Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans Thu, 19 Feb 2015 17:48:50 +0000 Purpose. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. Methods. Thirty nondiabetic control rats (NC) and 30 untreated diabetic (UD) rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. Results. UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. Conclusion. Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis. Amanda Natália Lucchesi, Lucas Langoni Cassettari, and César Tadeu Spadella Copyright © 2015 Amanda Natália Lucchesi et al. All rights reserved. The Role of Some Chemokines from the CXC Subfamily in a Mouse Model of Diabetic Neuropathy Thu, 19 Feb 2015 11:51:33 +0000 The mechanism involved in the development of diabetic neuropathy is complex. Currently, it is thought that chemokines play an important role in this process. The aim of this study was to determine how the level of some chemokines from the CXC subfamily varies in diabetic neuropathy and how the chemokines affect nociceptive transmission. A single intraperitoneal (i.p.) injection of streptozotocin (STZ; 200 mg/kg) resulted in an increased plasma glucose. The development of allodynia and hyperalgesia was measured at day 7 after STZ administration. Using Antibody Array techniques, the increases in CXCL1 (KC), CXCL5 (LIX), CXCL9 (MIG), and CXCL12 (SDF-1) protein levels were detected in STZ-injected mice. No changes in CXCL11 (I-TAC) or CXCL13 (BLC) protein levels were observed. The single intrathecal (i.t.) administration of CXCL1, CXCL5, CXCL9, and CXCL12 (each in doses of 10, 100, and 500 ng/5 μL) shows their pronociceptive properties as measured 1, 4, and 24 hours after injection using the tail-flick, von Frey, and cold plate tests. These findings indicate that the chemokines CXCL1, CXCL5, CXCL9, and CXCL12 are important in nociceptive transmission and may play a role in the development of diabetic neuropathy. Magdalena Zychowska, Ewelina Rojewska, Dominika Pilat, and Joanna Mika Copyright © 2015 Magdalena Zychowska et al. All rights reserved. Combination Therapy with Oleanolic Acid and Metformin as a Synergistic Treatment for Diabetes Thu, 19 Feb 2015 06:08:29 +0000 Aims and Background. Type 2 diabetes is a chronic disease that cannot be treated adequately using the known monotherapies, especially when the disease progresses to an advanced stage. In this study, we explore the possibility of treating the disease with a novel combination approach of oleanolic acid (OA), a glycogen phosphorylase (GP) inhibitor, and metformin. Methods. Db/db mice were randomly divided into four groups: a db/db control group, db/db mice treated with OA (250 mg/kg), db/db mice treated with metformin (100 mg/kg), and db/db mice treated with a combination of OA and metformin. All mice were treated for four weeks. The effects of the treatments on glucose homeostasis were measured using an OGTT, an assessment of insulin sensitivity and signaling in the liver, and the hepatic glucose production. Results. Combination therapy with OA and metformin significantly reduced the blood glucose and insulin levels and improved the liver pathology compared with that for the monotherapy in the db/db diabetic mouse model. We also found that the combination therapy significantly increased the mRNA expression of glycogen synthesis and decreased the GP, PGC-1α, PEPCK1, and G-6-Pase levels. In addition, the combination therapy with OA and metformin significantly increased the phosphorylation of AKT, PI3K, AMPK, and ACC and decreased the protein expression levels of G-6-Pase, PEPCK1, and TORC compared with those for either monotherapy. The combination therapy also reduced the phosphorylation of mTOR and CREB. Conclusions. Our results suggest that the combination therapy with OA and metformin has synergistic effects on the symptoms of db/db diabetic mice by improving glucose and insulin homeostasis. Xue Wang, Yupeng Chen, Daoud Abdelkader, Waseem Hassan, Hongbin Sun, and Jun Liu Copyright © 2015 Xue Wang et al. All rights reserved. Topically Applied Connective Tissue Growth Factor/CCN2 Improves Diabetic Preclinical Cutaneous Wound Healing: Potential Role for CTGF in Human Diabetic Foot Ulcer Healing Wed, 18 Feb 2015 08:14:34 +0000 Aims/Hypothesis. Topical application of CTGF/CCN2 to rodent diabetic and control wounds was examined. In parallel research, correlation of CTGF wound fluid levels with healing rate in human diabetic foot ulcers was undertaken. Methods. Full thickness cutaneous wounds in diabetic and nondiabetic control rats were treated topically with 1 μg rhCTGF or vehicle alone, on 2 consecutive days. Wound healing rate was observed on day 14 and wound sites were examined for breaking strength and granulation tissue. In the human study across 32 subjects, serial CTGF regulation was analyzed longitudinally in postdebridement diabetic wound fluid. Results. CTGF treated diabetic wounds had an accelerated closure rate compared with vehicle treated diabetic wounds. Healed skin withstood more strain before breaking in CTGF treated rat wounds. Granulation tissue from CTGF treatment in diabetic wounds showed collagen IV accumulation compared with nondiabetic animals. Wound α-smooth muscle actin was increased in CTGF treated diabetic wounds compared with untreated diabetic wounds, as was macrophage infiltration. Endogenous wound fluid CTGF protein rate of increase in human diabetic foot ulcers correlated positively with foot ulcer healing rate (; ). Conclusions/Interpretation. These data collectively increasingly substantiate a functional role for CTGF in human diabetic foot ulcers. F. R. Henshaw, P. Boughton, L. Lo, S. V. McLennan, and S. M. Twigg Copyright © 2015 F. R. Henshaw et al. All rights reserved. Women’s Views on Their Diagnosis and Management for Borderline Gestational Diabetes Mellitus Mon, 16 Feb 2015 13:15:33 +0000 Introduction. Little is known about women’s views relating to a diagnosis of borderline gestational diabetes mellitus (GDM) and the subsequent management. This study aimed to explore women’s experiences after being diagnosed with borderline GDM, their attitudes about treatment, and factors important to them for achieving any lifestyle changes. Methods. We conducted face-to-face, semistructured interviews with women diagnosed with borderline GDM. Results. A total of 22 women were interviewed. After a diagnosis of borderline GDM, 14 (64%) women reported not being concerned or worried. Management of borderline GDM was thought by 21 (95%) women to be very important or important. Eighteen (82%) women planned to improve their diet and/or exercise to manage their borderline GDM. The most frequently mentioned enabler for achieving intended lifestyle change was being more motivated to improve the health of their baby and/or themselves (15 women). The most frequent barrier was tiredness and/or being physically unwell (11 women). Conclusions. A diagnosis of borderline GDM caused some concern to one-third of women interviewed. The majority of women believed managing their borderline GDM was important and they planned to improve their lifestyle. Women’s own and their babies’ future health were powerful motivators for lifestyle change. Shanshan Han, Philippa F. Middleton, Tanya K. Bubner, and Caroline A. Crowther Copyright © 2015 Shanshan Han et al. All rights reserved. Ameliorative Effect of Allopurinol on Vascular Complications of Insulin Resistance Sun, 15 Feb 2015 14:38:31 +0000 The aim of the current study was to evaluate the possible protective effect of allopurinol (Allo) on experimentally induced insulin resistance (IR) and vascular complications. Rats were divided into four groups: control, IR, allopurinol-treated IR (IR-Allo), and allopurinol-treated control (Allo). IR was induced by adding fructose and high fat, high salt diet for 12 weeks. The results showed that Allo has alleviated the increased level of TNF-α and the systolic, diastolic, mean, and notch pressure observed in IR with no change in pulse pressure. In addition, Allo decreased the heart rate in the treated group compared to IR rats. On the other hand, it has no effect on increased levels of insulin, glucose, fructosamine, or body weight gain compared to IR group, while it increased significantly the insulin level and body weight without hyperglycemia in the control group. Moreover, Allo treatment ameliorated increased level of 4HNE, Ang II, and Ang R1. In conclusion, the results of the current study show that Allo has a protective effect on vascular complications of IR which may be attributed to the effect of Allo on decreasing the TNF-α, 4HNE, Ang II, and Ang R1 as well as increasing the level of insulin secretion. Hany M. El-Bassossy, Ahmed A. Elberry, Ahmad Azhar, Salah A. Ghareib, and Abdulrahman M. Alahdal Copyright © 2015 Hany M. El-Bassossy et al. All rights reserved. Polymorphisms of GLP-1 Receptor Gene and Response to GLP-1 Analogue in Patients with Poorly Controlled Type 2 Diabetes Sun, 15 Feb 2015 13:13:38 +0000 Aim. The relationship between genetic polymorphisms of the glucagon-like peptide-1 (GLP-1) receptor (GLP1R) gene and unresponsiveness to GLP-1 analogue treatment in patients with poorly controlled type 2 diabetes mellitus (DM) is unclear. Methods. Thirty-six patients with poorly controlled type 2 DM were enrolled and they received six days of continuous subcutaneous insulin infusion for this study. After the normalization of blood glucose in the first 3 days, the patients then received a combination therapy with injections of the GLP-1 analogue, exenatide, for another 3 days. All 13 exons and intron-exon boundaries of the GLP1R gene were amplified to investigate the association. Results. The short tandem repeat at 8GA/7GA (rs5875654) had complete linkage disequilibrium (LD, with ) with single nucleotide polymorphism (SNP) rs761386. Quantitative trait loci analysis of GLP1R gene variation with clinical response of GLP1 analogue showed the missense rs3765467 and rs761386 significantly associated with changes in the standard deviation of plasma glucose () ( and 0.019, resp.). The reported values became insignificant after multiple testing adjustments. Conclusion. The variable response to the GLP-1 analogue was not statistically correlated with polymorphisms of the GLP1R gene in patients with poorly controlled type 2 DM. Chia-Hung Lin, Yun-Shien Lee, Yu-Yao Huang, Sheng-Hwu Hsieh, Zih-Syuan Chen, and Chi-Neu Tsai Copyright © 2015 Chia-Hung Lin et al. All rights reserved. Animal Models of Diabetic Macrovascular Complications: Key Players in the Development of New Therapeutic Approaches Sun, 15 Feb 2015 10:55:09 +0000 Diabetes mellitus is a lifelong, incapacitating metabolic disease associated with chronic macrovascular complications (coronary heart disease, stroke, and peripheral vascular disease) and microvascular disorders leading to damage of the kidneys (nephropathy) and eyes (retinopathy). Based on the current trends, the rising prevalence of diabetes worldwide will lead to increased cardiovascular morbidity and mortality. Therefore, novel means to prevent and treat these complications are needed. Under the auspices of the IMI (Innovative Medicines Initiative), the SUMMIT (SUrrogate markers for Micro- and Macrovascular hard end points for Innovative diabetes Tools) consortium is working on the development of novel animal models that better replicate vascular complications of diabetes and on the characterization of the available models. In the past years, with the high level of genomic information available and more advanced molecular tools, a very large number of models has been created. Selecting the right model for a specific study is not a trivial task and will have an impact on the study results and their interpretation. This review gathers information on the available experimental animal models of diabetic macrovascular complications and evaluates their pros and cons for research purposes as well as for drug development. Suvi E. Heinonen, Guillem Genové, Eva Bengtsson, Thomas Hübschle, Lina Åkesson, Katrin Hiss, Agnes Benardeau, Seppo Ylä-Herttuala, Ann-Cathrine Jönsson-Rylander, and Maria F. Gomez Copyright © 2015 Suvi E. Heinonen et al. All rights reserved. Inflammatory Cytokines in Diabetic Nephropathy Sun, 15 Feb 2015 08:59:21 +0000 Probably, the most paradigmatic example of diabetic complication is diabetic nephropathy, which is the largest single cause of end-stage renal disease and a medical catastrophe of worldwide dimensions. Metabolic and hemodynamic alterations have been considered as the classical factors involved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecular events of diabetic nephropathy remain incompletely understood. Nowadays, there are convincing data that relate the diabetes inflammatory component with the development of renal disease. This review is focused on the inflammatory processes that develop diabetic nephropathy and on the new therapeutic approaches with anti-inflammatory effects for the treatment of chronic kidney disease in the setting of diabetic nephropathy. Javier Donate-Correa, Ernesto Martín-Núñez, Mercedes Muros-de-Fuentes, Carmen Mora-Fernández, and Juan F. Navarro-González Copyright © 2015 Javier Donate-Correa et al. All rights reserved. Synergistic Activations of REG Iα and REG Iβ Promoters by IL-6 and Glucocorticoids through JAK/STAT Pathway in Human Pancreatic β Cells Thu, 12 Feb 2015 13:32:22 +0000 Reg (Regenerating gene) gene was originally isolated from rat regenerating islets and its encoding protein was revealed as an autocrine/paracrine growth factor for β cells. Rat Reg gene is activated in inflammatory conditions for β cell regeneration. In human, although five functional REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) were isolated, their expressions in β cells under inflammatory conditions remained unclear. In this study, we found that combined addition of IL-6 and dexamethasone (Dx) induced REG Iα and REG Iβ expression in human 1.1B4 β cells. Promoter assay revealed that a signal transducer and activator of transcription- (STAT-) binding site in each promoter of REG Iα (TGCCGGGAA) and REG Iβ (TGCCAGGAA) was essential for the IL-6+Dx-induced promoter activation. A Janus kinase 2 (JAK2) inhibitor significantly inhibited the IL-6+Dx-induced REG Iα and REG Iβ transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation revealed that IL-6+Dx stimulation increased STAT3 binding to the REG Iα promoter. Furthermore, small interfering RNA-mediated targeting of STAT3 blocked the IL-6+Dx-induced expression of REG Iα and REG Iβ. These results indicate that the expression of REG Iα and REG Iβ should be upregulated in human β cells under inflammatory conditions through the JAK/STAT pathway. Akiyo Yamauchi, Asako Itaya-Hironaka, Sumiyo Sakuramoto-Tsuchida, Maiko Takeda, Kiyomi Yoshimoto, Tomoko Miyaoka, Takanori Fujimura, Hiroki Tsujinaka, Chikatsugu Tsuchida, Hiroyo Ota, and Shin Takasawa Copyright © 2015 Akiyo Yamauchi et al. All rights reserved. Characterisation of Pain Responses in the High Fat Diet/Streptozotocin Model of Diabetes and the Analgesic Effects of Antidiabetic Treatments Tue, 10 Feb 2015 05:59:46 +0000 Chronic pain is a common complication of diabetes. The aim of the present study was to characterise pain behaviour in a high fat diet/streptozotocin (HFD/STZ) model of diabetes in the rat, investigate spinal mechanisms, and determine the effects of antidiabetic interventions. Three-week consumption of a high fat diet followed by single injection of STZ (45 mgkg−1) produced sustained changes in plasma insulin and glucose until day 120. Hindpaw mechanical withdrawal thresholds were significantly lowered in the model, but mechanically evoked responses of spinal neurones were unaltered, compared to HFD/vehicle rats. HFD/STZ rats had significantly lower numbers of spinal Iba-1 positive cells (morphologically identified as activated microglia) and spinal GFAP immunofluorescence (a marker of astrogliosis) in the spinal cord at day 50, compared to time-matched controls. The PPARγ ligand pioglitazone (10 mgkg−1) did not alter HFD/STZ induced metabolic changes or hindpaw withdrawal thresholds of HFD/STZ rats. Daily linagliptin (3 mgkg−1) and metformin (200 mgkg−1) from day 4 after model induction did not alter plasma glucose or insulin in HFD/STZ rats but significantly prevented changes in the mechanical withdrawal thresholds. The demonstration that currently prescribed antidiabetic drugs prevent aberrant pain behaviour supports the use of this model to investigate pain mechanisms associated with diabetes. Frederika Maria Byrne, Sharon Cheetham, Steven Vickers, and Victoria Chapman Copyright © 2015 Frederika Maria Byrne et al. All rights reserved. Importance of Maternal Diabetes on the Chronological Deregulation of the Intrauterine Development: An Experimental Study in Rat Mon, 09 Feb 2015 14:04:03 +0000 We investigated whether maternal diabetes induced in rats using streptozotocin (STZ) on Day 5 of pregnancy affects the intrauterine developmental timeline. A total of 30 pregnant Sprague-Dawley diabetic rats (DRs) and 20 control rats (CRs) were used to obtain 21-day fetuses (F21) and newborn (NB) pups. Gestational age, weight, and body size were recorded as were the maxillofacial morphometry and morphohistological characteristics of the limbs. In DRs, pregnancy continued for ∼1.7 days, and delivery occurred 23 days postcoitus (DPC). In this group, the number of pups was lower, and 13% had maxillofacial defects. F21 in the DR group had lower weights and were smaller; moreover, the morphological characteristics of the maxillofacial structures, derived from the neural crest, were discordant with their chronological gestational age, resembling 18- to 19-day-old fetuses. These deficiencies were counterbalanced in NB pups. We conclude that hyperglycemia, which results from maternal diabetes and precedes embryo implantation, deregulates the intrauterine developmental timeline, restricts embryo-fetal growth, and primarily delays the remodeling and maturation of the structures derived from neural crest cells. Marcela Salazar García, Elba Reyes Maldonado, María Cristina Revilla Monsalve, Laura Villavicencio Guzmán, Alfonso Reyes López, and Concepción Sánchez-Gómez Copyright © 2015 Marcela Salazar García et al. All rights reserved. The Relationship between Serum 25-Hydroxy Vitamin D and Insulin Sensitivity and  β-Cell Function in Newly Diagnosed Type 2 Diabetes Sun, 08 Feb 2015 09:57:08 +0000 The aim of this study was to investigate the relationship between serum 25-hydroxy vitamin D (25-OHD) and insulin sensitivity and β-cell function in newly diagnosed type 2 diabetes. 395 newly diagnosed type 2 diabetes patients were enrolled in this study. Venous blood samples were collected at 0 min, 30 min, and 120 min of OGTT to measure serum glucose and insulin. Matsuda ISI and HOMA-IR were used to determine insulin sensitivity. The ratio of 0–120 min area under curve of insulin to glucose (insulin release index, INSR) was calculated as surrogate index of β-cell insulin secretion function. The products of insulin secretion indices multiplied by Matsuda insulin sensitivity index were used as disposition indices. Patients were divided into three groups according to tertiles (T1, T2, and T3) of 25-OHD concentration. There was significant difference among three groups for HOMA-IR, Matsuda ISI, and INSR. HOMA-IR, Matsuda ISI, INSR, and DI were undifferentiated among three groups in male patients. But HOMA-IR, Matsuda ISI, and INSR were significantly different among three groups in female patients after being adjusted by confounding factors. In conclusion, serum 25-OHD is associated with insulin sensitivity and β-cell function for female newly diagnosed type 2 diabetes patients, and the association is ambiguous in males. Yuan Gao, Xinchi Wu, Qi Fu, Yanyun Li, Tao Yang, and Wei Tang Copyright © 2015 Yuan Gao et al. All rights reserved. Homocysteine, Cortisol, Diabetes Mellitus, and Psychopathology Sun, 01 Feb 2015 14:39:06 +0000 Objective. This study investigates the association of homocysteine and cortisol with psychological factors in type 2 diabetic patients. Method. Homocysteine, cortisol, and psychological variables were analyzed from 131 diabetic patients. Psychological factors were assessed with the Eysenck Personality Questionnaire (EPQ), Hostility and Direction of Hostility Questionnaire (HDHQ), the Symptom Checklist 90-R (SCL 90-R), the Zung Self-Rating Depression Scale (ZDRS), and the Maudsley O-C Inventory Questionnaire (MOCI). Blood samples were taken by measuring homocysteine and cortisol in both subgroups during the initial phase of the study (T0). One year later (T1), the uncontrolled diabetic patients were reevaluated with the use of the same psychometric instruments and with an identical blood analysis. Results. The relation of psychoticism and homocysteine is positive among controlled diabetic patients (P value = and negative among uncontrolled ones (P value = 0.137). Higher values of cortisol correspond to lower scores on extraversion subscale , P value = 0.010). Controlled diabetic patients showed a statistically significant negative relationship between homocysteine and the act-out hostility subscale , . There is a statistically significant relationship between homocysteine and somatization , . Conclusions. These findings support the notion that homocysteine and cortisol are related to trait and state psychological factors in patients with diabetes mellitus type 2. K. Kontoangelos, C. C. Papageorgiou, A. E. Raptis, P. Tsiotra, V. Lambadiari, G. N. Papadimitriou, A. D. Rabavilas, G. Dimitriadis, and S. A. Raptis Copyright © 2015 K. Kontoangelos et al. All rights reserved. Sex-Differences in Renal Expression of Selected Transporters and Transcription Factors in Lean and Obese Zucker Spontaneously Hypertensive Fatty Rats Thu, 29 Jan 2015 13:29:39 +0000 The aim of this study was to identify sex-dependent expression of renal transporter mRNA in lean and obese Zucker spontaneously hypertensive fatty (ZSF1) rats and to investigate the interaction of the most altered transporter, organic anion transporter 2 (Oat2), with diabetes-relevant metabolites and drugs. Higher incidence of glomerulosclerosis, tubulointerstitial fibrosis, and protein casts in Bowman’s space and tubular lumen was detected by PAS staining in obese male compared to female ZSF1 rats. Real-time PCR on RNA isolated from kidney cortex revealed that Sglt1-2, Oat1-3, and Oct1 were higher expressed in kidneys of lean females. Oct2 and Mrp2 were higher expressed in obese males. Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1β and Hnf4α in both sexes. The highest difference between lean and obese ZSF1 rats was found for Oat2. Therefore, we have tested the interaction of human OAT2 with various substances using tritium-labeled cGMP. Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors. However, OAT2-dependent uptake of cGMP was inhibited by furosemide. The strongly decreased expression of Oat2 and other transporters in female diabetic ZSF1 rats could possibly impair renal drug excretion, for example, of furosemide. Andrea Babelova, Birgitta C. Burckhardt, Waja Wegner, Gerhard Burckhardt, and Maja Henjakovic Copyright © 2015 Andrea Babelova et al. All rights reserved. Dairy Consumption and Insulin Resistance: The Role of Body Fat, Physical Activity, and Energy Intake Thu, 29 Jan 2015 10:12:31 +0000 The relationship between dairy consumption and insulin resistance was ascertained in 272 middle-aged, nondiabetic women using a cross-sectional design. Participants kept 7-day, weighed food records to report their diets, including dairy intake. Insulin resistance was assessed using the homeostatic model assessment (HOMA). The Bod Pod was used to measure body fat percentage, and accelerometry for 7 days was used to objectively index physical activity. Regression analysis was used to determine the extent to which mean HOMA levels differed across low, moderate, and high dairy intake categories. Results showed that women in the highest quartile of dairy consumption had significantly greater log-transformed HOMA values (0.41 ± 0.53) than those in the middle-two quartiles (0.22 ± 0.55) or the lowest quartile (0.19 ± 0.58) (F = 6.90, P = 0.0091). The association remained significant after controlling for each potential confounder individually and all covariates simultaneously. Adjusting for differences in energy intake weakened the relationship most, but the association remained significant. Of the 11 potential confounders, only protein intake differed significantly across the dairy categories, with those consuming high dairy also consuming more total protein than their counterparts. Apparently, high dairy intake is a significant predictor of insulin resistance in middle-aged, nondiabetic women. Larry A. Tucker, Andrea Erickson, James D. LeCheminant, and Bruce W. Bailey Copyright © 2015 Larry A. Tucker et al. All rights reserved. Diabetes-Resistant NOR Mice Are More Severely Affected by Streptozotocin Compared to the Diabetes-Prone NOD Mice: Correlations with Liver and Kidney GLUT2 Expressions Wed, 28 Jan 2015 15:08:03 +0000 Nonobese Diabetic (NOD) mice are susceptible strains for Type 1 diabetes development, and Nonobese Diabetes-Resistant (NOR) mice are defined as suitable controls for NOD mice in non-MHC-related research. Diabetes is often accelerated in NOD mice via Streptozotocin (STZ). STZ is taken inside cells via GLUT2 transmembrane carrier proteins, the major glucose transporter isoforms in pancreatic beta cells, liver, kidneys, and the small intestine. We observed severe adverse effects in NOR mice treated with STZ compared to NOD mice that were made diabetic with a similar dose. We suggested that the underlying mechanism could be differential GLUT2 expressions in pancreatic beta cells, yet immunofluorescent and immunohistochemical studies revealed similar GLUT2 expression levels. We also detected GLUT2 expression profiles in NOD and NOR hepatic and renal tissues by western blot analysis and observed considerably higher GLUT2 expression levels in liver and kidney tissues of NOR mice. Although beta cell GLUT2 expression levels are frequently evaluated as a marker predicting STZ sensitivity in animal models, we report here very different diabetic responses to STZ in two different animal strains, in spite of similar initial GLUT2 expressions in beta cells. Furthermore, use of NOR mice in STZ-mediated experimental diabetes settings should be considered accordingly. S. Kahraman, C. Aydin, G. O. Elpek, E. Dirice, and A. D. Sanlioglu Copyright © 2015 S. Kahraman et al. All rights reserved. The PI3K/Akt Signaling Pathway Mediates the High Glucose-Induced Expression of Extracellular Matrix Molecules in Human Retinal Pigment Epithelial Cells Wed, 28 Jan 2015 08:09:27 +0000 Prolonged hyperglycemia is an important risk factor of the pathogenesis of diabetic retinopathy (DR). Extracellular matrix molecules, such as fibronectin, collagen IV, and laminin, are associated with fibrotic membranes. In this study, we investigated the expression of fibronectin, collagen IV, and laminin in RPE cells under high glucose conditions. Furthermore, we also detected the phosphorylation of protein kinase B (Akt) under high glucose conditions in RPE cells. Our results showed that high glucose upregulated fibronectin, collagen IV, and laminin expression, and activated Akt in RPE cells. We also found that pretreatment with LY294002 (an inhibitor of phosphatidylinositol 3-kinase) abolished high glucose-induced expression of fibronectin, collagen IV, and laminin in RPE cells. Thus, high glucose induced the expression of fibronectin, collagen IV, and laminin through PI3K/Akt signaling pathway in RPE cells, and the PI3K/Akt signaling pathway may contribute to the formation of fibrotic membrane during the development of DR. Dong Qin, Guo-ming Zhang, Xun Xu, and Li-ya Wang Copyright © 2015 Dong Qin et al. All rights reserved. Retracted: Prognostic Utility of Coronary Computed Tomographic Angiography: A 5-Year Follow-Up in Type 2 Diabetes Patients with Suspected Coronary Artery Disease Tue, 27 Jan 2015 07:39:09 +0000 Journal of Diabetes Research Copyright © 2015 Journal of Diabetes Research. All rights reserved. Lower Extremity Function following Partial Calcanectomy in High-Risk Limb Salvage Patients Thu, 22 Jan 2015 14:21:00 +0000 Partial calcanectomy (PC) is an established limb salvage procedure for treatment of deep heel ulceration with concomitant calcaneal osteomyelitis. The purpose of this study is to determine if a relationship exists between the amount of calcaneus removed during PC and the resulting lower extremity function and limb salvage outcomes. Consecutive PC patients were retrospectively divided into two cohorts defined by the amount of calcaneus resected before wound closure: patients in cohort 1 retained = 50% of calcaneus, while patients in cohort 2 underwent resection of >50% of the calcaneus. The Lower Extremity Function Scale (LEFS) was used to assess postoperative lower extremity function. The average amount of calcaneus resected was 13% ± 9.2 (1–39%) and 74% ± 19.5 (51–100) in cohorts 1 and 2, respectively (). Below knee amputation was performed in 7 (28%) and 5 (29%) of subjects in cohorts 1 and 2, respectively (). The average LEFS score was 33.9 ± 15.0 for subjects in cohort 1 and 36.2 ± 19.9 for the subjects cohort 2 () which correlates to “moderate to quite a bit of difficulty.” Our study suggests that regardless of the amount of calcaneus resected, PC provides a viable treatment option for high-risk patients with calcaneal osteomyelitis. Noah G. Oliver, John S. Steinberg, Kelly Powers, Karen K. Evans, Paul J. Kim, and Christopher E. Attinger Copyright © 2015 Noah G. Oliver et al. All rights reserved. Determining Predictors of Early Response to Exenatide in Patients with Type 2 Diabetes Mellitus Tue, 20 Jan 2015 13:52:03 +0000 Exenatide is a GLP-1 analogue used in the management of T2DM yet within a subset of patients fails due to adverse side effects or from failure to attain the end goal. This retrospective observational study aimed to determine whether we could predict response to exenatide in patients with T2DM. 112 patients on exenatide were included with patient age, gender, duration of T2DM, medications alongside exenatide and weight, BMI, and HbA1c at baseline and 3 and 6 months of exenatide use being recorded. 63 responded with 11 mmol/mol reduction from baseline HbA1c after six months and 49 did not respond to exenatide. HbA1c solely differed significantly between cohorts at baseline, 3 months, and 6 months (P < 0.05). Regression analyses identified a negative linear relationship with higher baseline HbA1c correlating to greater reductions in HbA1c by 6 months (P < 0.0001). HbA1c was the sole predictor of exenatide response with higher baseline HbA1c increasing the odds of response by 5% (P = 0.004). Patients with HbA1c reductions ≥15–20% by 3 months were more likely to be responders by 6 months (P = 0.033). Our study identified that baseline HbA1c acted as the sole predictor of exenatide response and that response may be determined after 3 months of exenatide administration. Muhammad Khan, Jing Ouyang, Karen Perkins, Sunil Nair, and Franklin Joseph Copyright © 2015 Muhammad Khan et al. All rights reserved. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis Tue, 20 Jan 2015 06:52:55 +0000 To evaluate the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on weight reduction in patients with Type 2 diabetes mellitus (Type 2 DM), a network meta-analysis was conducted. MEDLINE, EMBASE, Cochrane Library, and were searched from 1950 to October 2013. Randomized controlled trials (RCTs) involving GLP-1 RAs were included if they provided information on body weight. A total of 51 RCTs were included and 17521 participants were enrolled. The mean duration of 51 RCTs was 31 weeks. Exenatide 10 μg twice daily (EX10BID) reduced weight compared with exenatide 5 μg twice daily (EX5BID), liraglutide 0.6 mg once daily (LIR0.6QD), liraglutide—1.2 mg once daily (LIR1.2QD), and placebo treatment, with mean differences of −1.07 kg (95% CI: −2.41, −0.02), −2.38 kg (95% CI: −3.71, −1.06), −1.62 kg (95% CI: −2.79, −0.43), and −1.92 kg (95% CI: −2.61, −1.24), respectively. Reductions of weight treated with liraglutide—1.8 mg once daily (LIR1.8QD) reach statistical significance (−1.43 kg (95% CI: −2.73, −0.15)) versus LIR1.2QD and (−0.98 kg (95% CI: −1.94, −0.02)) versus placebo. Network meta-analysis found that EX10BID, LIR1.8QD, and EX2QW obtained a higher proportion of patients with weight loss than other traditional hypoglycemic agents. Our results suggest GLP-1 RAs are promising candidates for weight control in comparison with traditional hypoglycemic drugs, and EX10BID, LIR1.8QD, and EX2QW rank the top three drugs. Feng Sun, Sanbao Chai, Lishi Li, Kai Yu, Zhirong Yang, Shanshan Wu, Yuan Zhang, Linong Ji, and Siyan Zhan Copyright © 2015 Feng Sun et al. All rights reserved. Differential Effects of Leptin and Adiponectin in Endothelial Angiogenesis Thu, 15 Jan 2015 06:32:45 +0000 Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality. Endothelial dysfunction is pivotal to the development of cardiovascular disease (CVD). In relation to this, adipose tissue secreted factors termed “adipokines” have been reported to modulate endothelial dysfunction. In this review, we focus on two of the most abundant circulating adipokines, that is, leptin and adiponectin, in the development of endothelial dysfunction. Leptin has been documented to influence a multitude of organ systems, that is, central nervous system (appetite regulation, satiety factor) and cardiovascular system (endothelial dysfunction leading to atherosclerosis). Adiponectin, circulating at a much higher concentration, exists in different molecular weight forms, essentially made up of the collagenous fraction and a globular domain, the latter being investigated minimally for its involvement in proinflammatory processes including activation of NF-κβ and endothelial adhesion molecules. The opposing actions of the two forms of adiponectin in endothelial cells have been recently demonstrated. Additionally, a local and systemic change to multimeric forms of adiponectin has gained importance. Thus detailed investigations on the potential interplay between these adipokines would likely result in better understanding of the missing links connecting CVD, adipokines, and obesity. Raghu Adya, Bee K. Tan, and Harpal S. Randeva Copyright © 2015 Raghu Adya et al. All rights reserved. Suppressive Effect of Insulin on the Gene Expression and Plasma Concentrations of Mediators of Asthmatic Inflammation Tue, 06 Jan 2015 12:52:36 +0000 Background and Hypothesis. Following our recent demonstration that the chronic inflammatory and insulin resistant state of obesity is associated with an increase in the expression of mediators known to contribute to the pathogenesis of asthma and that weight loss after gastric bypass surgery results in the reduction of these genes, we have now hypothesized that insulin suppresses the cellular expression and plasma concentrations of these mediators. Methods. The expression of IL-4, LIGHT, LTBR, ADAM-33, and TSLP in MNC and plasma concentrations of LIGHT, TGF-β1, MMP-9, MCP-1, TSLP, and NOM in obese patients with T2DM were measured before, during, and after the infusion of a low dose (2 U/h) infusion of insulin for 4 hours. The patients were also infused with dextrose or saline for 4 hours on two separate visits and served as controls. Results. Following insulin infusion, the mRNA expression of IL-4, ADAM-33, LIGHT, and LTBR mRNA expression fell significantly ( for all). There was also a concomitant reduction in plasma NOM, LIGHT, TGF-β1, MCP-1, and MMP-9 concentrations. Conclusions. Insulin suppresses the expression of these genes and mediators related to asthma and may, therefore, have a potential role in the treatment of asthma. Husam Ghanim, Kelly Green, Sanaa Abuaysheh, Manav Batra, Nitesh D. Kuhadiya, Reema Patel, Antoine Makdissi, Sandeep Dhindsa, Ajay Chaudhuri, and Paresh Dandona Copyright © 2015 Husam Ghanim et al. All rights reserved. An Altered Pattern of Myocardial Histopathological and Molecular Changes Underlies the Different Characteristics of Type-1 and Type-2 Diabetic Cardiac Dysfunction Mon, 05 Jan 2015 13:46:47 +0000 Increasing evidence suggests that both types of diabetes mellitus (DM) lead to cardiac structural and functional changes. In this study we investigated and compared functional characteristics and underlying subcellular pathological features in rat models of type-1 and type-2 diabetic cardiomyopathy. Type-1 DM was induced by streptozotocin. For type-2 DM, Zucker Diabetic Fatty (ZDF) rats were used. Left ventricular pressure-volume analysis was performed to assess cardiac function. Myocardial nitrotyrosine immunohistochemistry, TUNEL assay, hematoxylin-eosin, and Masson’s trichrome staining were performed. mRNA and protein expression were quantified by qRT-PCR and Western blot. Marked systolic dysfunction in type-1 DM was associated with severe nitrooxidative stress, apoptosis, and fibrosis. These pathological features were less pronounced or absent, while cardiomyocyte hypertrophy was comparable in type-2 DM, which was associated with unaltered systolic function and increased diastolic stiffness. mRNA-expression of hypertrophy markers c-fos, c-jun, and β-MHC, as well as pro-apoptotic caspase-12, was elevated in type-1, while it remained unaltered or only slightly increased in type-2 DM. Expression of the profibrotic TGF-β1 was upregulated in type-1 and showed a decrease in type-2 DM. We compared type-1 and type-2 diabetic cardiomyopathy in standard rat models and described an altered pattern of key pathophysiological features in the diabetic heart and corresponding functional consequences. Tamás Radovits, Sevil Korkmaz, Csaba Mátyás, Attila Oláh, Balázs Tamás Németh, Szabolcs Páli, Kristóf Hirschberg, Alina Zubarevich, Patricia Neh Gwanmesia, Shiliang Li, Sivakkanan Loganathan, Enikő Barnucz, Béla Merkely, and Gábor Szabó Copyright © 2015 Tamás Radovits et al. All rights reserved. Dendrobium chrysotoxum Lindl. Alleviates Diabetic Retinopathy by Preventing Retinal Inflammation and Tight Junction Protein Decrease Thu, 01 Jan 2015 14:10:12 +0000 Diabetic retinopathy (DR) is a serious complication of diabetes mellitus. This study aimed to observe the alleviation of the ethanol extract of Dendrobium chrysotoxum Lindl. (DC), a traditional Chinese herbal medicine, on DR and its engaged mechanism. After DC (30 or 300 mg/kg) was orally administrated, the breakdown of blood retinal barrier (BRB) in streptozotocin- (STZ-) induced diabetic rats was attenuated by DC. Decreased retinal mRNA expression of tight junction proteins (including occludin and claudin-1) in diabetic rats was also reversed by DC. Western blot analysis and retinal immunofluorescence staining results further confirmed that DC reversed the decreased expression of occludin and claudin-1 proteins in diabetic rats. DC reduced the increased retinal mRNA expressions of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor α (TNFα), interleukin- (IL-) 6, and IL-1β in diabetic rats. In addition, DC alleviated the increased 1 and phosphorylated p65, IκB, and IκB kinase (IKK) in diabetic rats. DC also reduced the increased serum levels of TNFα, interferon-γ (IFN-γ), IL-6, IL-1β, IL-8, IL-12, IL-2, IL-3, and IL-10 in diabetic rats. Therefore, DC can alleviate DR by inhibiting retinal inflammation and preventing the decrease of tight junction proteins, such as occludin and claudin-1. Zengyang Yu, Chenyuan Gong, Bin Lu, Li Yang, Yuchen Sheng, Lili Ji, and Zhengtao Wang Copyright © 2015 Zengyang Yu et al. All rights reserved. Novel KIF6 Polymorphism Increases Susceptibility to Type 2 Diabetes Mellitus and Coronary Heart Disease in Han Chinese Men Wed, 31 Dec 2014 12:47:34 +0000 Objectives. The effect of the KIF6 polymorphism Trp719Arg on the risk of T2DM and T2DM with CHD remains unclear. Methods. 946 unrelated subjects of Han Chinese origin were recruited, comprising 346 controls, 312 T2DM, and 288 T2DM + CHD patients. Genotyping was performed by high-resolution melting curve analysis using real-time qPCR. The impact of the variant on T2DM/T2DM + CHD and gene-sex interaction were evaluated by stepwise multiple regression analysis. Results. The frequencies of the Trp719 allele in T2DM and T2DM + CHD patients were similar to the control group, whereas significantly increased 719Arg allele frequencies were observed in male T2DM and T2DM + CHD patients compared with the corresponding control group. Further sex partition analysis revealed that only male 719Arg allele carriers had approximately 3-fold and 5-fold higher risk of T2DM and T2DM + CHD, respectively, than noncarriers. There was also a significant association between carriers and higher TG and lower HDL-C levels. Conclusion. The KIF6 719Arg allele may increase the risk of T2DM and T2DM + CHD only in Han Chinese men by modulating lipid metabolism, especially with regard to TG and HDL. Ge Wu, Gui-Bin Li, Bin Dai, and Dong-Qing Zhang Copyright © 2014 Ge Wu et al. All rights reserved. The Class I Histone Deacetylase Inhibitor MS-275 Prevents Pancreatic Beta Cell Death Induced by Palmitate Wed, 31 Dec 2014 08:32:57 +0000 Elevation of the dietary saturated fatty acid palmitate contributes to the reduction of functional beta cell mass in the pathogenesis of type 2 diabetes. The diabetogenic effect of palmitate is achieved by increasing beta cell death through induction of the endoplasmic reticulum (ER) stress markers including activating transcription factor 3 (Atf3) and CAAT/enhancer-binding protein homologous protein-10 (Chop). In this study, we investigated whether treatment of beta cells with the MS-275, a HDAC1 and HDAC3 activity inhibitor which prevents beta cell death elicited by cytokines, is beneficial for combating beta cell dysfunction caused by palmitate. We show that culture of isolated human islets and MIN6 cells with MS-275 reduced apoptosis evoked by palmitate. The protective effect of MS-275 was associated with the attenuation of the expression of Atf3 and Chop. Silencing of HDAC3, but not of HDAC1, mimicked the effects of MS-275 on the expression of the two ER stress markers and apoptosis. These data point to HDAC3 as a potential drug target for preserving beta cells against lipotoxicity in diabetes. Valérie Plaisance, Laure Rolland, Valéry Gmyr, Jean-Sébastien Annicotte, Julie Kerr-Conte, François Pattou, and Amar Abderrahmani Copyright © 2014 Valérie Plaisance et al. All rights reserved. Hyperglycemia Inhibits Complement-Mediated Immunological Control of S. aureus in a Rat Model of Peritonitis Wed, 31 Dec 2014 00:10:47 +0000 Hyperglycemia from diabetes is associated with increased risk of infection from S. aureus and increased severity of illness. Previous work in our laboratory demonstrated that elevated glucose (>6 mM) dramatically inhibited S. aureus-initiated complement-mediated immune effectors. Here we report in vivo studies evaluating the extent to which a hyperglycemic environment alters complement-mediated control of S. aureus infection in a rat peritonitis model. Rats were treated with streptozocin to induce diabetes or sham-treated and then inoculated i.p. with S. aureus. Rats were euthanized and had peritoneal lavage at 2 or 24 hours after infection to evaluate early and late complement-mediated effects. Hyperglycemia decreased the influx of IgG and complement components into the peritoneum in response to S. aureus infection and decreased anaphylatoxin generation. Hyperglycemia decreased C4-fragment and C3-fragment opsonization of S. aureus recovered in peritoneal fluids, compared with euglycemic or insulin-rescued rats. Hyperglycemic rats showed decreased phagocytosis efficiency compared with euglycemic rats, which correlated inversely with bacterial survival. These results suggest that hyperglycemia inhibited humoral effector recruitment, anaphylatoxin generation, and complement-mediated opsonization of S. aureus, suggesting that hyperglycemic inhibition of complement effectors may contribute to the increased risk and severity of S. aureus infections in diabetic patients. Clifford T. Mauriello, Pamela S. Hair, Reuben D. Rohn, Nicholas S. Rister, Neel K. Krishna, and Kenji M. Cunnion Copyright © 2014 Clifford T. Mauriello et al. All rights reserved. Hyperglycemia Induces Toll-Like Receptor-2 and -4 Expression and Activity in Human Microvascular Retinal Endothelial Cells: Implications for Diabetic Retinopathy Wed, 31 Dec 2014 00:10:46 +0000 Diabetic retinopathy (DR) causes visual impairment in working age adults and hyperglycemia-mediated inflammation is central in DR. Toll-like receptors (TLRs) play a key role in innate immune responses and inflammation. However, scanty data is available on their role in DR. Hence, in this study, we examined TLR2 and TLR4 mRNA and protein expression and activity in hyperglycemic human retinal endothelial cells (HMVRECs). HMVRECs were treated with hyperglycemia (HG) or euglycemia and mRNA and protein levels of TLR-2, TLR-4, MyD88, IRF3, and TRIF as well as NF-κB p65 activation were measured. IL-8, IL-1β, TNF-α and MCP-1, ICAM-1, and VCAM-1 as well as monocyte adhesion to HMVRECs were also assayed. HG (25 mM) significantly induced TLR2 and TLR4 mRNA and protein in HMVRECs. It also increased both MyD88 and non-MyD88 pathways, nuclear factor-κB (NF-κB), biomediators, and monocyte adhesion. This inflammation was attenuated by TLR-4 or TLR-2 inhibition, and dual inhibition by a TLR inhibitory peptide as well as TLR2 and 4 siRNA. Additionally, antioxidant treatment reduced TLR-2 and TLR4 expression and downstream inflammatory markers. Collectively, our novel data suggest that hyperglycemia induces TLR-2 and TLR-4 activation and downstream signaling mediating increased inflammation possibly via reactive oxygen species (ROS) and could contribute to DR. Uthra Rajamani and Ishwarlal Jialal Copyright © 2014 Uthra Rajamani and Ishwarlal Jialal. All rights reserved.