to Features of High Density Lipoproteins in Both HDL2 and HDL3 Wed, 17 May 2017 06:40:21 +0000 Persons with type 2 diabetes mellitus (T2DM) have an elevated risk of atherosclerosis. High-density lipoproteins (HDL) normally protect against cardiovascular disease (CVD), but this may be attenuated by serum amyloid A (SAA). In a case-control study of young females, blood samples were compared between subjects with T2DM () and individuals without T2DM (). SAA and apolipoprotein AI (apoAI) concentrations, paraoxonase-1 (PON-1), cholesteryl ester transfer protein (CETP), and lecithin-cholesterol acyltransferase (LCAT) activities were measured in the serum and/or HDL2 and HDL3 subfractions. SAA concentrations were higher in T2DM compared to controls: serum (30 mg/L (17, 68) versus 15 mg/L (7, 36); ), HDL2 (1.0 mg/L (0.6, 2.2) versus 0.4 mg/L (0.2, 0.7); ), and HDL3 (13 mg/L (8, 29) versus 6 mg/L (3, 13); ). Serum-PON-1 activity was lower in T2DM compared to that in controls (38,245 U/L (7025) versus 41,109 U/L (5690); ). CETP activity was higher in T2DM versus controls in HDL2 (232.6 μmol/L (14.1) versus 217.1 μmol/L (25.1); ) and HDL3 (279.5 μmol/L (17.7) versus 245.2 μmol/L (41.2); ). These results suggest that individuals with T2DM have increased SAA-related inflammation and dysfunctional HDL features. SAA may prove to be a useful biomarker in T2DM given its association with elevated CVD risk. Kayleigh Griffiths, Agnieszka Pazderska, Mohammed Ahmed, Anne McGowan, Alexander P. Maxwell, Jane McEneny, James Gibney, and Gareth J. McKay Copyright © 2017 Kayleigh Griffiths et al. All rights reserved. Soluble Urokinase Receptor and the Kidney Response in Diabetes Mellitus Wed, 17 May 2017 00:00:00 +0000 Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. DN typically manifests by glomerular hyperfiltration and microalbuminuria; then, the disease progresses to impaired glomerular filtration rate, which leads to ESRD. Treatment options for DN include the strict control of blood glucose levels and pressure (e.g., intraglomerular hypertension). However, the search for novel therapeutic strategies is ongoing. These include seeking specific molecules that contribute to the development and progression of DN to potentially interfere with these “molecular targets” as well as with the cellular targets within the kidney such as podocytes, which play a major role in the pathogenesis of DN. Recently, podocyte membrane protein urokinase receptor (uPAR) and its circulating form (suPAR) are found to be significantly induced in glomeruli and sera of DN patients, respectively, and elevated suPAR levels predicted diabetic kidney disease years before the occurrence of microalbuminuria. The intent of this review is to summarize the emerging evidence of uPAR and suPAR in the clinical manifestations of DN. The identification of specific pathways that govern DN will help us build a more comprehensive molecular model for the pathogenesis of the disease that can inform new opportunities for treatment. Ranadheer R. Dande, Vasil Peev, Mehmet M. Altintas, and Jochen Reiser Copyright © 2017 Ranadheer R. Dande et al. All rights reserved. The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling Thu, 11 May 2017 00:00:00 +0000 The metabolic syndrome is an escalating worldwide public health concern. Defined by a combination of physiological, metabolic, and biochemical factors, the metabolic syndrome is used as a clinical guideline to identify individuals with a higher risk for type 2 diabetes and cardiovascular disease. Although risk factors for type 2 diabetes and cardiovascular disease have been known for decades, the molecular mechanisms involved in the pathophysiology of these diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is widely expressed in several tissues. As a member of the LDL receptor family, LRP1 is involved in the clearance of chylomicron remnants from the circulation and has been demonstrated to be atheroprotective. Recently, studies have shown that LRP1 is involved in insulin receptor trafficking and regulation and glucose metabolism. This review summarizes the role of tissue-specific LRP1 in insulin signaling and its potential role as a link between lipoprotein and glucose metabolism in diabetes. Dianaly T. Au, Dudley K. Strickland, and Selen C. Muratoglu Copyright © 2017 Dianaly T. Au et al. All rights reserved. Prevalence of Positive Diabetes-Associated Autoantibodies among Type 2 Diabetes and Related Metabolic and Inflammatory Differences in a Sample of the Bulgarian Population Tue, 09 May 2017 00:00:00 +0000 Background. The study aimed to estimate the prevalence of unrecognized cases with positive autoantibodies among type 2 diabetes (T2D) in a sample of the Bulgarian population and to compare some metabolic and inflammatory markers to those of patients having negative autoantibodies and subjects with latent autoimmune diabetes (LADA). Methods. Patients with T2D, patients with LADA, and control participants were enrolled. Antiglutamic acid decarboxylase, anti-insulinoma-associated 2, and antizinc transporter 8 autoantibodies were assayed through ELISA. C-reactive protein and interleukin 6 (IL-6) and tumor necrosis factor alpha were assessed. Results. Ten percent of patients with T2D had positive autoantibodies. They had lower body mass index (), worse glycemic control (HbA1c, ), and better HDL cholesterol () than those in negative autoantibodies cases. Compared to LADA, glycemia and anthropometric data did not differ significantly but metabolic syndrome was more prevalent among newly found cases with positive autoantibodies (). Their level of inflammatory markers was similar to that of patients having negative autoantibodies (), but IL-6 was higher when compared to LADA (). Conclusion. Prevalence of patients having positive autoantibodies within T2D in the analyzed sample of the Bulgarian population was 10%. They shared common metabolic features with subjects with LADA, but inflammatory phenotype was closer to that of T2D. Emanuela Tsvetkova Zaharieva, Tsvetelina Veselinova Velikova, Adelina Dimitrova Tsakova, and Zdravko Asenov Kamenov Copyright © 2017 Emanuela Tsvetkova Zaharieva et al. All rights reserved. Cardio-Ankle Vascular Index and Indices of Diabetic Polyneuropathy in Patients with Type 2 Diabetes Tue, 09 May 2017 00:00:00 +0000 The cardio-ankle vascular index (CAVI) is used to test vascular function and is an arterial stiffness marker and potential predictor of cardiovascular events. This study aimed to analyze the relation between objective indices of diabetic polyneuropathy (DPN) and the CAVI. One hundred sixty-six patients with type 2 diabetes mellitus were included in this study. We used nerve conduction studies (NCSs) and the coefficient of variation of the R-R interval to evaluate DPN. We estimated arteriosclerosis by the CAVI. Simple and multiple linear regression analyses were performed between neuropathy indices and the CAVI. In univariate analysis, the CAVI showed significant associations with sural sensory nerve conduction velocity and median F-wave conduction velocity. Multiple linear regression analysis for the CAVI showed that sural nerve conduction velocity and median F-wave conduction velocity were significant explanatory variables second only to age. In multiple linear regression analysis for sural nerve conduction velocity among neuropathy indices, the CAVI remained the most significant explanatory variable. In multiple linear regression analysis for median nerve F-wave conduction velocity among neuropathy indices, the CAVI remained the second most significant explanatory variable following HbA1c. These results suggest a close relationship between macroangiopathy and DPN. Akihiko Ando, Michiaki Miyamoto, Kazuhiko Kotani, Kenta Okada, Shoichiro Nagasaka, and Shun Ishibashi Copyright © 2017 Akihiko Ando et al. All rights reserved. Not Only Glycaemic But Also Other Metabolic Factors Affect T Regulatory Cell Counts and Proinflammatory Cytokine Levels in Women with Type 1 Diabetes Wed, 03 May 2017 09:35:38 +0000 Type 1 diabetic (T1D) patients suffer from insulinopenia and hyperglycaemia. Studies have shown that if a patient’s hyperglycaemic environment is not compensated, it leads to complex immune dysfunctions. Similarly, T1D mothers with poor glycaemic control exert a negative impact on the immune responses of their newborns. However, questions concerning the impact of other metabolic disturbances on the immune system of T1D mothers (and their newborns) have been raised. To address these questions, we examined 28 T1D women in reproductive age for the relationship between various metabolic, clinical, and immune parameters. Our study revealed several unexpected correlations which are indicative of a much more complex relationship between glucose and lipid factors (namely, glycosylated haemoglobin Hb1Ac, the presence of one but not multiple chronic diabetic complications, and atherogenic indexes) and proinflammatory cytokines (IL-1alpha and TNF-alpha). Regulatory T cell counts correlated with HbA1c, diabetic neuropathy, lipid spectra parameters, and IL-6 levels. Total T-helper cell count was interconnected with BMI and glycaemia variability correlated with lipid spectra parameters, insulin dose, and vitamin D levels. These and other correlations revealed in this study provide broader insight into the association of various metabolic abnormalities with immune parameters that may impact T1D mothers or their developing child. Katerina Stechova, Jana Sklenarova-Labikova, Tereza Kratzerova, Pavlina Pithova, and Dominik Filipp Copyright © 2017 Katerina Stechova et al. All rights reserved. The CNDP1 (CTG)5 Polymorphism Is Associated with Biopsy-Proven Diabetic Nephropathy, Time on Hemodialysis, and Diabetes Duration Wed, 03 May 2017 03:55:45 +0000 Considering that the homozygous CNDP1 (CTG)5 genotype affords protection against diabetic nephropathy (DN) in female patients with type 2 diabetes, this study assessed if this association remains gender-specific when applying clinical inclusion criteria (CIC-DN) or biopsy proof (BP-DN). Additionally, it assessed if the prevalence of the protective genotype changes with diabetes duration and time on hemodialysis and if this occurs in association with serum carnosinase (CN-1) activity. Whereas the distribution of the (CTG)5 homozygous genotype in the no-DN and CIC-DN patients was comparable, a lower frequency was found in the BP-DN patients, particularly in females. We observed a significant trend towards high frequencies of the (CTG)5 homozygous genotype with increased time on dialysis. This was also observed for diabetes duration but only reached significance when both (CTG)5 homo- and heterozygous patients were included. CN-1 activity negatively correlated with time on hemodialysis and was lower in (CTG)5 homozygous patients. The latter remained significant in female subjects after gender stratification. We confirm the association between the CNDP1 genotype and DN to be likely gender-specific. Although our data also suggest that (CTG)5 homozygous patients may have a survival advantage on dialysis and in diabetes, this hypothesis needs to be confirmed in a prospective cohort study. Thomas Albrecht, Shiqi Zhang, Jana D. Braun, Li Xia, Angelica Rodriquez, Jiedong Qiu, Verena Peters, Claus P. Schmitt, Jacob van den Born, Stephan J. L. Bakker, Alexander Lammert, Hannes Köppel, Peter Schnuelle, Bernhard K. Krämer, Benito A. Yard, and Sibylle J. Hauske Copyright © 2017 Thomas Albrecht et al. All rights reserved. Diabetes Risk Score in a Young Student Population in Jordan: A Cross-Sectional Study Sun, 30 Apr 2017 00:00:00 +0000 Background. The Middle East is the home to the most obese population in the world, and type 2 diabetes mellitus is endemic in the region. However, little is known about risk factors for diabetes in the younger age groups. Methods. The Finnish Diabetes Risk Score (FINDRISC) is a simple, validated tool to identify persons at risk of diabetes. We investigated students at Hashemite University in Jordan with FINDRISC and measured fasting plasma glucose in those who were categorized in the high-risk group. Results. Overall, 1821 students (881 [48.4%] female) were included in the study. Risk factors for diabetes were common: 422 (23.2%) were overweight or obese and 497 (27.3%) had central obesity. Using the FINDRISC score, 94 (5.2%) students were at moderate risk and 32 (1.8%) at high risk of diabetes. The mean FINDRISC score was significantly higher in men than women (5.9 versus 5.4; ). Twenty-eight students in the high-risk group had a subsequent plasma glucose measurement, and 8 (29%) of them fulfilled the diagnostic criteria for diabetes. Conclusions. Risk factors for diabetes were common in a young student population in Jordan, suggesting that preventive measures should be initiated early in adulthood to turn the diabetes epidemic in the region. Abdel-Ellah Al-Shudifat, Amjad Al-Shdaifat, Ahmad Ali Al-Abdouh, Mohammad Ibrahim Aburoman, Sara Mohammad Otoum, Amro Ghaleb Sweedan, Ibrahim Khrais, Ibrahim Hisham Abdel-Hafez, and Asgeir Johannessen Copyright © 2017 Abdel-Ellah Al-Shudifat et al. All rights reserved. Relationships between Composition of Major Fatty Acids and Fat Distribution and Insulin Resistance in Japanese Sun, 30 Apr 2017 00:00:00 +0000 Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (, ), fasting glucose (, ), HbA1c (, ), and systolic blood pressure (, ). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (, ) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects. Chikako Fujii, Toshihide Kawai, Koichiro Azuma, Yuko Oguma, Fuminori Katsukawa, Hiroshi Hirose, Kumiko Tanaka, Shu Meguro, Hideo Matsumoto, and Hiroshi Itoh Copyright © 2017 Chikako Fujii et al. All rights reserved. Spatiotemporal Regulators for Insulin-Stimulated GLUT4 Vesicle Exocytosis Wed, 26 Apr 2017 00:00:00 +0000 Insulin increases glucose uptake and storage in muscle and adipose cells, which is accomplished through the mobilization of intracellular GLUT4 storage vesicles (GSVs) to the cell surface upon stimulation. Importantly, the dysfunction of insulin-regulated GLUT4 trafficking is strongly linked with peripheral insulin resistance and type 2 diabetes in human. The insulin signaling pathway, key signaling molecules involved, and precise trafficking itinerary of GSVs are largely identified. Understanding the interaction between insulin signaling molecules and key regulatory proteins that are involved in spatiotemporal regulation of GLUT4 vesicle exocytosis is of great importance to explain the pathogenesis of diabetes and may provide new potential therapeutic targets. Xiaoxu Zhou, Ping Shentu, and Yingke Xu Copyright © 2017 Xiaoxu Zhou et al. All rights reserved. Podocyte Autophagy: A Potential Therapeutic Target to Prevent the Progression of Diabetic Nephropathy Sun, 23 Apr 2017 00:00:00 +0000 Diabetic nephropathy (DN), a leading cause of end-stage renal disease (ESRD), becomes a worldwide problem. Ultrastructural changes of the glomerular filtration barrier, especially the pathological changes of podocytes, lead to proteinuria in patients with diabetes. Podocytes are major components of glomerular filtration barrier, lining outside of the glomerular basement membrane (GBM) to maintain the permeability of the GBM. Autophagy is a high conserved cellular process in lysosomes including impaired protein, cell organelles, and other contents in the cytoplasm. Recent studies suggest that activation of autophagy in podocytes may be a potential therapy to prevent the progression of DN. Here, we review the mechanisms of autophagy in podocytes and discuss the current studies about alleviating proteinuria via activating podocyte autophagy. Na Liu, Liuqing Xu, Yingfeng Shi, and Shougang Zhuang Copyright © 2017 Na Liu et al. All rights reserved. Role of Nuclear Factor Erythroid 2-Related Factor 2 in Diabetic Nephropathy Sun, 23 Apr 2017 00:00:00 +0000 Diabetic nephropathy (DN) is manifested as increased urinary protein level, decreased glomerular filtration rate, and final renal dysfunction. DN is the leading cause of end-stage renal disease worldwide and causes a huge societal healthcare burden. Since satisfied treatments are still limited, exploring new strategies for the treatment of this disease is urgently needed. Oxidative stress takes part in the initiation and development of DN. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the cellular response to oxidative stress. Thus, activation of Nrf2 seems to be a new choice for the treatment of DN. In current review, we discussed and summarized the therapeutic effects of Nrf2 activation on DN from both basic and clinical studies. Wenpeng Cui, Xu Min, Xiaohong Xu, Bing Du, and Ping Luo Copyright © 2017 Wenpeng Cui et al. All rights reserved. The Effectiveness of Lifestyle Adaptation for the Prevention of Prediabetes in Adults: A Systematic Review Sun, 16 Apr 2017 08:22:21 +0000 Diabetes prevalence is increasing exceptionally worldwide and with this come associated healthcare costs. The primary outcome of this systematic review was to assess glycaemic control and incidence of Type 2 diabetes mellitus (T2DM) diagnosis after exercise and dietary intervention (measured with any validated scale). The secondary outcome assessed body mass index change, weight change, and physical exercise capacity after diet and exercise intervention (measured with any validated scale). 1,780 studies were identified from searching electronic databases. Relevant studies went through a selection process. The inclusion criteria for all studies were people with prediabetes diagnosed by either impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). Lifestyle adaptation reduced the incidence of diabetes development more than standard treatment. Furthermore, better glycaemic control, improved physical exercise capacity, and increased weight reduction were observed with lifestyle intervention over standard treatment. Finally, improvements over the long term deteriorated, highlighting problems with long-term adherence to lifestyle changes. Overall, cumulative incidence of diabetes is drastically reduced in the intervention groups compared to control groups (standard care). Furthermore, glycaemic control was improved in the short term, with many participants reverting to normoglycaemia. George Kerrison, Richard B. Gillis, Shahwar I. Jiwani, Qushmua Alzahrani, Samil Kok, Stephen E. Harding, Ian Shaw, and Gary G. Adams Copyright © 2017 George Kerrison et al. All rights reserved. The Imbalance of B-Lymphocyte Subsets in Subjects with Different Glucose Tolerance: Relationship with Metabolic Parameter and Disease Status Sun, 16 Apr 2017 07:08:21 +0000 B lymphocytes are involved in inflammation and are related to insulin resistance in obesity and type 2 diabetes (T2D). This study investigated the phenotype and frequency of B-lymphocyte subsets in subjects recently diagnosed with T2D (), impaired glucose regulation (IGR, ), and normal glucose tolerance (NGT, ) by flow cytometry. T2D subjects had an increased percentage of CD19+CD23+ (B-2) cells and a decreased percentage of CD19+CD23− (B-1) cells attributing to CD19+CD23−CD5− (B-1b) cells, but not CD19+CD23−CD5+ (B-1a) cells, compared to NGT and IGR subjects. The proportion of CD19+CD5+CD1dhi (B10) cells did not differ between the IGR or T2D group and NGT controls. Of note, HbA1c and triglyceride showed a positive correlation with B-2 cells but an inverse correlation with B-1 and B-1b cells, which were independently associated with the presence of T2D by logistic regression models. In summary, this study shows an unbalanced proinflammatory phenotype of B-cell subsets correlated with glycemia and lipidemia in patients with T2D. Our data provide new insight into chronic activation of the immune system and subclinical inflammation in T2D. Further prospective studies are warranted to confirm our observations. Chao Deng, Yufei Xiang, Tingting Tan, Zhihui Ren, Chuqing Cao, Bingwen Liu, Gan Huang, Xiangbing Wang, and Zhiguang Zhou Copyright © 2017 Chao Deng et al. All rights reserved. Noninvasive Retinal Markers in Diabetic Retinopathy: Advancing from Bench towards Bedside Thu, 13 Apr 2017 05:13:49 +0000 The retinal vascular system is the only part of the human body available for direct, in vivo inspection. Noninvasive retinal markers are important to identity patients in risk of sight-threatening diabetic retinopathy. Studies have correlated structural features like retinal vascular caliber and fractals with micro- and macrovascular dysfunction in diabetes. Likewise, the retinal metabolism can be evaluated by retinal oximetry, and higher retinal venular oxygen saturation has been demonstrated in patients with diabetic retinopathy. So far, most studies have been cross-sectional, but these can only disclose associations and are not able to separate cause from effect or to establish the predictive value of retinal vascular dysfunction with respect to long-term complications. Likewise, retinal markers have not been investigated as markers of treatment outcome in patients with proliferative diabetic retinopathy and diabetic macular edema. The Department of Ophthalmology at Odense University Hospital, Denmark, has a strong tradition of studying the retinal microvasculature in diabetic retinopathy. In the present paper, we demonstrate the importance of the retinal vasculature not only as predictors of long-term microvasculopathy but also as markers of treatment outcome in sight-threatening diabetic retinopathy in well-established population-based cohorts of patients with diabetes. Søren Leer Blindbæk, Thomas Lee Torp, Kristian Lundberg, Kerstin Soelberg, Anna Stage Vergmann, Christina Døfler Poulsen, Ulrik Frydkjaer-Olsen, Rebecca Broe, Malin Lundberg Rasmussen, Jimmi Wied, Majbrit Lind, Anders Højslet Vestergaard, Tunde Peto, and Jakob Grauslund Copyright © 2017 Søren Leer Blindbæk et al. All rights reserved. Incidence and Contributing Factors of Persistent Hyperglycemia at 6–12 Weeks Postpartum in Iranian Women with Gestational Diabetes: Results from LAGA Cohort Study Wed, 12 Apr 2017 06:36:25 +0000 Background. A history of gestational diabetes is an important predictor of many metabolic disturbances later in life. Method. Life after gestational diabetes Ahvaz Study (LAGAs) is an ongoing population-based cohort study. Up to February 2016, 176 women with gestational diabetes underwent a 75 g oral glucose tolerance test (OGTT) at 6–12 weeks postpartum in Ahvaz (southwestern of Iran). Gestational diabetes was diagnosed according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria and the American Diabetes Association (ADA) criteria applied for diagnosis of postpartum prediabetes and diabetes. Univariate and multivariate regression analysis were done. Results. Overall incidence of early postpartum glucose intolerance was 22.2% (95% CI, 16.3–29.0), 17.6% prediabetes (95% CI, 12.3–24.1) and 4.5% diabetes (95% CI, 2.0–8.8%). Independent risk factors for glucose intolerance were FPG ≥ 100 at the time of OGTT (OR 3.86; 95% CI; 1.60–9.32), earlier diagnosis of GDM (OR 0.92; 95% CI; 0.88–0.97), systolic blood pressure (OR 1.02; 95% CI; 1.002–1.04), and insulin or metformin therapy (OR 3.14; 95% CI; 1.20–8.21). Conclusion. Results determined a relatively high rate of glucose intolerance at 6–12 weeks after GDM pregnancy. Early postpartum screening of type 2 diabetes is needed particularly in women at high risk of type 2 diabetes. Sedigheh Nouhjah, Hajieh Shahbazian, Nahid Shahbazian, Alireza Jahanshahi, Shayesteh Jahanfar, and Bahman Cheraghian Copyright © 2017 Sedigheh Nouhjah et al. All rights reserved. Adipose Tissue-Specialized Immunologic Features Might Be the Potential Therapeutic Target of Prospective Medicines for Obesity Thu, 30 Mar 2017 00:00:00 +0000 Excessive lipid accumulation in adipose tissue is either the source of obesity or the cause and result of chronic local inflammation, and recent studies indicate that the accumulation may induce many other specialized immunologic features with macrophages and epidemic diseases. We analyze the effective stages of immune cells in adipose tissue, including macrophage recruitment, macrophage polarization, and macrophage-like phenotype preadipocyte possession to find optimal sites as drug targets. Subsequently, some main signaling pathways are summarized in this review, including the AMP-activated protein kinase (AMPK) pathway, the JNK signaling pathway, and a novel one, the Notch signaling pathway. We illustrate all these points in order to determine the general pathogenesis of chronic low-grade local inflammation in adipose tissue and the related signaling pathways. In addition, signal-associated prospective compounds, such as berberine, are summarized and discussed with potential targets in pathogenesis. This might provide some possible thoughts and novel therapies for studying chronic inflammatory diseases, such as insulin resistance and type 2 diabetes mellitus. Fan Yao, Ming Zhang, and Li Chen Copyright © 2017 Fan Yao et al. All rights reserved. Serum 25-Hydroxyvitamin D3 Levels Are Associated with Carotid Intima-Media Thickness and Carotid Atherosclerotic Plaque in Type 2 Diabetic Patients Tue, 28 Mar 2017 07:44:29 +0000 Objective. To investigate the relationship between serum 25-hydroxyvitamin D3 [25(OH)D3] levels and carotid intima-media thickness (IMT) as well as carotid atherosclerotic plaque in patients with type 2 diabetes mellitus (T2DM). Methods. 314 patients with T2DM were enrolled in this study. The clinical data and laboratory examinations of subjects were recorded, such as serum 25(OH)D3, hemoglobin A1c (HbA1c), serum lipids, fasting blood glucose (FBG), and other biochemical parameters. Color Doppler ultrasound was used to measure carotid IMT and carotid atherosclerotic plaques. Patients were divided into four quartile groups according to the serum 25(OH)D3 levels from low to high: group Q1~group Q4. Results. From group Q1 to group Q4, carotid IMT and the incidence of plaque were gradually reduced. Serum 25(OH)D3 levels were lower in the plaque group compared with the nonplaque group (). Serum 25(OH)D3 levels were negatively correlated with the carotid IMT (, ). Multiple linear stepwise regression analysis showed that serum 25(OH)D3 was independently associated with carotid IMT (, ). Logistic regression analysis showed that serum 25(OH)D3 levels were independently associated with the presence of carotid plaque in T2DM (OR = 0.95; 95%CI: 0.92~0.98, ). Conclusions. Low vitamin D status may contribute to the incidence of carotid atherosclerosis in type 2 diabetic patients. Yurong Wang and Huijuan Zhang Copyright © 2017 Yurong Wang and Huijuan Zhang All rights reserved. MicroRNAs-Mediated Regulation of Skeletal Muscle GLUT4 Expression and Translocation in Insulin Resistance Mon, 27 Mar 2017 00:00:00 +0000 The solute carrier family 2 facilitated glucose transporter member 4 (GLUT4) plays a key role in the insulin-induced glucose uptake by muscle and adipose tissues. In prediabetes and diabetes, GLUT4 expression/translocation has been detected as reduced, participating in mechanisms that impair glycemic control. Recently, a class of short endogenous noncoding RNAs named microRNAs (miRNAs) has been increasingly described as involved in the posttranscriptional epigenetic regulation of gene expression. The present review focuses on miRNAs potentially involved in the expression of GLUT4 expression, and proteins related to GLUT4 and translocation in skeletal muscle, seeking to correlate them with insulin resistance and diabetes. So far, miR-21a-5p, miR-29a-3p, miR-29c-3p, miR-93-5p, miR-106b-5p, miR-133a-3p, miR-133b-3p, miR-222-3p, and miR-223-3p have been reported to directly and/or indirectly regulate the GLUT4 expression; and their expression is altered under diabetes-related conditions. Besides, some miRNAs that have been linked to the expression of proteins involved in GLUT4 translocation machinery in muscle could also impact glucose uptake. That makes these miRNAs promising targets for preventive and/or therapeutic approaches, which could improve glycemic control, thus deserving future new investigations. João Victor Esteves, Francisco Javier Enguita, and Ubiratan Fabres Machado Copyright © 2017 João Victor Esteves et al. All rights reserved. Therapeutic Effects of Static Magnetic Field on Wound Healing in Diabetic Rats Sun, 26 Mar 2017 00:00:00 +0000 Objective. To investigate the effects of static magnetic field (SMF) on cutaneous wound healing of Streptozotocin- (STZ-) induced diabetic rats. Methods. 20 STZ-induced diabetic rats were randomly divided into two groups (10 in each group): diabetic rats with SMF exposure group which were exposed to SMF by gluing one magnetic disk of 230 mT intensity and diabetic rats with sham SMF exposure group (sham group). 10 normal Wistar rats were used as the control group. One open circular wound with 2 cm diameter in the dorsum was generated on both normal and diabetic rats and then covered with sterile gauzes. Wound healing was evaluated by wound area reduction rate, mean time to wound closure, and wound tensile strength. Results. The wound area reduction rate in diabetic rats in comparison with the control group was significantly decreased (). Compared with sham magnet group, diabetic rats under 230 mT SMF exposure demonstrated significantly accelerated wound area reduction rate on postoperative days 7, 14, and 21 and decreased gross time to wound closure (), as well as dramatically higher wound tissue strength () on 21st day. Conclusion. 230 mT SMF promoted the healing of skin wound in diabetic rats and may provide a non-invasive therapeutic tool for impaired wound healing of diabetic patients. Jing Zhao, Yong-guo Li, Kai-qin Deng, Peng Yun, and Ting Gong Copyright © 2017 Jing Zhao et al. All rights reserved. The Preferential Impairment of Pupil Constriction Stimulated by Blue Light in Patients with Type 2 Diabetes without Autonomic Neuropathy Wed, 22 Mar 2017 00:00:00 +0000 The main aim of the present paper is to examine whether the pupillary light reflex (PLR) mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) is impaired in type 2 diabetic patients. One hundred and three diabetic patients without diabetic autonomic neuropathy (DAN) and 42 age-matched controls underwent a series of detailed neurological examinations. The patients were stratified into three groups: stage I, no neuropathy; stage II, asymptomatic neuropathy; stage III, symptomatic but without DAN. The PLR to 470 and 635 nm light at 20 cd/m2 was recorded. Small fiber neuropathy was assessed by corneal confocal microscopy and quantifying corneal nerve fiber (CNF) morphology. The 470 nm light induced a stronger and faster PLR than did 635 nm light in all subjects. The PLR to both lights was impaired equally across all of the diabetic subgroups. The postillumination pupil response (PIPR) after 470 nm light offset at ≥1.7 sec was attenuated in diabetic patients without differences between subgroups. Receiver operating characteristic analysis revealed that the PIPR mediated by ipRGCs in patients with stage II and stage III neuropathy was different from that of the control subjects. Clinical factors, nerve conduction velocity, and CNF measures were significantly correlated with PLR parameters with 470 nm light. PLR kinetics were more impaired by stimulation with blue light than with red light in diabetic patients without DAN. Fukashi Ishibashi, Rie Kojima, Miki Taniguchi, Aiko Kosaka, Harumi Uetake, and Mitra Tavakoli Copyright © 2017 Fukashi Ishibashi et al. All rights reserved. The Increased Circulating Plasma Levels of Vascular Endothelial Growth Factor in Patients with Type 1 Diabetes Do Not Correlate to Metabolic Control Tue, 21 Mar 2017 08:19:39 +0000 Aim. To characterize the plasma levels of vascular endothelial growth factor (VEGF) in type 1 diabetes mellitus (T1D) and its relation to both present and historical metabolic control and microvascular complications. Methods. Plasma levels of VEGF and routine clinical parameters were analyzed in 115 patients with long-standing T1D and 45 healthy controls (HC). All patients were under clinical routine diabetes treatment at Uppsala University Hospital. Results. The plasma levels of VEGF were increased by 37% in patients with T1D when compared to HC ( versus  pg/ml, ). The levels of VEGF correlated to insulin needs and BMI but not to present or historical metabolic control. The levels of VEGF were similar in patients with T1D and microvascular complications (microalbuminuria and retinopathy) when compared with patients without microvascular complications. Historical HbA1c levels were found to be the best predictor for present metabolic control. Conclusion. Circulating plasma levels of VEGF do not correlate to present or historical metabolic control in long-standing T1D and the levels are not affected by the presence of microvascular complications. Kailash Singh, Stellan Sandler, and Daniel Espes Copyright © 2017 Kailash Singh et al. All rights reserved. Diabetic Cardiomyopathy: Current Approach and Potential Diagnostic and Therapeutic Targets Tue, 21 Mar 2017 00:00:00 +0000 Although ischemic heart disease is the major cause of death in diabetic patients, diabetic cardiomyopathy (DCM) is increasingly recognized as a clinically relevant entity. Considering that it comprises a variety of mechanisms and effects on cardiac function, increasing the risk of heart failure and worsening the prognosis of this patient category, DCM represents an important complication of diabetes mellitus, with a silent development in its earlier stages, involving intricate pathophysiological mechanisms, including oxidative stress, defective calcium handling, altered mitochondrial function, remodeling of the extracellular matrix, and consequent deficient cardiomyocyte contractility. While DCM is common in diabetic asymptomatic patients, it is frequently underdiagnosed, due to few diagnostic possibilities in its early stages. Moreover, since a strategy for prevention and treatment in order to improve the prognosis of DCM has not been established, it is important to identify clear pathophysiological landmarks, to pinpoint the available diagnostic possibilities and to spot potential therapeutic targets. Georgiana-Emmanuela Gilca, Gabriela Stefanescu, Oana Badulescu, Daniela-Maria Tanase, Iris Bararu, and Manuela Ciocoiu Copyright © 2017 Georgiana-Emmanuela Gilca et al. All rights reserved. Synergistic Effect of the MTHFR C677T and EPHX2 G860A Polymorphism on the Increased Risk of Ischemic Stroke in Chinese Type 2 Diabetic Patients Mon, 20 Mar 2017 09:07:48 +0000 The aim of this study was to investigate the relationship between the combined effect of MTHFR C677T (rs1801133) and EPHX2 G860A (rs751141) polymorphism and ischemic stroke in Chinese T2DM patients. This case-control study included a total of 626 Chinese T2DM patients (236 T2DM patients with ischemic stroke and 390 T2DM patients without ischemic stroke). The rs1801133 and rs751141 were genotyped using real-time polymerase chain reaction. Statistical analysis was performed with SPSS 17.0. Results showed that the combined effect of MTHFR TT and EPHX2 GG or GA + AA genotype has a higher risk of ischemic stroke compared with the control group (combined effect of MTHFR CC and EPHX2 GA + AA genotypes; OR = 3.46 and OR = 3.42, resp.; and , resp.). The A allele showed marked association with a lower risk of ischemic stroke in patients with the lowest Hcy levels under additive, recessive, and dominant genetic models (OR = 0.45, OR = 0.11, and OR = 0.44, resp.; , , and , resp.), which was not observed in medium or high Hcy level groups. In conclusion, the T allele of rs1801133 and the G allele of rs751141 may be risk factors of ischemic stroke in the Chinese T2DM population. Liang Ma, Yongwei Jiang, Xiaomu Kong, Meihua Yan, Tingting Zhao, Hailing Zhao, Qian Liu, Haojun Zhang, Yongtong Cao, and Ping Li Copyright © 2017 Liang Ma et al. All rights reserved.