Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. A Modified Method of Insulin Producing Cells’ Generation from Bone Marrow-Derived Mesenchymal Stem Cells Wed, 22 Oct 2014 13:50:05 +0000 Type 1 diabetes mellitus is a result of autoimmune destruction of pancreatic insulin producing β-cells and so far it can be cured only by insulin injection, by pancreas transplantation, or by pancreatic islet cells’ transplantation. The methods are, however, imperfect and have a lot of disadvantages. Therefore new solutions are needed. The best one would be the use of differentiated mesenchymal stem cells (MSCs). In the present study, we investigated the potential of the bone marrow-derived MSCs line for in vitro differentiation into insulin producing cells (IPSs). We applied an 18-day protocol to differentiate MSCs. Differentiating cells formed cell clusters some of which resembled pancreatic islet-like cells. Using dithizone we confirmed the presence of insulin in the cells. What is more, the expression of proinsulin C-peptide in differentiated IPCs was analyzed by flow cytometry. For the first time, we investigated the influence of growth factors’ concentration on IPCs differentiation efficiency. We have found that an increase in the concentration of growth factors up to 60 ng/mL of β-FGF/EGF and 30 ng/mL of activin A/β-cellulin increases the percentage of IPCs. Further increase of growth factors does not show any increase of the percentage of differentiated cells. Our findings suggest that the presented protocol can be adapted for differentiation of insulin producing cells from stem cells. Paweł Czubak, Agnieszka Bojarska-Junak, Jacek Tabarkiewicz, and Lechosław Putowski Copyright © 2014 Paweł Czubak et al. All rights reserved. Impact of Diabetic Foot on Selected Psychological or Social Characteristics Tue, 21 Oct 2014 09:41:29 +0000 Ugur Cakir, Ertugrul Kargi, Hakan Sarman, and Cengiz Isik Copyright © 2014 Ugur Cakir et al. All rights reserved. Targets and Candidate Agents for Type 2 Diabetes Treatment with Computational Bioinformatics Approach Tue, 21 Oct 2014 07:55:57 +0000 We sought to explore the molecular mechanism of type 2 diabetes (T2D) and identify potential drug targets and candidate agents for T2D treatment. The differentially expressed genes (DEGs) were assessed between human pancreatic islets with T2D and normal islets. The dysfunctional pathways, the potential transcription factor, and microRNA targets were analyzed by bioinformatics methods. Moreover, a group of bioactive small molecules were identified based on the connectivity map database. The pathways of Eicosanoid Synthesis, TGF-beta signaling pathway, Prostaglandin Synthesis and Regulation, and Integrated Pancreatic Cancer Pathway were found to be significantly dysregulated in the progression of T2D. The genes of ZADH2 (zinc binding alcohol dehydrogenase domain containing 2), BTBD3 (BTB (POZ) domain containing 3), Cul3-based ligases,  LTBP1 (latent-transforming growth factor beta binding protein 1), PDGFRA (alpha-type platelet-derived growth factor receptor), and FST (follistatin) were determined to be significant nodes regulated by potential transcription factors and microRNAs. Besides, two small molecules (sanguinarine and DL-thiorphan) were identified to be capable of reverse T2D. In the present study, a systematic understanding for the mechanism underlying T2D development was provided with biological informatics methods. The significant nodes and bioactive small molecules may be drug targets and candidate agents for T2D treatment. Qiong Wang, Zhigang Zhao, Jing Shang, and Wei Xia Copyright © 2014 Qiong Wang et al. All rights reserved. BlockingαVβ3 Integrin Ligand Occupancy Inhibits the Progression of Albuminuria in Diabetic Rats Mon, 20 Oct 2014 11:42:20 +0000 This study determined if blocking ligand occupancy of the αVβ3 integrin could inhibit the pathophysiologic changes that occur in the early stages of diabetic nephropathy (DN). Diabetic rats were treated with either vehicle or a monoclonal antibody that binds the β3 subunit of the αVβ3 integrin. After 4 weeks of diabetes the urinary albumin to creatinine ratio (UACR) increased in both diabetic animals that subsequently received vehicle and in the animals that subsequently received the anti-β3 antibody compared with control nondiabetic rats. After 8 weeks of treatment the UACR continued to rise in the vehicle-treated rats; however it returned to levels comparable to control nondiabetic rats in rats treated with the anti-β3 antibody. Treatment with the antibody prevented the increase of several profibrotic proteins that have been implicated in the development of DN. Diabetes was associated with an increase in phosphorylation of the β3 subunit in kidney homogenates from diabetic animals, but this was prevented by the antibody treatment. This study demonstrates that, when administered after establishment of early pathophysiologic changes in renal function, the anti-β3 antibody reversed the effects of diabetes normalizing albuminuria and profibrotic proteins in the kidney to the levels observed in nondiabetic control animals. Laura A. Maile, Katherine Gollahon, Christine Wai, Paul Dunbar, Walker Busby, and David Clemmons Copyright © 2014 Laura A. Maile et al. All rights reserved. Nonhuman Primate Models of Type 1 Diabetes Mellitus for Islet Transplantation Mon, 20 Oct 2014 06:43:37 +0000 Islet transplantation is an attractive treatment of type 1 diabetes mellitus (T1DM). Animal models of diabetes mellitus (DM) contribute a lot to the experimental studies of islet transplantation and to evaluations of isolated islet grafts for future clinical applications. Diabetic nonhuman primates (NHPs) represent the suitable models of DMs to better evaluate the effectiveness of islet transplantation, to assess new strategies for controlling blood glucose (BG), relieving immune rejection, or prolonging islet survival, and eventually to translate the preclinical data into tangible clinical practice. This review introduces some NHP models of DM, clarifies why and how the models should be used, and elucidates the usefulness and limitations of the models in islet transplantation. Haitao Zhu, Liang Yu, Yayi He, and Bo Wang Copyright © 2014 Haitao Zhu et al. All rights reserved. Renal Protective Effect of Sirtuin 1 Thu, 16 Oct 2014 07:15:56 +0000 Silent information regulator 2 (Sir2) is a nicotinamide adenine dinucleotide- (NAD+-) dependent deacetylase. The homology of SIRT1 and Sir2 has been extensively studied. SIRT1 deacetylates target proteins using the coenzyme NAD+ and is therefore linked to cellular energy metabolism and the redox state through multiple signalling and survival pathways. During the past decade, investigators have reported that SIRT1 activity is essential in cancer, neurodegenerative diseases, diabetes, cardiovascular disease, and other age-related diseases. In the kidneys, SIRT1 may inhibit renal cell apoptosis, inflammation, and fibrosis. Therefore its activation may also become a new therapeutic target in the patients with chronic kidney disease including diabetic nephropathy. In this paper, we would like to review the protective functions of sirtuins and the role of SIRT1 in the onset of kidney disease based on previous studies, including diabetic nephropathy, acute renal injury, chronic kidney disease as well as lupus nephritis. Yi-jun Dong, Nian Liu, Zhi Xiao, Tao Sun, Shu-hui Wu, Wei-xia Sun, Zhong-gao Xu, and Hang Yuan Copyright © 2014 Yi-jun Dong et al. All rights reserved. Downregulation of Type II Diabetes Mellitus and Maturity Onset Diabetes of Young Pathways in Human Pancreatic Islets from Hyperglycemic Donors Tue, 14 Oct 2014 12:59:58 +0000 Although several molecular pathways have been linked to type 2 diabetes (T2D) pathogenesis, it is uncertain which pathway has the most implication on the disease. Changes in the expression of an entire pathway might be more important for disease pathogenesis than changes in the expression of individual genes. To identify the molecular alterations in T2D, DNA microarrays of human pancreatic islets from donors with hyperglycemia and normoglycemia were subjected to Gene Set Enrichment Analysis (GSEA). About 178 KEGG pathways were investigated for gene expression changes between hyperglycemic donors compared to normoglycemic. Pathway enrichment analysis showed that type II diabetes mellitus (T2DM) and maturity onset diabetes of the young (MODY) pathways are downregulated in hyperglycemic donors, while proteasome and spliceosome pathways are upregulated. The mean centroid of gene expression of T2DM and MODY pathways was shown to be associated positively with insulin secretion and negatively with HbA1c level. To conclude, downregulation of T2DM and MODY pathways is involved in islet function and might be involved in T2D. Also, the study demonstrates that gene expression profiles from pancreatic islets can reveal some of the biological processes related to regulation of glucose hemostats and diabetes pathogenesis. Jalal Taneera, Petter Storm, and Leif Groop Copyright © 2014 Jalal Taneera et al. All rights reserved. Vitamin D Status and Its Relationship with Metabolic Markers in Persons with Obesity and Type 2 Diabetes in the UAE: A Cross-Sectional Study Mon, 13 Oct 2014 11:34:19 +0000 Aim. To report vitamin D status and its impact on metabolic parameters in people in the United Arab Emirates with obesity and type 2 diabetes (T2D). Methodology. This cross-sectional study included 309 individuals with obesity and T2D who were randomly selected based on study criteria. Serum concentrations of 25-hydroxy vitamin D (s-25(OH)D), calcium, phosphorus, parathyroid hormone, alkaline phosphatase, glycemic profile, and cardiometabolic parameters were assessed in fasting blood samples, and anthropometric measurements were recorded. Results. Vitamin D deficiency (s-25(OH)D < 50 nmol/L) was observed in 83.2% of the participants, with a mean s-25(OH)D of 33.8 ± 20.3 nmol/L. Serum 25(OH)D correlated negatively () with body mass index, fat mass, waist circumference, parathyroid hormone, alkaline phosphatase, triglycerides, LDL-cholesterol, and apolipoprotein B and positively () with age and calcium concentration. Waist circumference was the main predictor of s-25(OH)D status. There was no significant association between serum 25(OH)D and glycemic profile. Conclusion. There is an overwhelming prevalence of vitamin D deficiency in our sample of the Emirati population with obesity and T2D. Association of s-25(OH)D with body mass index, waist circumference, fat mass, markers of calcium homeostasis and cardiometabolic parameters suggests a role of vitamin D in the development of cardiometabolic disease-related process. Amena Sadiya, Solafa M. Ahmed, Sijomol Skaria, and Salah Abusnana Copyright © 2014 Amena Sadiya et al. All rights reserved. Role of Endothelial Nitric Oxide Synthase in Diabetic Nephropathy: Lessons from Diabetic eNOS Knockout Mice Mon, 13 Oct 2014 11:28:27 +0000 Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in many countries. The animal models that recapitulate human DN undoubtedly facilitate our understanding of this disease and promote the development of new diagnostic markers and therapeutic interventions. Based on the clinical evidence showing the association of eNOS dysfunction with advanced DN, we and others have created diabetic mice that lack eNOS expression and shown that eNOS-deficient diabetic mice exhibit advanced nephropathic changes with distinct features of progressive DN, including pronounced albuminuria, nodular glomerulosclerosis, mesangiolysis, and arteriolar hyalinosis. These studies clearly defined a critical role of eNOS in DN and developed a robust animal model of this disease, which enables us to study the pathogenic mechanisms of progressive DN. Further, recent studies with this animal model have explored the novel mechanisms by which eNOS deficiency causes advanced DN and provided many new insights into the pathogenesis of DN. Therefore, here we summarize the findings obtained with this animal model and discuss the roles of eNOS in DN, unresolved issues, and future investigations of this animal model study. Takamune Takahashi and Raymond C. Harris Copyright © 2014 Takamune Takahashi and Raymond C. Harris. All rights reserved. Characterization of Diabetic Neuropathy in the Zucker Diabetic Sprague-Dawley Rat: A New Animal Model for Type 2 Diabetes Mon, 13 Oct 2014 08:40:52 +0000 Recently a new rat model for type 2 diabetes the Zucker diabetic Sprague-Dawley (ZDSD/Pco) was created. In this study we sought to characterize the development of diabetic neuropathy in ZDSD rats using age-matched Sprague-Dawley rats as a control. Rats were examined at 34 weeks of age 12 weeks after the onset of hyperglycemia in ZDSD rats. At this time ZDSD rats were severely insulin resistant with slowing of both motor and sensory nerve conduction velocities. ZDSD rats also had fatty livers, elevated serum free fatty acids, triglycerides, and cholesterol, and elevated sciatic nerve nitrotyrosine levels. The corneas of ZDSD rats exhibited a decrease in subbasal epithelial corneal nerves and sensitivity. ZDSD rats were hypoalgesic but intraepidermal nerve fibers in the skin of the hindpaw were normal compared to Sprague-Dawley rats. However, the number of Langerhans cells was decreased. Vascular reactivity of epineurial arterioles, blood vessels that provide circulation to the sciatic nerve, to acetylcholine and calcitonin gene-related peptide was impaired in ZDSD rats. These data indicate that ZDSD rats develop many of the neural complications associated with type 2 diabetes and are a good animal model for preclinical investigations of drug development for diabetic neuropathy. Eric P. Davidson, Lawrence J. Coppey, Amey Holmes, Sergey Lupachyk, Brian L. Dake, Christine L. Oltman, Richard G. Peterson, and Mark A. Yorek Copyright © 2014 Eric P. Davidson et al. All rights reserved. Chronic Treatment with Ang-(1-7) Reverses Abnormal Reactivity in the Corpus Cavernosum and Normalizes Diabetes-Induced Changes in the Protein Levels of ACE, ACE2, ROCK1, ROCK2 and Omega-Hydroxylase in a Rat Model of Type 1 Diabetes Tue, 16 Sep 2014 08:46:52 +0000 Angiotensin-(1-7) [Ang-(1-7)] may have beneficial effects in diabetes mellitus-induced erectile dysfunction (DMIED) but its molecular actions in the diabetic corpus cavernosum (CC) are not known. We characterized the effects of diabetes and/or chronic in vivo administration of Ang-(1-7) on vascular reactivity in the rat corpus cavernosum (CC) and on protein expression levels of potential downstream effectors of the renin-angiotensin-aldosterone system (RAAS) such as angiotensin-converting enzyme (ACE), ACE2, Rho kinases 1 and 2 (ROCK1 and ROCK2), and omega-hydroxylase, the cytochrome-P450 enzyme that metabolizes arachidonic acid to form the vasoconstrictor, 20-hydroxyeicosatetraenoic acid. Streptozotocin-treated rats were chronicically administered Ang-(1-7) with or without A779, a Mas receptor antagonist, during weeks 4 to 6 of diabetes. Ang-(1-7) reversed diabetes-induced abnormal reactivity to vasoactive agents (endothelin-1, phenylepherine, and carbachol) in the CC without correcting hyperglycemia. Six weeks of diabetes led to elevated ACE, ROCK1, ROCK 2, and omega-hydroxylase and a concomitant decrease in ACE2 protein expression levels that were normalized by Ang-(1-7) treatment but not upon coadministration of A779. These data are supportive of the notion that the beneficial effects of Ang-(1-7) in DMIED involve counterregulation of diabetes-induced changes in ACE, ACE2, Rho kinases, and omega-hydroxylase proteins in the diabetic CC via a Mas receptor-dependent mechanism. Mariam H. M. Yousif, Batoul Makki, Ahmed Z. El-Hashim, Saghir Akhtar, and Ibrahim F. Benter Copyright © 2014 Mariam H. M. Yousif et al. All rights reserved. Ocular Inflammation in Uveal Tract in Aged Obese Type 2 Diabetic Rats (Spontaneously Diabetic Torii Fatty Rats) Sun, 14 Sep 2014 13:05:14 +0000 We report uveitis observed in an obese type 2 diabetes rat model, Spontaneously Diabetic Torii Leprfa (SDT fatty) rats aged over 50 weeks. The eyes of SDT fatty rats (16 animals: 7 males and 9 females with 50 or 60 weeks of age) were examined histopathologically. Infiltration of inflammatory cells in the uveal tract was observed in 13 of 16 animals. One female showed severe inflammation affecting the entire uveal tract including the iris, ciliary body, and choroid with a variety of inflammatory cells (neutrophils, lymphocytes, and macrophages). Those changes clinically mimic the findings of diabetic iridocyclitis in diabetic patients. Uveitis associated with diabetes can occur in diabetic patients but the pathogenesis still remains unknown. Since increased extramedullary hematopoiesis in the spleen and abscess in the genital and lower urinary tracts were observed in some SDT fatty rats, increased susceptibility to infection, prolongation of inflammatory states, and disorders of the immune system were considered to be possible factors of the uveitis in aged SDT fatty rats. There have been few reports on how diabetes has influence on the development of uveitis associated with bacterial infection. The SDT fatty rat can be an animal model to investigate diabetes-associated uveitis. Yusuke Kemmochi, Katsuhiro Miyajima, Takeshi Ohta, Tomohiko Sasase, Yuzo Yasui, Kaoru Toyoda, Kochi Kakimoto, Toshiyuki Shoda, and Akihiro Kakehashi Copyright © 2014 Yusuke Kemmochi et al. All rights reserved. The Influence of Peripheral Neuropathy, Gender, and Obesity on the Postural Stability of Patients with Type 2 Diabetes Mellitus Tue, 02 Sep 2014 12:04:07 +0000 Aim. To assess the influence of peripheral neuropathy, gender, and obesity on the postural stability of patients with type 2 diabetes mellitus. Methods. 151 patients with no history of otology, neurology, or orthopaedic or balance disorders accepted to participate in the study. After a clinical interview and neuropathy assessment, postural stability was evaluated by static posturography (eyes open/closed on hard/soft surface) and the “Up & Go” test. Results. During static posturography, on hard surface, the length of sway was related to peripheral neuropathy, gender, age, and obesity; on soft surface, the length of sway was related to peripheral neuropathy, gender, and age, the influence of neuropathy was larger in males than in females, and closing the eyes increased further the difference between genders. The mean time to perform the “Up & Go” test was 11.6 ± 2.2 sec, with influence of peripheral neuropathy, gender, and age. Conclusion. In order to preserve the control of static upright posture during conditions with deficient sensory input, male patients with type 2 diabetes mellitus with no history of balance disorders may be more vulnerable than females, and obesity may decrease the static postural control in both males and females. Aline Herrera-Rangel, Catalina Aranda-Moreno, Teresa Mantilla-Ochoa, Lylia Zainos-Saucedo, and Kathrine Jáuregui-Renaud Copyright © 2014 Aline Herrera-Rangel et al. All rights reserved. The Role of MicroRNAs in Diabetic Nephropathy Mon, 01 Sep 2014 11:24:42 +0000 Diabetic nephropathy (DN), as one of the chronic complications of diabetes, is the major cause of end-stage renal disease. However, the pathogenesis of this disease is not fully understood. In recent years, research on microRNAs (miRNAs) has become a hotspot because of their critical role in regulating posttranscriptional levels of protein-coding genes that may serve as key pathogenic factors in diseases. Several miRNAs were found to participate in the pathogenesis of DN, while others showed renal protective effects. Therefore, targeting miRNAs that are involved in DN may have a good prospect in the treatment of the disease. The aim of this review is to summarize DN-related miRNAs and provide potential targets for diagnostic strategies and therapeutic intervention. Hao Wu, Lili Kong, Shanshan Zhou, Wenpeng Cui, Feng Xu, Manyu Luo, Xiangqi Li, Yi Tan, and Lining Miao Copyright © 2014 Hao Wu et al. All rights reserved. Characteristics and Determinants of Partial Remission in Children with Type 1 Diabetes Using the Insulin-Dose-Adjusted A1C Definition Sun, 31 Aug 2014 09:18:38 +0000 To evaluate the characteristics and determinants of partial remission (PR) in Belgian children with type 1 diabetes (T1D), we analyzed records of 242 children from our center. Clinical and biological features were collected at diagnosis and during follow-up. PR was defined using the insulin-dose-adjusted A1C definition. PR occurred in 56.2% of patients and lasted 9.2 months (0.5 to 56.6). 25.6% of patients entered T1D with DKA, which correlated with lower PR incidence (17.6% versus 82.3% when no DKA). In our population, lower A1C levels at diagnosis were associated with higher PR incidence and in young children (0–4 years) initial A1C levels negatively correlated with longer PR. Early A1C levels were predictive of PR duration since 34% of patients had long PRs (>1 year) when A1C levels were ≤6% after 3 months whereas incidence of long PR decreased with higher A1Cs. C-peptide levels were higher in patients entering PR and remained higher until 3 years after diagnosis. Initial antibody titers did not influence PR except for anti-IA2 titers that correlated with A1C levels after 2 years. Presence of 2 versus 1 anti-islet antibodies correlated with shorter PR. PR duration did not influence occurrence of severe hypoglycemia or diabetes-related complications but was associated with lower A1C levels after 18 months. We show that, at diagnosis of T1D, parameters associated with -cell mass reserve (A1C, C-peptide, and DKA) correlate with the occurrence of PR, which affects post-PR A1C levels. Further research is needed to determine the long-term significance of PR. Aurore Pecheur, Thierry Barrea, Valérie Vandooren, Véronique Beauloye, Annie Robert, and Philippe A. Lysy Copyright © 2014 Aurore Pecheur et al. All rights reserved. Continuous Electrical Current and Zinc Sulphate Administered by Transdermal Iontophoresis Improves Skin Healing in Diabetic Rats Induced by Alloxan: Morphological and Ultrastructural Analysis Thu, 28 Aug 2014 08:44:09 +0000 Purpose. Evaluated the effects of continuous electrical current (CEC) or zinc administrated by transdermal iontophoresis (Zn+TDI). Methods. 120 male Wistar rats were submitted to an incision surgery at the anterior region of abdomen and distributed into 6 experimental groups with 40 animals: 3 diabetic groups and 3 normal groups, untreated and treated with CEC alone or with Zn + TDI. Each group was further divided into 4 subgroups with 10 rats each to be evaluated on the 4th, 7th, 14th, and 21st day after surgery. In each period, clinical and laboratory parameters from the animals were analyzed. Results. The analysis by optical and scanning electron microscopy showed a delay in the phases of wound healing in diabetic rats without treatment in all periods of the experiment; breaking strength (BS) was significantly reduced in skin scars of untreated diabetic rats when compared to other groups. In contrast, BS in skin scars of nondiabetic groups and diabetic rats treated with Zn + TDI showed significant increase in those, besides not presenting delayed healing. Conclusion. Electrical stimulation of surgical wounds used alone or in association with zinc by TDI is able to consistently improve the morphological and ultrastructural changes observed in the healing of diabetic animals. Lucas Langoni Cassettari, Pedro Colli Rocha Dias, Amanda Natália Lucchesi, Maurício Ferraz de Arruda, Érika Veruska Paiva Ortolan, Mariângela Esther A. Marques, and César Tadeu Spadella Copyright © 2014 Lucas Langoni Cassettari et al. All rights reserved. Histone Lysine Methylation in Diabetic Nephropathy Mon, 25 Aug 2014 10:52:46 +0000 Diabetic nephropathy (DN) belongs to debilitating microvascular complications of diabetes and is the leading cause of end-stage renal diseases worldwide. Furthermore, outcomes from the DCCT/EDIC study showed that DN often persists and progresses despite intensive glucose control in many diabetes patients, possibly as a result of prior episode of hyperglycemia, which is called “metabolic memory.” The underlying mechanisms responsible for the development and progression of DN remain poorly understood. Activation of multiple signaling pathways and key transcription factors can lead to aberrant expression of DN-related pathologic genes in target renal cells. Increasing evidence suggests that epigenetic mechanisms in chromatin such as DNA methylation, histone acetylation, and methylation can influence the pathophysiology of DN and metabolic memory. Exciting researches from cell culture and experimental animals have shown that key histone methylation patterns and the related histone methyltransferases and histone demethylases can play important roles in the regulation of inflammatory and profibrotic genes in renal cells under diabetic conditions. Because histone methylation is dynamic and potentially reversible, it can provide a window of opportunity for the development of much-needed novel therapeutic potential for DN in the future. In this minireview, we discuss recent advances in the field of histone methylation and its roles in the pathogenesis and progression of DN. Guang-dong Sun, Wen-peng Cui, Qiao-yan Guo, and Li-ning Miao Copyright © 2014 Guang-dong Sun et al. All rights reserved. Effect of Ranirestat, a New Aldose Reductase Inhibitor, on Diabetic Retinopathy in SDT Rats Mon, 25 Aug 2014 07:51:42 +0000 Purpose. To evaluate the effect of ranirestat, a new aldose reductase inhibitor (ARI), on diabetic retinopathy (DR) in Spontaneously Diabetic Torii (SDT) rats. Methods. The animals were divided into six groups, normal Sprague-Dawley rats , untreated SDT rats , ranirestat-treated SDT rats (0.1, 1.0, and 10 mg/kg/day, , and , resp.), and epalrestat-treated SDT rats (100 mg/kg/day, . Treated rats received oral ranirestat or epalrestat once daily for 40 weeks after the onset of diabetes. After the eyes were enucleated, the retinal thickness and the area of stained glial fibrillary acidic protein (GFAP) were measured. Results. The retinas in the untreated group were significantly thicker than those in the normal and ranirestat-treated (0.1, 1.0, and 10 mg/kg/day) groups. The immunostained area of GFAP in the untreated group was significantly larger than that in the normal and ranirestat-treated (1.0 and 10 mg/kg/day) groups. There were no significant differences between the untreated group and epalrestat-treated group in the retinal thickness and the area of stained GFAP. Conclusion. Ranirestat reduced the retinal thickness and the area of stained GFAP in SDT rats and might suppress DR and have a neuroprotective effect on diabetic retinas. Fumihiko Toyoda, Yoshiaki Tanaka, Ayumi Ota, Machiko Shimmura, Nozomi Kinoshita, Hiroko Takano, Takafumi Matsumoto, Junichi Tsuji, and Akihiro Kakehashi Copyright © 2014 Fumihiko Toyoda et al. All rights reserved. Vitamin D Insufficiency Is Associated with Lower Physical Function in Patients with Heart Failure and Diabetes Mon, 25 Aug 2014 05:48:14 +0000 Vitamin D deficiency is frequent among patients with heart failure (HF) and diabetes, disorders associated with exercise intolerance and muscle weakness. This study aims to search for associations between vitamin D sufficiency and physical function indexes in patients with HF and diabetes. A cross-sectional study of 146 HF patients, 39.7% with diabetes, at a Brazilian tertiary outpatient clinic was performed. Patients underwent clinical evaluation, 6-minute walk test (6 MWT), handgrip strength, physical activity level (IPAQ), and biochemical evaluations including serum 25-hydroxyvitamin D. Classification was done according to vitamin D status (≥30 ng/dL, sufficient) and presence/absence of diabetes in vitamin sufficient, no diabetes (DS-C, ), vitamin sufficient, diabetes (DS-DM, ), vitamin deficient, no diabetes (DD-C, ), and vitamin deficient, diabetes (DD-DM, ). Patients age was 55.4 ± 8 yrs; 70.5% had vitamin D deficiency. Clinical characteristics were similar among groups. Total time expended in physical activity was similar among groups . DS-C covered higher distances in the 6 MWT (392 ± 60 m) versus DD-DM (309 ± 116 m); . Handgrip strength was similar among groups but tended to lower levels in DD-DM even after being adjusted to physical activity . Vitamin D deficiency can influence physical function in HF diabetic patients. M. R. Lopes, Paula A. B. Ribeiro, Priscila Ledur, Gabriela C. Souza, Nadine Clausell, and Beatriz D. Schaan Copyright © 2014 M. R. Lopes et al. All rights reserved. Evaluating the Mechanisms of Improved Glucose Homeostasis after Bariatric Surgery in Ossabaw Miniature Swine Sun, 24 Aug 2014 07:36:19 +0000 Background. Roux-en-Y gastric bypass (RYGB) is the most common bariatric operation; however, the mechanism underlying the profound weight-independent effects on glucose homeostasis remains unclear. Large animal models of naturally occurring insulin resistance (IR), which have been lacking, would provide opportunities to elucidate such mechanisms. Ossabaw miniature swine naturally exhibit many features that may be useful in evaluating the anti diabetic effects of bariatric surgery. Methods. Glucose homeostasis was studied in 53 Ossabaw swine. Thirty-two received an obesogenic diet and were randomized to RYGB, gastrojejunostomy (GJ), gastrojejunostomy with duodenal exclusion (GJD), or Sham operations. Intravenous glucose tolerance tests and standardized meal tolerance tests were performed prior to, 1, 2, and 8 weeks after surgery and at a single time-point for regular diet control pigs. Results. High-calorie-fed Ossabaws weighed more and had greater IR than regular diet controls, though only 70% developed IR. All operations caused weight-loss-independent improvement in IR, though only in pigs with high baseline IR. Only RYGB induced weight loss and decreased IR in the majority of pigs, as well as increasing /. Conclusions. Similar to humans, Ossabaw swine exhibit both obesity-dependent and obesity-independent IR. RYGB promoted weight loss, IR improvement, and increased /, compared to the smaller changes following GJ and GJD, suggesting a combination of upper and lower gut mechanisms in improving glucose homeostasis. Jonathan G. Sham, Vlad V. Simianu, Andrew S. Wright, Skye D. Stewart, Mouhamad Alloosh, Michael Sturek, David E. Cummings, and David R. Flum Copyright © 2014 Jonathan G. Sham et al. All rights reserved. Subjects with Impaired Fasting Glucose: Evolution in a Period of 6 Years Wed, 20 Aug 2014 07:49:03 +0000 Aim. To study the evolution of impaired fasting glucose (IFG), considering glucose and HbA1c levels and risk factors associated, in a period of 6 years. Methods. We studied 94 subjects with impaired fasting glucose (IFG) that were diagnosed in 2005 and followed up to 2012. Glucose and HbA1c levels were determined. A descriptive analysis of contingence charts was performed in order to study the evolution in the development of type-2 diabetes mellitus (T2DM). Results. Twenty-eight of ninety-four subjects became T2DM; 51/94 remained with IFG; and 20/94 presented normal fasting glucose. From the 28 diabetic subjects, 9 had already developed diabetes and were under treatment with oral hypoglycemic agents; 5 were diagnosed with plasma glucose < 126 mg/dL, but with HbA1c over 6.5%. In those who developed diabetes, 15/28 had a family history of T2DM in first relative degree. Also, diabetic subjects had a BMI significantly higher than nodiabetics (t test: P < 0.01). The individuals that in 2005 had the highest BMI are those who currently have diabetes. Conclusion. The IFG constitutes a condition of high risk of developing T2DM in a few years, especially over 110 mg/dL and in obesity patients. E. Leiva, V. Mujica, R. Orrego, S. Wehinger, A. Soto, G. Icaza, M. Vásquez, L. Díaz, M. Andrews, and M. Arredondo Copyright © 2014 E. Leiva et al. All rights reserved. Vanadyl Sulfate Treatment Stimulates Proliferation and Regeneration of Beta Cells in Pancreatic Islets Tue, 19 Aug 2014 06:18:23 +0000 We examined the effects of vanadium sulfate (VOSO4) treatment at 5 and 10 mg/kg for 30 days on endocrine pancreas activity and histology in nondiabetic and STZ-induced diabetic rats. In diabetic group, blood glucose levels significantly increased while insulinemia level markedly decreased. At the end of treatment, VOSO4 at a dose of 10 mg/Kg normalized blood glucose level in diabetic group, restored insulinemia, and significantly improved insulin sensitivity. VOSO4 also increased in a dose-dependent manner the number of insulin immunopositive beta cells in pancreatic islets of nondiabetic rats. Furthermore, in the STZ-diabetic group, the decrease in the number of insulin immunopositive beta cells was corrected to reach the control level mainly with the higher dose of vanadium. Therefore, VOSO4 treatment normalized plasma glucose and insulin levels and improved insulin sensitivity in STZ-experimental diabetes and induced beta cells proliferation and/or regeneration in normal or diabetic rats. Samira Missaoui, Khémais Ben Rhouma, Mohamed-Tahar Yacoubi, Mohsen Sakly, and Olfa Tebourbi Copyright © 2014 Samira Missaoui et al. All rights reserved. Brain Aging and AD-Like Pathology in Streptozotocin-Induced Diabetic Rats Thu, 14 Aug 2014 08:25:10 +0000 Objective. Numerous epidemiological studies have linked diabetes mellitus (DM) with an increased risk of developing Alzheimer’s disease (AD). However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. Research Design and Methods. Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ-) induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC). Aβ aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. Results. Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβ aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. Conclusions. Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies. Jian-Qin Wang, Jie Yin, Yan-Feng Song, Lang Zhang, Ying-Xiang Ren, De-Gui Wang, Li-Ping Gao, and Yu-Hong Jing Copyright © 2014 Jian-Qin Wang et al. All rights reserved. Insulin Detemir Causes Lesser Weight Gain in Comparison to Insulin Glargine: Role on Hypothalamic NPY and Galanin Thu, 14 Aug 2014 00:00:00 +0000 Objective. Compared with other insulin analogues, insulin detemir induces less weight gain. This study investigated whether this effect was achieved by influencing the hypothalamic appetite regulators neuropeptide Y (NPY) and galanin (GAL). Methods. Type  2 diabetic rat models were established with a high-fat diet and intraperitoneal injection of STZ. All rats were divided into NC, DM, DM+DE and DM+GLA groups. Glycemic levels of all study groups were checked at study onset and after 4 weeks of insulin treatment. Food intake and body weight were monitored during treatment. After 4 weeks, the hypothalamus of rats was examined for NPY and GAL mRNA and protein expression. Results. After 4 weeks of treatment, compared with the DM+GLA group, the DM+DE group exhibited less food intake () and less weight gain (), but showed similar glycemic control. The expression of hypothalamic NPY and GAL at both mRNA and protein level were significantly lower () in the DM+DE group. Conclusion. Insulin detemir decreased food intake in type 2 diabetic rats, which led to reduced weight gain when compared to insulin glargine treatment. This effect is likely due to downregulation of hypothalamic NPY and GAL. Mohammad Ishraq Zafar, Cuining Hu, Danfeng Liu, Raja Adeel Shafqat, and Feng Gao Copyright © 2014 Mohammad Ishraq Zafar et al. All rights reserved. Expression of CTRP3, a Novel Adipokine, in Rats at Different Pathogenic Stages of Type 2 Diabetes Mellitus and the Impacts of GLP-1 Receptor Agonist on It Mon, 11 Aug 2014 00:00:00 +0000 This study aimed to investigate the expression of C1q/TNF-related protein-3 (CTRP3) in rats at different pathogenic stages of type 2 diabetes mellitus (T2DM) and the impacts of glucagon-like peptide-1 (GLP-1) receptor agonist on it. Male wistar rats were fed with high-fat diet for 10 weeks to induce insulin resistance (IR) and then were given low-dose streptozotocin (STZ) intraperitoneal injection to induce T2DM. Exendin-4 (Ex-4), a GLP-1 receptor agonist, was subcutaneous injected to the IR rats and T2DM rats for 4 weeks. The expression of CTRP3 mRNA and protein in epididymis adipose tissue of rats at the stage of IR was lower significantly than that of normal control (NC) rats and decreased more when they were at the stage of overt T2DM (all or ). After the treatment with Ex-4, the mRNA and protein expressions of CTRP3 were increased by 15.5% and 14.8% respectively, in IR rats and increased by 20.6% and 16.5% respectively, in T2DM rats. Overall, this study found that the expression of CTRP3 in visceral adipose tissue was progressively decreased in a T2DM rat model from the pathogenic stage of IR to overt diabetes, while Ex-4 treatment increased its expression in such animals. Xin Li, Li Jiang, Miao Yang, Yu-wen Wu, Su-xin Sun, and Jia-zhong Sun Copyright © 2014 Xin Li et al. All rights reserved. Effects of Unilateral Nephrectomy on Renal Function in Male Spontaneously Diabetic Torii Fatty Rats: A Novel Obese Type 2 Diabetic Model Sun, 10 Aug 2014 12:41:54 +0000 The Spontaneously Diabetic Torii (SDT) fatty rat is a new model for obese type 2 diabetes. The aim of the present study was to investigate the effect of 1/2 nephrectomy (Nx) on renal function and morphology and on blood pressure in SDT fatty rats. Male SDT fatty rats underwent 1/2 Nx or a sham operation (Sham). Subsequently, animals were studied with respect to renal function and histological alterations. Induction of 1/2 Nx in SDT fatty rats led to functional and morphological damage to the remnant kidney and to hypertension, which are considered main characteristics of chronic kidney disease, at a younger age compared with the sham group. In conclusion, the SDT fatty rat is useful in investigations to elucidate the pathogenesis of human diabetic nephropathy and in new drug discovery. Yoshiaki Katsuda, Yusuke Kemmochi, Mimi Maki, Ryuhei Sano, Yasufumi Toriniwa, Yukihito Ishii, Katsuhiro Miyajima, Kochi Kakimoto, and Takeshi Ohta Copyright © 2014 Yoshiaki Katsuda et al. All rights reserved. Peripheral Neuropathy and Tear Film Dysfunction in Type 1 Diabetes Mellitus Thu, 07 Aug 2014 11:37:23 +0000 Purpose. To compare tear film metrics in patients with type 1 diabetes mellitus (DM) and healthy controls and investigate the association between peripheral neuropathy and ocular surface quality. Methods. Dry eye symptoms were quantified in 53 patients with type 1 DM and 40 age-matched controls. Ocular examination included tear film lipid layer thickness grading, tear film stability and quantity measurement, and retinal photography. DM individuals additionally underwent a detailed neuropathy assessment. Results. Neither mean age nor dry eye symptom scores differed significantly between the DM and control groups ( and , resp.). Tear lipid thickness (), stability (), and quantity () were significantly lower in the DM group. Corneal sensitivity was also reduced in the DM group () and tear film stability was inversely associated with total neuropathy score (, ). Conclusion. The DM group exhibited significantly reduced tear film stability, secretion, and lipid layer quality relative to the age-matched control group. The negative correlation between tear film parameters and total neuropathy score suggests that ocular surface abnormalities occur in parallel with diabetic peripheral neuropathy. Stuti L. Misra, Dipika V. Patel, Charles N. J. McGhee, Monika Pradhan, Dean Kilfoyle, Geoffrey D. Braatvedt, and Jennifer P. Craig Copyright © 2014 Stuti L. Misra et al. All rights reserved. Early Detection of Atrophy of Foot Muscles in Chinese Patients of Type 2 Diabetes Mellitus by High-Frequency Ultrasonography Wed, 06 Aug 2014 11:42:14 +0000 The aim of this study was to evaluate the diagnostic value of high-frequency ultrasonography in detecting atrophy of foot muscles in Chinese patients of type 2 diabetes mellitus (T2DM). Chinese patients of T2DM with () or without () diabetic peripheral neuropathy (DPN) and the control subjects () were enrolled. The nondominant foot of all subjects was examined with high-frequency ultrasonography. The transverse diameter, thickness, and cross-sectional area of the extensor digitorum brevis muscle (EDB) and the thickness of the muscles of the first interstitium (MILs) were measured. The results showed that the ultrasonographic transverse diameter, thickness, and cross-sectional area of EDB and the thickness of MILs in patients of T2DM with DPN were significantly smaller than those in patients of T2DM without DPN (all ) and those in the control subjects (all ). The transverse diameter and cross-sectional area of the EDB and thickness of MILs in patients of T2DM without DPN were significantly smaller than those of the control subjects (all ). In conclusion, the atrophy of foot muscle in Chinese T2DM patients can be detected by high-frequency ultrasonography. Notably, ultrasonography may detect early atrophy of foot muscles in patients without DPN. Xiaohui Wang, Liang Chen, Weiwei Liu, Benli Su, and Yuhong Zhang Copyright © 2014 Xiaohui Wang et al. All rights reserved. Study of Postprandial Lipaemia in Type 2 Diabetes Mellitus: Exenatide versus Liraglutide Mon, 04 Aug 2014 11:36:34 +0000 Therapeutic approaches based on the actions of the incretin hormone GLP-1 have been widely established in the management of T2DM. Nevertheless, much less research has been aimed at elucidating the role of GLP-1 in lipid metabolism and in particular postprandial dyslipidemia. Exenatide and liraglutide are two GLP-1 receptor agonists which are currently available as subcutaneously administered treatment for T2DM but their chronic effects on postprandial lipaemia have not been well investigated. The aim of this study is to examine the effect of treatment with either liraglutide or exenatide for two weeks on postprandial lipaemia in obese subjects with T2DM. This study was a single-center, two-armed, randomized, controlled 2-week prospective intervention trial in 20 subjects with T2DM. Patients were randomized to receive either liraglutide or exenatide treatment and underwent a standardized meal tolerance test early in the morning after 10 h fast at baseline (visit 1, beginning of treatment) and after a two-week treatment period (visit 2). Exenatide and liraglutide both appear to be equally effective in lowering postprandial lipaemia after the first administration and after a two-week treatment. The mechanisms which lead to this phenomenon, which seem to be independent of gastric emptying, are yet to be studied. Maria Voukali, Irene Kastrinelli, Sapfo Stragalinou, Dimitra Tasiopoulou, Pinelopi Paraskevopoulou, Nicholas Katsilambros, Alexandros Kokkinos, Nicholas Tentolouris, and Ioannis Ioannidis Copyright © 2014 Maria Voukali et al. All rights reserved. Remodeling Intestinal Flora with Sleeve Gastrectomy in Diabetic Rats Mon, 04 Aug 2014 06:09:34 +0000 Objective. As a complicated symbiotic system, intestinal flora is reported closely related to the development of type 2 diabetes recently. Sleeve gastrectomy is one of the approaches of bariatric surgery and could improve blood glucose control in type 2 diabetes patients. This study was to explore the relationship between remodeled intestinal flora and glucose metabolism in diabetic rats. Methods. 20 male diabetic rats were operated; 10 of them underwent sleeve gastrectomy, and 10 of them underwent sham operation. Meanwhile 10 male normal rats underwent sleeve gastrectomy as control. The animals’ weight and FBG had been measured. The composition changes of intestinal flora were detected by 16S rDNA sequence analysis. Results. In diabetic rats, weight and fasting blood glucose decreased significantly after sleeve gastrectomy. However, there was no significant change for weight and blood glucose in normal rats after operation. The intestinal flora of diabetic rats reduced in the proportion of Firmicutes and increased in the proportion of Bacteroidetes after sleeve gastrectomy. Conclusion. The change of dominant microorganisms in intestinal flora might play an important role in the glucose metabolism. Xiaofei Huang, Pan Weng, Huixin Zhang, and Yingli Lu Copyright © 2014 Xiaofei Huang et al. All rights reserved.