Introduction: The liver plays a critical role in glucose and lipid homeostasis. Insulin resistance (IR) has been increasingly recognized as a primary etiological factor in metabolic disorders. Hepatic insulin resistance (HIR) is a specific manifestation of IR characterized by the liver's reduced responsiveness to insulin despite elevated circulating insulin levels. Objective: This review aims to elucidate the role of HIR in the pathogenesis of metabolic disorders, focusing on its relationship with metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM). Methods: A comprehensive literature search was conducted to explore the underlying mechanisms of HIR, its clinical implications, and its association with MAFLD and T2DM. Results: HIR is characterized by impaired insulin-mediated glucose uptake and increased hepatic glucose output. This metabolic dysfunction contributes to the development of hepatic steatosis, dyslipidemia, and insulin resistance in peripheral tissues. The interplay between HIR and lipogenesis is important in the progression of MAFLD and its association with T2DM, and could be described as a hepatic equivalent of T2DM. Conclusion: The understanding of a T2DM-like condition in the liver is decisive for developing more targeted and effective treatments.

Introdução: O fígado desempenha um papel crítico na homeostase da glicose e lipídios. A resistência à insulina (RI) tem sido cada vez mais reconhecida como um fator etiológico primário em distúrbios metabólicos. A resistência à insulina hepática (RIH) é uma manifestação específica da RI caracterizada pela redução da resposta hepática à insulina, apesar dos níveis elevados de insulina circulante. Objetivo: Este manuscrito visa avaliar o papel da RIH na patogênese dos distúrbios metabólicos, com foco em sua relação com a doença hepática gordurosa associada à disfunção metabólica (DHGDM) e o diabetes mellitus tipo 2 (DMT2). Métodos: Foi realizada uma busca abrangente na literatura para explorar os mecanismos subjacentes da RIH, suas implicações clínicas e sua associação com a DHGDM e o DMT2. Resultados: A RIH é caracterizada pela redução da captação de glicose mediada pela insulina e pelo aumento da produção hepática de glicose. Essa disfunção metabólica contribui para o desenvolvimento de esteatose hepática, dislipidemia e RI em tecidos periféricos. A interação entre RIH e lipogênese é importante na progressão da DHGDM e sua associação com o DMT2, podendo ser descrita como um equivalente hepático do DMT2. Conclusão: A compreensão de uma condição semelhante ao DMT2 no fígado é decisiva para o desenvolvimento de tratamentos mais direcionados e eficazes.

RESUMO. A incapacidade das células de reagir à insulina, ocasionando intolerância à glicose e hiperglicemia, é chamada de resistência à insulina. Essa condição clínica, que tem sido bem pesquisada em órgãos como tecido adiposo, músculo e fígado, tem sido associada às doenças neurodegenerativas como a doença de Alzheimer (DA) quando ocorre no cérebro. Objetivo: O objetivo dos autores foi reunir os dados da literatura atual sobre a resistência insulínica cerebral (RIC) e sua provável repercussão em doenças neurodegenerativas, mais especificamente na DA, por meio de uma revisão sistemática da literatura. Métodos: Foi realizada uma pesquisa abrangente em vários bancos de dados médicos, incluindo o Cochrane Central Register of Controlled Trials, EMBASE, Medical Literature Analysis and Retrieval System Online (Medline) e PubMed, empregando os descritores: “resistência à insulina”, “resistência insulínica cerebral”, “doença de Alzheimer”, “neurodegeneração” e “cognição”. Os autores concentraram sua busca em estudos no idioma inglês publicados entre 2000 e 2023 que investigaram a influência da RIC em distúrbios neurodegenerativos ou ofereceram insights sobre os mecanismos subjacentes da RIC. Dezessete estudos que atenderam aos critérios de inclusão foram selecionados. Resultados: Os resultados demonstram que a RIC é um fenômeno observado em uma variedade de doenças neurodegenerativas, incluindo a DA. Estudos sugerem que a utilização e captação prejudicadas de glicose, a produção reduzida de trifosfato de adenosina (ATP) e as alterações na plasticidade sinápticas causadas pela RIC estão ligadas a problemas cognitivos. No entanto, foram observados resultados conflitantes com relação à associação entre DA e RIC, com alguns estudos sugerindo nenhuma associação. Conclusão: Com base nos estudos avaliados, pode-se concluir que a associação entre DA e RIC ainda é inconclusiva, e pesquisas adicionais são necessárias para elucidar essa relação. RESUMO insulina hiperglicemia clínica adiposo fígado (DA cérebro Objetivo (RIC Métodos médicos Trials EMBASE Medline (Medline PubMed descritores , insulina” cerebral, cerebral” Alzheimer, Alzheimer” neurodegeneração “neurodegeneração cognição. cognição . “cognição” 200 202 selecionados Resultados ATP (ATP cognitivos entanto Conclusão avaliados podese pode se inconclusiva “cognição 20 2

ABSTRACT. The disability of cells to react to insulin, causing glucose intolerance and hyperglycemia, is referred to as insulin resistance. This clinical condition, which has been well-researched in organs such as adipose tissue, muscle, and liver, has been linked to neurodegenerative diseases like Alzheimer’s disease (AD) when it occurs in the brain. Objective: The authors aimed to gather data from the current literature on brain insulin resistance (BIR) and its likely repercussions on neurodegenerative disorders, more specifically AD, through a systematic review. Methods: A comprehensive search was conducted in multiple medical databases, including the Cochrane Central Register of Controlled Trials, EMBASE, Medical Literature Analysis and Retrieval System Online (Medline), and PubMed®, employing the descriptors: “insulin resistance”, “brain insulin resistance”, “Alzheimer’s disease”, “neurodegeneration”, and “cognition”. The authors focused their search on English-language studies published between 2000 and 2023 that investigated the influence of BIR on neurodegenerative disorders or offered insights into BIR’s underlying mechanisms. Seventeen studies that met the inclusion criteria were selected. Results: The results indicate that BIR is a phenomenon observed in a variety of neurodegenerative disorders, including AD. Studies suggest that impaired glucose utilization and uptake, reduced adenosine triphosphate (ATP) production, and synaptic plasticity changes caused by BIR are linked to cognitive problems. However, conflicting results were observed regarding the association between AD and BIR, with some studies suggesting no association. Conclusion: Based on the evaluated studies, it can be concluded that the association between AD and BIR remains inconclusive, and additional research is needed to elucidate this relationship. ABSTRACT hyperglycemia condition wellresearched well researched tissue muscle liver Alzheimers Alzheimer s (AD Objective (BIR review Methods databases Trials EMBASE Medline, Medline , (Medline) PubMed PubMed® descriptors resistance, resistance” disease, disease” neurodegeneration, neurodegeneration “neurodegeneration” cognition. cognition . “cognition” Englishlanguage English language 200 202 BIRs mechanisms selected Results uptake ATP (ATP production problems However Conclusion inconclusive relationship (Medline “neurodegeneration “cognition 20 2

ABSTRACT Objective To analyze in silico the evidence of molecular mimicry between human beta-cell autoantigens and cow’s milk proteins as a potential type 1 diabetes mellitus (T1DM) trigger. Materials and methods The in silico analysis was performed using bioinformatics tools to compare the amino acid sequences of cow’s milk proteins (bovine serum albumin [BSA] and beta-lactoglobulin [BLG]) and human beta-cell autoantigens (glutamic acid decarboxylase-65 [GAD-65], insulin, and zinc transporter 8 [ZnT8]). The structural and functional characteristics of the proteins were analyzed to identify potential molecular mimicry mechanisms. Results The results of the in silico analysis showed significant sequence similarity between BSA/BLG and GAD-65/human insulin/ZnT8, ranging from 19.64% to 27.27%. The cow’s milk proteins evaluated shared structural features with the beta-cell antigens selected for comparison, indicating a potential for molecular mimicry between these proteins. Conclusion The findings of this study provide further evidence for a potential role of cow’s milk proteins in triggering T1DM. The in silico analysis suggests that molecular mimicry mechanisms between cow’s milk proteins and human beta-cell antigens may contribute to the autoimmune response leading to T1DM. betacell beta cell cows cow s T1DM TDM T DM (T1DM trigger bovine BSA [BSA betalactoglobulin lactoglobulin BLG [BLG] glutamic decarboxylase65 decarboxylase 65 decarboxylase-6 GAD65, GAD65 GAD , [GAD-65] insulin ZnT8. ZnT8 ZnT . [ZnT8]) BSABLG GAD65/human GAD65human GADhuman 65/human insulinZnT8 insulinZnT insulin/ZnT8 1964 19 64 19.64 2727 27 27.27% comparison [BLG decarboxylase6 6 decarboxylase- GAD6 [GAD-65 [ZnT8] 65human insulin/ZnT 196 19.6 272 2 27.27 [GAD-6 [ZnT8 19. 27.2 [GAD- [ZnT 27. [GAD

RESUMO Contexto: Os ácidos biliares (ABs) são moléculas esteróides sintetizadas exclusivamente no fígado, sendo produtos finais do catabolismo do colesterol. Os ABs são conhecidos por estarem envolvidos em várias alterações metabólicas, incluindo a síndrome metabólica e o diabetes mellitus tipo 2 (DM2). A DM2 é uma doença crônica degenerativa caracterizada pela resistência insulínica, deficiência de insulina devido à produção insuficiente de células ß pancreáticas e hiperglicemia levando a múltiplas complicações. Objetivo: O objetivo deste estudo é investigar o papel dos ABs na fisiopatologia da DM2, destacando as possibilidades no desenvolvimento de procedimentos terapêuticos visando os ABs como uma via opcional no tratamento da DM2. Métodos: A pesquisa foi realizada por meio de revisão narrativa e publicações sobre a relação entre ABs e DM2. As bases de dados usadas para a pesquisa incluem PubMed, Scopus e Web of Science. As palavras-chave usadas para a pesquisa incluíram: ácidos biliares, diabetes mellitus tipo 2, síndrome metabólica e distúrbios metabólicos. Resultados: Os estudos relataram o envolvimento dos ABs na fisiopatologia da DM2. Os ABs atuam como ligantes para o receptor nuclear farnesoide X, regulando o metabolismo da glicose, metabolismo lipídico e produção de energia celular. Além disso, os ABs regulam a produção, eliminação e mobilização de ABs através do receptor farnesoide X. Os ABs também atuam como uma via de sinalização através do receptor acoplado à proteína G Takeda 5, contribuindo ainda mais para a regulação metabólica. Esses achados sugerem que o ABs pode oferecer uma nova abordagem terapêutica no tratamento da DM2. Conclusão: Este estudo destaca o papel importante do ABs na DM2, especificamente por meio de suas interações com vias metabólicas-chave. O redirecionamento ao ABs pode representar uma abordagem inovadora e eficaz para o tratamento da DM2. Contexto (ABs fígado colesterol metabólicas DM . (DM2) insulínica complicações Objetivo Métodos PubMed Science palavraschave palavras chave incluíram metabólicos Resultados X glicose celular disso 5 Conclusão metabólicaschave. metabólicaschave chave. metabólicas-chave (DM2 (DM

ABSTRACT Background: Bile acids (BAs) are steroid molecules synthesized exclusively in the liver, being end products of cholesterol catabolism. BAs are known to be involved in several metabolic alterations, including metabolic syndrome and type 2 diabetes mellitus (DM2). DM2 is a chronic degenerative disease characterized by insulin resistance, insulin deficiency due to insufficient production of pancreatic ß-cells, and elevated serum glucose levels leading to multiple complications. Objective: The objective of this study is to investigate the role of BAs in the pathophysiology of DM2, highlighting the possibilities in the development of therapeutic procedures targeting BAs as an optional pathway in the treatment of DM2. Methods: The research was carried out through narrative review and publications on the relationship between BAs and DM2. The databases used for the search include PubMed, Scopus, and Web of Science. The keywords used for the search include bile acids, type 2 diabetes mellitus, metabolic syndrome, and metabolic disorders. Results: The studies have reported the involvement of BAs in the pathophysiology of DM2. BAs act as a ligand for the nuclear farnesoid X receptor, regulating glucose metabolism, lipid metabolism, and cellular energy production. Additionally, BAs modulate the production, elimination, and mobilization of BAs through the farnesoid X receptor. BAs also act as a signaling pathway through Takeda G protein-coupled receptor 5, further contributing to metabolic regulation. These findings suggest that targeting BAs may offer a novel therapeutic approach in the treatment of DM2. Conclusion: This study highlights the important role of BAs in DM2, specifically through their interactions with key metabolic pathways. Targeting BAs may represent an innovative and effective approach to the treatment of DM2. Background (BAs liver catabolism alterations DM . (DM2) resistance ßcells, ßcells ß cells, cells ß-cells complications Objective Methods PubMed Scopus Science disorders Results metabolism Additionally elimination proteincoupled protein coupled 5 regulation Conclusion pathways (DM2 (DM

RESUMO Contexto: A doença pancreática gordurosa não alcoólica (DPGNA) é um aumento de gordura pancreática, e tem uma importante associação com a resistência à insulina (RI) e com diabetes mellitus tipo 2. Pesquisas confirmaram que o índice triglicérides/glicemia (TyG) determina a RI tanto quanto a avaliação da clamp hiperinsulinêmico-euglicêmico como o teste do modelo de homeostasia da RI (HOMA-IR). Objetivo: Avaliar a associação entre o grau de DPGNA e o índice TyG. Métodos: Em 72 pacientes submetidos a ultrassonografia do abdome com diagnóstico de DPGNA, foram avaliados os níveis de insulina, glicose e triglicérides. Os índices HOMA-IR e TyG foram usados como referência para RI. Os graus de DGPNA e o índice TyG foram apresentados através da curva ROC com o objetivo de avaliar a associação entre diferentes graus de DPGNA, e a correlação do DGPNA com o HOMA-IR também foi avaliada. Resultados: Houve uma correlação estatisticamente significativa entre o grau de DPGNA e o índice TyG. A curva AUROC para o índice TyG para prever o grau do NADPD foi 0,855 (0,840-0,865). As probabilidades ajustadas de intensidade do grau de NAFPD foram mais fortemente associadas aos valores de TyG quando comparadas com o HOMA-IR. Conclusão: Neste estudo, o índice TyG correlacionou-se positivamente com o grau de DPGNA, tendo um desempenho melhor que o índice HOMA-IR. Contexto (DPGNA (RI 2 triglicéridesglicemia triglicérides glicemia (TyG hiperinsulinêmicoeuglicêmico hiperinsulinêmico euglicêmico HOMAIR. HOMAIR HOMA IR . (HOMA-IR) Objetivo Métodos 7 avaliada Resultados 0855 0 855 0,85 0,8400,865. 08400865 0,840 0,865 840 865 (0,840-0,865) IR. Conclusão estudo correlacionouse correlacionou se (HOMA-IR 085 85 0,8 8400 0,8400,865 0840086 0840 0,84 0865 0,86 84 86 (0,840-0,865 08 8 0, 0,8400,86 084008 084 086 (0,840-0,86 0,8400,8 08400 (0,840-0,8 0,8400, (0,840-0, 0,8400 (0,840-0 (0,840- (0,840 (0,84 (0,8 (0, (0 (

ABSTRACT Background: Nonalcoholic fatty pancreatic disease (NAFPD) is an increase of fat in the pancreas, and has an important association with insulin resistance (IR) and type 2 diabetes mellitus. Research has confirmed that the triglyceridemia/glycemia (TyG) index determines IR as much as does the hyperinsulinemic-euglycemic clamp assessment as the homeostasis model testing of IR (HOMA-IR). Objective: To evaluate the association between degree of NAFPD and TyG index. Methods: In 72 patients undergoing ultrasound of abdomen with a diagnosis of NAFPD, insulin, glucose, and triglycerides levels were evaluated. The HOMA-IR and TyG indexes were used as a reference for IR. The degrees of NAFPD and the TyG index were presented through the receiver operating characteristics (ROC) curves in order to evaluate the association between different degrees of NAFPD, and the correlation of NAFPD with HOMA-IR was also evaluated. Results: There was a statistically significant correlation between the degree of NAFPD and the TyG index. The AUROC curve for the TyG index for predicting the degree of NADPD was 0.855 (0.840-0.865). The intensity-adjusted probabilities of the degree of NAFPD were more strongly associated with TyG values when compared with HOMA-IR. Conclusion: In this study the TyG index correlated positively with the degree of NAFPD, performing better than HOMA-IR. Background (NAFPD pancreas (IR mellitus triglyceridemiaglycemia triglyceridemia glycemia (TyG hyperinsulinemiceuglycemic hyperinsulinemic euglycemic HOMAIR. HOMAIR HOMA . (HOMA-IR) Objective Methods 7 glucose evaluated ROC (ROC Results 0855 0 855 0.85 0.8400.865. 08400865 0.840 0.865 840 865 (0.840-0.865) intensityadjusted intensity adjusted Conclusion (HOMA-IR 085 85 0.8 8400 0.8400.865 0840086 0840 0.84 0865 0.86 84 86 (0.840-0.865 08 8 0. 0.8400.86 084008 084 086 (0.840-0.86 0.8400.8 08400 (0.840-0.8 0.8400. (0.840-0. 0.8400 (0.840-0 (0.840- (0.840 (0.84 (0.8 (0. (0 (

Bile acids (BAs) are steroid molecules that have a hydrophilic and a hydrophobic end, and are synthesized exclusively in the liver, being end product of cholesterol catabolism. Type 2 diabetes mellitus (DM2) is a chronic degenerative disease, with a pathophysiology characterized by insulin resistance (IR), insulin deficiency due to insufficient production of pancreatic ß-cells, and elevated serum glucose levels leading to multiple complications. BAs are related to several metabolic alterations, including metabolic syndrome and DM2. It is currently known that BAs act as a ligand for the nuclear farnesoid X receptor, a receptor with an important role in glucose metabolism, lipids and cellular energy production, as well as in the regulation of production, elimination and mobilization of BAs. BAs have also been reported to act as a signaling pathway through of Takeda G protein-coupled receptor 5. In this manuscript, we describe the interface between BAs and metabolic disorders, in particular DM2, including discussing possibilities in the development of therapeutic procedures targeting BAs as an optional pathway in the treatment of DM2.

ABSTRACT Objective: To define the mathematical relationship between fructosamine levels and average glucose values. Subjects and methods: The study comprised laboratory data of 1,227 patients with type 1 or 2 diabetes mellitus. Fructosamine levels measured at the end of a 3-week period were compared against the average blood glucose levels of the previous 3 weeks. Average glucose levels were determined by the weighted average of the daily fasting capillary glucose results performed during the study period, and the plasma glucose measured in the same sample collected for fructosamine measurement. Results: In total, 9,450 glucose measurements were performed. Linear regression analysis between fructosamine levels and average glucose levels showed that for each 1.0 µmol/L increase in fructosamine level there was a 0.5 mg/dL increase in average glucose level, as estimated by the equation Mean glucose level = (0.5157 x Fructosamine) – 20. The coefficient of determination (r2 = 0.353492, p < 0.006881) allowed the calculation of the estimated average glucose based on fructosamine level. Conclusion: Our study demonstrated a linear correlation between fructosamine level and mean blood glucose level, suggesting that fructosamine levels can be a proxy for the average glucose level in assessing the metabolic control of patients with diabetes. Objective values methods 1227 227 1,22 mellitus 3week week weeks measurement Results total 9450 9 450 9,45 10 0 1. µmolL µmol L 05 5 0. mgdL mg dL 0.5157 05157 5157 (0.515 20 r2 r (r 0353492 353492 0.353492 0.006881 0006881 006881 Conclusion 122 22 1,2 945 45 9,4 0.515 0515 515 (0.51 035349 35349 0.35349 0.00688 000688 00688 12 1, 94 4 9, 0.51 051 51 (0.5 03534 3534 0.3534 0.0068 00068 0068 (0. 0353 353 0.353 0.006 0006 006 (0 035 35 0.35 0.00 000 00 ( 03 0.3 0.0

Background: The low available of Glut-4 transporters in sarcolemma of the cardiac cells is what characterizes the myocardial insulin resistance (MIR), which is triggered separately of generalized insulin resistance. Insulin receptors are quite evident in the heart muscle and vessels, and mitochondrial activity performs a significant function in MIR preserving cellular homeostasis by cell reproduction, cells livelihoods, and energy generation. Objective: To evaluate the MIR mechanism and through the signaling pathway design. Methods: PubMed database was employed to search for reviews publications with MIR. The referenced data of the signaling pathway was chosen aggregating references of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A signaling pathway was designed based on MIR research manuscripts, where we show several mechanisms included in the MIR. The KEGG server was employed to exploit the interrelationship protein-protein, and elaborate signaling pathway diagram. The signaling pathway mapping was carried out with PathVisio software. Results: We selected 42 articles from a total of 450 articles in the PubMed database that presented a significant association between the terms "insulin resistance myocardial" AND "signaling pathway". Founded on database-validated research papers, we choose well-founded pathways and we succeeded representative description of these pathways. The reproduction contigs taken from the KEGG database designed the signaling pathway of the bio-molecules that lead to MIR. Thus, the acting among multiple mechanisms releases factors that participate of the development of MIR. Conclusion: The interaction among various mechanisms and molecular interactions are important factors in development of MIR.

Contact with viruses which have an aminoacid (AA) sequence simile to that of the auto-antigens can lead to autoimmune diseases in genetically susceptible individuals. SARS-CoV-2 has been implied as a possible causer of new-onset type 1 diabetes mellitus (DM1), however, no consistent evidence yet that SARS-CoV-2 take to DM1 on your own initiative. Objective: Evaluate the possible similarity between the AA sequences of human insulin and human glutamic acid decarboxylase-65 (GAD65) with SARS-CoV-2/COVID proteins, to explain the possible trigger of DM1. Methods: AA sequences of the human insulin (4F0N), GAD65 (2OKK), and SARS-CoV-2 (SARS-Cov2 S protein at open state (7DDN), SARS-Cov2 S protein at close state (7DDD), SARS CoV-2 Spike protein (6ZB5), Crystal structure of SARS-CoV-2 nucleocapsid protein N-terminal RNA binding domain (6M3M), Crystal structure of SARS-CoV-2 nucleocapsid protein C-terminal RNA binding domain (7DE1), Crystal Structure of NSP1 from SARS-CoV-2 (7K3N), and SARS-CoV-2 S trimer (7DK3)) available in the Protein Data Bank were compared using the Pairwise Structure Alignment. Results: Sequence identity percentage (SI%) and sequence similarity percentage (SS%) were found among the 4F0N, 2OKK and SARS-CoV-2. The SI% between the 4F0N and SARS-CoV-2 ranged from 4.76% to 14.29% and SS% ranged from 5.00% to 45.45%, distributed like this: 4F0N and 7DDN = SI% 4.76 and SS% 28.57; 4F0N and 7DDD = SI% 14.39 and SS% 23.81; 4F0N and 6ZB5 = SI% 4.76 and SS% 28.57; 4F0N and 6M3M = SI% 5.00 and SS% 5;00; 4F0N and 7DE1 = SI% 4.76 and SS% 9.21; 4F0N and 7K3N = SI% 9.09 and SS% 45.45; 4F0N and 7DK3 = SI% 4.76 and SS% 28.57. The SI% between the between the 2OKK and SARS-CoV-2 ranged from 3.19% to 6,70% and SS% ranged from 10.45 % to 22.22%, distributed like this: 2OKK and 7DDN = SI% 6.70 and SS% 15.64; 2OKK and 7DDD = SI% 7.53 and SS% 18.84; 2OKK and 6ZB5 = SI% 6.68 and SS% 17.38; 2OKK and 6M3M = SI% 4.48 and SS% 10.45; 2OKK and 7DE1 = SI% 6.67 and SS% 22.22; 2OKK and 7K3N = SI% 3.19 and SS% 15.97; 2OKK and 7DK3 = SI% 3.95 and 17.98. Conclusion: Immunoinformatics data suggest a potential pathogenic link between DM1 and SARS-CoV-2/COVID. Thus, by means of molecular mimicking we check that sequences similarity among SARS-CoV-2/COVID and human insulin and human glutamic acid decarboxylase-65 may lead to production of an immune cross-response to self-antigens, with breakage of self-tolerance that can trigger DM1.

O contato com vírus que têm uma sequência de aminoácidos (AA) semelhante à dos autoantígenos podem desencadear doenças autoimunes em indivíduos geneticamente suscetíveis. SARS-CoV-2 foi sugerido como um possível causador de diabetes mellitus tipo 1 de início recente (DM1), no entanto, não há evidências consistentes de que o SARS-CoV-2 possa desencadear DM1. Objetivo: Avaliar a possível semelhança entre as sequências AA da insulina humana e da descarboxilase-65 do ácido glutâmico humano (GAD65) com as proteínas SARS-CoV-2 / COVID, para explicar o possível desencadeamento do DM1. Métodos: Sequências de AA da insulina humana (4F0N), GAD65 (2OKK) e SARS-CoV-2 SARS-Cov2 S protein at open state (7DDN), SARS-Cov2 S protein at close state (7DDD), SARS CoV-2 Spike protein (6ZB5), Crystal structure of SARS-CoV-2 nucleocapsid protein N-terminal RNA binding domain (6M3M), Crystal structure of SARS-CoV-2 nucleocapsid protein C-terminal RNA binding domain (7DE1), Crystal Structure of NSP1 from SARS-CoV-2 (7K3N), and SARS-CoV-2 S trimer (7DK3)) nbsp;disponíveis no Protein Data Bank foram comparadas utilizando o Pairwise Structure Alignment. Resultados: O percentual de identidade de sequências (SI%) e o percentual de similaridade de sequências (SS%) foram encontrados entre o 4F0N, 2OKK e o SARS-CoV-2. O SI% entre o 4F0N e o SARS-CoV-2 variou de 4,76% a 14,29% e o SS% variou de 5,00% a 45,45%, assim distribuídos: 4F0N e 7DDN = SI% 4,76 e SS% 28,57; 4F0N e 7DDD = SI% 14,39 e SS% 23,81; 4F0N e 6ZB5 = SI% 4,76 e SS% 28,57; 4F0N e 6M3M = SI% 5,00 e SS% 5; 00; 4F0N e 7DE1 = SI% 4,76 e SS% 9,21; 4F0N e 7K3N = SI% 9,09 e SS% 45,45; 4F0N e 7DK3 = SI% 4,76 e SS% 28,57. O SI% entre o 2OKK e o SARS-CoV-2 variou de 3,19% a 6,70% e o SS% variou de 10,45% a 22,22%, assim distribuídos: 2OKK e 7DDN = SI% 6,70 e SS% 15,64; 2OKK e 7DDD = SI% 7,53 e SS% 18,84; 2OKK e 6ZB5 = SI% 6,68 e SS% 17,38; 2OKK e 6M3M = SI% 4,48 e SS% 10,45; 2OKK e 7DE1 = SI% 6,67 e SS% 22,22; 2OKK e 7K3N = SI% 3,19 e SS% 15,97; 2OKK e 7DK3 = SI% 3,95 e 17,98. Conclusão: Os dados de imunoinformática sugerem uma potencial ligação patogênica entre SARS-CoV-2 / COVID e o DM1. Assim, por meio de mimetização molecular, verificamos que a similaridade das sequências de AA entre SARS-CoV-2 / COVID e insulina humana e a descarboxilase-65 do ácido glutâmico humano pode levar à produção de uma resposta cruzada imunológica para autoantígenos, com quebra de auto-tolerância, podendo desencadear o DM1.

Introduction: Complexes of monomeric hormone molecules immunoglobulin-associated lead to the formation of macro-complexes biologically inactive that are called macro-hormones. Patients’ presenting unexpectedly elevated hormones values indicates the need that the existence of macro-hormones must be researched. Objective: To describe the macro-hormones discovered incidentally in laboratory tests, which we refer to as "incidentalormones". Methods: An integrative review was conducted, and data was gathered from the published articles in medical database. The different forms of macro-hormones are reviewed; the biochemical significance and laboratory assays of macro-hormones are also revised within the ambit of current laboratory medicine. We discussed diagnostic difficulty encountered in patients with "incidentalormones”, as well as methods of macro-hormone detection, immunoglobulin involved, clinical significance and associations with other diseases. Conclusion: The presence of macro-hormones, often guides us to intervention in laboratory trials, and could result in false-positive diagnosis with inadequate therapy. Laboratories should follow a diagnostic algorithm to carefully recognize and examine possible immunoassay interferences.

Introduction: The mechanisms by which hepatitis C virus (HCV) infection induces autoimmune thyroiditis (AIT) have been studied, and it was suggested that inflammatory cytokines during HCV infection would change the thyroperoxidase (TPO) signaling cascade and thyroglobulin (Tg) determining autoimmune thyroid disease. Objective: To show the signaling pathway, of TPO and Tg, and their potential targets mediated HCV in individuals with hepatitis C. Methods: The mapping of the signaling pathway was based on a review study approach and performed using the automatic annotation server of the Kyoto and Genome Encyclopedia (KEGG). PathVisio is free software for analysis and design of open source routes, and was used for the graphic representation of the signaling pathway. Results: The contigs were extracted from the KEGG database and their mapped transcription represents the signaling pathway of the main biomolecules that triggers the AIT. The action of HCV or its treatment can trigger AIT that is characterized by the presence of autoantibodies against TPO and Tg. In AIT, autoreactive CD4 + T lymphocytes recruit B cells and CD8 + T cells in the thyroid. The progression of the disease leads to the death of thyroid cells and hypothyroidism. Conclusion: HCV or its treatment activates several signaling pathways with thyroid cells damage resulting in AIT and secondary hypothyroidism to cellular apoptosis.

RESUMO Contexto - A exposição a antígenos virais que compartilham sequência de aminoácidos semelhantes a auto-antígenos pode provocar doenças auto-imunes em indivíduos predispostos geneticamente, e a teoria do mimetismo molecular sugere que o mimetismo entre epítopos de vírus e proteínas humanas pode ativar doenças auto-imunes. Objetivo - O objetivo deste estudo foi explorar a possível semelhança entre as sequências de aminoácidos de auto-proteinas da tireóide e proteínas do vírus da hepatite C, utilizando bancos de dados de proteínas e peptídeos imunogênicos, para explicar a doença auto-imune da tireóide. Métodos - Foram realizadas comparações entre as sequências de aminoácidos de poliproteínas do vírus da hepatite C e auto-proteinas da tireóide humana, disponível na base de dados do National Center for Biotechnology Information no Basic Local Alignment Search Tool. Resultados - A semelhança de sequências foi relacionada para cada genótipo de vírus da hepatite C e proteínas da tireóide. As semelhanças entre proteínas da tireóide e os peptídeos virais variaram de 21,0% (31 resíduos idênticos da sequência de 147 aminoácidos) a 71,0% (cinco resíduos idênticos da sequência de 7 aminoácidos). Conclusão - Dados de bioinformática sugerem uma possível ligação entre vírus da hepatite C e doença auto-imune da tireóide. Através de mimetismo molecular observa-se que as semelhanças entre as sequências de poliproteínas virais e auto-proteínas da tireóide pode ser um mecanismo de indução de resposta imune resultando em doença auto-imune da tireóide.

ABSTRACT Background - Exposure to viral antigens that share amino acid sequence similar with self- antigens might trigger autoimmune diseases in genetically predisposed individuals, and the molecular mimicry theory suggests that epitope mimicry between the virus and human proteins can activate autoimmune disease. Objective - The purpose of this study is to explore the possible sequence similarity between the amino acid sequences of thyroid self-protein and hepatitis C virus proteins, using databanks of proteins and immunogenic peptides, to explain autoimmune thyroid disease. Methods - Were performed the comparisons between the amino acid sequence of the hepatitis C virus polyprotein and thyroid self-protein human, available in the database of National Center for Biotechnology Information on Basic Local Alignment Search Tool. Results - The sequence similarity was related each hepatitis C virus genotype to each thyroid antigen. The similarities between the thyroid and the viral peptides ranged from 21.0 % (31 identical residues out of 147 amino acid in the sequence) to 71.0% (5 identical residues out of 7 amino acid in the sequence). Conclusion - Bioinformatics data, suggest a possible pathogenic link between hepatitis C virus and autoimmune thyroid disease. Through of molecular mimicry is observed that sequences similarities between viral polyproteins and self-proteins thyroid could be a mechanism of induction of crossover immune response to self-antigens, with a breakdown of self-tolerance, resulting in autoimmune thyroid disease.

A prescrição de um medicamento sem as indicações para as quais a droga foi originalmente aprovada por órgãos reguladores é internacionalmente conhecida como prescrição off-label. Descrevemos a terapia off-label em pé diabético, relatada na literatura científica internacional, por meio de uma revisão bibliográfica qualitativa, descritiva, através de pesquisa na base de dados internacional Medline, para seleção dos artigos. Os critérios para revisão foram publicações entre janeiro de 1985 e novembro de 2013, sendo as palavras-chave MeSH "off-label use" OR "off-label" OR "off-label prescribing" plus "diabetic foot" – colocadas no formulário de busca. Foram selecionados nove artigos com informações sobre a terapia off-labelem pé diabético. Conclui-se que a prática de prescrição off-labelpossui benefícios potenciais em muitas situações. Em algumas circunstâncias, uma prescrição off-label é o único tratamento disponível, seja por não existir uma droga específica, seja porque outros métodos de tratamento são ineficazes ou não disponíveis por intolerância.

Prescription of a drug outside of the indications for which it was originally approved by regulators is internationally known as "off-label" prescription. We describe off-label treatments for the diabetic foot reported in international scientific literature. This is a qualitative and descriptive bibliographical review based on the results of a search of the Medline international database. The criteria for review were publication between January 1985 and November 2013, and the MeSH (Medical Subject Heading) keywords "off-label use" OR "off-label" OR "off-label prescribing" plus "diabetic foot" were input on the search form. Nine studies were selected that contained information about off-label treatments for the diabetic foot. We conclude that the practice of off-label prescribing has potential benefits. In some situations an off-label prescription is the only treatment available for patients, either because a more targeted drug does not exist, or because other methods of treatment are ineffective or unavailable due to patient intolerance.

ContextoA gordura mesentérica é drenada pelo sistema venoso portal, estando relacionada à síndrome metabólica, que é um importante fator de risco para doença de infiltração gordurosa do fígado.ObjetivosGraduar a espessura do tecido adiposo visceral e correlacionar com o grau de doença de infiltração gordurosa do fígado através do exame ultrassonográfico.MétodosForam estudados 352 indivíduos, avaliando-se idade, gênero, medidas da espessura da gordura subcutânea e tecido adiposo visceral, a presença e o grau de doença de infiltração gordurosa do fígado. Foi analisada a relação independente entre tecido adiposo visceral e doença de infiltração gordurosa do fígado, e a regressão linear foi utilizada para prever a tecido adiposo visceral pela espessura da gordura subcutânea.ResultadosA idade média de 225 (63,9%) mulheres e 127 (36,1%) homens foi 47,5 ± 14,0 (18-77) anos, 255 indivíduos apresentaram exames normais, 97 apresentaram doença de infiltração gordurosa do fígado assim distribuídos: 37 grau 1, 32 grau 2 e 28 grau 3. A espessura da gordura subcutânea variou de 0,26 e 3,50 cm, com uma média de 1,3 ± 0,6 cm e a tecido adiposo visceral variou de 0,83 a 8,86 cm, com uma média de 3,6 ± 1,7 cm. A regressão linear demonstrou que para cada aumento de 1 cm da espessura da gordura subcutânea o tecido adiposo visceral aumentará 0,9 cm.ConclusãoO tecido adiposo visceral medido por ultrassonografia é um instrumento útil e parece ser capaz de estimar o risco de doença de infiltração gordurosa do fígado.

ContextThe mesenteric fat is drained by the portal system, being related to the metabolic syndrome which is an important risk factor for non-alcoholic fatty liver disease (NAFLD).ObjectivesGraduate of visceral fat thickness and correlate with the NAFLD degree through ultrasonography method.MethodsWe studied 352 subjects for age, gender, measures of subcutaneous fat thickness and visceral fat thickness as well as the presence and degree of liver fatty. Was analyzed the independent relationship between visceral fat thickness and NAFLD, and linear regression analysis was used in order to predict the visceral fat thickness from subcutaneous fat thickness.ResultsThe mean age of 225 women (63.9%) and 127 men (36.1%) was 47.5 ± 14.0 (18-77) years, 255 subjects had normal examinations, 97 had NAFLD thus distributed, 37 grade 1, 32 grade 2, and 28 grade 3. The subcutaneous fat thickness ranged from 0.26 to 3.50 cm with a mean of 1.3 ± 0.6 cm and visceral fat thickness ranged from 0.83 to 8.86 cm with a mean of 3.6 ± 1.7 cm. Linear regression showed that for every increase of 1 cm in subcutaneous fat thickness the visceral fat thickness will increase 0.9 cm.ConclusionsThe visceral fat thickness measured by ultrasonography is a useful and seems to be able to help estimate the risk of NAFLD.

Aneurisma da artéria hepática (AAH) foi relatado pela primeira vez através de autópsia em 1809, representa um quinto dos aneurismas viscerais, e a mortalidade por ruptura espontânea é alta na maioria dos casos. Relatamos o caso de uma mulher de 48 anos de idade com um AAH extra-hepático assintomático, diagnosticado inicialmente, e incidentalmente, com ultrassonografia abdominal e confirmado através de angiorressonância tridimensional e angiografia contrastada. O tratamento endovascular foi considerado viável, sendo tratada com sucesso através de embolização com molas.

Hepatic artery aneurysm (HAA) was first reported at autopsy in 1809, represents one fifth of visceral aneurysms and the mortality from spontaneous rupture is high in most of cases. We are reporting a case of an asymptomatic 48-year-old woman with an extrahepatic HAA, diagnosed initially and incidentally with abdominal ultrasonography, confirmed by a three-dimensional contrast-enhanced magnetic resonance imaging and angiography. Endovascular treatment was considered feasible and was successfully treated with coil embolization.