RESUMO
Currently, there are several drugs used for the treatment of type 2 diabetes (T2D); however, all of them have adverse effects. Benzothiazoles have a broad spectrum of biological activities such as antidiabetic. This study aimed to evaluate in silico and in vivo two series of 2-aminobenzothiazole derivatives linked to isothioureas (3a-w) or guanidines (4a-z) for the treatment of T2D. The ADMET properties were determined in silico, from which it was possible to select nine compounds (two isothioureas and seven guanidines), and, with molecular docking, it was shown that compounds methyl (E)-N'-(benzo[d]thiazol-2-yl)-N-methylcarbamimidothioate (3b) and 2-(benzo[d]thiazol-2-yl)-1,3-di-tert-butylguanidine (4y) showed a high affinity for PPARγ (ΔG = -7.8 and -8.4 kcal/mol, respectively). In vivo, the LD50 value was estimated in rats based on OECD Guideline 425, being >1750 mg/kg for both compounds. The pharmacological effect of 3b and 4y was evaluated in the T2D rat model, showing that after oral administration in an equimolar ratio to pioglitazone (15 mg/kg) for 4 weeks, both compounds were able to reduce blood glucose levels (<200 mg/dL) and improve the lipid profile. Therefore, 3b and 4y could be used in the future as antidiabetic agents.
Assuntos
Benzotiazóis , Hipoglicemiantes , Simulação de Acoplamento Molecular , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Animais , Benzotiazóis/química , Benzotiazóis/farmacologia , Ratos , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , PPAR gama/metabolismo , Simulação por Computador , Glicemia/efeitos dos fármacos , Humanos , Ratos WistarRESUMO
People Living with HIV (PLWHIV) present an increased risk of developing non-communicable diseases, such as type 2 diabetes (T2D), making it crucial to optimize glycemic control and assess metabolic markers. HbA1c is considered the gold standard for evaluating glycemic control, while fructosamine (FA) offers advantages in assessing non-glycemic determinants. Discrepancies between HbA1c and FA are common and may be influenced by temporal factors. The Glycation Gap (G-gap) emerges as a tool to clarify these discrepancies. A cross-sectional analytical study was conducted involving PLWHIV with various glycemic statuses, as well as patients with T2D and controls. Sociodemographic data were collected along with blood samples to measure biochemical profiles and FA. HbA1c predicted from FA (pHbA1c) was calculated using a linear regression equation, facilitating G-gap determination. A positive correlation was found between G-gap and levels of VLDL-C and triglycerides (TG). Additionally, a negative correlation was observed between HDL-C levels < 40 mg/dL and a positive G-gap. These associations suggest that the G-gap may be a useful tool for metabolic evaluation in PLWHIV and a preventive method for identifying individuals at risk of developing chronic complications related to T2D.
Assuntos
HDL-Colesterol , Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Infecções por HIV , Humanos , Feminino , Masculino , Infecções por HIV/sangue , Infecções por HIV/metabolismo , Pessoa de Meia-Idade , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , HDL-Colesterol/sangue , Estudos Transversais , Adulto , Biomarcadores/sangue , Glicosilação , Frutosamina/sangue , Glicemia/metabolismoRESUMO
Glutamine availability may be reduced in chronic diseases, such as type 2 diabetes mellitus (T2DM)-induced by obesity. Herein, the antioxidant, anti-inflammatory and lipid metabolism effects of chronic oral glutamine supplementation in its free and dipeptide form were assessed in ob/ob mice. Adult male C57BL/6J ob/ob mice were supplemented with L-alanyl-L-glutamine (DIP) or free L-glutamine (GLN) in the drinking water for 40 days, whilst C57BL/6J Wild-type lean (WT) and control ob/ob mice (CTRL) received fresh water only. Plasma and tissue (skeletal muscle and liver) glutamine levels, and insulin resistance parameters (e.g., GTT, ITT, insulin) were determined. Oxidative stress (e.g., GSH system, Nrf2 translocation), inflammatory (e.g., NFkB translocation, TNF-α gene expression) and lipid metabolism parameters (e.g., plasma and liver triglyceride levels, SRBP-1, FAS, ACC, and ChRBP gene expression) were also analyzed. CTRL ob/ob mice showed lower glutamine levels in plasma and tissue, as well as increased insulin resistance and fat in the liver. Conversely, chronic DIP supplementation restored glutamine levels in plasma and tissues, improved glucose homeostasis and reduced plasma and liver lipid levels. Also, Nrf2 restoration, reduced NFkB translocation, and lower TNF-α gene expression was observed in the DIP group. Interestingly, chronic free GLN only increased muscle glutamine stores but reduced overall insulin resistance, and attenuated plasma and liver lipid metabolic biomarkers. The results presented herein indicate that restoration of body glutamine levels reduces oxidative stress and inflammation in obese and T2DM ob/ob mice. This effect attenuated hepatic lipid metabolic changes observed in obesity.
Assuntos
Suplementos Nutricionais , Glutamina , Inflamação , Resistência à Insulina , Metabolismo dos Lipídeos , Fígado , Camundongos Endogâmicos C57BL , Camundongos Obesos , Estresse Oxidativo , Animais , Glutamina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Masculino , Fígado/metabolismo , Inflamação/metabolismo , Obesidade/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , DipeptídeosRESUMO
AIMS: Type 2 diabetes (T2D) is a prevalent metabolic disease linked to obesity and metabolic syndrome (MS). The glucolipotoxic environment (GLT) impacts tissues causing low-grade inflammation, insulin resistance and the gradual loss of pancreatic ß-cell function, leading to hyperglycemia. We have previously shown that Compound A (CpdA), a plant-derived dissociative glucocorticoid receptor-modulator with inflammation-suppressive activity, displays protective effects on ß-cells in type 1 diabetes murine models. This study aimed to evaluate whether the administration of CpdA can attenuate GLT effects and improve pathophysiological parameters in a murine model of T2D/MS. MAIN METHODS: Eight-week-old male C57BL/6NCrl mice were fed either a standard chow diet or a high-fat/high-sucrose diet (HFHS) for 15 weeks. From week 5 of feeding, each group received i.p. injections of CpdA (2.5 µg/g) or vehicle three times a week. We also examined CpdA in vitro effect against GLT using the insulinoma cell line INS-1E and naïve isolated mouse islets. KEY FINDINGS: CpdA administration in HFHS fed mice improved glucose homeostasis and insulin sensitivity with no apparent side effects. CpdA treatment also preserved pancreatic islet architecture and insulin expression, while reducing hepatic steatosis and visceral adipose tissue inflammation induced by HFHS diet. In vitro assays in INS-1E cells and naïve isolated mouse islets demonstrated that CpdA counteracted GLT-induced inhibition of glucose-stimulated insulin secretion and supported the expression of key ß-cell identity genes under GLT conditions. SIGNIFICANCE: These findings highlight the potential protective effect of CpdA in preserving ß-cell functionality and peripheral tissue physiology in the context of T2D/MS.
Assuntos
Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Ilhotas Pancreáticas , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides , Animais , Masculino , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Modelos Animais de Doenças , Insulina/metabolismo , Resistência à Insulina , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Glucose/metabolismoRESUMO
OBJECTIVE: This study aimed to compare the salivary protein profile in individuals with Type 2 Diabetes Mellitus (DM2) and periodontitis and their respective controls. METHODS: Eighty participants were included in the study. The four groups were formed by individuals with DM2 and periodontitis (DM2 + P, n = 20), DM2 without periodontitis (DM2, n = 20), periodontitis without DM2 (P, n = 20) and individuals without periodontitis and without DM2 (H, n = 20). Periodontal clinical examinations were performed and unstimulated saliva was collected. Proteomic analysis was performed by shotgun mass spectrometry. The results were obtained by searching the Homo sapiens database of the UniProt catalog. RESULTS: A total of 220 proteins were identified in saliva samples. In the comparison between DM2 + P and DM2 groups, 27 proteins were up-regulated [e.g. S100-A8 was 6 times up-regulated (humoral immune response pathway)]. The DM2 + P and P groups had 26 up-regulated proteins [e.g. Immunoglobulin lambda constant 7 more than 2 times up-regulated (complement activation pathway)]. The non-DM2 groups (P and H) presented 22 up-regulated proteins [e.g. Glyceraldehyde-3-phosphate dehydrogenase more than 2 times up-regulated (Peptidyl-cysteine S-nitrosylation pathway)]. The groups without periodontitis (DM2 and H) showed 23 were up-regulated proteins [e.g. Hemoglobin subunit alpha that was more than 10 times up-regulated (cellular oxidant detoxification pathway)]. CONCLUSION: The presence of DM2 and periodontitis significantly impacts the salivary proteome. Our proteomic analysis demonstrated that changes in the S100 family proteins (S100A8 and S100 A9) are highly related to the presence of DM2 and periodontitis. CLINICAL RELEVANCE: Diabetes Mellitus (DM) and periodontitis are highly prevalent chronic diseases that present a wide variety of signs and symptoms. They present a bidirectional relationship, where patients with DM have a higher prevalence and severity of periodontitis, and patients with periodontitis have a higher prevalence of DM, worse glycemic control, and more diabetic complications. Diagnosing periodontitis requires specific clinical examinations, which require a highly trained operator. In this study, we used high throughput proteomics in order to evaluate non-invasive biomarkers for periodontitis in type 2 DM subjects. The results can contribute to earlier, more accurate, and less costly diagnosis of periodontitis in diabetic subjects, enabling better diabetes control.
Assuntos
Diabetes Mellitus Tipo 2 , Periodontite , Proteômica , Saliva , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicações , Feminino , Saliva/metabolismo , Saliva/química , Masculino , Periodontite/metabolismo , Pessoa de Meia-Idade , Estudos de Casos e Controles , Proteínas e Peptídeos Salivares/metabolismo , Proteínas e Peptídeos Salivares/análise , Espectrometria de Massas , Adulto , Biomarcadores/metabolismo , Biomarcadores/análiseRESUMO
The incretins (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]), along with amylin/islet amyloid polypeptide (IAPP) and insulin-degrading enzyme (IDE), are hormones/enzymes that have been pharmacological targets, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, due to their insulinotropic actions. Physical training is recommended as a treatment for type 2 diabetes mellitus (T2DM); however, its effects on the concentrations of these hormones/enzymes are not well known. Thus, the present study aimed to evaluate the effects of combined training (CT) on the concentrations of hormones/enzymes with insulinotropic actions in individuals with T2DM and overweight. Individuals of both sexes with T2DM (age 51.73 ± 4.19 years; body mass index [BMI] 29.46 ± 3.39 kg/m2) were randomly distributed in the control group (CG, n = 17) and the combined training group (CTG, n = 17). The CT consisted of strength followed by erobic training, 3 times/week, for 16 weeks. Functional variables, body composition, and serum biochemical analyses (clinical markers, GLP-1, GIP, DPP-4, amylin/IAPP, and IDE) were evaluated. The CTG showed a decrease in GLP-1 (pre: 32.8 ± 12.1, post: 28.4 ± 13.5, and p = 0.04) in the group/time analysis. In the evaluation of the Δ% of variation, CTG presented a decrease for GLP-1 (-9.3%; p = 0.03) and amylin/IAPP (-13.4%; p < 0.01), in addition to an increase for DPP-4 (6.2%; p = 0.04) enzyme. CT decreases the baseline levels of important hormones with insulinotropic actions in individuals with T2DM and overweight. The improvement in overall metabolism provided by CT must be the main reason for these effects. These results broaden the understanding of the effects and relationships between CT and glucose metabolism.
Assuntos
Diabetes Mellitus Tipo 2 , Sobrepeso , Humanos , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangue , Masculino , Pessoa de Meia-Idade , Sobrepeso/terapia , Sobrepeso/metabolismo , Feminino , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Polipeptídeo Inibidor Gástrico/sangue , Treinamento Resistido , Polipeptídeo Amiloide das Ilhotas Pancreáticas/sangue , Incretinas/sangue , Glicemia/metabolismo , Índice de Massa CorporalRESUMO
Type 2 diabetes mellitus is a dramatically increasing global public health challenge. The prevalence is projected almost double, from 194 million in 2003 to 333 million in 2025 with type 2 diabetes mellitus representing approximately 90%-95% of cases. Dual inhibitors for antidiabetic targets is still novel and promising strategy for discovery of more effective therapies. Ester and triazole derivatives of p-coumaric acid were obtained from Williamson synthesis and Microwave-assisted click reaction, respectively. Chemical structures were finely characterized through IR, 1H, and 13C NMR and HRMS. They were tested for their dual inhibitory activity against GSK-3ß kinase and DPP-IV. The complexes resulting from docking were used for all-atom molecular dynamics simulations, including the enzymes in the apo form, using the GROMACS 2022.3. Two inhibitors 2 and 5 demonstrated promising inhibition at low and submicromolar against both proteins. Molecular Dynamic simulations revealed that the binding pattern of the control inhibitors were reproduced by p-coumaric acid derivatives 2 and 5 with crucial interactions involving the same residues. The p-coumaric skeleton can be considered as a promising core for GSK-3ß kinase and DPP-IV dual inhibitors.
Assuntos
Ácidos Cumáricos , Dipeptidil Peptidase 4 , Glicogênio Sintase Quinase 3 beta , Hipoglicemiantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Humanos , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/química , Propionatos/química , Propionatos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Sítios de Ligação , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/síntese químicaRESUMO
Diabetes mellitus (DM) is a significant public health problem and it is known that the identification of molecular markers involved in glycemic control can impact disease control. Although the rs266729 polymorphism located in the promoter of the adiponectin gene (ADP) has been shown to be a candidate for involvement in glycemic control, the genotypic groups have never been characterized in terms of metabolomic aspects. Objective: Analyze the metabolites present in the rs266729 genotype groups. 127 diabetic individuals were compared according to the rs266729 genotype groups CC and GC + GG (RFLP-PCR). Blood plasma metabolites were classified by nuclear magnetic resonance (NMR), and the metabolic pathways of each group using the MetaboAnalyst tool. Insulin therapy (p = 0.049) was more frequent in the GC + GG rs266729 group. Lactate, alanine, glutamine, aspartate, lipid, lysine, isoleucine, citrulline, cholesterol, and fucose impacted the CC group and aspartate, beta-glucose, glutamate, pyruvate, proline, and 2-oxoglutarate impacted the CG + GG group. The glucose-alanine pathway, malate-aspartate transport, and urea cycle impacted the CC group (D-glucose, glutamic acid, L-alanine, oxoglutaric acid, and pyruvic acid). The glutamine/glutamate ratio is likely to be related to the causes of rs266729 influencing the risk of diabetes.
Assuntos
Adiponectina , Diabetes Mellitus Tipo 2 , Genótipo , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Adiponectina/genética , Adiponectina/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Idoso , Metabolômica/métodos , Metaboloma , AdultoRESUMO
Type 2 diabetes mellitus (T2DM) is a multifactorial disease, influenced by dietary and environmental factors that can modify the intestinal microbiota. The aim of this study was to evaluate changes in the composition and diversity of the intestinal microbiota associated with carbohydrate (CHO) consumption in T2DM patients. Forty patients participated, with and without T2DM. Fecal samples were collected for the characterization of microbial diversity from the massive sequencing of the 16S rRNA gene. Carbohydrate consumption was quantified using the Frequency Consumption Foods questionnaire (FCF), the groups were categorized according to Body Mass Index (BMI) and BMI + CHO consumption. The group without T2DM showed normal biochemical and anthropometric parameters, although they had a high carbohydrate consumption compared to the group with T2DM. At the phylum level, there were differences in relative abundance; the control overweight group (CL-OW > CHO) and T2DM-Normal Weight > CHO patients had increased Bacteroides and decreased Firmicutes. In contrast, the CL-OW > CHO and T2DM-OW < CHO patients, showed reduced Bacteroidetes and an elevated amount of Firmicutes. At the genus level, the differences were in the relative abundance of Roseburia, Clostridium_IV, Prevotella, and Sporobacter, associated with the consumption of carbohydrates. The groups that consumed high amounts of carbohydrates, regardless of whether they had diabetes mellitus or were overweight, had a significantly reduced proportion of Faecalibacterium, an altered proportion of Bacteroides. The high consumption of carbohydrates showed considerable modifications in the composition and diversity of the bacterial communities.
Assuntos
Diabetes Mellitus Tipo 2 , Carboidratos da Dieta , Microbioma Gastrointestinal , RNA Ribossômico 16S , Humanos , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Carboidratos da Dieta/metabolismo , Fezes/microbiologia , Idoso , Adulto , Índice de Massa Corporal , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , BiodiversidadeRESUMO
Introduction: Heart failure (HF) and type 2 diabetes mellitus (DM2) are global health problems that often lead to muscle atrophy. These conditions are associated with increased autophagy and apoptosis in the muscle cells, resulting in decreased muscle mass. Physical exercise associated with photobiomodulation (PBM) seems promising to attenuate the skeletal muscle changes caused by HF and DM2, due to its direct effects on mitochondria, which may result in an increase in antioxidant capacity. Objective: To verify the influence of physical exercise and the association with PBM on autophagy, apoptosis, and cell survival signaling pathways in myocytes from rats with HF and DM2. Materials and Methods: Male rats were assigned to one of four groups: control (CT), HF+DM (disease model), exercise+HF+DM (EX+HF+DM), and EX+HF+DM+PBM (EX+HF+DM+PBM). To induce DM2, we administered streptozotocin (STZ) (0.25 mL/kg, intraperitoneally). HF was induced by coronary ligation. One week post-induction, an 8-week aerobic exercise and PBM protocol was initiated. Western blot analysis was used to measure the expression of apoptosis-related proteins and autophagy. Results: The EX+HF+DM+PBM group showed a substantial increase in Nrf2, p-AKT, and LC3-I levels compared to the HF+DM group. Conclusions: These findings suggest that physical exercise combined with PBM can upregulate proteins that promote myocyte survival in rats with HF and DM2.
Assuntos
Apoptose , Autofagia , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Terapia com Luz de Baixa Intensidade , Músculo Esquelético , Condicionamento Físico Animal , Animais , Masculino , Ratos , Insuficiência Cardíaca/radioterapia , Insuficiência Cardíaca/metabolismo , Músculo Esquelético/efeitos da radiação , Músculo Esquelético/metabolismo , Autofagia/efeitos da radiação , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/radioterapia , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Ratos WistarRESUMO
Diabetes is a metabolic disease with a high worldwide prevalence and an important factor in mortality and disability in the population. Complications can be reduced or prevented with lifestyle changes in physical activity, dietary habits, and smoking cessation. High-protein diets (HPDs, >30% or >1.0 g/Kg/day) decrease hyperglycemia in part due to their content of branched-chain amino acids (BCAAs), mainly leucine. Leucine (and other BCAAs) improve glucose metabolism by directly signaling in the medio-basal hypothalamus (MBH), increasing liver insulin sensitivity. To determine the effectiveness of an HPD to lower hyperglycemia, we analyzed the results of published clinical studies focusing on the levels of fasting plasma glucose and/or glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). We carried out a systematic search for clinical studies using HPDs. We searched five databases (Scopus, Web of Science, PubMed, Epistemonikos, and Cochrane), collecting 179 articles and finally selecting 8 articles to analyze their results. In conclusion, HPDs are an effective alternative to reduce hyperglycemia in patients with T2DM, especially so-called Paleolithic diets, due to their higher-quality protein from animal and vegetal sources and their exclusion of grains, dairy products, salt, refined fats, and added sugars.
Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Dieta Rica em Proteínas , Humanos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análise , Hiperglicemia/sangue , Hiperglicemia/dietoterapia , Hiperglicemia/metabolismoRESUMO
BACKGROUND: As the predominant leisure-time sedentary behavior, television viewing was documented to increase cardiovascular diseases in observational studies, yet the causal relationship and potential mechanisms remain to be determined. OBJECTIVES: To systematically investigate the causal relationship between television viewing time, cardiovascular diseases, and potential mechanisms. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis to estimate causal associations with cardiovascular diseases and biomarkers of cardiometabolic risk. The random inverse-variance weighted method was used as the primary estimate. To account for multiple comparisons, a Bonferroni correction p value for cardiovascular diseases and biomarkers of cardiometabolic risk was 0.0045 and 0.0024, respectively. RESULTS: Genetically instrumented television viewing time was associated with higher risks of type 2 diabetes (odd ratio [OR]=2.51; 95% confidence interval [CI]: 1.89-3.33; p<0.00001), hypertension (OR=2.11; 95% CI: 1.67-2.66; p<0.00001), coronary heart disease (OR=1.53; 95% CI: 1.23-1.91; p=0.00015), and heart failure (OR=1.42; 95% CI: 1.18-1.70; p=0.00017). Suggestive evidence of harmful associations was also observed for peripheral artery disease (OR=1.58; 95% CI: 1.07-2.34; p=0.02253) and ischemic stroke (OR=1.34; 95% CI: 1.10-1.63; p=0.00328). Biomarkers of cardiometabolic risk, including interleukin 10, leptin, visceral adipose, abdominal subcutaneous adipose, liver fat, body mass index, waist circumference, triglycerides, and C-reactive protein, were increased. Systolic blood pressure, heart rate, low-density lipoprotein, and total cholesterol were potentially increased while high-density lipoprotein was decreased. However, television viewing time had no effect on venous thromboembolism or pulmonary embolism. CONCLUSION: Television viewing time was causally associated with increased risks of cardiovascular diseases, which may be explained by metabolic and inflammatory mechanisms. BACKGROUND: An overview of the effect of television viewing time on cardiovascular diseases and biomarkers of cardiometabolic risk.
Assuntos
Doenças Cardiovasculares , Tempo de Tela , Televisão , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Polimorfismo de Nucleotídeo Único , Comportamento Sedentário , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Biomarcadores/análise , Biobanco do Reino Unido , Atividades de LazerRESUMO
BACKGROUND The relationship between different subgroups of type 2 diabetes (T2D) and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis has not been thoroughly studied. This study aims to determine the association between T2D subgroups and the risk of developing advanced liver fibrosis using the Fibrosis-4 (FIB-4) index, a non-invasive marker for assessing liver fibrosis risk. MATERIAL AND METHODS A total of 1205 patients with T2D were categorized into 4 distinct subgroups: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The FIB-4 index was calculated for each patient to estimate the degree of liver fibrosis, with the following cutoff points: <1.3 indicating no or mild fibrosis, 1.3-2.67 suggesting moderate fibrosis, and >2.67 indicating advanced fibrosis (F3-F4). Logistic regression was used to compare the odds of advanced fibrosis across these subgroups. RESULTS The SIRD subgroup exhibited significantly higher odds of advanced liver fibrosis (F3-F4), compared with the other subgroups, as indicated by elevated FIB-4 scores (P<0.05). In contrast, the SIDD and MOD subgroups had lower odds of advanced fibrosis, while the MARD subgroup showed an intermediate association. CONCLUSIONS The findings suggest that the FIB-4 index, as a noninvasive assessment tool, effectively stratifies liver fibrosis risk among different T2D subgroups. This stratification can inform more personalized management strategies for patients with MASLD, underscoring the importance of accounting for the heterogeneity within T2D in clinical assessments of liver fibrosis risk.
Assuntos
Diabetes Mellitus Tipo 2 , Progressão da Doença , Cirrose Hepática , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Resistência à Insulina , Idoso , Adulto , Biomarcadores/metabolismo , Obesidade/complicações , Obesidade/metabolismoRESUMO
In recent years, the knowledge of the physiological and pathophysiological roles of the renin-angiotensin system (RAS) in glucose metabolism has advanced significantly. It is now well-established that blockade of the angiotensin AT1 receptor (AT1R) improves insulin sensitivity. Activation of the AT2 receptor (AT2R) and the MAS receptor are significant contributors to this beneficial effect. Elevated availability of angiotensin (Ang) II) for interaction with the AT2R and increased Ang-(1-7) formation during AT1R blockade mediate these effects. The ongoing development of selective AT2R agonists, such as compound 21 and the novel Ang III peptidomimetics, has significantly advanced the exploration of the role of AT2R in metabolism and its potential as a therapeutic target. These agents show promise, particularly when RAS inhibition is contraindicated. Additionally, other RAS peptides, including Ang IV, des-Asp-Ang I, Ang-(1-9), and alamandine, hold therapeutic capability for addressing metabolic disturbances linked to type 2 diabetes. The possibility of AT2R heteromerization with either AT1R or MAS receptor offers an exciting area for future research, particularly concerning therapeutic strategies to improve glycemic control. This review focuses on therapeutic opportunities to improve insulin sensitivity, taking advantage of the protective arm of the RAS.
Assuntos
Resistência à Insulina , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Resistência à Insulina/fisiologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Proto-Oncogene MasRESUMO
Type 2 diabetes (T2D) is associated with insulin resistance and progressive dysfunction of ß-pancreatic cells, leading to persistent hyperglycemia. Macrophages play a crucial role in this context, influencing both the development and progression of insulin resistance. These innate immune cells respond to inflammatory stimuli and reprogram their metabolism, directly impacting the pathophysiology of T2D. Macrophages are highly plastic and can adopt either pro-inflammatory or pro-resolutive phenotypic profiles. In T2D, pro-inflammatory macrophages, which rely on glycolysis, exacerbate insulin resistance through increased production of pro-inflammatory cytokines and nitric oxide. In contrast, pro-resolutive macrophages, which prioritize fatty acid metabolism, have different effects on glucose homeostasis. Metaflammation, a chronic low-grade inflammation, is induced by pro-inflammatory macrophages and significantly contributes to the progression of T2D, creating an environment conducive to metabolic dysfunction. This review aims to clarify the contribution of macrophages to the progression of T2D by detailing how their inflammatory responses and metabolic reprogramming influence insulin resistance and the disease's pathophysiology. The review seeks to deepen the understanding of the biochemical and metabolic mechanisms involved, offering broader insights into the impact on the quality of life for millions of patients worldwide.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Macrófagos , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Inflamação/metabolismo , Animais , Reprogramação Celular , Reprogramação MetabólicaRESUMO
Obesity causes insulin resistance (IR) through systemic low-grade inflammation and can lead to type 2 diabetes mellitus (T2DM). However, the mechanisms that cause IR and T2DM in non-obese individuals are unclear. The Goto-Kakizaki (GK) rat develops IR spontaneously and is a model of non-obese T2DM. These rats exhibit hyperglycemia beginning at weaning and exhibit lower body mass than control Wistar rats. Herein, we tested the hypothesis that macrophages of GK rats are permanently in a pro-inflammatory state, which may be associated with a systemic inflammation condition that mimics the pathogenesis of obesity-induced T2DM. Using eighteen-week-old GK and control Wistar rats, we investigated the proportions of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages isolated from the peritoneal cavity. Additionally, the production of inflammatory cytokines and reactive oxygen species (ROS) in cultured macrophages under basal and stimulated conditions was assessed. It was found that phorbol myristate acetate (PMA) stimulation increased GK rat macrophage ROS production 90-fold compared to basal levels. This response was also three times more pronounced than in control cells (36-fold). The production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), tended to be upregulated in cultured macrophages from GK rats under basal conditions. Macrophages from GK rats produced 1.6 times more granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.5 times more monocyte chemoattractant protein-1 (MCP-1) and 3.3 times more TNF-α than control cells when stimulated with lipopolysaccharide (LPS) (p = 0.0033; p = 0.049; p = 0.002, respectively). Moreover, compared to control cells, GK rats had 60% more M1 (p = 0.0008) and 23% less M2 (p = 0.038) macrophages. This study is the first to report macrophage inflammatory reprogramming towards a pro-inflammatory state in GK rats.
Assuntos
Diabetes Mellitus Tipo 2 , Inflamação , Macrófagos , Ratos Wistar , Espécies Reativas de Oxigênio , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/imunologia , Ratos , Macrófagos/metabolismo , Macrófagos/imunologia , Espécies Reativas de Oxigênio/metabolismo , Inflamação/patologia , Inflamação/metabolismo , Masculino , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Modelos Animais de Doenças , Resistência à InsulinaRESUMO
BACKGRUOUND: This study investigated the prognostic importance of the hemoglobin glycation index (HGI) for macrovascular and microvascular outcomes, mortality, and hypoglycemia occurrence in a type 2 diabetes cohort and compared it to glycated hemoglobin (HbA1c). METHODS: Baseline and mean first-year HGI and HbA1c, and the variability thereof, were assessed in 687 individuals with type 2 diabetes (median follow-up, 10.6 years). Multivariable Cox regression was conducted to evaluate the associations of HGI and HbA1c parameters with macrovascular (total and major cardiovascular events) and microvascular outcomes (microalbuminuria, advanced renal failure, retinopathy, and peripheral neuropathy), mortality (all-cause and cardiovascular), and moderate/severe hypoglycemia occurrence. RESULTS: During follow-up, there were 215 total cardiovascular events (176 major) and 269 all-cause deaths (131 cardiovascular). Microalbuminuria developed in 126 patients, renal failure in 104, retinopathy in 161, and neuropathy in 177. There were 90 hypoglycemia episodes. Both HGI and HbA1c predicted all adverse outcomes, except microalbuminuria and hypoglycemia. Their adjusted risks were roughly equivalent for all outcomes. For example, the adjusted hazard ratios (HRs) with 95% confidence intervals (CIs), estimated for 1 standard deviation increments, of mean first-year HGI were 1.23 (1.05 to 1.44), 1.20 (1.03 to 1.38), 1.36 (1.11 to 1.67), 1.28 (1.09 to 1.67), and 1.29 (1.09 to 1.54), respectively, for cardiovascular events, all-cause mortality, renal failure, retinopathy, and neuropathy; whereas the respective HRs (95% CIs) of mean HbA1c were 1.31 (1.12 to 1.53), 1.28 (1.11 to 1.48), 1.36 (1.11 to 1.67), 1.33 (1.14 to 1.55), and 1.29 (1.09 to 1.53). CONCLUSION: HGI was no better than HbA1c as a predictor of adverse outcomes in individuals with type 2 diabetes, and its clinical use cannot be currently advised.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Feminino , Hemoglobinas Glicadas/análise , Pessoa de Meia-Idade , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/etiologia , Idoso , Prognóstico , Angiopatias Diabéticas/mortalidade , Angiopatias Diabéticas/etiologia , Fatores de Risco , Seguimentos , Hipoglicemia/mortalidadeRESUMO
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.
Assuntos
Metilação de DNA , Epigênese Genética , Doenças Metabólicas , RNA não Traduzido , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/terapia , Doenças Metabólicas/dietoterapia , RNA não Traduzido/genética , Medicina de Precisão , Redução de Peso , Obesidade/genética , Obesidade/metabolismo , Obesidade/dietoterapia , Nutrientes , MicroRNAs/metabolismo , Dieta , Suplementos Nutricionais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/metabolismo , Padrões DietéticosRESUMO
Pancreatic ßcells are the only cells that synthesize insulin to regulate blood glucose levels. Various conditions can affect the mass of pancreatic ßcells and decrease insulin levels. Diabetes mellitus is a disease characterized by insulin resistance and chronic hyperglycemia, mainly due to the loss of pancreatic ßcells caused by an increase in the rate of apoptosis. Additionally, hyperglycemia has a toxic effect on ßcells. Although the precise mechanism of glucotoxicity is not fully understood, several mechanisms have been proposed. The most prominent changes are increases in reactive oxygen species, the loss of mitochondrial membrane potential and the activation of the intrinsic pathway of apoptosis due to p53. The present review analyzed the location of p53 in the cytoplasm, mitochondria and nucleus in terms of posttranslational modifications, including phosphorylation, OGlcNAcylation and polyADPribosylation, under hyperglycemic conditions. These modifications protect p53 from degradation by the proteasome and, in turn, enable it to regulate the intrinsic pathway of apoptosis through the regulation of antiapoptotic and proapoptotic elements. Degradation of p53 occurs in the proteasome and depends on its ubiquitination by Mdm2. Understanding the mechanisms that activate the death of pancreatic ßcells will allow the proposal of treatment alternatives to prevent the decrease in pancreatic ßcells.
Assuntos
Apoptose , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Processamento de Proteína Pós-Traducional , Proteína Supressora de Tumor p53 , Proteína Supressora de Tumor p53/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , AnimaisRESUMO
The accumulation of advanced glycation end-products (AGEs) elicits morphofunctional kidney impairment. AGEs levels can be noninvasively estimated by skin autofluorescence (SAF). We explored whether high SAF predicts kidney outcomes in type 2 diabetes (T2D) individuals. The study was conducted as a predefined analysis of the Brazilian Diabetes Study, a prospective single-center cohort of T2D adults. Data from 155 individuals followed for up to 1716 days were considered. The incidence of major adverse kidney events (MAKE) was 9.6%. Individuals with above-median SAF had a higher incidence of MAKEs (4.6% vs. 21%; p = 0.002), with an HR of 3.39 [95% CI: 1.06-10.85; p = 0.040] after adjustment by age and gender. The mean adjusted eGFR change was 1.08 units (SE: 1.15; 95%CI: -1.20, 3.37) in the low SAF and -5.19 units [SE: 1.93; 95%CI: -9.10, -1.29] in the high SAF groups (between-subject difference: F: 5.62, p = 0.019). The high-SAF group had a greater prevalence of rapid decliners than the low-SAF group (36.7% vs. 15.8%; p = 0.028). In conclusion, high SAF was related to increased incidence of MAKEs and faster decline in eGFR among T2D subjects. This should be considered by healthcare providers when identifying individuals more prone to diabetes-related kidney complications.