Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Small Islets Transplantation Superiority to Large Ones: Implications from Islet Microcirculation and Revascularization Wed, 16 Apr 2014 12:31:45 +0000 Pancreatic islet transplantation is a promising therapy to regain glycemic control in diabetic patients. The selection of ideal grafts is the basis to guarantee short-term effectivity and longevity of the transplanted islets. Contradictory to the traditional notion, recent findings implied the superiority of small islets for better transplantation outcomes rather than the large and intact ones. However, the mechanisms remain to be elucidated. Recent evidences emphasized the major impact of microcirculation on islet β-cell mass and function. And potentials in islet graft revascularization are crucial for their survival and preserved function in the recipient. In this study, we verified the distinct histological phenotype and functionality of small islets versus large ones both in vitro and in vivo. With efforts to exploring the differences in microcirculation and revascularization of islet grafts, we further evaluated local expressions of angiotensin and vascular endothelial growth factor A (VEGF-A) at different levels. Our findings reveal that, apart from the higher density of insulin-producing β-cells, small islets express less angiotensin and more angiotrophic VEGF-A. We therefore hypothesized a logical explanation of the small islet superiority for transplantation outcome from the aspects of facilitated microcirculation and revascularization intrinsically in small islets. Wenjuan Li, Ruxing Zhao, Jidong Liu, Meng Tian, Yiran Lu, Tianyi He, Meng Cheng, Kai Liang, Xia Li, Xiangdong Wang, Yu Sun, and Li Chen Copyright © 2014 Wenjuan Li et al. All rights reserved. The Visualization of Biofilms in Chronic Diabetic Foot Wounds Using Routine Diagnostic Microscopy Methods Tue, 15 Apr 2014 14:05:49 +0000 Diabetic foot wounds are commonly colonised by taxonomically diverse microbial communities and may additionally be infected with specific pathogens. Since biofilms are demonstrably less susceptible to antimicrobial agents than are planktonic bacteria, and may be present in chronic wounds, there is increasing interest in their aetiological role. In the current investigation, the presence of structured microbial assemblages in chronic diabetic foot wounds is demonstrated using several visualization methods. Debridement samples, collected from the foot wounds of diabetic patients, were histologically sectioned and examined using bright-field, fluorescence, and environmental scanning electron microscopy and assessed by quantitative differential viable counting. All samples (n = 26) harboured bioburdens in excess of 5 log10 CFU/g. Microcolonies were identified in 4/4 samples by all three microscopy methods, although bright-field and fluorescence microscopy were more effective at highlighting putative biofilm morphology than ESEM. Results in this pilot study indicate that bacterial microcolonies and putative biofilm matrix can be visualized in chronic wounds using florescence microscopy and ESEM, but also using the simple Gram stain. Angela Oates, Frank L. Bowling, Andrew J. M. Boulton, Philip G. Bowler, Daniel G. Metcalf, and Andrew J. McBain Copyright © 2014 Angela Oates et al. All rights reserved. Serum Fibroblast Growth Factor 21 Levels Are Correlated with the Severity of Diabetic Retinopathy Tue, 15 Apr 2014 13:25:53 +0000 The aim of the study was to assess serum fibroblast growth factor 21 (FGF21) concentrations in Chinese type 2 diabetic patients with and without retinopathy and to assess the association between FGF21 and the severity of retinopathy. 117 diabetic patients were compared with 68 healthy controls. Fasting blood glucose, serum total cholesterol, serum triglycerides, serum insulin, and serum FGF21 levels were estimated. FGF21 concentrations in the patients were significantly higher than those in control. In the patient group there was a significant positive correlation between FGF21, insulin level, and homeostasis model assessment index. Serum FGF21 concentrations in patients with proliferative diabetic retinopathy or nonproliferative diabetic retinopathy were significantly higher than those in patients without diabetic retinopathy. When the presence of diabetes was defined as the final variable in the conditional logistic regression model with the FGF21 concentration as the continuous variable, FGF21 was significantly involved in the model. This study shows that the increase in serum concentration of FGF21 was associated with the severity of diabetic retinopathy and suggests that FGF21 may play a role in the pathogenesis of diabetic retinopathy and its degree. Yuan Lin, Ye-cheng Xiao, Hong Zhu, Qing-yan Xu, Lei Qi, Yu-bin Wang, Xiu-juan Li, Ma-li Zheng, Rui-sheng Zhong, Yi Zhang, Xiang-dong Xu, Bo-le Wu, Zhu-mei Xu, and Xiang-hong Lu Copyright © 2014 Yuan Lin et al. All rights reserved. Impaired Cell Function in Chinese Newly Diagnosed Type 2 Diabetes Mellitus with Hyperlipidemia Mon, 14 Apr 2014 08:21:49 +0000 The objective is to explore the effects of hyperlipidemia on β cell function in newly diagnosed type 2 diabetes mellitus (T2DM). 208 patients were enrolled in the study and were divided into newly diagnosed T2DM with hyperlipidemia (132 patients) and without hyperlipidemia (76 patients). Demographic data, glucose levels, insulin levels, lipid profiles, homeostasis model assessment for β cell function index (HOMA-β), homeostasis model assessment for insulin resistance index (HOMA-IR), and quantitative insulin-sensitivity check index (QUICKI) were compared between the two groups. We found that comparing with those of normal lipid levels, the subjects of newly diagnosed T2DM with hyperlipidemia were younger, and had declined HOMA-β. However, the levels of HOMA-β were comparable regardless of different lipid profiles (combined hyperlipidemia, hypertriglyceridemia, and hypercholesterolemia). Multiple stepwise linear regression analysis showed that high fasting plasma glucose (FPG), decreased fasting insulin level (FINS), and high triglyceride (TG) were independent risk factors of β cell dysfunction in newly diagnosed T2DM. Therefore, the management of dyslipidemia, together with glucose control, may be beneficial for T2DM with hyperlipidemia. Yuhang Ma, Yufan Wang, Qianfang Huang, Qian Ren, Su Chen, Aifang Zhang, Li Zhao, Qin Zhen, and Yongde Peng Copyright © 2014 Yuhang Ma et al. All rights reserved. Downregulation of Bcl-2 Expression by miR-34a Mediates Palmitate-Induced Min6 Cells Apoptosis Mon, 14 Apr 2014 06:48:04 +0000 Recent studies have demonstrated that the expression of miR-34a is significantly upregulated and associated with cell apoptosis in pancreatic β-cell treated with palmitate. Nevertheless, the underlying detailed mechanism is largely unknown. Here, we showed that miR-34a was significantly induced in Min6 pancreatic β-cell upon palmitate treatment. Elevated miR-34a promoted Min6 cell apoptosis. Intriguingly, ectopic expression of miR-34a lowered the expression of Bcl-2, an antiapoptotic protein. Luciferase reporter assay indicated the direct interaction of miR-34a with the Bcl-2 3′-UTR. Moreover, downregulated expression of Bcl-2 induced by palmitate could be restored by inhibition of miR-34a. We conclude that direct suppression of Bcl-2 by miR-34a accounts for palmitate-induced increased apoptosis rate in pancreatic β-cell. Xiaojie Lin, Hongyu Guan, Zhimin Huang, Juan Liu, Hai Li, Guohong Wei, Xiaopei Cao, and Yanbing Li Copyright © 2014 Xiaojie Lin et al. All rights reserved. Ketosis Onset Type 2 Diabetes Had Better Islet -Cell Function and More Serious Insulin Resistance Sun, 13 Apr 2014 13:03:25 +0000 Diabetic ketosis had been identified as a characteristic of type 1 diabetes mellitus (T1DM), but now emerging evidence has identified that they were diagnosed as T2DM after long time follow up. This case control study was aimed at comparing the clinical characteristic, -cell function, and insulin resistance of ketosis and nonketotic onset T2DM and providing evidence for treatment selection. 140 cases of newly diagnosed T2DM patients were divided into ketosis (62 cases) and nonketotic onset group (78 cases). After correction of hyperglycemia and ketosis with insulin therapy, plasma C-peptide concentrations were measured at 0, 0.5, 1, 2, and 3 hours after 75 g glucose oral administration. Area under the curve (AUC) of C-peptide was calculated. Homoeostasis model assessment was used to estimate basal -cell function (HOMA-) and insulin resistance (HOMA-IR). Our results showed that ketosis onset group had higher prevalence of nonalcoholic fatty liver disease (NAFLD) than nonketotic group (). Ketosis onset group had increased plasma C-peptide levels at 0 h, 0.5 h, and 3 h and higher , , (). Moreover, this group also had higher HOMA- and HOMA-IR than nonketotic group (). From these data, we concluded that ketosis onset T2DM had better islet -cell function and more serious insulin resistance than nonketotic onset T2DM. Hongyun Lu, Fang Hu, Yingjuan Zeng, Lingling Zou, Shunkui Luo, Ying Sun, Hong Liu, and Liao Sun Copyright © 2014 Hongyun Lu et al. All rights reserved. Management of Cardiorenal Metabolic Syndrome in Diabetes Mellitus: A Phytotherapeutic Perspective Sun, 13 Apr 2014 00:00:00 +0000 Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidney are simultaneously affected and their deleterious declining functions are reinforced in a feedback cycle, with an accelerated progression. Although the coexistence of kidney and heart failure in the same individual carries an extremely bad prognosis, the exact cause of deterioration and the pathophysiological mechanisms underlying the initiation and maintenance of the interaction are complex, multifactorial in nature, and poorly understood. Current therapy includes diuretics, natriuretic hormones, aquaretics (arginine vasopressin antagonists), vasodilators, and inotropes. However, large numbers of patients still develop intractable disease. Moreover, the development of resistance to many standard therapies, such as diuretics and inotropes, has led to an increasing movement toward utilization and development of novel therapies. Herbal and traditional natural medicines may complement or provide an alternative to prevent or delay the progression of CRS. This review provides an analysis of the possible mechanisms and the therapeutic potential of phytotherapeutic medicines for the amelioration of the progression of CRS. Min Kyong Song, Neal M. Davies, Basil D. Roufogalis, and Tom Hsun-Wei Huang Copyright © 2014 Min Kyong Song et al. All rights reserved. Evaluation of Serum Fibrinogen, Plasminogen, α2-Anti-Plasmin, and Plasminogen Activator Inhibitor Levels (PAI) and Their Correlation with Presence of Retinopathy in Patients with Type 1 DM Thu, 10 Apr 2014 17:33:10 +0000 Background. Diabetic retinopathy (DR) is the leading cause of blindness in the world. Retinopathy can still progress despite optimal metabolic control. The aim of the study was to determine whether different degrees of DR (proliferative or nonproliferative) were associated with abnormally modulated hemostatic parameters in patients with T1DM. Method. 52 T1DM patients and 40 healthy controls were enrolled in the study. Patients were subdivided into three categories. Group I was defined as those without retinopathy, group II with NPRP, and group III with PRP. We compared these subgroups with each other and the control group (Group IV) according to the serum fibrinogen, plasminogen, alpha2-anti-plasmin (α2-anti-plasmin), and PAI. Results. We detected that PAI-1, serum fibrinogen, and plasminogen levels were similar between the diabetic and control groups (, , and , resp.), whereas α2-anti-plasmin was higher in Groups I, II, and III compared to the control group (, , and , resp.). There was a positive correlation between serum α2-anti-plasmin and HbA1c levels (, ). Conclusion. To our knowledge there is scarce data in the literature about α2-anti-plasmin levels in type 1 diabetes. A positive correlation between α2-anti-plasmin with HbA1c suggests that fibrinolytic markers may improve with disease regulation and better glycemic control. Sefika Burcak Polat, Nagihan Ugurlu, Fatma Yulek, Huseyin Simavli, Reyhan Ersoy, Bekir Cakir, and Ozcan Erel Copyright © 2014 Sefika Burcak Polat et al. All rights reserved. Lipoprotein-Associated Phospholipase A2 Mass Level Is Increased in Elderly Subjects with Type 2 Diabetes Mellitus Thu, 10 Apr 2014 12:52:43 +0000 Objective. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is extensively expressed by advanced atherosclerotic lesions and may play a role in plaque instability. We selected a group of elderly subjects that underwent transcatheter aortic valve implantation (TAVI) or balloon angioplasty (BA) and separated them into two groups, diabetic and nondiabetic, to compare the level of Lp-PLA2 mass between them. Methods. 44 patients aged years with symptomatic severe aortic valve stenosis underwent TAVI () or BA (). 21 subjects had confirmed type 2 diabetes mellitus. Lp-PLA2 mass was measured using an enzyme-linked immunosorbent assay kit (USCN Life Science, China) before and 3 days after the procedure. Results. Lp-PLA2 mass was significantly elevated in this population ( ng/mL before TAVI;  ng/mL before BA) and further increased after TAVI ( ng/mL, ) or BA ( ng/mL, ). Lp-PLA2 mass was significantly increased on the diabetic group before these interventions. Conclusion. Lp-PLA2 may be a novel biomarker for the presence of rupture-prone atherosclerotic lesions in elderly patients. Levels of Lp-PLA2 in diabetic patients may accompany the higher amount of small dense LDL particles seen in these subjects. J. Fortunato, V. Bláha, J. Bis, J. Št’ásek, C. Andrýs, J. Vojáček, B. Jurašková, L. Sobotka, P. Polanský, and M. Brtko Copyright © 2014 J. Fortunato et al. All rights reserved. Role of the Unfolded Protein Response in β Cell Compensation and Failure during Diabetes Wed, 09 Apr 2014 12:28:31 +0000 Pancreatic β cell failure leads to diabetes development. During disease progression, β cells adapt their secretory capacity to compensate the elevated glycaemia and the peripheral insulin resistance. This compensatory mechanism involves a fine-tuned regulation to modulate the endoplasmic reticulum (ER) capacity and quality control to prevent unfolded proinsulin accumulation, a major protein synthetized within the β cell. These signalling pathways are collectively termed unfolded protein response (UPR). The UPR machinery is required to preserve ER homeostasis and β cell integrity. Moreover, UPR actors play a key role by regulating ER folding capacity, increasing the degradation of misfolded proteins, and limiting the mRNA translation rate. Recent genetic and biochemical studies on mouse models and human UPR sensor mutations demonstrate a clear requirement of the UPR machinery to prevent β cell failure and increase β cell mass and adaptation throughout the progression of diabetes. In this review we will highlight the specific role of UPR actors in β cell compensation and failure during diabetes. Nabil Rabhi, Elisabet Salas, Philippe Froguel, and Jean-Sébastien Annicotte Copyright © 2014 Nabil Rabhi et al. All rights reserved. Metformin Rescues the MG63 Osteoblasts against the Effect of High Glucose on Proliferation Wed, 09 Apr 2014 08:50:43 +0000 Aims. To study the proliferation of osteoblasts and genes expression under normal glucose, high glucose, and metformin (Met). Methods. MG63 osteoblast-like cells were cultured in osteogenic medium supplemented with normal glucose (glucose 5.5 mmol/L) or high glucose (glucose 16.7 mmol/L) and metformin + high glucose (Met 300 μmol/L + glucose 16.7 mmol/L). Proliferation was detected with CCK-8 assay at days 1, 3, and 7. Real-time PCR and Western blot were performed to compare the expression of collagen I (Col I), osteocalcin (OCN), osteoprotegerin (OPG), receptor activator for NF-κB ligand (RANKL), and metal matrix proteinases 1 and 2 (MMP1, MMP2). Alkaline phosphatase (ALP) activity was also detected at days 6, 12, and 18. Results. Exposure to high glucose inhibited the proliferation of osteoblasts (), with suppressed OCN and OPG. Meanwhile, Col I, RANKL, MMP1, and MMP2 were unaffected. Metformin attenuated the suppression on proliferation with increased expression of Col I, OCN, and OPG, meanwhile suppressing MMP1 and MMP2. High glucose lowered the intracellular ALP, while metformin raised it. Metformin attenuated the downregulation of ALP completely at day 6, partly at day 12, but not at day 18. Conclusions. Metformin attenuated the suppression effect of high glucose to the osteoblast proliferation and gene expression, more prominently in earlier stage. Xinyu Shao, Xiaojun Cao, Ge Song, Yuan Zhao, and Bimin Shi Copyright © 2014 Xinyu Shao et al. All rights reserved. miR-375 and miR-30d in the Effect of Chromium-Containing Chinese Medicine Moderating Glucose Metabolism Wed, 09 Apr 2014 08:49:25 +0000 In China, TianMai Xiaoke tablet (TM) is used to treat type 2 diabetes. However, the exact mechanism of TM is not clear. This study is to investigate the effect of TM on glucose metabolism in diabetic rats and to identify whether TM takes a direct action through microRNAs on islet. Rats were divided into control group, diabetic group, low dose of TM group (TML), and high dose of TM group (TMH). Pancreas samples were analyzed using microRNA array and Q-PCR. Eight-week treatment with TM significantly decreased fasting blood glucose. The blood glucose was significantly reduced in TM-treated groups before and after oral glucose administration. Fasting insulin and HOMA-IR were suppressed in TM-treated groups. miR-448, let-7b, miR-540, miR-296, miR-880, miR-200a, miR-500, miR-10b, miR-336, miR-30d, miR-208, let-7e, miR-142-5p, miR-874, miR-375, miR-879, miR-501, and miR-188 were upregulated, while miR-301b, miR-134, and miR-652 were downregulated in TMH group. Through target gene analysis and real-time PCR verification, we found that these miRNAs, especially miR-375 and miR-30d, can stimulate insulin secretion in islet. Our data suggest that TM can improve blood glucose in diabetic rats which involved increasing the expression of miR-375 and miR-30d to activate insulin synthesis in islet. Qian Zhang, Xinhua Xiao, Ming Li, Wenhui Li, Miao Yu, Huabing Zhang, Fan Ping, Zhixin Wang, Jia Zheng, and HongDing Xiang Copyright © 2014 Qian Zhang et al. All rights reserved. Injury to the Endothelial Surface Layer Induces Glomerular Hyperfiltration Rats with Early-Stage Diabetes Wed, 09 Apr 2014 07:30:38 +0000 Glomerular endothelial surface layer (ESL) may play a role in the mechanisms of albuminuria in diabetic nephropathy, which lack evidence in vivo. The effects of high glucose on the passage of albumin across the glomerular ESL were analysed in streptozotocin-induced diabetic Sprague-Dawley rats for 4 weeks. Albuminuria and glomerular mesangial matrix were significantly increased in diabetic rats. The passage of albumin across the ESL, as measured by albumin-colloid gold particle density in the glomerular basement membrane (GBM), was increased significantly in diabetic rats. The thickness of the glomerular ESL, examined indirectly by infusing Intralipid into vessels using an electron microscope, was significantly decreased and the GBM exhibited little change in diabetic rats. In summary, the glomerular ESL may play a role in the pathogenesis of albuminuria in rats with early-stage diabetes. Chunyang Zhang, Yao Meng, Qi Liu, Miao Xuan, Lanyu Zhang, Bo Deng, Keqin Zhang, Zhimin Liu, and Tao Lei Copyright © 2014 Chunyang Zhang et al. All rights reserved. Relation of Asymmetric Dimethylarginine Levels to Macrovascular Disease and Inflammation Markers in Type 2 Diabetic Patients Thu, 03 Apr 2014 12:29:54 +0000 Aim. We aimed to determine the relation of asymmetric dimethyl arginine (ADMA) levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetes. Methods. We recruited 50 type 2 diabetic patients with atherosclerosis, 50 type 2 diabetic patients without atherosclerosis, and 31 healthy control patients into our study. We obtained fasting serum and plasma samples and measured HbA1c, fasting blood glucose, C-peptide, creatinine, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, hsCRP, fibrinogen, erythrocyte sedimentation rate, total homocysteine, and ADMA levels. In addition, all of the patients were evaluated for carotid artery intima media thickness by ultrasound. We evaluated ADMA levels in healthy controls, diabetic patients with macrovascular complications, and diabetic patients without macrovascular complications and evaluated the relationship between ADMA levels and total homocysteine, inflammation markers, and macrovascular disease. Results. Mean ADMA values in non-MVD and control groups were significantly lower than in MVD group (, , , , resp.). These three variables (carotid intima-media thickness, inflammatory markers, and ADMA levels) were significantly higher in diabetes group than control (). Conclusion. There is a relationship between ADMA and macrovascular disease in type 2 diabetes, but further studies are needed to understand whether increased ADMA levels are a cause of macrovascular disease or a result of macrovascular disease. Mustafa Celik, Serkan Cerrah, Mahmut Arabul, and Aysen Akalin Copyright © 2014 Mustafa Celik et al. All rights reserved. Ang (1–7) Protects Islet Endothelial Cells from Palmitate-Induced Apoptosis by AKT, eNOS, p38 MAPK, and JNK Pathways Wed, 02 Apr 2014 13:17:16 +0000 This study aimed to explore the effect of angiotensin (1–7) (Ang (1–7)) on palmitate-induced apoptosis in islet endothelial cells and the mechanism of action. MS-1 cells were treated with palmitate in the presence or absence of Ang (1–7). The percentage of apoptotic cells was determined by DNA fragmentation and flow cytometry. Reactive oxygen species (ROS) production was measured using a Reactive Oxygen Species Assay Kit. Expression of AKT, eNOS, C-Jun N-terminal kinase (JNK), and p38 was detected by western blotting. Compared with palmitate treated group, palmitate-induced apoptosis was decreased in MS-1 cells which were preincubated with Ang (1–7) (). Palmitate decreased the phosphorylation of AKT and eNOS, and Ang (1–7) increased the phosphorylation of these kinases (), with a concomitant reduction in MS-1 cells apoptosis. Ang (1–7) also inhibited the palmitate-induced ROS production and attenuated the apoptosis-related signaling molecule JNK and p38 activation (all ). PI3K/AKT, eNOS, p38 MAPK, and JNK inhibitors blocked the antilipoapoptosis of Ang (1–7) (all ). Our findings suggest that Ang (1–7) reduces palmitate-induced islet endothelial cells apoptosis. AKT/eNOS/NO signaling and JNK and p38 pathway are involved in the Ang (1–7)-mediated modulation of islet endothelial cells lipoapoptosis. Li Yuan, Chun-Li Lu, Ying Wang, Yang Li, and Xiao-Ya Li Copyright © 2014 Li Yuan et al. All rights reserved. Does the Diabetic Foot Have a Significant Impact on Selected Psychological or Social Characteristics of Patients with Diabetes Mellitus? Tue, 25 Mar 2014 12:38:11 +0000 The aim of our case-control study was to compare selected psychological and social characteristics between diabetic patients with and without the DF (controls). Methods. 104 patients with and 48 without DF were included into our study. Both study groups were compared in terms of selected psychosocial characteristics. Results. Compared to controls, patients with DF had a significantly worse quality of life in the area of health and standard of living as shown by lower physical health domain ( versus ; ) and environment domain ( versus ; ) that negatively correlated with diabetes duration (; ). Patients with DF subjectively felt more depressed in contrast to controls (24.5 versus 7.3%; ); however, the depressive tuning was objectively proven in higher percentage in both study groups (83.2 versus 89.6; NS). We observed a significantly lower level of achieved education (), more patients with disability pensions (), and low self-support () in patients with the DF compared to controls. In the subgroup of patients with a previous major amputation and DF (), there were significantly worse outcomes as in the environment domain (), employment status, and stress readaptation () in contrast to the main study groups. Conclusions. Patients with DF had a predominantly worse standard of living. In contrast to our expectations, patients with DF appeared to have good stress tolerability and mental health (with the exception of patients with previous major amputation) and did not reveal severe forms of depression or any associated consequences. Vladimíra Fejfarová, Alexandra Jirkovská, Eva Dragomirecká, Frances Game, Robert Bém, Michal Dubský, Veronika Wosková, Marta Křížová, Jelena Skibová, and Stephanie Wu Copyright © 2014 Vladimíra Fejfarová et al. All rights reserved. Insulin Resistance, Type 1 and Type 2 Diabetes, and Related Complications: Current Status and Future Perspective Tue, 18 Mar 2014 11:59:09 +0000 Joseph Fomusi Ndisang, Sharad Rastogi, and Alfredo Vannacci Copyright © 2014 Joseph Fomusi Ndisang et al. All rights reserved. Association and Predictive Value Analysis for Resting Heart Rate and Diabetes Mellitus on Cardiovascular Autonomic Neuropathy in General Population Tue, 18 Mar 2014 00:00:00 +0000 Background. The purpose of this study was to evaluate the predictive value of DM and resting HR on CAN in a large sample derived from a Chinese population. Materials and Methods. We conducted a large-scale, population-based, cross-sectional study to explore the relationships of CAN with DM and resting HR. A total of 387 subjects were diagnosed with CAN in our dataset. The associations of CAN with DM and resting HR were assessed by a multivariate logistic regression (MLR) analysis (using subjects without CAN as a reference group) after controlling for potential confounding factors. The area under the receiver-operating characteristic curve (AUC) was used to evaluate the predictive performance of resting HR and DM. Results. A tendency toward increased CAN prevalence with increasing resting HR was reported (P for trend ). MLR analysis showed that DM and resting HR were very significantly and independently associated with CAN ( for both). Resting HR alone or combined with DM (DM-HR) both strongly predicted CAN (AUC = 0.719, 95% CI 0.690–0.748 for resting HR and AUC = 0.738, 95% CI 0.710–0.766 for DM-HR). Conclusion. Our findings signify that resting HR and DM-HR have a high value in predicting CAN in the general population. Zi-Hui Tang, Fangfang Zeng, Zhongtao Li, and Linuo Zhou Copyright © 2014 Zi-Hui Tang et al. All rights reserved. The Cytotoxic Role of Intermittent High Glucose on Apoptosis and Cell Viability in Pancreatic Beta Cells Mon, 17 Mar 2014 14:17:38 +0000 Objectives. Glucose fluctuations are both strong predictor of diabetic complications and crucial factor for beta cell damages. Here we investigated the effect of intermittent high glucose (IHG) on both cell apoptosis and proliferation activity in INS-1 cells and the potential mechanisms. Methods. Cells were treated with normal glucose (5.5 mmol/L), constant high glucose (CHG) (25 mmol/L), and IHG (rotation per 24 h in 11.1 or 25 mmol/L) for 7 days. Reactive oxygen species (ROS), xanthine oxidase (XOD) level, apoptosis, cell viability, cell cycle, and expression of cyclinD1, p21, p27, and Skp2 were determined. Results. We found that IHG induced more significant apoptosis than CHG and normal glucose; intracellular ROS and XOD levels were more markedly increased in cells exposed to IHG. Cells treated with IHG showed significant decreased cell viability and increased cell proportion in G0/G1 phase. Cell cycle related proteins such as cyclinD1 and Skp2 were decreased significantly, but expressions of p27 and p21 were increased markedly. Conclusions. This study suggested that IHG plays a more toxic effect including both apoptosis-inducing and antiproliferative effects on INS-1 cells. Excessive activation of cellular stress and regulation of cyclins might be potential mechanism of impairment in INS-1 cells induced by IHG. Zhen Zhang, Jing Li, Lei Yang, Rongping Chen, Rui Yang, Hua Zhang, Dehong Cai, and Hong Chen Copyright © 2014 Zhen Zhang et al. All rights reserved. Combination Therapy of an Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein and Peroxisome Proliferator-Activated Receptor γ Agonist in Diabetic Rat Mon, 17 Mar 2014 13:08:35 +0000 We investigated effects on glucose and lipid metabolism in combination of JTT-130, a novel intestine-specific microsomal triglyceride transfer protein (MTP) inhibitor, and pioglitazone, peroxisome proliferator-activated receptor (PPAR) γ agonist. Male Zucker diabetic fatty rats were divided into 4 groups: control group, JTT-130 treatment group, pioglitazone treatment group, and combination group. The Zucker diabetic fatty rats were fed a regular powdered diet with JTT-130 and/or pioglitazone as a food admixture for 6 weeks. Effects on glucose and lipid metabolism were compared mainly between JTT-130 treatment group and combination group. JTT-130 treatment showed good glycemic control, while the plasma glucose and glycated hemoglobin levels in combination group were significantly decreased as compared with those JTT-130 treatment group. The reduction in the plasma triglyceride and free fatty acid levels in combination group was higher than that in JTT-130 treatment group, and glucose utilization was significantly elevated in adipose tissues. In Zucker diabetic fatty rats, combination treatment of JTT-130 and pioglitazone showed better glycemic control and a strong hypolipidemic action with an enhancement of insulin sensitivity. Combination therapy of MTP inhibitor and PPARγ agonist might be more useful in the treatment of type 2 diabetes accompanied with obesity and insulin resistance. Shohei Sakata, Yasuko Mera, Yukiharu Kuroki, Reiko Nashida, Makoto Kakutani, and Takeshi Ohta Copyright © 2014 Shohei Sakata et al. All rights reserved. Tracing Fasting Glucose Fluxes with Unstressed Catheter Approach in Streptozotocin Induced Diabetic Rats Mon, 17 Mar 2014 11:32:53 +0000 Objective. Blood glucose concentrations of type 1 diabetic rats are vulnerable, especially to stress and trauma. The present study aimed to investigate the fasting endogenous glucose production and skeletal muscle glucose uptake of Streptozotocin induced type 1 diabetic rats using an unstressed vein and artery implantation of catheters at the tails of the rats as a platform. Research Design and Methods. Streptozotocin (65 mg·kg−1) was administered to induce type 1 diabetic state. The unstressed approach of catheters of vein and artery at the tails of the rats was established before the isotope tracer injection. Dynamic measurement of fasting endogenous glucose production was assessed by continuously infusing stable isotope [6, 6-2H2] glucose, while skeletal muscle glucose uptake by bolus injecting radioactively labeled [1-14C]-2-deoxy-glucose. Results. Streptozotocin induced type 1 diabetic rats displayed polydipsia, polyphagia, and polyuria along with overt hyperglycemia and hypoinsulinemia. They also had enhanced fasting endogenous glucose production and reduced glucose uptake in skeletal muscle compared to nondiabetic rats. Conclusions. The dual catheters implantation at the tails of the rats together with isotope tracers injection is a save time, unstressed, and feasible approach to explore the glucose metabolism in animal models in vivo. Shichun Du, Hui Wu, Xiao Xu, Ying Meng, Fangzhen Xia, Hualing Zhai, and Yingli Lu Copyright © 2014 Shichun Du et al. All rights reserved. Altered Expression Profile of Renal -Adrenergic Receptor in Diabetes and Its Modulation by PPAR Agonists Mon, 17 Mar 2014 07:34:41 +0000 -adrenergic receptor (-AR) plays important roles in regulating physiological and pathological responses mediated by catecholamines, particularly in the cardiovascular and urinary systems. The present study was designed to investigate the expression profile of -AR in the diabetic kidneys and its modulation by activation of peroxisome proliferator-activated receptors (PPARs). 12-week-old Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with fenofibrate or rosiglitazone for 8–10 weeks. Gene microarray, real-time PCR, and confocal immunofluorescence microscopy were performed to assess mRNA and protein expression of -AR in rat kidney tissue. Using microarray, we found that -AR gene was dramatically upregulated in 22-week-old ZD rats compared to ZL controls. Quantitative PCR analysis verified a 16-fold increase in -AR mRNA in renal cortex from ZD animals compared to normal controls. Chronic treatment with fenofibrate or rosiglitazone reduced renal cortical -AR gene. Immunofluorescence staining confirmed that -AR protein was induced in the glomeruli and tubules of diabetic rats. Moreover, dual immunostaining for -AR and kidney injury molecule-1 indicated that -AR was expressed in dedifferentiated proximal tubules of diabetic Zucker rats. Taken together, our results show that -AR expression is upregulated in the diabetic kidneys. PPAR activation suppressed renal expression of -AR in diabetic nephropathy. Xueying Zhao, Yuanyuan Zhang, Michelle Leander, Lingyun Li, Guoshen Wang, and Nerimiah Emmett Copyright © 2014 Xueying Zhao et al. All rights reserved. Proinflammatory and Prothrombotic State in Subjects with Different Glucose Tolerance Status before Cardiovascular Disease Mon, 17 Mar 2014 06:30:37 +0000 Background. Inflammation has been associated with insulin resistance, type 2 diabetes mellitus (T2DM), and atherothrombosis. Aim. To determine differences in levels of proinflammatory and prothrombotic markers such as high sensitivity C-reactive protein (hs-CRP) and fibrinogen in subjects with normal glucose tolerance (NGT), prediabetes, and T2DM and to establish their relationship with other cardiovascular risk factors before clinical manifestations of cardiovascular disease. Methods. We conducted a nonrandomized, cross-sectional assay in a hospital at México City. The levels of hs-CRP and fibrinogen were measured and compared according to glucose tolerance status. Results. We enrolled 1047 individuals and they were distributed into NGT , pre-DM , and T2DM . There was a statistical difference between NGT and T2DM groups for fibrinogen () and hs-CRP (). Fibrinogen and hs-CRP showed a significant positive correlation coefficient (, ). In a multiple stepwise regression analysis, the variability in fibrinogen levels was explained by age, HbA1c, and hs-CRP (adjusted , ), and for hs-CRP it was explained by BMI and fibrinogen (adjusted , ). Conclusion. Inflammation and prothrombotic state are present in people with T2DM lacking cardiovascular disease. Fibrinogen and Hs-CRP are positively correlated. Fibrinogen and hs-CRP concentrations are predominantly determined by BMI rather than glucose levels. Irma Isordia-Salas, María Eugenia Galván-Plata, Alfredo Leaños-Miranda, Eberth Aguilar-Sosa, Francisco Anaya-Gómez, Abraham Majluf-Cruz, and David Santiago-Germán Copyright © 2014 Irma Isordia-Salas et al. All rights reserved. The Protective Effects of Insulin and Natural Honey against Hippocampal Cell Death in Streptozotocin-Induced Diabetic Rats Thu, 13 Mar 2014 11:48:06 +0000 We investigated the effects of insulin and honey as antioxidants to prevent the hippocampal cell death in streptozotocin-induced diabetic rats. We selected sixty Wister rats (5 groups of 12 animals each), including the control group (C), and four diabetic groups (control (D) and 3 groups treated with insulin (I), honey (H), and insulin plus honey (I + H)). Diabetes was induced by streptozotocin injection (IP, 60 mg/kg). Six weeks after the induction of diabetes, the group I received insulin (3-4 U/kg/day, SC), group H received honey (5 mg/kg/day, IP), and group I + H received a combination of the above at the same dose. Groups C and D received normal saline. Two weeks after treatment, rats were sacrificed and the hippocampus was extracted. Neuronal cell death in the hippocampal region was examined using trypan blue assay, “H & E” staining, and TUNEL assay. Cell viability assessment showed significantly lower number of living cells in group D than in group C. Besides, the mean number of living cells was significantly higher in group I, H, and I + H compared to group D. Therefore, it can be concluded that the treatment of the diabetic rats with insulin, honey, and a combination of insulin and honey can prevent neuronal cell death in different hippocampal areas of the studied samples. Iraj Jafari Anarkooli, Hossein Barzegar Ganji, and Maryam Pourheidar Copyright © 2014 Iraj Jafari Anarkooli et al. All rights reserved. Low Protein Diet Inhibits Uric Acid Synthesis and Attenuates Renal Damage in Streptozotocin-Induced Diabetic Rats Thu, 13 Mar 2014 08:56:12 +0000 Aim. Several studies indicated that hyperuricemia may link to the worsening of diabetic nephropathy (DN). Meanwhile, low protein diet (LPD) retards exacerbation of renal damage in chronic kidney disease. We then assessed whether LPD influences uric acid metabolism and benefits the progression of DN in streptozotocin- (STZ-) induced diabetic rats. Methods. STZ-induced and control rats were both fed with LPD (5%) and normal protein diet (18%), respectively, for 12 weeks. Vital signs, blood and urinary samples for UA metabolism were taken and analyzed every 3 weeks. Kidneys were removed at the end of the experiment. Results. Diabetic rats developed into constantly high levels of serum UA (SUA), creatinine (SCr) and 24 h amounts of urinary albumin excretion (UAE), creatintine (UCr), urea nitrogen (UUN), and uric acid (UUA). LPD significantly decreased SUA, UAE, and blood glucose, yet left SCr, UCr, and UUN unchanged. A stepwise regression showed that high UUA is an independent risk factor for DN. LPD remarkably ameliorated degrees of enlarged glomeruli, proliferated mesangial cells, and hyaline-degenerated tubular epithelial cells in diabetic rats. Expression of TNF-α in tubulointerstitium significantly decreased in LPD-fed diabetic rats. Conclusion. LPD inhibits endogenous uric acid synthesis and might accordingly attenuate renal damage in STZ-induced diabetic rats. Jianmin Ran, Jing Ma, Yan Liu, Rongshao Tan, Houqiang Liu, and Gancheng Lao Copyright © 2014 Jianmin Ran et al. All rights reserved. Ethnic Differences in MicroRNA-375 Expression Level and DNA Methylation Status in Type 2 Diabetes of Han and Kazak Populations Tue, 11 Mar 2014 16:44:48 +0000 Han population is six times as likely as Kazak population to present with type 2 diabetes mellitus (T2DM) in China. We hypothesize that differential expression and CpG methylation of miR-375 may be an ethnic-related factor that influences the incidence of T2DM. The expression level of miR-375 was examined using real-time PCR on Kazak and Han T2DM plasma samples. Furthermore, the methylation levels of CpG sites of miR-375 promoter were determined by MassARRAY Spectrometry in these samples. The relative expression levels of plasma miR-375 in Kazak T2DM samples are 1, and the relative expression levels of plasma miR-375 in Han T2DM samples are 3. The mean level of miR-375 methylation, calculated from the methylation levels of the CpG sites, was 8.47% for the Kazak T2DM group and 10.38% for the Han T2DM group. Further, five CpG units showed a statistically significant difference between Kazak and Han T2DM samples, and, among them, four were hypomethylated and only one CpG unit showed hypermethylation in Kazak T2DM samples. These findings indicate that the expression levels of plasma miR-375 and its CpG methylation in the promoter region are ethnically different, which may contribute to the different incidence of diabetes observed in Kazak and Han populations. Xiangyun Chang, Siyuan Li, Jun Li, Liang Yin, Ting Zhou, Chen Zhang, Xuan Chen, and Kan Sun Copyright © 2014 Xiangyun Chang et al. All rights reserved. Combat Diabetic Nephropathy: From Pathogenesis to Treatment Tue, 11 Mar 2014 13:57:57 +0000 Tomohito Gohda, Akira Mima, Ju-Young Moon, and Keizo Kanasaki Copyright © 2014 Tomohito Gohda et al. All rights reserved. Prognostic Utility of Coronary Computed Tomographic Angiography: A 5-Year Follow-Up in Type 2 Diabetes Patients with Suspected Coronary Artery Disease Sun, 09 Mar 2014 09:30:46 +0000 Objectives. To analyze the predictive value of coronary computed tomography angiography on acute coronary artery events in patients with type 2 diabetes. Methods. Coronary computed tomography angiography was performed in 250 type 2 diabetic patients. After a follow-up for 5 years, 145 patients were excluded as they did not have any coronary events. The remaining 95 patients were divided into study group and control group. According to their density and shape, the coronary artery plaques were classified into 3 types and 4 types, respectively. Results. There is no statistically significant difference in the degree of stenosis between two groups. The proportion of calcified plaques in the study group was lower than in the control group. The proportion of mixed-calcified plaques in the study group was higher than in the other. Type III plaques have a 76.2% sensitivity and negative predictive value was 64.5% for acute coronary events; type IV plaques have a sensitivity of 52.6% and positive predictive value of 63% for chronic coronary events. Conclusions. CCTA may be used as a non-invasive modality for evaluating and predicting vulnerable coronary atherosclerosis plaques in patients with type 2 diabetes. Daliang Liu, Huijuan Jia, Yucun Fu, Wen He, and Daqing Ma Copyright © 2014 Daliang Liu et al. All rights reserved. P38 Plays an Important Role in Glucolipotoxicity-Induced Apoptosis in INS-1 Cells Wed, 05 Mar 2014 16:53:09 +0000 Objectives. The mechanism underlying the regulation of glucolipotoxicity-induced apoptosis by MAPKs was examined in INS-1 cells. Methods. The rat insulinoma cell line INS-1 was cotreated with glucose (30 mM) and palmitic acid (0.2 mM) (GLU+PA). Apoptosis was assessed by cell morphology and detection of PARP cleavage. The activation of MAPKs was examined by Western blotting using specific antibodies against the phosphorylated forms of JNK, ERK1/2, and P38. Results. (1) Live cell imaging studies showed that treatment with GLU+PA for 72 h induced significant cell death, concomitant with PARP-1 cleavage and caspase-3 activation, which peaked at 96 h of treatment. (2) Western blot analysis of the activation of MAPKs during GLU+PA-induced INS-1 cell apoptosis showed that phosphorylation of P38 increased gradually and reached a peak at 96 h, which coincided with PARP-1 cleavage. A transient increase of ERK activation was followed by a rapid decline at 96 h, whereas JNK phosphorylation status remained unchanged in response to GLU+PA. (3) Phosphorylation of insulin receptor substrate (IRS)-2 at 48 h of treatment triggered its degradation, which coincided with P38 activation. (4) Inhibition of P38, but not JNK or ERK, blocked GLU+PA-induced INS-1 cell apoptosis. Conclusions. P38 may be involved in the regulation of glucolipotoxicity-induced apoptosis through the phosphorylation of IRS-2. Lingli Zhou, Xiaoling Cai, Xueyao Han, and Linong Ji Copyright © 2014 Lingli Zhou et al. All rights reserved. Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes Wed, 05 Mar 2014 16:40:58 +0000 Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes. Valérie Plaisance, Gérard Waeber, Romano Regazzi, and Amar Abderrahmani Copyright © 2014 Valérie Plaisance et al. All rights reserved.