Journal of Diabetes Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Vitamin D Deficiency Is Associated with the Presence and Severity of Diabetic Retinopathy in Type 2 Diabetes Mellitus Wed, 20 May 2015 12:03:23 +0000 There is very few evidences on the role of vitamin D in the development of diabetic retinopathy. The aim of the current study was to explore whether there is an association of vitamin D status and diabetic retinopathy in type 2 diabetes. Two groups of patients were selected: 139 and 144 patients with and without retinopathy, respectively, as assessed by an experienced ophthalmologist. Subjects with advanced late diabetic complications were excluded to avoid confounding biases. 25-Hydroxy-vitamin D3 (25(OH)D) concentrations and vitamin D deficiency were associated with the presence of diabetic retinopathy. Additionally, patients with more advanced stages of retinopathy (grades 2–4) had lower concentrations of 25(OH)D and were more frequently vitamin D deficient as compared with patients not carrying this eye complication. In conclusion, our study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes. Further experimental and prospective studies on this issue are clearly warranted. Nuria Alcubierre, Joan Valls, Esther Rubinat, Gonzalo Cao, Aureli Esquerda, Alicia Traveset, Minerva Granado-Casas, Carmen Jurjo, and Didac Mauricio Copyright © 2015 Nuria Alcubierre et al. All rights reserved. Altered Expression of NF-κB and SP1 after Exposure to Advanced Glycation End-Products and Effects of Neurotrophic Factors in AGEs Exposed Rat Retinas Wed, 20 May 2015 07:54:12 +0000 To determine the effect of advanced glycation end-products (AGEs) on neurite regeneration, and also to determine the regenerative effects of different neurotrophic factors (NTFs) on rat retinal explants, the retinas of SD rats were cultured in three-dimensional collagen gels and incubated in 6 types of media: (1) serum-free control culture media; (2) 100 μg/mL AGEs-BSA media; (3) AGEs-BSA + 100 ng/mL neurotrophin-4 (NT-4) media; (4) AGEs-BSA + 100 ng/mL hepatocyte growth factor media; (5) AGEs-BSA + 100 ng/mL glial cell line-derived neurotrophic factor media; or (6) AGEs-BSA + 100 µM tauroursodeoxycholic acid media. After 7 days, the number of regenerating neurites was counted. The explants were immunostained for nuclear factor-κB (NF-κB) and specificity protein 1 (SP1). Statistical analyses were performed by one-way ANOVA. In retinas incubated with AGEs, the numbers of neurites were fewer than in control. All of the NTFs increased the number of neurites, and the increase was more significant in the NT-4 group. The number of NF-κB and SP1 immunopositive cells was higher in retinas exposed to AGEs than in control. All of the NTFs decreased the number of NF-κB immunopositive cells but did not significantly affect SP1 expression. These results demonstrate the potential of the NTFs as axoprotectants in AGEs exposed retinal neurons. Guzel Bikbova, Toshiyuki Oshitari, Takayuki Baba, and Shuichi Yamamoto Copyright © 2015 Guzel Bikbova et al. All rights reserved. Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus Tue, 19 May 2015 12:50:49 +0000 This study examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) alter in prediabetes and correlate with insulin resistance (IR) and beta cell function in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM). Subjects without previous history of diabetes were recruited and grouped as control, prediabetes, and newly diagnosed T2DM. The control subjects () and people with prediabetes () and diabetes () were similar in terms of age, sex, BMI, systolic and diastolic BP, and fasting insulin level. HOMA-IR was found significantly higher in people with diabetes than control subjects () and people with prediabetes (); and HOMA-%B was found significantly deteriorated in people with diabetes () compared to control subjects and people with prediabetes. However, serum sRAGE levels did not show any significant alteration in people with prediabetes compared to control subjects. Moreover, univariate and multivariate analyses did not identify any significant correlation and statistical association of sRAGE with HOMA-IR and HOMA-%B in people with prediabetes and newly diagnosed T2DM. Our data suggest that serum sRAGE levels do not alter in people with prediabetes compared to control subjects and do not correlate or associate with IR and beta cell function during development of T2DM. Subrata Kumar Biswas, Sabreena Mohtarin, Sonchita Rani Mudi, Taznuva Anwar, Laila Anjuman Banu, Sheikh Md. Khorshed Alam, Md. Fariduddin, and M. Iqbal Arslan Copyright © 2015 Subrata Kumar Biswas et al. All rights reserved. Histidine Decarboxylase Deficiency Prevents Autoimmune Diabetes in NOD Mice Mon, 18 May 2015 14:05:16 +0000 Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC−/− mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γ in HDC−/− mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC−/− mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response. Manal Alkan, François Machavoine, Rachel Rignault, Julie Dam, Michel Dy, and Nathalie Thieblemont Copyright © 2015 Manal Alkan et al. All rights reserved. Diabetes Complications at Presentation and One Year by Glycated Haemoglobin at Diagnosis in a Multiethnic and Diverse Socioeconomic Population: Results from the South London Diabetes Study Mon, 18 May 2015 12:29:33 +0000 Background. WHO’s recommendation of  mmol/mol (6.5%) as diagnostic for type 2 diabetes mellitus (T2DM) was adopted by three UK London boroughs in May 2012. The South London Diabetes (SOUL-D) study has recruited people with newly diagnosed T2DM since 2008. We compared participants diagnosed before May 2012 with  mmol/mol to those with diagnostic  mmol/mol. Methods. A prospective cohort study of newly diagnosed T2DM participants from 96 primary care practices, comparing demographic and biomedical variables between those with diagnostic  mmol/mol or  mmol/mol at recruitment and after one year. Results. Of 1488 participants, 22.8% had diagnostic  mmol/mol. They were older and more likely to be white (). At recruitment and one year, there were no between-group differences in the prevalence of diabetic complications, except that those diagnosed with  mmol/mol had more sensory neuropathy at recruitment () and, at one year, had new myocardial infarction () but less microalbuminuria (). Conclusions. Use of  mmol/mol as the sole T2DM diagnostic criterion may miss almost a quarter of those previously diagnosed in South London yet  mmol/mol may not exclude clinically important diabetes. Mohsin Azam, Lindsey Marwood, Khalida Ismail, Tyrrell Evans, Sobha Sivaprasad, Kirsty Winkley, and Stephanie Anne Amiel Copyright © 2015 Mohsin Azam et al. All rights reserved. Associations of Haplotypes Upstream of IRS1 with Insulin Resistance, Type 2 Diabetes, Dyslipidemia, Preclinical Atherosclerosis, and Skeletal Muscle LOC646736 mRNA Levels Mon, 18 May 2015 06:51:11 +0000 The genomic region ~500 kb upstream of IRS1 has been implicated in insulin resistance, type 2 diabetes, adverse lipid profile, and cardiovascular risk. To gain further insight into this chromosomal region, we typed four SNPs in a cross-sectional cohort and subjects with type 2 diabetes recruited from the same geographic region. From 16 possible haplotypes, 6 haplotypes with frequencies >0.01 were observed. We identified one haplotype that was protective against insulin resistance (determined by HOMA-IR and fasting plasma insulin levels), type 2 diabetes, an adverse lipid profile, increased C-reactive protein, and asymptomatic atherosclerotic disease (assessed by intima media thickness of the common carotid arteries). BMI and total adipose tissue mass as well as visceral and subcutaneous adipose tissue mass did not differ between the reference and protective haplotypes. In 92 subjects, we observed an association of the protective haplotype with higher skeletal muscle mRNA levels of LOC646736, which is located in the same haplotype block as the informative SNPs and is mainly expressed in skeletal muscle, but only at very low levels in liver or adipose tissues. These data suggest a role for LOC646736 in human insulin resistance and warrant further studies on the functional effects of this locus. Selma M. Soyal, Thomas Felder, Simon Auer, Hannes Oberkofler, Bernhard Iglseder, Bernhard Paulweber, Silvia Dossena, Charity Nofziger, Markus Paulmichl, Harald Esterbauer, Franz Krempler, and Wolfgang Patsch Copyright © 2015 Selma M. Soyal et al. All rights reserved. The Place of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapeutics: A “Me Too” or “the Special One” Antidiabetic Class? Sun, 17 May 2015 14:26:42 +0000 Incretin-based therapies, the most recent therapeutic options for type 2 diabetes mellitus (T2DM) management, can modify various elements of the disease, including hypersecretion of glucagon, abnormal gastric emptying, postprandial hyperglycaemia, and, possibly, pancreatic β cell dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) increase glucagon-like peptide-1 (GLP-1) availability and correct the “incretin defect” seen in T2DM patients. Clinical studies have shown good glycaemic control with minimal risk of hypoglycaemia or any other adverse effects, despite the reports of pancreatitis, whose association remains to be proved. Recent studies have been focusing on the putative ability of DPP-4 inhibitors to preserve pancreas function, in particular due to the inhibition of apoptotic pathways and stimulation of β cell proliferation. In addition, other cytoprotective effects on other organs/tissues that are involved in serious T2DM complications, including the heart, kidney, and retina, have been increasingly reported. This review outlines the therapeutic potential of DPP-4 inhibitors for the treatment of T2DM, focusing on their main features, clinical applications, and risks, and discusses the major challenges for the future, in particular the possibility of becoming the preferred therapy for T2DM due to their ability to modify the natural history of the disease and ameliorate nephropathy, retinopathy, and cardiovascular complications. Ricardo Godinho, Cristina Mega, Edite Teixeira-de-Lemos, Eugénia Carvalho, Frederico Teixeira, Rosa Fernandes, and Flávio Reis Copyright © 2015 Ricardo Godinho et al. All rights reserved. Recent Advances in Dipeptidyl-Peptidase-4 Inhibition Therapy: Lessons from the Bench and Clinical Trials Thu, 14 May 2015 13:29:15 +0000 DPP4 inhibitors (DPP4i) are a class of newly developed antidiabetic drugs which preserve incretin hormones and promote postprandial insulin secretion. Although the cardiovascular effect of DPP4 inhibition has been substantially studied, the exact role of DPP4 in cardiovascular disease especially in humans remains elusive. Previous small studies and meta-analyses have suggested a benefit in both surrogate outcomes and cardiovascular events for these agents. However, there was growing evidence in recent years questioning the cardioprotective effect of DPP4i. Further, a signal of heart failure hospitalization in a recent large scale clinical trial SAVOR-TIMI 53 has called into question the safety of these agents and their utility in the treatment of cardiovascular disease. In this review, we will revisit the physiologic function of DPP4 and discuss its role in cardiometabolic disease based on recent experimental and clinical studies. Jixin Zhong, Quan Gong, Aditya Goud, Srividya Srinivasamaharaj, and Sanjay Rajagopalan Copyright © 2015 Jixin Zhong et al. All rights reserved. A Qualitative Exploration of Motivation to Self-Manage and Styles of Self-Management amongst People Living with Type 2 Diabetes Thu, 14 May 2015 12:24:06 +0000 The study examined the motives that people living with type 2 diabetes (T2D) had for self-managing their condition and ways they used to assess the success of their self-management efforts. Using semistructured interviews (), focus groups (3 ×   participants), and open-ended questionnaires (), people living with and self-managing T2D were recruited from a community-based T2D participation group. Most participants were older (aged 60+) and lived in a socioeconomically deprived area in the United Kingdom. Data were analysed thematically using framework analysis. Patients’ motives for self-management included (i) concern about the anticipative effects of T2D; (ii) wishing to “stay well”; (iii) maintaining independence; (iv) reducing the need for healthcare professionals; and (v) improving quality of life. Six self-management styles were found and pertained to self-managing: (i) through routinisation; (ii) as a burden; (iii) as maintenance; (iv) through delegation; (v) through comanagement; and (vi) through autonomy. Motivators for self-management shaped the criteria people used to judge the success of their self-management practices and influenced their self-management style. The findings show that styles of T2D self-management are mediated and moderated by sociocontextual issues. Healthcare professionals should take these into account when supporting people living with T2D. Paul Newton, Koula Asimakopoulou, and Sasha Scambler Copyright © 2015 Paul Newton et al. All rights reserved. Metformin Ameliorates Podocyte Damage by Restoring Renal Tissue Podocalyxin Expression in Type 2 Diabetic Rats Wed, 13 May 2015 08:52:11 +0000 Podocalyxin (PCX) is a signature molecule of the glomerular podocyte and of maintaining integrity of filtration function of glomerulus. The aim of this study was to observe the effect of different doses of metformin on renal tissue PCX expression in type 2 diabetic rats and clarify its protection on glomerular podocytes. Type 2 diabetic Sprague-Dawley (SD) rats in which diabetes was induced by high-fat diet/streptozotocin (HFD-STZ) were treated with different doses of metformin (150, 300, and 500 mg/kg per day, resp.) for 8 weeks. Various biochemical parameters, kidney histopathology, and renal tissue PCX expression levels were examined. In type 2 diabetic rats, severe hyperglycemia and hyperlipidemia were developed. Urinary albumin and PCX were markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, protein and mRNA expression of renal tissue PCX were highly decreased. However, treatment of rats with different doses of metformin restored all these changes to a varying degree. These results suggested that metformin can ameliorate glomerular podocyte damage in type 2 diabetic rats, which may be partly associated with its role in restoring PCX expression and inhibiting urinary excretion of PCX with dose dependence. Limin Zhai, Junfei Gu, Di Yang, Wei Wang, and Shandong Ye Copyright © 2015 Limin Zhai et al. All rights reserved. Automated Quantification of Neuropad Improves Its Diagnostic Ability in Patients with Diabetic Neuropathy Tue, 12 May 2015 11:50:54 +0000 Neuropad is currently a categorical visual screening test that identifies diabetic patients at risk of foot ulceration. The diagnostic performance of Neuropad was compared between the categorical and continuous (image-analysis (Sudometrics)) outputs to diagnose diabetic peripheral neuropathy (DPN). 110 subjects with type 1 and 2 diabetes underwent assessment with Neuropad, Neuropathy Disability Score (NDS), peroneal motor nerve conduction velocity (PMNCV), sural nerve action potential (SNAP), Deep Breathing-Heart Rate Variability (DB-HRV), intraepidermal nerve fibre density (IENFD), and corneal confocal microscopy (CCM). 46/110 patients had DPN according to the Toronto consensus. The continuous output displayed high sensitivity and specificity for DB-HRV (91%, 83%), CNFD (88%, 78%), and SNAP (88%, 83%), whereas the categorical output showed high sensitivity but low specificity. The optimal cut-off points were 90% for the detection of autonomic dysfunction (DB-HRV) and 80% for small fibre neuropathy (CNFD). The diagnostic efficacy of the continuous Neuropad output for abnormal DB-HRV (AUC: 91%, ) and CNFD (AUC: 82%, ) was better than for PMNCV (AUC: 60%). The categorical output showed no significant difference in diagnostic efficacy for these same measures. An image analysis algorithm generating a continuous output (Sudometrics) improved the diagnostic ability of Neuropad, particularly in detecting autonomic and small fibre neuropathy. Georgios Ponirakis, Hassan Fadavi, Ioannis N. Petropoulos, Shazli Azmi, Maryam Ferdousi, Mohammad A. Dabbah, Ahmad Kheyami, Uazman Alam, Omar Asghar, Andrew Marshall, Mitra Tavakoli, Ahmed Al-Ahmar, Saad Javed, Maria Jeziorska, and Rayaz A. Malik Copyright © 2015 Georgios Ponirakis et al. All rights reserved. Association of Plasma Adiponectin and Oxidized Low-Density Lipoprotein with Carotid Intima-Media Thickness in Diabetic Nephropathy Tue, 12 May 2015 09:12:43 +0000 Aims. We sought to determine the association between levels of adiponectin and oxidized low-density lipoprotein (ox-LDL) in patients with diabetic nephropathy as well as their effect on carotid intima-media thickness (cIMT). Methods. Adiponectin and ox-LDL were determined in 25 diabetic patients without nephropathy and 94 patients at different stages of diabetic nephropathy including subjects on hemodialysis. cIMT was measured using real-time B-mode ultrasonography. Results. Plasma adiponectin levels increased significantly with severity of diabetic nephropathy (), on the contrary to ox-LDL which decreased with disease severity (). cIMT was significantly higher at late stages of diabetic nephropathy compared with early stages (). Adiponectin was a significant negative predictor of ox-LDL levels (, ), independently of confounding factors. There was no significant correlation between cIMT and adiponectin or ox-LDL either in the total sample population or according to disease staging. Cluster analysis showed that patients with the highest cIMT values, highest levels of adiponectin, and lowest levels of ox-LDL were included in one cluster and all assigned to stage 5 of diabetic nephropathy. Conclusions. There was no significant association between adiponectin or ox-LDL and cIMT and, therefore, other factors affecting this surrogate marker of cardiovascular disease in diabetic nephropathy should be sought. Anna Tavridou, Anastasia Georgoulidou, Athanasios Roumeliotis, Stefanos Roumeliotis, Efstathia Giannakopoulou, Nikolaos Papanas, Ploumis Passadakis, Vangelis G. Manolopoulos, and Vassilis Vargemezis Copyright © 2015 Anna Tavridou et al. All rights reserved. Testicular Metabolic Reprogramming in Neonatal Streptozotocin-Induced Type 2 Diabetic Rats Impairs Glycolytic Flux and Promotes Glycogen Synthesis Tue, 12 May 2015 06:18:35 +0000 Defects in testicular metabolism are directly implicated with male infertility, but most of the mechanisms associated with type 2 diabetes- (T2DM) induced male infertility remain unknown. We aimed to evaluate the effects of T2DM on testicular glucose metabolism by using a neonatal-streptozotocin- (n-STZ) T2DM animal model. Plasma and testicular hormonal levels were evaluated using specific kits. mRNA and protein expression levels were assessed by real-time PCR and Western Blot, respectively. Testicular metabolic profile was assessed by 1H-NMR spectroscopy. T2DM rats showed increased glycemic levels, impaired glucose tolerance and hyperinsulinemia. Both testicular and serum testosterone levels were decreased, whereas those of 17β-estradiol were not altered. Testicular glycolytic flux was not favored in testicles of T2DM rats, since, despite the increased expression of both glucose transporters 1 and 3 and the enzyme phosphofructokinase 1, lactate dehydrogenase activity was severely decreased contributing to lower testicular lactate content. However, T2DM enhanced testicular glycogen accumulation, by modulating the availability of the precursors for its synthesis. T2DM also affected the reproductive sperm parameters. Taken together these results indicate that T2DM is able to reprogram testicular metabolism by enhancing alternative metabolic pathways, particularly glycogen synthesis, and such alterations are associated with impaired sperm parameters. L. Rato, M. G. Alves, T. R. Dias, J. E. Cavaco, and Pedro F. Oliveira Copyright © 2015 L. Rato et al. All rights reserved. Species-Related Differences in the Proteome of Rat and Human Pancreatic Beta Cells Sun, 10 May 2015 14:31:09 +0000 The core proteomes of human and rat pancreatic beta cells were compared by label-free LC-MS/MS: this resulted in quantification of relative molar abundances of 707 proteins belonging to functional pathways of intermediary metabolism, protein synthesis, and cytoskeleton. Relative molar abundances were conserved both within and between pathways enabling the selection of a housekeeping network for geometric normalization and the analysis of potentially relevant differential expressions. Human beta cells differed from rat beta cells in their lower level of enzymes involved in glucose sensing (MDH1, PC, and ACLY) and upregulation of lysosomal enzymes. Human cells also expressed more heat shock proteins and radical scavenging systems: apart from SOD2, they expressed high levels of H2O2-scavenger peroxiredoxin 3 (PRDX3), confirmed by microarray, Western blotting, and microscopy. Besides conferring lower susceptibility to oxidative stress to human cells PRDX3 might also play a role in physiological redox regulation as, in rat, its expression was restricted to a beta cell subset with higher metabolic glucose responsiveness. In conclusion, although their core proteomic architecture is conserved, human and rat beta cells differ in their molar expression of key enzymes involved in glucose sensing and redox control. G. A. Martens Copyright © 2015 G. A. Martens. All rights reserved. Daily Physical Activity Assessed by a Triaxial Accelerometer Is Beneficially Associated with Waist Circumference, Serum Triglycerides, and Insulin Resistance in Japanese Patients with Prediabetes or Untreated Early Type 2 Diabetes Sun, 10 May 2015 12:31:28 +0000 Aim. To investigate the association between daily physical activity and metabolic risk factors in Japanese adults with prediabetes or untreated early type 2 diabetes (T2D). Methods. Daily physical activity level was measured using a triaxial accelerometer. We assessed correlations between physical activity level and waist circumference, blood pressure, fasting levels of plasma glucose, serum triglycerides, and insulin and homeostasis model assessment-insulin resistance (HOMA-IR). Results. A total of 80 patients were studied. After adjustment for age and body mass index, in all subjects, physical activity level was negatively associated with waist circumference (, ) and fasting serum triglycerides (, ), insulin (, ). In men, physical activity level was negatively associated with systolic blood pressure (, ), fasting plasma glucose (, ) and insulin (, ), and HOMA-IR (, ). No significant associations were found between physical activity level and metabolic risk factors in women. Conclusion. Objectively measured daily physical activity is beneficially associated with waist circumference, serum triglycerides, and insulin resistance in individuals with prediabetes or untreated early T2D. (This trial is registered with UMIN000015774.) Hidetaka Hamasaki, Mitsuhiko Noda, Sumie Moriyama, Reo Yoshikawa, Hisayuki Katsuyama, Akahito Sako, Shuichi Mishima, Masafumi Kakei, Osamu Ezaki, and Hidekatsu Yanai Copyright © 2015 Hidetaka Hamasaki et al. All rights reserved. Maternal Hyperglycemia Directly and Rapidly Induces Cardiac Septal Overgrowth in Fetal Rats Thu, 07 May 2015 14:26:13 +0000 Cardiac septal overgrowth complicates 10–40% of births from diabetic mothers, but perplexingly hyperglycemia markers during pregnancy are not reliably predictive. We thus tested whether fetal exposure to hyperglycemia is sufficient to induce fetal cardiac septal overgrowth even in the absence of systemic maternal diabetes. To isolate the effects of hyperglycemia, we infused glucose into the blood supply of the left but not right uterine horn in nondiabetic pregnant rats starting on gestational day 19. After 24 h infusion, right-sided fetuses and dams remained euglycemic while left-sided fetuses were moderately hyperglycemic. Echocardiograms in utero demonstrated a thickened cardiac septum among left-sided (glucose-exposed, 0.592 ± 0.016 mm) compared to right-sided (control, 0.482 ± 0.016 mm) fetuses. Myocardial proliferation was increased 1.5 ± 0.2-fold among left-sided compared to right-sided fetuses. Transcriptional markers of glucose-derived anabolism were not different between sides. However, left-sided fetuses exhibited higher serum insulin and greater JNK phosphorylation compared to controls. These results show that hyperglycemic exposure is sufficient to rapidly induce septal overgrowth even in the absence of the myriad other factors of maternal diabetes. This suggests that even transient spikes in glucose may incite cardiac overgrowth, perhaps explaining the poor clinical correlation of septal hypertrophy with chronic hyperglycemia. Erin E. Gordon, Benjamin E. Reinking, Shanming Hu, Jianrong Yao, Kok L. Kua, Areej K. Younes, Chunlin Wang, Jeffrey L. Segar, and Andrew W. Norris Copyright © 2015 Erin E. Gordon et al. All rights reserved. Small Molecule Kaempferol Promotes Insulin Sensitivity and Preserved Pancreatic β-Cell Mass in Middle-Aged Obese Diabetic Mice Thu, 07 May 2015 08:29:29 +0000 Insulin resistance and a progressive decline in functional β-cell mass are hallmarks of developing type 2 diabetes (T2D). Thus, searching for natural, low-cost compounds to target these two defects could be a promising strategy to prevent the pathogenesis of T2D. Here, we show that dietary intake of flavonol kaempferol (0.05% in the diet) significantly ameliorated hyperglycemia, hyperinsulinemia, and circulating lipid profile, which were associated with the improved peripheral insulin sensitivity in middle-aged obese mice fed a high-fat (HF) diet. Kaempferol treatment reversed HF diet impaired glucose transport-4 (Glut4) and AMP-dependent protein kinase (AMPK) expression in both muscle and adipose tissues from obese mice. In vitro, kaempferol increased lipolysis and prevented high fatty acid-impaired glucose uptake, glycogen synthesis, AMPK activity, and Glut4 expression in skeletal muscle cells. Using another mouse model of T2D generated by HF diet feeding and low doses of streptozotocin injection, we found that kaempferol treatment significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in obese diabetic mice, which are associated with the improved islet β-cell mass. These results demonstrate that kaempferol may be a naturally occurring anti-diabetic agent by improving peripheral insulin sensitivity and protecting against pancreatic β-cell dysfunction. Hana Alkhalidy, William Moore, Yanling Zhang, Ryan McMillan, Aihua Wang, Mostafa Ali, Kyung-Shin Suh, Wei Zhen, Zhiyong Cheng, Zhenquan Jia, Matthew Hulver, and Dongmin Liu Copyright © 2015 Hana Alkhalidy et al. All rights reserved. Vinegar Consumption Increases Insulin-Stimulated Glucose Uptake by the Forearm Muscle in Humans with Type 2 Diabetes Wed, 06 May 2015 13:45:55 +0000 Background and Aims. Vinegar has been shown to have a glucose-lowering effect in patients with glucose abnormalities. However, the mechanisms of this effect are still obscure. The aim of this randomised, crossover study was to investigate the effect of vinegar on glucose metabolism in muscle which is the most important tissue for insulin-stimulated glucose disposal. Materials and Methods. Eleven subjects with DM2 consumed vinegar or placebo (at random order on two separate days, a week apart), before a mixed meal. Plasma glucose, insulin, triglycerides, nonesterified fatty acids (NEFA), and glycerol were measured preprandially and at 30–60 min for 300 min postprandially from the radial artery and from a forearm vein. Muscle blood flow was measured with strain-gauge plethysmography. Glucose uptake was calculated as the arteriovenous difference of glucose multiplied by blood flow. Results. Vinegar compared to placebo (1) increased forearm glucose uptake , (2) decreased plasma glucose (), insulin , and triglycerides , and (3) did not change NEFA and glycerol. Conclusions. In DM2 vinegar reduces postprandial hyperglycaemia, hyperinsulinaemia, and hypertriglyceridaemia without affecting lipolysis. Vinegar’s effect on carbohydrate metabolism may be partly accounted for by an increase in glucose uptake, demonstrating an improvement in insulin action in skeletal muscle. This trial is registered with NCT02309424. Panayota Mitrou, Eleni Petsiou, Emilia Papakonstantinou, Eirini Maratou, Vaia Lambadiari, Panayiotis Dimitriadis, Filio Spanoudi, Sotirios A. Raptis, and George Dimitriadis Copyright © 2015 Panayota Mitrou et al. All rights reserved. Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System Wed, 06 May 2015 09:23:34 +0000 Pancreatic β-cell loss induced by saturated free fatty acids (FFAs) is believed to contribute to type 2 diabetes. Previous studies have shown induction of endoplasmic reticulum (ER) stress, increased ubiquitinated proteins, and deregulation of the Bcl-2 family in the pancreas of type 2 diabetic patients. However, the precise mechanism of β-cell death remains unknown. In the present study we demonstrate that the FFA palmitate blocks the ubiquitin-proteasome system (UPS) and causes apoptosis through induction of ER stress and deregulation of Bcl-2 proteins. We found that palmitate and the proteasome inhibitor MG132 induced ER stress in β-cells, resulting in decreased expression of the prosurvival proteins Bcl-2, Mcl-1, and Bcl-XL, and upregulation of the prodeath BH3-only protein PUMA. On the other hand, pharmacological activation of the UPS by sulforaphane ameliorated ER stress, upregulated prosurvival Bcl-2 proteins, and protected β-cells from FFA-induced cell death. Furthermore, transgenic overexpression of Bcl-2 protected islets from FFA-induced cell death in vitro and improved glucose-induced insulin secretion in vivo. Together our results suggest that targeting the UPS and Bcl-2 protein expression may be a valuable strategy to prevent β-cell demise in type 2 diabetes. Sara A. Litwak, Jibran A. Wali, Evan G. Pappas, Hamdi Saadi, William J. Stanley, L. Chitra Varanasi, Thomas W. H. Kay, Helen E. Thomas, and Esteban N. Gurzov Copyright © 2015 Sara A. Litwak et al. All rights reserved. Association of a Large Panel of Cytokine Gene Polymorphisms with Complications and Comorbidities in Type 2 Diabetes Patients Wed, 06 May 2015 08:24:30 +0000 Aims. The polymorphisms of pro- and anti-inflammatory cytokines may be involved in type 2 diabetes (T2D) pathogenesis and its complications. Methods. We investigated in 102 T2D patients the association of the cytokine polymorphisms in the TNF-α, IL-10, IL-6, TGF-β1, and IFN-γ genes with the T2D microvascular complications and comorbidities (hypertension, dyslipidemia, and obesity). Cytokine genotypes were determined by PCR using Cytokine Genotyping Tray kit. Results. Diabetic retinopathy was associated with GG genotype and G allele in TGF-β1 codon 25C/G polymorphism ( and ) and the nephropathy was associated the lower frequency of GG genotype in IL-10 -1082G/A polymorphism (). Hypertension was associated with the CC genotype and C allele for IL-10 -592C/A polymorphism ( and ) and higher frequencies of T () and C () alleles of the TGF-β1 codon 10T/C and IL-10 -819T/C polymorphisms, respectively. The TGF-β1 codon 10T/C polymorphism was associated with the BMI groups (): the CC genotype was more frequent in the group with BMI < 25 Kg/m2, while the TC genotype was more frequent in the group with BMI = 30 Kg/m2. Conclusions. Our findings suggest that TGF-β1 and IL-10 polymorphisms are involved in complications and comorbidities in T2D patients. K. F. Rodrigues, N. T. Pietrani, V. C. Sandrim, C. M. A. F. Vieira, A. P. Fernandes, A. A. Bosco, and K. B. Gomes Copyright © 2015 K. F. Rodrigues et al. All rights reserved. Irisin and Myonectin Regulation in the Insulin Resistant Muscle: Implications to Adipose Tissue: Muscle Crosstalk Tue, 05 May 2015 14:05:18 +0000 Myokines are peptides produced and secreted by the skeletal muscle, with autocrine, paracrine, and endocrine actions. Many of them are overexpressed during physical exercise and appear to contribute to the benefits of exercise to metabolic homeostasis. Irisin, resulting from the cleavage of the membrane protein FNDC5, was shown to induce adipocyte browning, with increased lipid oxidation and thermogenesis. Myonectin was only recently discovered and initial studies revealed a role in fatty acid uptake and oxidation in adipose tissue and liver. However, the mechanisms of their regulation by exercise are not entirely established. Impaired secretion and action of myokines, such as irisin and myonectin, may have a role in the establishment of insulin resistance. On the other hand, several studies have shown that insulin resistance in the skeletal muscle may change myokines expression and secretion. This may have consequences on lipid and glucose metabolism in adipose tissue and lead to a vicious cycle between impaired myokines production and insulin resistance. This review summarizes the current knowledge about the influence of skeletal muscle insulin resistance on the secretion of irisin and myonectin, as well as its impact on adipose tissue metabolism. Luis Gamas, Paulo Matafome, and Raquel Seiça Copyright © 2015 Luis Gamas et al. All rights reserved. Role of Electrophysiology in the Early Diagnosis and Follow-Up of Diabetic Retinopathy Tue, 05 May 2015 11:47:55 +0000 Retinopathy is a severe and common complication of diabetes, representing a leading cause of blindness among working-age people in developed countries. It is estimated that the number of people with diabetic retinopathy (DR) will increase from 126.6 million in 2011 to 191 million by 2030. The pathology seems to be characterized not only by the involvement of retinal microvessels but also by a real neuropathy of central nervous system, similar to what happens to the peripheral nerves, particularly affected by diabetes. The neurophysiological techniques help to assess retinal and nervous (optic tract) function. Electroretinography (ERG) and visual evoked potentials (VEP) allow a more detailed study of the visual function and of the possible effects that diabetes can have on the visual function. These techniques have an important role both in the clinic and in research: the central nervous system, in fact, has received much less attention than the peripheral one in the study of the complications of diabetes. These techniques are safe, repeatable, quick, and objective. In addition, both the ERG (especially the oscillatory potentials and the flicker-ERG) and VEP have proved to be successful tools for the early diagnosis of the disease and, potentially, for the ophthalmologic follow-up of diabetic patients. Nicola Pescosolido, Andrea Barbato, Alessio Stefanucci, and Giuseppe Buomprisco Copyright © 2015 Nicola Pescosolido et al. All rights reserved. Diabetic Kidney Disease: Pathophysiology and Therapeutic Targets Thu, 30 Apr 2015 17:20:01 +0000 Diabetes is a worldwide epidemic that has led to a rise in diabetic kidney disease (DKD). Over the past two decades, there has been significant clarification of the various pathways implicated in the pathogenesis of DKD. Nonetheless, very little has changed in the way clinicians manage patients with this disorder. Indeed, treatment is primarily centered on controlling hyperglycemia and hypertension and inhibiting the renin-angiotensin system. The purpose of this review is to describe the current understanding of how the hemodynamic, metabolic, inflammatory, and alternative pathways are all entangled in pathogenesis of DKD and detail the various therapeutic targets that may one day play a role in quelling this epidemic. Stephanie Toth-Manikowski and Mohamed G. Atta Copyright © 2015 Stephanie Toth-Manikowski and Mohamed G. Atta. All rights reserved. Skewed Epigenetics: An Alternative Therapeutic Option for Diabetes Complications Thu, 30 Apr 2015 13:59:25 +0000 Vascular complications are major causes of morbidity and mortality in type 2 diabetes patients. Mitochondrial reactive oxygen species (ROS) generation and a lack of efficient antioxidant machinery, a result of hyperglycaemia, mainly contribute to this problem. Although advances in therapy have significantly reduced both morbidity and mortality in diabetic individuals, diabetes-associated vascular complications are still one of the most challenging health problems worldwide. New healing options are urgently needed as current therapeutics are failing to improve long-term outcomes. Particular effort has recently been devoted to understanding the functional relationship between chromatin structure regulation and the persistent change in gene expression which is driven by hyperglycaemia and which accounts for long-lasting diabetic complications. A detailed investigation into epigenetic chromatin modifications in type 2 diabetes is underway. This will be particularly useful in the design of mechanism-based therapeutics which interfere with long-lasting activating epigenetics and improve patient outcomes. We herein provide an overview of the most relevant mechanisms that account for hyperglycaemia-induced changes in chromatin structure; the most relevant mechanism is called “metabolic memory.” Gabriele Togliatto, Patrizia Dentelli, and Maria Felice Brizzi Copyright © 2015 Gabriele Togliatto et al. All rights reserved. Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome Thu, 30 Apr 2015 13:45:43 +0000 Sympathetic tone is well recognised as being implicit in cardiovascular control. It is less readily acknowledged that activation of the sympathetic nervous system is integral in energy homeostasis and can exert profound metabolic effects. Accumulating data from animal and human studies suggest that central sympathetic overactivity plays a pivotal role in the aetiology and complications of several metabolic conditions that can cluster to form the Metabolic Syndrome (MetS). Given the known augmented risk for type 2 diabetes, cardiovascular disease, and premature mortality associated with the MetS understanding the complex pathways underlying the metabolic derangements involved has become a priority. Many factors have been proposed to contribute to increased sympathetic nerve activity in metabolic abnormalities including obesity, impaired baroreflex sensitivity, hyperinsulinemia, and elevated adipokine levels. Furthermore there is mounting evidence to suggest that chronic sympathetic overactivity can potentiate two of the key metabolic alterations of the MetS, central obesity and insulin resistance. This review will discuss the regulatory role of the sympathetic nervous system in metabolic control and the proposed pathophysiology linking sympathetic overactivity to metabolic abnormalities. Pharmacological and device-based approaches that target central sympathetic drive will also be discussed as possible therapeutic options to improve metabolic control in at-risk patient cohorts. Alicia A. Thorp and Markus P. Schlaich Copyright © 2015 Alicia A. Thorp and Markus P. Schlaich. All rights reserved. In Vitro and In Vivo Effects of Metformin on Osteopontin Expression in Mice Adipose-Derived Multipotent Stromal Cells and Adipose Tissue Thu, 30 Apr 2015 11:10:32 +0000 Metformin is applied not only as antidiabetic drug, but also in the treatment of obesity or as antiaging drug. The first part of the research discussed the effect of metformin at concentrations of 1 mM, 5 mM, and 10 mM on the morphology, ultrastructure, and proliferation potential of mice adipose-derived multipotent mesenchymal stromal cells (ASCs) in vitro. Additionally, we determined the influence of metformin on mice adipose tissue metabolism. This study has shown for the first time that metformin inhibits the proliferative potential of ASCs in vitro in a dose- and time-dependent manner. In addition, we have found a significant correlation between the activity of ASCs and osteopontin at the mRNA and protein level. Furthermore, we have demonstrated that 5 mM and 10 mM metformin have cytotoxic effect on ASCs, causing severe morphological, ultrastructural, and apoptotic changes. The reduced level of OPN in the adipose tissue of metformin-treated animals strongly correlated with the lower expression of Ki67 and CD105 and increased caspase-3. The metformin influenced also circulating levels of OPN, which is what was found with systemic and local action of metformin. The results are a valuable source of information regarding the in vitro effect of metformin on adipose-derived stem cells. Agnieszka Śmieszek, Katarzyna Basińska, Klaudia Chrząstek, and Krzysztof Marycz Copyright © 2015 Agnieszka Śmieszek et al. All rights reserved. Impact of Gender on the Association of Epicardial Fat Thickness, Obesity, and Circadian Blood Pressure Pattern in Hypertensive Patients Thu, 30 Apr 2015 07:38:24 +0000 This study aimed to investigate the effects of gender on the association between epicardial fat thickness (EFT) and circadian blood pressure (BP) changes in patients with recently diagnosed essential hypertension (EH). A total of 441 patients with EH (male/female: 236/205, mean age: 50.7 ± 13.8) and 83 control patients underwent 24-hour ambulatory BP monitoring and echocardiography. Obese EH patients had higher circadian BP profile with BP variability, wall thickness, and left ventricular mass than nonobese EH patients and controls (all p’s ) without gender differences. EFT was higher in female than in male patients (7.0 ± 2.5 versus 5.9 ± 2.2 mm, ) and higher in the obese female EH group (7.5 ± 2.6 mm) than in the control (6.4 ± 2.8 mm) or nonobese EH group (6.7 ± 2.8 mm) among women, whereas EFT did not vary among males (5.9 ± 1.9 versus 6.0 ± 2.7 versus 5.9 ± 2.4 mm, ). Multivariate logistic regression analysis demonstrated that the 24-hour mean BP variability was associated with SBP () and EFT () in female patients, but not in male patients. The relationships among circadian BP variability, obesity, and EFT were affected by gender in different manners. EFT may be a more valuable parameter in the evaluation of BP severity and obesity in women than in men. In Kyoung Shim, Kyoung-Im Cho, Hyun-Su Kim, Jung-Ho Heo, and Tae Joon Cha Copyright © 2015 In Kyoung Shim et al. All rights reserved. The Effects of Atorvastatin on Arterial Stiffness in Male Patients with Type 2 Diabetes Thu, 30 Apr 2015 07:13:57 +0000 Statin therapy improves lipid profiles and reduces vascular inflammation, but its effects on central arterial stiffness in type 2 diabetes are unclear. The aim of this study was to determine whether statin therapy reduces central arterial stiffness, in a dose-dependent manner, in male patients with type 2 diabetes. Fifty-one patients ceased statin therapy for 6 weeks, followed by randomisation to either 10 or 80 mg of atorvastatin. At randomization, 3 and 12 months, central arterial stiffness was measured via carotid-femoral pulse wave velocity (PWV), along with serum markers of vascular inflammation including high-sensitivity c-reactive protein (hsCRP) and osteoprotegerin (OPG). PWV decreased from 10.37 ± 1.30 to 9.68 ± 1.19 m/sec ( from baseline) at 3 months and 9.10 ± 1.17 m/sec ( from baseline) at 12 months. hsCRP and OPG decreased significantly at 3 and 12 months. Reductions in PWV did not differ significantly between the groups. Baseline PWV and OPG values correlated strongly (, ), as did their response to atorvastatin over 12 months ( delta-OPG and delta-PWV, ). Atorvastatin therapy appeared to reduce central arterial stiffness in male type 2 diabetes, with no dose-dependent effect observed. The correlation observed between reductions in PWV and OPG suggests that atorvastatin reduces PWV via direct anti-inflammatory effects on the vasculature. Colin Davenport, David T. Ashley, Eoin P. O’Sullivan, Claire M. McHenry, Amar Agha, Christopher J. Thompson, Donal J. O’Gorman, and Diarmuid Smith Copyright © 2015 Colin Davenport et al. All rights reserved. Flow Mediated Dilatation Is Reduced with the Progressive Stages of Glomerular Filtration Rate and Albuminuria in Type 2 Diabetic Patients without Coronary Heart Disease Wed, 29 Apr 2015 08:11:07 +0000 We aimed to clarify the usefulness of measuring the flow mediated dilatation (FMD) in patients with type 2 diabetes mellitus without and with coronary heart disease (CHD). The FMD was measured in 480 patients with type 2 diabetes and in 240 nondiabetic subjects. The FMD was significantly lower in the subjects with CHD ( = 145, %) than in those without CHD ( = 95, %) among the nondiabetic subjects. The FMD was also lower in the subjects both with CHD ( = 161, %) and without CHD ( = 319, %) among the patients with diabetes compared to those without both diabetes and CHD. The FMD showed a significant positive correlation with the estimated glomerular filtration rate (eGFR) in the diabetic patients without CHD, while there was no significant association in those with CHD. The FMD was significantly lower with the progressive stages of the GFR or albuminuria in the patients without CHD among those with diabetes, although the FMD was not different in those with CHD. In conclusion, the FMD is considered to be useful for the detection of atherosclerosis in patients with type 2 diabetes, even if overt macroangiopathy is not diagnosed. Hiroyuki Ito, Mina Nakashima, Kentaro Meguro, Haruki Furukawa, Hitomi Yamashita, Akifusa Takaki, Chizuko Yukawa, Takashi Omoto, Masahiro Shinozaki, Shinya Nishio, Mariko Abe, Shinichi Antoku, Mizuo Mifune, and Michiko Togane Copyright © 2015 Hiroyuki Ito et al. All rights reserved. Positive Psychological Interventions for Patients with Type 2 Diabetes: Rationale, Theoretical Model, and Intervention Development Wed, 29 Apr 2015 07:56:24 +0000 Most patients with type 2 diabetes (T2D) have suboptimal adherence to recommended diet, physical activity, and/or medication. Current approaches to improve health behaviors in T2D have been variably effective, and successful interventions are often complex and intensive. It is therefore vital to develop interventions that are simple, well-accepted, and applicable to a wide range of patients who suffer from T2D. One approach may be to boost positive psychological states, such as positive affect or optimism, as these constructs have been prospectively and independently linked to improvements in health behaviors. Positive psychology (PP) interventions, which utilize systematic exercises to increase optimism, well-being, and positive affect, consistently increase positive states and are easily delivered to patients with chronic illnesses. However, to our knowledge, PP interventions have not been formally tested in T2D. In this paper, we review a theoretical model for the use of PP interventions to target health behaviors in T2D, describe the structure and content of a PP intervention for T2D patients, and describe baseline data from a single-arm proof-of-concept () intervention study in T2D patients with or without depression. We also discuss how PP interventions could be combined with motivational interviewing (MI) interventions to provide a blended psychological-behavioral approach. Jeff C. Huffman, Christina M. DuBois, Rachel A. Millstein, Christopher M. Celano, and Deborah Wexler Copyright © 2015 Jeff C. Huffman et al. All rights reserved.