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Crops and livestock play a synergistic role in global food production and farmer livelihoods. Increasingly, however, crops and livestock are produced in isolation, particularly in farms operating at the commercial scale. It has been suggested that re-integrating crop and livestock systems at the field and farm level could help reduce the pollution associated with modern agricultural production and increase yields. Despite this potential, there has been no systematic review to assess remaining knowledge gaps in both the social and ecological dimensions of integrated crop and livestock systems (ICLS), particularly within commercial agricultural systems. Based on a multi-disciplinary workshop of international experts and additional literature review, we assess the current knowledge and remaining uncertainties about large-scale, commercial ICLS and identify the source of remaining knowledge gaps to establish priorities for future research. We find that much is understood about nutrient flows, soil quality, crop performance, and animal weight gain in commercial ICLS, but there is little knowledge about its spatial extent, animal behavior or welfare in ICLS, or the tradeoffs between biodiversity, pest and disease control, greenhouse gas (GHG) mitigation, and drought and heat tolerance in ICLS. There is some evidence regarding the economic outcomes in commercial ICLS and supply chain and policy barriers to adoption, but little understanding of broader social outcomes or cultural factors influencing adoption. Many of these knowledge gaps arise from a basic lack of data at both the field and system scales, which undermines both statistical analysis and modeling efforts. Future priorities for the international community of researchers investigating the tradeoffs and scalability of ICLS include: methods standardization to better facilitate international collaborations and comparisons, continued social organization for better data utilization and collaboration, meta-analyses to answer key questions from existing data, the establishment of long term experiments and surveys in key regions, a portal for citizen science, and more engagement with ICLS farmers.

Background: Type 2 diabetes mellitus (T2D) is a global health concern with a rising prevalence, particularly in Brazil. Insulin therapy plays a crucial role in managing T2D, helping to maintain glucose and energy homeostasis. Moreover, early initiation of insulin is crucial for hyperglycemic control and prevention of chronic complications. Clinical guidelines recommend initiating insulin when other treatments fail. However, several barriers may delay its initiation, contributing to therapeutic inertia and patients' non-adherence. These barriers include fear of hypoglycemia, lack of adherence, the need for glucose monitoring, the injection method of insulin administration, social rejection associated with the stigma of injections, fear of weight gain, a sense of therapeutic failure at initiation, and lack of experience among some healthcare professionals. : In this context, the development of once-weekly insulin formulations could improve initial acceptance, adherence, treatment satisfaction, and consequently, the quality of life for patients. Currently, two once-weekly insulin treatments, insulin icodec and efsitora alfa, have shown promise in clinical trials, demonstrating efficacy and safety profiles similar or better than those of daily insulin therapies., Short Conclusion: These once-weekly insulins have the potential to emerge as landmark achievements in the evolution of insulin therapy. This narrative review aims to evaluate the role of weekly insulins in managing T2D, providing insights into the potential benefits, challenges, and opportunities associated with a new weekly insulin therapy, specially within the Brazilian context., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: A.G.D.V. received funding from Novo Nordisk. R.R.R. received funding from Novo Nordisk. D.F.A. is an employee of IQVIA. T.S.A. is an employee of IQVIA., (© 2024. The Author(s).)

Background: Precision nutrition is based on the integration of individual's phenotypical and biological characteristics including genetic variants, epigenetic marks, gut microbiota profiles, and metabolite fingerprints as well as medical history, lifestyle practices, and environmental and cultural factors. Thus, nutriomics areas including nutrigenomics, nutrigenetics, nutriepigenetics, nutrimetabolomics, and nutrimetagenomics have emerged to comprehensively understand the complex interactions between nutrients, diet, and the human body's molecular processes through precision nutrition., Summary: This document from the Ibero-American Network of Nutriomics and Precision Nutrition (RINN22; https://rinn22.com/) provides a comprehensive overview of the concepts of precision nutrition approaches to guide their application in clinical and public health as well as establish the position of RINN22 regarding the current and future state of precision nutrition., Key Messages: The progress and participation of nutriomics to precision nutrition is an essential pillar for addressing diet-related diseases and developing innovative managing strategies, which will be promoted by advances in bioinformatics, machine learning, and integrative software, as well as the description of specific novel biomarkers. In this context, synthesizing and critically evaluating the latest developments, potential applications, and future needs in the field of nutrition is necessary with a holistic perspective, incorporating progress in omics technologies aimed at precision nutrition interventions. This approach must address and confront healthy, social, food security, physically active lifestyle, sanitation, and sustainability challenges with preventive, participatory, and predictive strategies of personalized, population, and planetary nutrition for a precision tailored health., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

We explored key microRNAs (miRNAs) related to tumorigenesis and immune modulation in glioblastoma (GBM), employing in silico, in vitro, and ex vivo analysis along with an assessment of the cellular impacts resulting from miRNA inhibition. GBM and T cells miRNA expression profiles from public datasets were used to evaluate differentially expressed miRNAs (DEmiRNAs). Some DEmiRNAs were chosen for validation in GBM cell lines, primary cell cultures, and brain tumor patient samples, using RT-qPCR. Target genes and pathways were identified with bioinformatic analyses. In silico functional enrichment analysis revealed that miR-27a-3p and miR-155-5p modulate immune, metabolic, and GBM-related pathways. A172 cells were transfected with miRNA inhibitors and the effects on cellular processes and immunomodulation were analyzed by co-culture assays and flow cytometry. Upon validation, miR-27a-3p and miR-155-5p miRNAs expressions were consistently increased. Inhibiting these two miRNAs reduced cell viability, but only the inhibition of miR-27a-3p led to apoptosis. Co-culture assays showed an increase in Th1 cells along with elevated Th1/Treg and Th17/Treg ratios, and an increase in Th17 cells exclusively with miR-155-5p inhibition. Immune cells' gene expression modulation induced an antitumor profile, concomitant with an increase in the expression of apoptotic genes in cancer cells after co-culture. This study unveils potential targets for immune and tumor regulation, highlighting overexpressed miRNAs modulation as a novel therapeutic approach for GBM., (© 2024 Federation of American Societies for Experimental Biology.)

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; p < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS.

Background: Dysregulation of epigenetic processes and abnormal epigenetic profiles are associated with various metabolic disorders. Nutrition, as an environmental factor, can induce epigenetic changes through both direct exposure and transgenerational inheritance, continuously altering gene expression and shaping the phenotype. Nutrients consumed through food or supplementation, such as vitamin B12, folate, vitamin B6, and choline, play a pivotal role in DNA methylation, a critical process for gene regulation. Additionally, there is mounting evidence that the expression of non-coding RNAs (ncRNAs) can be modulated by the intake of specific nutrients and natural compounds, thereby influencing processes involved in the onset and progression of metabolic diseases., Summary: Evidence suggests that dietary patterns, weight loss interventions, nutrients and nutritional bioactive compounds can modulate the expression of various microRNA (miRNAs) and DNA methylation levels, contributing to the development of metabolic disorders such as obesity and type 2 diabetes. Furthermore, several studies have proposed that DNA methylation and miRNA expression could serve as biomarkers for the effects of weight loss programs., Key Message: Despite ongoing debate regarding the effects of nutrient supplementation on DNA methylation levels and the expression of ncRNAs, certain DNA methylation marks and ncRNA expressions might predict the risk of metabolic disorders and act as biomarkers for forecasting the success of therapies within the framework of precision medicine and nutrition. The role of DNA methylation and miRNA expression as potential mediators of the effects of weight loss underscores their potential as biomarkers for the outcomes of weight loss programs. This highlights the influence of dietary patterns and weight loss interventions on the regulation of miRNA expression and DNA methylation levels, suggesting an interaction between these epigenetic factors and the body's response to weight loss., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The transforming growth factor beta 1 (TGFB1) is a pro-inflammatory cytokine that plays a key role in the mechanisms of angiogenesis and breakdown of the blood-retina barrier, which are implicated in the pathogenesis of diabetic retinopathy (DR). Polymorphisms in the TGFB1 gene have been associated with DR; however, results are still contradictory. Therefore, the aim of this study was to investigate the potential association between two TGFB1 polymorphisms and DR. This study included 992 patients with diabetes mellitus (DM): 546 patients with DR (cases) and 446 patients without DR and with ≥10 years of DM (controls). The TGFB1 rs1800469 and rs1800470 polymorphisms were genotyped by real-time PCR. Frequency of rs1800469 T/T genotype was higher in controls compared to DR cases (18.3% vs. 12.7%, P= 0.022). This genotype remained associated with protection for DR, adjusting for covariables (OR= 0.604; 95% CI 0.395 - 0.923; P= 0.020, recessive model). The rs1800470 C/C genotype was observed in 25.4% of the controls and 18.0% of the cases (P= 0.015); thus, being associated with protection against DR under the recessive model (OR= 0.589; 95% CI 0.405 - 0.857; P= 0.006), adjusting for covariables. In conclusion, the TGFB1 rs1800469 and rs1800470 polymorphisms are associated with protection against DR in DM patients from Southern Brazil.

Long non-coding RNAs (lncRNAs) are RNAs with >200 nucleotides that are unable to encode proteins and are involved in gene expression regulation. LncRNAs have a key role in many physiological and pathological processes and, consequently, they have been associated with several human diseases, including diabetes chronic complications, such as diabetes kidney disease (DKD). In this context, some studies have identified the dysregulation of the lncRNAs MALAT1 and TUG1 in patients with DKD; nevertheless, available data are still contradictory. Thus, the objective of this study was to compare MALAT1 and TUG1 expressions in urine of patients with type 1 diabetes mellitus (T1DM) categorized according to DKD presence. This study comprised 18 T1DM patients with DKD (cases) and 9 long-duration T1DM patients without DKD (controls). MALAT1 and TUG1 were analyzed using qPCR. Bioinformatics analyses were done to identify both lncRNA target genes and the signaling pathways under their regulation. The lncRNA MALAT1 was upregulated in urine of T1DM patients with DKD vs. T1DM controls (P = 0.007). The expression of lncRNA TUG1 did not differ between groups (P = 0.815). Bioinformatics analysis showed these two lncRNAs take part in metabolism-related pathways. The present study shows that the lncRNA MALAT1 is upregulated in T1DM patients presenting DKD.

Objective: The objective of this study was to investigate the association between SNPs in the TIE2 and ANGPT-1 genes and diabetic retinopathy (DR)., Subjects and Methods: This study comprised 603 patients with type 2 diabetes mellitus (T2DM) and DR (cases) and 388 patients with T2DM for more than 10 years and without DR (controls). The TIE2 rs639225 (A/G) and rs638203 (A/G) SNPs and the ANGPT-1 rs4324901 (G/T) and rs2507800 (T/A) SNPs were genotyped by real-time PCR using TaqMan MGB probes., Results: The G/G genotype of the rs639225/ TIE2 , the G/G genotype of the rs638203/ TIE2 and the T allele of the rs4324901/ ANGPT-1 SNPs were associated with protection against DR after adjustment for age, glycated hemoglobin, gender, and presence of hypertension (P = 0.042, P = 0.003, and P = 0.028, respectively). No association was found between the rs2507800/ ANGPT-1 SNP and DR., Conclusion: We demonstrated, for the first time, the association of TIE2 rs638203 and rsrs939225 SNPs and ANGPT-1 rs4324901 SNP with protection against DR in a Brazilian population.

Objective: To identify DNA methylation and gene expression profiles involved in obesity by implementing an integrated bioinformatics approach., Materials and Methods: Gene expression (GSE94752, GSE55200, and GSE48964) and DNA methylation (GSE67024 and GSE111632) datasets were obtained from the GEO database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) in subcutaneous adipose tissue of patients with obesity were identified using GEO2R. Methylation-regulated DEGs (MeDEGs) were identified by overlapping DEGs and DMGs. The protein-protein interaction (PPI) network was constructed with the STRING database and analyzed using Cytoscape. Functional modules and hub-bottleneck genes were identified by using MCODE and CytoHubba plugins. Functional enrichment analyses were performed based on Gene Ontology terms and KEGG pathways. To prioritize and identify candidate genes for obesity, MeDEGs were compared with obesity-related genes available at the DisGeNET database., Results: A total of 54 MeDEGs were identified after overlapping the lists of significant 274 DEGs and 11,556 DMGs. Of these, 25 were hypermethylated-low expression genes and 29 were hypomethylated-high expression genes. The PPI network showed three hub-bottleneck genes ( PTGS2 , TNFAIP3 , and FBXL20 ) and one functional module. The 54 MeDEGs were mainly involved in the regulation of fibroblast growth factor production, the molecular function of arachidonic acid, and ubiquitin-protein transferase activity. Data collected from DisGeNET showed that 11 of the 54 MeDEGs were involved in obesity., Conclusion: This study identifies new MeDEGs involved in obesity and assessed their related pathways and functions. These results data may provide a deeper understanding of methylation-mediated regulatory mechanisms of obesity.

Changes in gut microbiota composition and in epigenetic mechanisms have been proposed to play important roles in energy homeostasis, and the onset and development of obesity. However, the crosstalk between epigenetic markers and the gut microbiome in obesity remains unclear. The main objective of this study was to establish a link between the gut microbiota and DNA methylation patterns in subjects with obesity by identifying differentially methylated DNA regions (DMRs) that could be potentially regulated by the gut microbiota. DNA methylation and bacterial DNA sequencing analysis were performed on 342 subjects with a BMI between 18 and 40 kg/m 2 . DNA methylation analyses identified a total of 2648 DMRs associated with BMI, while ten bacterial genera were associated with BMI. Interestingly, only the abundance of Ruminococcus was associated with one BMI-related DMR, which is located between the MACROD2 / SEL1L2 genes. The Ruminococcus abundance negatively correlated with BMI, while the hypermethylated DMR was associated with reduced MACROD2 protein levels in serum. Additionally, the mediation test showed that 19% of the effect of Ruminococcus abundance on BMI is mediated by the methylation of the MACROD2 / SEL1L2 DMR. These findings support the hypothesis that a crosstalk between gut microbiota and epigenetic markers may be contributing to obesity development.

Background: Long non-coding RNAs (lncRNAs) are key regulators of gene expression. Some studies have reported the association of polymorphisms in lncRNA genes with diabetes mellitus (DM) and its chronic complications, including diabetic kidney disease (DKD); however, the results are still inconclusive. Thus, we investigated the association of the rs3200401/MALAT1, rs1894720/MIAT, rs3931283/PVT1, rs11993333/PVT1, rs5749201/TUG1, and rs7158663/MEG3 polymorphisms with DKD in patients with type 2 DM (T2DM)., Methods and Results: This study comprised 902 patients with T2DM and DKD (cases) and 394 patients with T2DM without DKD (controls). The six polymorphisms of interest were genotyped by real-time PCR using TaqMan probes. Frequency of the rs3931283/PVT1 G/G genotype was 36.2% in cases and 31.9% in controls (P = 0.331). After adjustment for gender, glycated hemoglobin, HDL cholesterol, ethnicity, hypertension, and diabetic retinopathy, the G/G genotype was associated with risk for DKD (OR = 1.625, 95% CI 1.020-2.588; P = 0.041). The rs3931283/PVT1 G/G genotype was also associated with higher urinary albumin excretion levels compared to A allele carriers (P = 0.017). No difference was found in rs7158663/MEG3 genotype frequencies between T2DM controls and DKD patients (OR = 1.087, 95% CI 0.686-1.724; P = 0.722). However, the rs7158663/MEG3 G/G genotype was associated with protection against severe DKD (OR = 0.694, 95% CI 0.488-0.989; P = 0.043, for patients with severe DKD vs. T2DM controls). The rs7158663/MEG3 G/G genotype was also associated with lower creatinine levels (P = 0.007) and higher estimated glomerular filtration rate (P = 0.010) compared to A allele carriers. No association was found between the rs11993333/PVT1, rs3200401/MALAT1, rs1894720/MIAT, and rs5749201/TUG1 polymorphisms and DKD or its laboratory markers., Conclusion: The rs3931283/PVT1 G/G and rs7158663/MEG3 G/G are associated with DKD and markers of renal function in T2DM patients from a Brazilian population., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Pulmonary arterial hypertension (PAH) is a severe and progressive disease characterized by increased pulmonary vascular resistance, ultimately leading to right heart failure and death. Registries are a valuable tool in the research of rare conditions such as PAH. Moreover, the risk assessment strategy has been validated in European and North American registries and has been reported to provide an accurate prediction of mortality and the clinical advantage of reaching low-risk status. However, there is no available data from Brazil. Thus, the aim of the present study was to describe the characteristics of a sample of PAH from Southern Brazil and to retrospectively validate the risk assessment at our population. The RESPHIRAR is a retrospective and multicentric registry on pulmonary hypertension. With a join collaboration from nine centers in Southern Brazil, demographics, clinical presentation, and hemodynamics data of PAH were collected between 2007 and 2017. Moreover, the REVEAL 2.0 and REVEAL 2.0 Lite risk assessments were validated in our population. Overall, 370 PAH patients were included in the present study. Patients were predominantly female (78.5%) and had a mean age of 41.8 ± 18.8 years. Most patients (33.4%) had idiopathic PAH, 30.2% had PAH associated with congenital heart disease, and 23.5% had PAH associated with connective tissue disease. The low-risk group showed significantly lower mortality than the intermediated- or high-risk group at diagnosis ( p  < 0.05). In conclusion, our data suggest that REVEAL 2.0 and REVEAL 2.0 Lite risk assessments can predict mortality risk in PAH patients in Southern Brazil., Competing Interests: Gláucia Maria Barbieri reports speaker and sponsorships in scientific events by Janssen and Bayer. Ariovaldo Leal Fagundes reports lectures to GlaxoSmithKline, Pfizer, and AstraZeneca. Scientific consultancy fee from Ache, Boehringer Ingelheim, and Chiesi. Roger Pirath Rodrigues reports lectures to Janssen, Bayer, Astra‐Zeneca, GSK. Rogerio Souza reports lecture and consultancy fees from Acceleron, Bayer, and Merck. Gisela Martina Bohns Meyer reports lecture and consultancy fees from Aceeleron, Bayer, and GSK. The remaining authors declare no conflict of interest. Conflict of interest outside the submitted work., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Introduction: The Erb-b2 receptor tyrosine kinase 3 (ERBB3) is involved in autoimmune processes related to type 1 diabetes mellitus (T1DM) pathogenesis. Accordingly, some studies have suggested that single nucleotide polymorphisms (SNPs) in the ERBB3 gene confer risk for T1DM. Proliferation-associated protein 2G4 (PA2G4) is another candidate gene for this disease because it regulates cell proliferation and adaptive immunity. Moreover, PA2G4 regulates ERBB3. To date, no study has evaluated the association of PA2G4 SNPs and T1DM., Aim: To evaluate the association of ERBB3 rs705708 (G/A) and PA2G4 rs773120 (C/T) SNPs with T1DM and its clinical and laboratory characteristics., Methods: This case-control study included 976 white subjects from Southern Brazil, categorized into 501 cases with T1DM and 475 non-diabetic controls. The ERBB3 and PA2G4 SNPs were genotyped by allelic discrimination-real-time PCR., Results: ERBB3 rs705708 and PA2G4 rs773120 SNPs were not associated with T1DM considering different inheritance models and also when controlling for covariables. However, T1DM patients carrying the ERBB3 rs705708 A allele developed T1DM at an earlier age vs. G/G patients. Interestingly, in the T1DM group, the rs705708 A allele was associated with lower prevalence of diabetic retinopathy and arterial hypertension as well as with improved renal function (higher estimated glomerular filtration rate and lower urinary albumin excretion levels) compared to G/G patients., Conclusions: Although no association was observed between the ERBB3 rs705708 and PA2G4 rs773120 SNPs and T1DM, the rs705708 A allele was associated, for the first time in literature, with lower prevalence of diabetic retinopathy and arterial hypertension. Additionally, this SNP was associated with improved renal function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Recent studies have associated several microRNAs (miRNAs) with childhood obesity and energy homeostasis, suggesting that an individual miRNA profile could be used as an early predictor to estimate the response to weight loss interventions in the design of precision nutrition., Objective: To investigate associations between the expression of circulating adiposity-related miRNAs and the response to a weight loss intervention., Methods: A total of 51 Spanish girls (age 7-16 years) with abdominal obesity underwent 8 weeks of a multidisciplinary intervention for weight loss. Participants were stratified into two groups in accordance with changes in body mass index (BMI) standard deviation score: low-responders (LR) and high-responders (HR). The expression of 39 circulating miRNAs (c-miRNAs) was evaluated in plasma of all subjects before the intervention., Results: Six miRNAs were differentially expressed between LR and HR. However, after adjustment for Tanner stage, the association was maintained only for miR-126-3p and miR-221-3p with a higher expression in HR group compared to LR group. After the intervention, miR-221-3p expression decreased in all subjects with a significant difference in the change within groups. However, changes in miR-126-3p levels were not significant. The expression of miR-221-3p was positively correlated with body weight, BMI and waist circumference, and negatively correlated with quantitative insulin sensitivity check index., Conclusions: Bioinformatic analysis evidenced that miR-221-3p participates in several obesity-related pathways, and more interestingly, this miRNA targets several candidate genes to childhood obesity according to DisGeNet database. Thus, miR-221-3p could be used for predicting the response to a multidisciplinary intervention for weight loss in young girls., (© 2022 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Pulmonary hypertension (PH) is a rare and complex disease with poor prognosis, which requires lifelong treatment., Objective: To describe 3-year follow-up real-life data on treatment with soluble guanylate cyclase stimulators (Riociguat) of patients with PH, measuring current risk assessment parameters., Methods: This study retrospectively collected clinical and epidemiological data of patients with PH of group 1 (pulmonary arterial hypertension) and group 4 (chronic thromboembolic PH). Non-invasive and invasive parameters corresponding to the risk assessment were analyzed at baseline and follow-up. Statistical analyses were performed using the SPSS 18.0 software, and p-values < 0.050 were considered statistically significant., Results: In total, 41 patients receiving riociguat were included in the study. Of them, 31 had already completed 3 years of treatment and were selected for the following analysis. At baseline, 70.7% of patients were in WHO functional class III or IV. After 3 years of treatment, the WHO functional class significantly improved in all patients. In addition, the median of the 6-minute walk test (6MWT) significantly increased from 394 ± 91 m at baseline to 458 ± 100 m after 3 years of follow-up (p= 0.014). The three-year survival rate was 96.7%., Conclusion: In our real-life cohort, most patients with PH treated with riociguat showed stable or improved risk parameters, especially in the 6MWT, at 3 years of follow-up.

Dietary lipids have a major role in nutrition, not only for their fuel value, but also as essential and bioactive nutrients. This narrative review aims to describe the current evidence on nutrigenomic effects of dietary lipids. Firstly, the different chemical and biological properties of fatty acids contained both in plant- and animal-based food are illustrated. A description of lipid bioavailability, bioaccessibility, and lipotoxicity is provided, together with an overview of the modulatory role of lipids as pro- or anti-inflammatory agents. Current findings concerning the metabolic impact of lipids on gene expression, epigenome, and gut microbiome in animal and human studies are summarized. Finally, the effect of the individual's genetic make-up on lipid metabolism is described. The main goal is to provide an overview about the interaction between dietary lipids and the genome, by identifying and discussing recent scientific evidence, recognizing strengths and weaknesses, to address future investigations and fill the gaps in the current knowledge on metabolic impact of dietary fats on health.

Background and Purpose: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. MiRNA-126 and miRNA-146a have been described as having abnormal expressions in diabetic retinopathy (DR) patients. Polymorphisms in genes codifying miRNAs (miRSNPs) may alter the expression of the corresponding miRNA and, thus, interfere with susceptibility to DR. Therefore, miRSNPs in miR-126 and miR-146a genes could be associated with DR susceptibility. The purpose of this study was to investigate the association between miR-126 rs4636297 (G/A) and miR-146a rs2910164 (G/C) miRSNPs and DR., Methods: This case-control study included 195 type 1 diabetes mellitus (T1DM) patients with DR (cases) and 215 patients without DR and with ≥10 years of T1DM (controls). MiRSNPs were genotyped by real-time PCR., Results: Genotype distributions of two analysed miRSNPs were in Hardy-Weinberg equilibrium in controls (p > 0.050). Frequencies of the miR-126 rs4636297 miRSNP were not significantly different between case and control groups (p = 0.169). However, after adjustment for age, glycated haemoglobin, triglycerides, estimated glomerular filtration rate and ethnicity, the A allele of this miRSNP was associated with protection for DR under additive [OR: 0.444 (95% CI: 0.211-0.936), p = 0.033] and dominant [OR: 0.512 (95% CI: 0.303-0.865), p = 0.012] inheritance models. Genotype and allele frequencies of miR-146a rs2910164 miRSNP did not differ between groups (p = 0.368 and p = 0.957), and this polymorphism was not associated with DR when assuming different inheritance models., Conclusion: Our results suggest an association between the A allele of miR-126 rs4636297 miRSNP and protection for DR in a Southern Brazilian population., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Long non-coding RNAs (lncRNAs) are non-coding transcripts that have emerged as one of the largest and diverse RNA families that regulate gene expression. Accumulating evidence has suggested a number of lncRNAs are involved in diabetes mellitus (DM) pathogenesis. However, results about lncRNA expressions in DM patients are still inconclusive. Thus, we performed a systematic review of the literature on the subject followed by bioinformatics analyses to better understand which lncRNAs are dysregulated in DM and in which pathways they act. Pubmed, Embase, and Gene Expression Omnibus (GEO) repositories were searched to identify studies that investigated lncRNA expression in cases with DM and non-diabetic controls. LncRNAs consistently dysregulated in DM patients were submitted to bioinformatics analysis to retrieve their target genes and identify potentially affected signaling pathways under their regulation. Fifty-three eligible articles were included in this review after the application of the inclusion and exclusion criteria. Six hundred and thirty-eight lncRNAs were differentially expressed between cases and controls in at least one study. Among them, six lncRNAs were consistently dysregulated in patients with DM ( Anril , Hotair , Malat1 , Miat , Kcnq1ot1 , and Meg3 ) compared to controls. Moreover, these six lncRNAs participate in several metabolism-related pathways, evidencing their importance in DM. This systematic review suggests six lncRNAs are dysregulated in DM, constituting potential biomarkers of this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dieter, Lemos, Corrêa, Assmann and Crispim.)

Using near-infrared (NIR) spectroscopy for poultry litter characterization can be a rapid, non-destructive, and low-cost alternative. This study aims to estimate the C, N, P, and K content in poultry litter samples using for first time NIR spectroscopy. For these purposes, the building models were carried out using Partial Least Squares (PLS) and Support Vector Machines (SVM) methods. A total of 160 litter samples were analyzed in poultry houses of different rearing systems, seeking the highest possible variability in their chemical composition. NIR spectroscopy, combined with PLS and SVM methods, is an alternative method for non-destructive C, N, P, and K determination in poultry samples. The regression models using SVM provide better accuracy for all elements, laying the basis for the nonlinear regression approach's application. The K determination on poultry litter using NIR was possible only by the SVM model (R 2  = 0.8620 and RPD = 2.7330). Conclusively, the predictive ability was improved using the SVM method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The determinants that mediate the interactions between microRNAs and the gut microbiome impacting on obesity are scarcely understood. Thus, the aim of this study was to investigate possible interactions between circulating microRNAs and gut microbiota composition in obesity., Method: The sample comprised 78 subjects with obesity (cases, body mass index (BMI): 30-40 kg/m 2 ) and 25 eutrophic individuals (controls, BMI ≤ 25 kg/m 2 ). The expression of 96 microRNAs was investigated in plasma of all individuals using miRCURY LNA miRNA Custom PCR Panels. Bacterial DNA sequencing was performed following the Illumina 16S protocol. The FDR correction was used for multiple comparison analyses., Results: A total of 26 circulating microRNAs and 12 bacterial species were found differentially expressed between cases and controls. Interestingly, an interaction among three miRNAs (miR-130b-3p, miR-185-5p and miR-21-5p) with Bacteroides eggerthi and BMI levels was evidenced ( r 2 = 0.148, p = 0.004). Moreover, these microRNAs regulate genes that participate in metabolism-related pathways, including fatty acid degradation, insulin signaling and glycerolipid metabolism., Conclusions: This study characterized an interaction between the abundance of 4 bacterial species and 14 circulating microRNAs in relation to obesity. Moreover, the current study also suggests that miRNAs may serve as a communication mechanism between the gut microbiome and human hosts.

Circulating microRNAs (miRNAs) are valuable biomarkers that may provide important insight into the pathogenesis of metabolic syndrome (MetS). Moreover, there is an association between chronotypical characteristics and MetS predisposition. Considering that expression of some miRNAs is circadian-rhythm-dependent, the aim of this study was to investigate the circulating miRNA profile in subjects with and without MetS in association with chronotype. The expression of 86 metabolic syndrome-related miRNAs was investigated in the plasma of 21 subjects with MetS and in 82 subjects without MetS using miRCURY LNA miRNA PCR System technology. Chronotype was assessed using the Horne and Östberg Morningness-Eveningness Questionnaire. Bioinformatic analyses were performed to explore the target genes and biological pathways regulated by the selected miRNAs. Subjects with MetS were more often evening chronotype compared to non-MetS controls. Additionally, four miRNAs (miR-140-3p, miR-150-5p, miR-375, and miR-29 c-3p) demonstrated interaction with MetS and chronotype. Interestingly, the target genes of these four miRNAs participate in pathways related to the circadian clock. In conclusion, we identified four circulating miRNAs whose circulating levels could interact with MetS and chronotype.

The aim of this study was to compare the expression of UCP2, NLRP3, IL1B, IL18, and miR-133a-3p in subcutaneous adipose tissue (SAT) of 61 patients divided according to BMI: Group 1 (n = 8; BMI<25.0 kg/m 2 ), Group 2 (n = 24; BMI 30.0-39.9 kg/m 2 ), and Group 3 (n = 29; BMI≥40.0 kg/m 2 ). SAT biopsies were obtained from individuals who underwent bariatric surgery or elective abdominal surgery. Gene expressions were quantified using qPCR. Bioinformatics analyses were employed to investigate target genes and pathways related to miR-133a-3p. UCP2 and miR-133a-3p expressions were decreased in SAT of Groups 2 and 3 while IL18 was increased compared to Group 1. NLRP3 and IL1B expressions did not differ between groups; however, NLRP3 was positively correlated with waist circumference and excess weight. Bioinformatics analysis demonstrated that UCP2 and NLRP3 are targets of miR-133a-3p. In conclusion, UCP2 and miR-133a-3p expressions are downregulated in patients with obesity, while IL18 is upregulated. NRLP3 is correlated with waist circumference and weight excess., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by a complex interaction between environmental and genetic risk factors. BTB domain and CNC homolog 2 (BACH2) gene encodes a transcription factor that acts on the differentiation and formation of B and T lymphocytes. BACH2 is also involved in the suppression of apoptosis and inflammation in pancreatic beta-cells, indicating a role for it in the development of T1DM. Therefore, the aim of this study was to evaluate the association of the BACH2 rs11755527 single nucleotide polymorphism (SNP) with T1DM. Subjects and methods This case-control study comprised 475 patients with T1DM and 598 nondiabetic individuals. The BACH2 rs11755527 (C/G) SNP was genotyped using real-time PCR with TaqMan MGB probes. Results Genotype distributions of rs11755527 SNP were in accordance with frequencies predicted by the Hardy-Weinberg equilibrium in case and control groups and were similar between groups (P = 0.729). The minor allele frequency was 43.6% in cases and 42.5% in controls (P = 0.604). Moreover, the G allele frequency did not differ between groups when considering different inheritance models and adjusting for age, gender, body mass index, and HLA DR/DQ genotypes of high-risk for T1DM. Although, well-known high-risk T1DM HLA DR/DQ genotypes were associated with T1DM in our population [OR= 7.42 (95% CI 3.34 - 17.0)], this association was not influenced by the rs11755527 SNP. Conclusion The BACH2 rs11755527 SNP seems not to be associated with T1DM in a Brazilian population.

Uncoupling protein 2 (UCP2) decreases reactive oxygen species (ROS). ROS overproduction is a key contributor to the pathogenesis of diabetic kidney disease (DKD). Thus, UCP2 polymorphisms are candidate risk factors for DKD; however, their associations with this complication are still inconclusive. Here, we describe a case-control study and a meta-analysis conducted to investigate the association between UCP2 -866G/A and Ins/Del polymorphisms and DKD. The case-control study comprised 385 patients with type 1 diabetes mellitus (T1DM): 223 patients without DKD and 162 with DKD. UCP2 -866G/A (rs659366) and Ins/Del polymorphisms were genotyped by real-time PCR and conventional PCR, respectively. For the meta-analysis, a literature search was conducted to identify all studies that investigated associations between UCP2 polymorphisms and DKD in patients with T1DM or type 2 diabetes mellitus. Pooled odds ratios were calculated for different inheritance models. Allele and genotype frequencies of -866G/A and Ins/Del polymorphisms did not differ between T1DM case and control groups. Haplotype frequencies were also similar between groups. Four studies plus the present one were eligible for inclusion in the meta-analysis. In agreement with case-control data, the meta-analysis results showed that the -866G/A and Ins/Del polymorphisms were not associated with DKD. In conclusion, our case-control and meta-analysis studies did not indicate an association between the analyzed UCP2 polymorphisms and DKD.

Recent studies have revealed the critical role of several microRNAs (miRNAs) in energy homeostasis and metabolic processes and suggest that circulating miRNAs can be used as early predictors of weight loss in the design of precision nutrition. Thus, the aim of this study was to investigate circulating adiposity-related miRNAs as biomarkers of the response to two specific weight loss dietary treatments. The expression of 86 miRNAs was investigated in plasma of 78 subjects with obesity randomized to two different diets [moderately high-protein diet (n = 38) and low-fat diet (n = 40)] and in 25 eutrophic controls (BMI ≤ 25 kg/m 2 ). Bioinformatic analyses were performed to explore the target genes and biological pathways regulated by the dysregulated miRNAs. As results, 26 miRNAs were found differently expressed in eutrophic and volunteers with obesity. Moreover, 7 miRNAs (miR-130a-3p, miR-142-5p, miR-144-5p, miR-15a-5p, miR-22-3p, miR-221-3p and miR-29c-3p) were differentially expressed between responders and non-responders to a low-fat diet. Furthermore, after adjustment for basal glucose levels, 1-SD increase in miR-22-3p expression was associated with reduction in the risk of non-response to low-fat diet [OR = 0.181, 95% CI (0.084-0.947), P = .043]. Bioinformatic analyses evidenced that these 7 miRNAs regulate the expression of genes participating in important metabolic pathways. Conclusively, 7 circulating miRNAs related to adiposity could be used for predicting the response to a low-fat diet intervention prescribed to lose weight., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

MicroRNAs (miRNAs/miRs) are small non‑coding RNAs (ncRNAs) that regulate gene expression. Emerging knowledge has suggested that miRNAs have a role in the pathogenesis of metabolic disorders, supporting the hypothesis that miRNAs may represent potential biomarkers or targets for this set of diseases. However, the current evidence is often controversial. Therefore, the aim of the present study was to determine the associations between miRNAs‑target genes, miRNA‑long ncRNAs (lncRNAs), and miRNAs‑small molecules in human metabolic diseases, including obesity, type 2 diabetes and non‑alcoholic fatty liver disease. The metabolic disease‑related miRNAs were obtained from the Human MicroRNA Disease Database (HMDD) and miR2Disease database. A search on the databases Matrix Decomposition and Heterogeneous Graph Inference (MDHGI) and DisGeNET were also performed. miRNAs target genes were obtained from three independent sources: Microcosm, TargetScan and miRTarBase. The interactions between miRNAs‑lncRNA and miRNA‑small molecules were performed using the miRNet web tool. The network analyses were performed using Cytoscape software. As a result, a total of 20 miRNAs were revealed to be associated with metabolic disorders in the present study. Notably, 6 miRNAs (miR‑17‑5p, miR‑29c‑3p, miR‑34a‑5p, miR‑103a‑3p, miR‑107 and miR‑132‑3p) were found in the four resources (HMDD, miR2Disease, MDHGI, and DisGeNET) used for these analyses, presenting a stronger association with the diseases. Furthermore, the target genes of these miRNAs participate in several pathways previously associated with metabolic diseases. In addition, interactions between miRNA‑lncRNA and miRNA‑small molecules were also found, suggesting that some molecules can modulate gene expression via such an indirect way. Thus, the results of this data mining and integration analysis provide further information on the possible molecular basis of the metabolic disease pathogenesis as well as provide a path to search for potential biomarkers and therapeutic targets concerning metabolic diseases.

Introduction: Diabetic kidney disease (DKD) is a common microvascular complication that affects 40% of patients with diabetes mellitus (DM). Emerging evidence suggests a role for several microRNAs (miRNAs) in the development of DKD. In this context, miR-15a-5p and miR-30e-5p have been shown to regulate the expression of the uncoupling protein 2 (UCP2), a mitochondrial protein that decreases reactive oxygen species (ROS) formation by the mitochondria. Since ROS overproduction is a key contributor to the pathogenesis of DKD, dysregulation of these two miRNAs could be involved in DKD pathogenesis. Thus, the aim of this study was to compare the expressions of miR-15a-5p and miR-30e-5p in type 1 DM (T1DM) patients with DKD (cases) and without this complication (controls), and to perform bioinformatics analyses to investigate their putative targets and biological pathways under their regulation., Methods: MiR-15a-5p and miR-30e-5p expressions were analyzed in plasma and urine of 17 T1DM controls and 23 DKD cases (12 with moderate DKD and 11 with severe DKD) using qPCR. Bioinformatics analyses were performed in Cytoscape software., Results: MiR-30e-5p expression was downregulated in plasma of patients with moderate and severe DKD compared to T1DM controls. Moreover, this miRNA was also downregulated in urine of patients with severe DKD compared to the other groups. No difference was found in miR-15a-5p expression between groups. Bioinformatics analyses indicated that miR-30e-5p and miR-15a-5p regulate various genes that participate in pathways related to angiogenesis, apoptosis, cell differentiation, oxidative stress, and hypoxia., Conclusion: MiR-30e-5p seems to be downregulated in plasma and urine of patients with DKD.

Aims: The aim of this study was to investigate a miRNA expression profile in type 1 diabetes mellitus (T1DM) patients with DKD (cases) or without this complication (controls)., Methods: Expression of 48 miRNAs was screened in plasma of 58 T1DM patients (23 controls, 18 with moderate DKD, and 17 with severe DKD) using TaqMan Low Density Array cards (Thermo Fisher Scientific). Then, five of the dysregulated miRNAs were selected for validation in an independent sample of 10 T1DM controls and 19 patients with DKD (10 with moderate DKD and 9 with severe DKD), using RT-qPCR. Bioinformatic analyses were performed to explore the putative target genes and biological pathways regulated by the validated miRNAs., Results: Among the 48 miRNAs investigated in the screening analysis, 9 miRNAs were differentially expressed between DKD cases and T1DM controls. Among them, the five most dysregulated miRNAs were chosen for validation in an independent sample. In the validation sample, miR-21-3p and miR-378-3p were confirmed to be upregulated in patients with severe DKD, while miR-16-5p and miR-29a-3p were downregulated in this group compared to T1DM controls and patients with moderate DKD. MiR-503-3p expression was not validated. Bioinformatic analyses indicate that the four validated miRNAs regulate genes from PI3K/Akt, fluid shear stress and atherosclerosis, AGE-RAGE, TGF-β1, and relaxin signaling pathways., Conclusions: Our study found four miRNAs differentially expressed in patients with severe DKD, providing significant information about the biological pathways in which they are involved.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Emerging evidence has suggested a role for miRNAs in the development of diabetic kidney disease (DKD), indicating that miRNAs may represent potential biomarkers of this disease. However, results are still inconclusive. Therefore, we performed a systematic review of the literature on the subject, followed by bioinformatic analysis. PubMed and EMBASE were searched to identify all studies that compared miRNA expressions between patients with DKD and diabetic patients without this complication or healthy subjects. MiRNA expressions were analyzed in kidney biopsies, urine/urinary exosomes or total blood/plasma/serum. MiRNAs consistently dysregulated in DKD patients were submitted to bioinformatic analysis to retrieve their putative target genes and identify potentially affected pathways under their regulation. As result, twenty-seven studies were included in the systematic review. Among 151 dysregulated miRNAs reported in these studies, 6 miRNAs were consistently dysregulated in DKD patients compared to controls: miR-21-5p, miR-29a-3p, miR-126-3p, miR-192-5p, miR-214-3p, and miR-342-3p. Bioinformatic analysis indicated that these 6 miRNAs are involved in pathways related to DKD pathogenesis, such as apoptosis, fibrosis, and extracellular matrix accumulation. In conclusion, six miRNAs seem to be dysregulated in patients with different stages of DKD, constituting potential biomarkers of this disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: To investigate a miRNA expression profile in plasma of type 1 diabetes (T1DM) patients and control subjects and analyze the putative pathways involved., Methods: Expressions of 48 miRNAs were analyzed in plasma of 33 T1DM patients and 26 age-and-gender-matched controls using Stem-loop RT-PreAmp PCR and TaqMan Low Density Arrays (Thermo Fisher Scientific). Five dysregulated miRNAs were then chosen for validation in an independent sample of 27 T1DM patients and 14 controls, using RT-qPCR. Bioinformatic analyses were performed to determine in which pathways these miRNAs are involved., Results: Nine miRNAs were differentially expressed between recently-diagnosed T1DM patients (<5 years of diagnosis) and controls. No differences were observed between patients with ≥5 years of diagnosis and controls. After validation in an independent sample of T1DM patients, miR-103a-3p, miR-155-5p, miR-200a-3p, and miR-210-3p were confirmed as being upregulated in recently-diagnosed T1DM patients compared with controls or patients with ≥5 years of diagnosis. Moreover, miR-146a-5p was downregulated in recently-diagnosed T1DM patients compared with the other groups. These five miRNAs regulate several genes from innate immune system-, MAPK-, apoptosis-, insulin- and cancer-related pathways., Conclusion: Five miRNAs are dysregulated in recently-diagnosed T1DM patients and target several genes involved in pathways related to T1DM pathogenesis, thus representing potential T1DM biomarkers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The Erb-b2 receptor tyrosine kinase 3 (ERBB3) belongs to a family of epidermal growth factor receptors of protein tyrosine kinases, and regulates cell survival, differentiation and proliferation in several cell types. Previous studies have suggested that ERBB3 contributes to T1DM pathogenesis by modulating antigen presenting cell function, autoimmunity and cytokine-induced beta-cell apoptosis. Accordingly, some genome-wide association studies identified ERBB3 gene as a susceptibility locus for T1DM, with the strongest association signal being observed for the rs2292239 single nucleotide polymorphism (SNP) in intron 7 of the gene. Therefore, the aim of the present study was to replicate the association of the ERBB3 rs2292239 SNP with T1DM in a Brazilian population. We analyzed 421 T1DM patients (cases) and 510 nondiabetic subjects (controls). All subjects were self-declared as white. The ERBB3 rs2292239 (A/C) SNP was genotyped by real-time PCR using TaqMan MGB probes. Genotype (P=0.001) and allele (P=0.002) frequencies of the ERBB3 rs2292239 SNP were differently distributed between T1DM patients and nondiabetic controls. Moreover, the A allele was significantly associated with risk for T1DM when considering recessive (OR=1.58, 95% CI 1.11-2.27; P=0.015), additive (OR=1.78, 95% CI 1.21-2.62; P=0.004), and dominant (OR=1.39, 95% CI 1.07-1.81; P=0.016) models of inheritance. However, after adjustment for presence of high-risk HLA DR/DQ genotypes, the rs2292239 SNP remained independently associated with T1DM only for the additive model (OR=1.62, 95% CI 1.02-2.59; P=0.043). Our results suggest that the A/A genotype of the ERBB3 rs2292239 SNP is associated with risk for T1DM in a white Brazilian population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Growing evidence indicates that microRNAs (miRNAs) have a key role in processes involved in type 1 diabetes mellitus (T1DM) pathogenesis, including immune system functions and beta-cell metabolism and death. Although dysregulated miRNA profiles have been identified in T1DM patients, results are inconclusive; with only few miRNAs being consistently dysregulated among studies. Thus, we performed a systematic review of the literature on the subject, followed by bioinformatic analysis, to point out which miRNAs are dysregulated in T1DM-related tissues and in which pathways they act. PubMed and EMBASE were searched to identify all studies that compared miRNA expressions between T1DM patients and non-diabetic controls. Search was completed in August, 2017. Those miRNAs consistently dysregulated in T1DM-related tissues were submitted to bioinformatic analysis, using six databases of miRNA-target gene interactions to retrieve their putative targets and identify potentially affected pathways under their regulation. Thirty-three studies were included in the systematic review: 19 of them reported miRNA expressions in human samples, 13 in murine models and one in both human and murine samples. Among 278 dysregulated miRNAs reported in these studies, 25.9% were reported in at least 2 studies; however, only 48 of them were analyzed in tissues directly related to T1DM pathogenesis (serum/plasma, pancreas and peripheral blood mononuclear cells (PBMCs)). Regarding circulating miRNAs, 11 were consistently dysregulated in T1DM patients compared to controls: miR-21-5p, miR-24-3p, miR-100-5p, miR-146a-5p, miR-148a-3p, miR-150-5p, miR-181a-5p, miR-210-5p, miR-342-3p, miR-375 and miR-1275. The bioinformatic analysis retrieved a total of 5867 validated and 2979 predicted miRNA-target interactions for human miRNAs. In functional enrichment analysis of miRNA target genes, 77 KEGG terms were enriched for more than one miRNA. These miRNAs are involved in pathways related to immune system function, cell survival, cell proliferation and insulin biosynthesis and secretion. In conclusion, eleven circulating miRNAs seem to be dysregulated in T1DM patients in different studies, being potential circulating biomarkers of this disease., (© 2017 The authors.)

Aims: The transcription factor Gli-similar 3 (GLIS3) plays a key role in the development and maintenance of pancreatic beta cells as well as in the regulation of Insulin gene expression in adults. Accordingly, genome-wide association studies identified GLIS3 as a susceptibility locus for type 1 diabetes mellitus (T1DM) and glucose metabolism traits. Therefore, the aim of this study was to replicate the association of the rs10758593 and rs7020673 single nucleotide polymorphisms (SNPs) in the GLIS3 gene with T1DM in a Brazilian population., Methods: Frequencies of the rs7020673 (G/C) and rs10758593 (A/G) SNPs were analyzed in 503 T1DM patients (cases) and in 442 non-diabetic subjects (controls). Haplotypes constructed from the combination of these SNPs were inferred using a Bayesian statistical method., Results: Genotype and allele frequencies of rs7020673 and rs10758593 SNPs did not differ significantly between case and control groups. However, the frequency of ≥3 minor alleles of the analyzed SNPs in haplotypes was higher in T1DM patients compared to non-diabetic subjects (6.2 vs. 1.6%; P = 0.001). The presence of ≥3 minor alleles remained independently associated with risk of T1DM after adjustment for T1DM high-risk HLA DR/DQ haplotypes, age and ethnicity (OR = 3.684 95% CI 1.220-11.124). Moreover, levels of glycated hemoglobin seem to be higher in T1DM patients with rs10758593 A/A genotype than patients carrying the G allele of this SNP (P = 0.038), although this association was not kept after Bonferroni correction., Conclusions: Our results indicate that individually the rs7020673 and rs10758593 SNPs are not significantly associated with T1DM but seem to interact in the predisposition for this disease.

Aims: Type 1 diabetes mellitus (T1DM) is characterized by severe autoimmune destruction of pancreatic beta-cells. The triggering of autoimmunity against beta-cells is probably caused by a combination of environmental and genetic risk factors. Even though much is known about the genetic of T1DM, more information is needed to completely unravel this tangled disease. MicroRNAs (miRNAs) are a class of small noncoding RNAs molecules that negatively regulate gene expression by inducing target mRNA cleavage or by inhibiting protein translation. Abnormal miRNA expressions have been described in autoimmune diseases and T1DM. Polymorphisms in genes codifying miRNAs may alter the expression of the corresponding miRNA and, thus, confer susceptibility for a given disease. Therefore, the aim of this study was to investigate whether polymorphisms in genes encoding miR-155, miR-146a, and miR-375 are associated with T1DM., Methods: Frequencies of the miRNA-146a rs2910164, miRNA-155 rs767649 and miRNA-375 rs6715345 polymorphisms were analyzed in 490 T1DM patients and in 469 nondiabetic subjects., Results: The miR-146a rs2910164 and miR-155 rs767649 polymorphisms were associated with protection for T1DM, and the strongest association was observed for the dominant model [odds ratio (OR) = 0.557 95% CI 0.355-0.874 and OR = 0.508, 95% CI 0.265-0.973, respectively, after adjustment for age, ethnicity, and risk HLA loci]. However, miR-375 rs6715345 frequencies did not differ between cases and controls., Conclusion: MiR-146a rs2910164 and miR-155 rs767649 polymorphisms were associated with protection for T1DM.

Background: Altered serum nitric oxide (NO) levels in patients with diabetes mellitus (DM) have been reported by different studies; however, results are still controversial. Until this date, no meta-analysis evaluated the association of NO levels with DM. Thus, this paper describes a meta-analysis conducted to evaluate if there is a relationship between NO levels and type 1 DM (T1DM) or type 2 DM (T2DM)., Methods: A literature search was done to identify all studies that investigated NO levels between T1DM or T2DM patients (cases) and non-diabetic subjects (controls). Measurement of nitrate and nitrite (NOx - the stable NO products) were used to estimate NO concentrations because they closely reflect NO bioavailability. Weighted mean differences (WMD) of NOx levels between case and control samples were calculated for T1DM and T2DM groups., Results: Thirty studies were eligible for inclusion in the meta-analysis (8 in T1DM samples and 22 in T2DM samples). NOx levels were increased in European T1DM patients compared with controls [random effect model (REM) WMD = 8.55, 95% CI 2.88 - 14.21]. No other ethnicity was evaluated in T1DM studies. NOx levels were also increased in both European (REM WMD = 18.76, 95% CI 1.67 - 35.85) and Asian (REM WMD = 18.41, 95% CI 8.01 - 28.81) T2DM patients, but not in Latin American patients compared with controls., Conclusions: This meta-analysis detected a significant increase in NOx levels in European T1DM patients as well as European and Asian T2DM patients. Further studies in other ethnicities are necessary to confirm these data., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pattern classification of ingestive behavior in grazing animals has extreme importance in studies related to animal nutrition, growth and health. In this paper, a system to classify chewing patterns of ruminants in in vivo experiments is developed. The proposal is based on data collected by optical fiber Bragg grating sensors (FBG) that are processed by machine learning techniques. The FBG sensors measure the biomechanical strain during jaw movements, and a decision tree is responsible for the classification of the associated chewing pattern. In this study, patterns associated with food intake of dietary supplement, hay and ryegrass were considered. Additionally, two other important events for ingestive behavior were monitored: rumination and idleness. Experimental results show that the proposed approach for pattern classification is capable of differentiating the five patterns involved in the chewing process with an overall accuracy of 94%.

Introduction: Irisin has recently been described as a novel myokine, which reduces visceral obesity and improves glucose metabolism in mice. Thus, polymorphisms in the gene encoding irisin, fibronectin type III domain containing 5 (FNDC5), may be associated with type 2 diabetes mellitus (T2DM) and related disorders. However, to date, no study has investigated the association between FNDC5 polymorphisms and susceptibility to T2DM., Objective: To investigate the association of FNDC5 rs3480 (A/G) and rs1746661 (G/T) polymorphisms, alone or in combination, with T2DM and its clinical features., Methods: We analyzed 1006 T2DM patients and 434 nondiabetic subjects. Polymorphisms were genotyped by real-time PCR using TaqMan MGB probes. Haplotypes constructed from the combination of rs1746661 and rs3480 polymorphisms were inferred using the Phase 2.1 program., Results: Genotype, allele and haplotype frequencies of rs1746661 and rs3480 polymorphisms did not differ significantly between nondiabetic subjects and T2DM patients. Women with T2DM carrying the G allele of rs3480 showed increased HbA1c levels compared with A/A carriers, adjusted for age. The T allele of rs1746661 was associated with increased systolic blood pressure, total cholesterol and LDL-cholesterol and decreased HDL-cholesterol in women with T2DM, adjusted for covariates. Moreover, prevalence of hypercholesterolemia was higher in women carrying the T allele of rs1746661 than in G/G carriers (72.4% vs. 58.7%, OR=2.010, 95% CI=1.210-3.390), but it was not significantly different in men., Conclusions: These results indicate that, although not associated with T2DM, the G allele of rs3480 appears to be associated with increased HbA1c, while the T allele of rs1746661 appears to be associated with higher systolic blood pressure and dyslipidemia in women with T2DM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with "brittle T1DM", who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre - Rio Grande do Sul, Brazil.

The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I² < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27-2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations.

Type 1 diabetes mellitus (T1DM) is a chronic, progressive autoimmune disease characterized by metabolic decompensation often leading to dehydration and ketoacidosis. Viral agents seem to play an important role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, the enterovirus family has been consistently associated with the onset of T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The Toll-like receptor 3 (TLR3) gene codes for an endoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, plays an important role in the innate immune response triggered by viral infection. Binding of dsRNA to the TLR3 triggers the release of proinflammatory cytokines, such as interferons, which exhibit potent antiviral action; thus, protecting uninfected cells and inducing apoptosis of infected ones. Therefore, the TLR3 gene is a good candidate for the development of T1DM. Within this context, the objective of the present review was to address the role of the TLR3 gene in the development of T1DM.

Objective: The aim of this study was to investigate the association between the rs7903146 (C/T) polymorphism in the TCF7L2 gene and type 2 diabetes mellitus, in a Southern-Brazilian population., Materials and Methods: The TCF7L2 rs7903146 polymorphism was genotyped in 953 type 2 diabetic patients and 535 non-diabetic subjects. All subjects were white. The polymorphism was genotyped by Real-Time PCR using TaqMan MGB probes (Life Technologies). Odds ratios (OR) and 95% confidence intervals (CI) were calculated for additive, recessive and dominant inheritance models., Results: Genotype and allele frequencies of the rs7903146 polymorphism differed significantly between type 2 diabetic patients and non-diabetic subjects (P = 0.001 and P = 0.0001, respectively). The frequency of the minor allele was 38% in type 2 diabetes group and 31% in non-diabetic subjects, and this allele was significantly associated with type 2 diabetes risk (OR = 1.42, 95% CI 1.15 - 1.76 for the dominant model of inheritance). Moreover, the T/T genotype was associated with a higher risk for type 2 diabetes (OR = 1.83, 95% CI 1.3-2.5) than the presence of only one copy of the T allele (OR = 1.31, 95% CI 1.1-1.6). Both results were adjusted for age and gender., Conclusions: Our results confirm the association between the TCF7L2 rs7903146 polymorphism and increase risk for type 2 diabetes in Southern-Brazil.

This paper describes a case-control study and a meta-analysis performed to evaluate if the following polymorphisms are associated with presence of obesity: -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3). The case-control study enrolled 282 obese and 483 non-obese patients with type 2 diabetes. A literature search was made to identify all studies that evaluated associations between UCP1-3 polymorphisms and obesity. In the case-control study the distributions of the UCP variants did not differ between obese and non-obese groups (P > 0.05). Forty-seven studies were eligible for the meta-analysis and the results showed that the UCP2 -866G/A and UCP3 -55C/T polymorphisms were associated with protection to obesity in Europeans (OR = 0.89, 95% CI 0.82-0.97 and OR = 0.88, 95% CI 0.80-0.97, respectively). The UCP2 Ala55 val polymorphism was associated with obesity in Asians (OR = 1.61, 95% CI 1.13-2.30). The UCP2 Ins/Del polymorphism was associated with obesity mainly in Europeans (OR = 1.19, 95% CI 1.00-1.42). There was no significant association of the UCP1 -3826A/G polymorphism with obesity. In our case-control study we were not able to demonstrate any association between UCP polymorphisms and obesity in T2DM patients; however, in the meta-analysis we detected a significant association of UCP2 -866G/A, Ins/Del, Ala55Val and UCP3 -55C/T polymorphisms with obesity.

Background: The relationship between uncoupling protein (UCP) 1-3 polymorphisms and susceptibility to obesity has been investigated in several genetic studies. However, the impact of these polymorphisms on obesity is still under debate, with contradictory results being reported. Until this date, no meta-analysis evaluated the association of UCP polymorphisms with body mass index (BMI) variability. Thus, this paper describe a meta-analysis conducted to evaluate if the -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3) polymorphisms are associated with BMI changes., Methods: A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and BMI. Weighted mean differences (WMD) were calculated for different inheritance models., Results: Fifty-six studies were eligible for inclusion in the meta-analysis. Meta-analysis results showed that UCP2 55Val/Val genotype was associated with increased BMI in Europeans [Random Effect Model (REM) WMD 0.81, 95% CI 0.20, 1.41]. Moreover, the UCP2 Ins allele and UCP3-55T/T genotype were associated with increased BMI in Asians [REM WMD 0.46, 95% CI 0.09, 0.83 and Fixed Effect Model (FEM) WMD 1.63, 95% CI 0.25, 3.01]. However, a decreased BMI mean was observed for the UCP2-866 A allele in Europeans under a dominant model of inheritance (REM WMD -0.18, 95% CI -0.35, -0.01). There was no significant association of the UCP1-3826A/G polymorphism with BMI mean differences., Conclusions: The meta-analysis detected a significant association between the UCP2-866G/A, Ins/Del, Ala55Val and UCP3-55C/T polymorphisms and BMI mean differences.

Introduction: Viral pathogens seem to play a role in triggering the autoimmune destruction that leads to the development of type 1 diabetes mellitus (T1DM). Toll-like receptor 3 (TLR3) has been shown to recognize double-stranded RNA, a molecular signature of most viruses. It is expressed at high levels in pancreatic β-cells and immune cells, suggesting a role for it in the pathogenesis of T1DM. Therefore, the aim of this study was to investigate whether TLR3 polymorphisms are associated with T1DM., Methods: Frequencies of the TLR3 rs11721827, rs13126816, rs5743313, rs7668666, and rs3775291 polymorphisms were analyzed in 449 T1DM patients and in 507 nondiabetic subjects. Haplotypes constructed from the combination of these polymorphisms were inferred using a Bayesian statistical method., Results: The rs3775291 and rs13126816 polymorphisms were associated with T1DM, and the strongest association was observed for the additive model (odds ratio (OR)=2.3, 95% CI 1.3-4.2 and OR=2.1, 95% CI 1.3-3.1 respectively). In the same way, the frequency of T1DM was higher as more risk alleles of the five polymorphisms were present (P-trend=0.001). Moreover, in T1DM patients, the minor alleles of the rs5743313 and rs117221827 polymorphisms were associated with an early age at diagnosis and worse glycemic control., Conclusion: The TLR3 rs3775291 and rs13126816 polymorphisms are associated with risk for T1DM, while the rs5743313 and rs11721827 polymorphisms are associated with age at T1DM diagnosis and poor glycemic control. The number of risk alleles of the five TLR3 polymorphisms in the haplotypes seems to influence the risk for T1DM, suggesting that these polymorphisms might interact in the susceptibility for the disease.

It is well established that genetic factors play an important role in the development of both type 2 diabetes mellitus (DM2) and obesity, and that genetically susceptible subjects can develop these metabolic diseases after being exposed to environmental risk factors. Therefore, great efforts have been made to identify genes associated with DM2 and/or obesity. Uncoupling protein 1 (UCP1) is mainly expressed in brown adipose tissue, and acts in thermogenesis, regulation of energy expenditure, and protection against oxidative stress. All these mechanisms are associated with the pathogenesis of DM2 and obesity. Hence, UCP1 is a candidate gene for the development of these disorders. Indeed, several studies have reported that polymorphisms -3826A/G, -1766A/G and -112A/C in the promoter region, Ala64Thr in exon 2 and Met299Leu in exon 5 of UCP1 gene are possibly associated with obesity and/or DM2. However, results are still controversial in different populations. Thus, the aim of this study was to review the role of UCP1 in the development of these metabolic diseases.

Uncoupling protein 2 (UCP2) is a mitochondrial transporter present in the inner membrane of mitochondria, and it uncouples substrate oxidation from ATP synthesis, thereby dissipating the membrane potential energy and consequently decreasing ATP production by mitochondrial respiratory chain. As a consequence of the uncoupling, UCP2 decreases the reactive oxygen species (ROS) formation by mitochondria. ROS overproduction is related to diabetic retinopathy (DR), a chronic complication of diabetes mellitus (DM). Recently, our group reported that the -866A/55Val/Ins haplotype (-866G/A, Ala55Val and Ins/Del polymorphisms) of the UCP2 gene was associated with increased risk for DR in patients with DM. The purpose of this study was to analyze the effect of this haplotype on UCP2 gene expression in human retina. In addition, MnSOD2 gene expression was also investigated according to different UCP2 haplotypes. This cross-sectional study included 188 cadaveric cornea donors. In a subset of 91 retinal samples differentiated according to the presence of the mutated UCP2 haplotype and risk alleles of the -866G/A and Ins/Del polymorphisms, UCP2 and MnSOD2 gene expressions were measured by semi-quantitative RT-qPCR. Mutated UCP2 haplotype carriers (homozygous + heterozygous) had a lower UCP2 gene expression than reference haplotype carriers (8.4 ± 7.6 vs. 18.8 ± 23.7 arbitrary units; P = 0.046). Accordingly, UCP2 gene expression was decreased in -866A carriers when compared with G/G carriers (P = 0.010). UCP2 gene expression did not differ between Ins allele carriers and Del/Del carriers (P = 0.556). Interestingly, subjects carrying the heterozygous UCP2 haplotype showed increased MnSOD2 gene expression (P = 0.025). This is the first report suggesting that the presence of the -866A/55Val/Ins haplotype is associated with decreased UCP2 gene expression in human retina. Possibly, MnSOD2 expression might influence the UCP2 effect in the protection against oxidative stress., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

It is well established that genetic factors play an important role in the development of type 2 diabetes mellitus (DM2) and its chronic complications, and that genetically susceptible subjects can develop the disease after being exposed to environmental risk factors. Therefore, great efforts have been made to identify genes associated with DM2. Uncoupling protein 2 (UCP2) is expressed in several tissues, and acts in the protection against oxidative stress; in the negative regulation of insulin secretion by beta cells, and in fatty acid metabolism. All these mechanisms are associated with DM2 pathogenesis and its chronic complications. Therefore, UCP2 is a candidate gene for the development of these disorders. Indeed, several studies have reported that three common polymorphisms in UCP2 gene are possibly associated with DM2 and/or obesity. Only a few studies investigated these polymorphisms in relation to chronic complications of diabetes, with inconclusive results.