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Inflammation, oxidative stress, and mitochondrial function are implicated in the development of obesity and its comorbidities. The purpose of this study was to assess the impact of weight loss through calorie restriction on the metabolic profile, inflammatory and oxidative stress parameters, and mitochondrial respiration in an obese population. A total of 109 subjects underwent two cycles of a very low-calorie diet alternated with a low-calorie diet (24 weeks). We analyzed biochemical and inflammatory parameters in serum, as well as oxidative stress markers, mRNA antioxidant gene expression, and mitochondrial respiration in peripheral blood mononuclear cells (PBMCs). After the intervention, there was an improvement in both insulin resistance and lipid profiles, including cholesterol subfractions. Weight loss produced a significant reduction in mitochondrial ROSs content and an increase in glutathione levels, coupled with an enhancement in the mRNA expression of antioxidant systems (SOD1, GSR, and CAT). In addition, a significant improvement in basal oxygen consumption, maximal respiration, and ATP production was observed. These findings demonstrate that moderate weight loss can improve insulin resistance, lipid profiles and subfractions, inflammatory and oxidative stress parameters, and mitochondrial respiration. Therefore, we can affirm that dietary intervention can simultaneously achieve significant weight loss and improve metabolic profile and mitochondrial function in obesity.
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Avocado ripening entails intricate physicochemical transformations resulting in desirable characteristics for consumption; however, its impact on specific metabolites and its cultivar dependence remains largely unexplored. This study employed LC-MS to quantitatively monitor 30 avocado pulp metabolites, including phenolic compounds, amino acids, nucleosides, vitamins, phytohormones, and related compounds, from unripe to overripe stages, in three commercial varieties (Hass, Fuerte, and Bacon). Multivariate statistical analysis revealed significant metabolic variations between cultivars, leading to the identification of potential varietal markers. Most monitored metabolites exhibited dynamic quantitative changes. Although phenolic compounds generally increased during ripening, exceptions such as epicatechin and chlorogenic acid were noted. Amino acids and derivatives displayed a highly cultivar-dependent evolution, with Fuerte demonstrating the highest concentrations and most pronounced fluctuations. In contrast to penstemide, uridine and abscisic acid levels consistently increased during ripening. Several compounds characteristic of the Bacon variety were delineated but require further research for identification and role elucidation.
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AIMS/HYPOTHESIS: Alterations in circadian rhythms increase the likelihood of developing type 2 diabetes and CVD. Circadian rhythms are controlled by several core clock genes, which are expressed in nearly every cell, including immune cells. Immune cells are key players in the pathophysiology of type 2 diabetes, and participate in the atherosclerotic process that underlies cardiovascular risk in these patients. The role of the core clock in the leukocytes of people with type 2 diabetes and the inflammatory process associated with it are unknown. We aimed to evaluate whether the molecular clock system is impaired in the leukocytes of type 2 diabetes patients and to explore the mechanism by which this alteration leads to an increased cardiovascular risk in this population. METHODS: This is an observational cross-sectional study performed in 25 participants with type 2 diabetes and 28 healthy control participants. Clinical and biochemical parameters were obtained. Peripheral blood leukocytes were isolated using magnetic bead technology. RNA and protein lysates were obtained to assess clock-related gene transcript and protein levels using real-time PCR and western blot, respectively. Luminex XMAP technology was used to assess levels of inflammatory markers. Leukocyte-endothelial interaction assays were performed by perfusing participants' leukocytes or THP-1 cells (with/without CLK8) over a HUVEC monolayer in a parallel flow chamber using a dynamic adhesion system. RESULTS: Participants with type 2 diabetes showed increased BMAL1 and NR1D1 mRNA levels and decreased protein levels of circadian locomotor output cycles kaput (CLOCK), cryptochrome 1 (CRY1), phosphorylated basic helix-loop-helix ARNT like 1 (p-BMAL1) and period circadian protein homologue 2 (PER2). Correlation studies revealed that these alterations in clock proteins were negatively associated with glucose, HbA1c, insulin and HOMA-IR levels and leukocyte cell counts. The leukocyte rolling velocity was reduced and rolling flux and adhesion were enhanced in individuals with type 2 diabetes compared with healthy participants. Interestingly, inhibition of CLOCK/BMAL1 activity in leukocytes using the CLOCK inhibitor CLK8 mimicked the effects of type 2 diabetes on leukocyte-endothelial interactions. CONCLUSIONS/INTERPRETATION: Our study demonstrates alterations in the molecular clock system in leukocytes of individuals with type 2 diabetes, manifested in increased mRNA levels and decreased protein levels of the core clock machinery. These alterations correlated with the impaired metabolic and proinflammatory profile of the participants with type 2 diabetes. Our findings support a causal role for decreased CLOCK/BMAL1 activity in the increased level of leukocyte-endothelial interactions. Overall, our data suggest that alterations in core clock proteins accelerate the inflammatory process, which may ultimately precipitate the onset of CVD in patients with type 2 diabetes.
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The purpose of the study was to determine the impact of weight loss through calorie restriction on metabolic profile, and inflammatory and oxidative stress parameters in metabolically healthy (MHO) and unhealthy (MUHO) obese individuals. A total of 74 subjects (34 MHO and 40 MUHO) received two cycles of a very low-calorie diet, alternating with a hypocaloric diet for 24 weeks. Biochemical, oxidative stress, and inflammatory markers, as well as serum metabolomic analysis by nuclear magnetic resonance, were performed at baseline and at the end of the intervention. After the diet, there was an improvement in insulin resistance, as well as a significant decrease in inflammatory parameters, enhancing oxidative damage, mitochondrial membrane potential, glutathione, and antioxidant capacity. This improvement was more significant in the MUHO group. The metabolomic analysis showed a healthier profile in lipoprotein profile. Lipid carbonyls also decrease at the same time as unsaturated fatty acids increase. We also display a small decrease in succinate, glycA, alanine, and BCAAs (valine and isoleucine), and a slight increase in taurine. These findings show that moderate weight reduction leads to an improvement in lipid profile and subfractions and a reduction in oxidative stress and inflammatory markers; these changes are more pronounced in the MUHO population.
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Daily rhythms of metabolic function are supported by molecular circadian clock systems that are strongly regulated by feeding and fasting. Intermittent fasting diets have been associated with weight loss and improved metabolism. However, the effects of time-restricted eating (TRE) on glycemic parameters are still under debate. In this review, we aim to systematically analyze the effects of TRE on glycemic parameters. We searched on PubMed, EMBASE, and the Cochrane Library for controlled studies in which subjects followed TRE for at least 4 weeks. 20 studies were included in the qualitative systematic review, and 18 studies (n = 1169 subjects) were included in the meta-analysis. Overall, TRE had no significant effect on fasting glucose (Hedges's g = -0.08; 95% CI:-0.31,0.16; p = 0.52), but it did reduce HbA1c levels (Hedges's g = -0.27; 95% CI: -0.47, -0.06; p = 0.01). TRE significantly reduced fasting insulin (Hedges's g = -0.40; 95% CI: -0.73,-0.08; p = 0.01) and showed a tendency to decrease HOMA-IR (Hedges's g = -0.32; 95% CI:-0.66,0.02; p = 0.06). Interestingly, a cumulative analysis showed that the beneficial effects of TRE regarding glucose levels were less apparent as studies with later TRE windows (lTRE) were being included. Indeed, a subgroup analysis of the early TRE (eTRE) studies revealed that fasting glucose was significantly reduced by eTRE (Hedges's g = -0.38; 95% CI:-0.62, -0.14; p < 0.01). Our meta-analysis suggests that TRE can reduce HbA1c and insulin levels, and that timing of food intake is a crucial factor in the metabolic benefit of TRE, as only eTRE is capable of reducing fasting glucose levels in subjects with overweight or obesity.PROSPERO registration number CRD42023405946.
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Glucose , Controle Glicêmico , Humanos , Hemoglobinas Glicadas , Insulina , Ingestão de AlimentosRESUMO
Introduction: In recent years, it has been described that the dysbiosis of the intestinal microbiota plays a transcendental role in several pathologies. In this sense, the importance of the gut microbiota in the gut-brain axis, with a bidirectional communication, has been demonstrated. Furthermore, the gut microbiota has been linked with mood disorders and neuropsychiatric disorders. Methods: A systematic review of two databases - PubMed and Scopus - was carried out following PRISMA guidelines. We included original studies in humans with a control group published in the last 11 years, which were assessed by the Critical Appraisal Skills Program (CASP) to confirm their quality. Eighteen articles met all the selection criteria. Results: A review of the articles revealed an association between psychiatric disorders and different bacterial phyla. The studies we have reviewed have demonstrated differences between subjects with psychiatric disorders and controls and highlight a clear relationship between depression, stress, autism spectrum disorder (ASD), psychotic episodes, eating disorders, anxiety and brain function and the gut microbiota composition. Conclusion: A reduction of fermentative taxa has been observed in different psychiatric disorders, resulting in a decrease in the production of short-chain fatty acids (SCFAs) and an increase in pro-inflammatory taxa, both of which may be consequences of the exacerbation of these pathologies.
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OBJECTIVE: Type 2 diabetes (T2D) is linked to metabolic, mitochondrial and inflammatory alterations, atherosclerosis development and cardiovascular diseases (CVDs). The aim was to investigate the potential therapeutic benefits of GLP-1 receptor agonists (GLP-1 RA) on oxidative stress, mitochondrial respiration, leukocyte-endothelial interactions, inflammation and carotid intima-media thickness (CIMT) in T2D patients. RESEARCH DESIGN AND METHODS: Type 2 diabetic patients (255) and control subjects (175) were recruited, paired by age and sex, and separated into two groups: without GLP-1 RA treatment (196) and treated with GLP-1 RA (59). Peripheral blood polymorphonuclear leukocytes (PMNs) were isolated to measure reactive oxygen species (ROS) production by flow cytometry and oxygen consumption with a Clark electrode. PMNs were also used to assess leukocyte-endothelial interactions. Circulating levels of adhesion molecules and inflammatory markers were quantified by Luminex's technology, and CIMT was measured as surrogate marker of atherosclerosis. RESULTS: Treatment with GLP-1 RA reduced ROS production and recovered mitochondrial membrane potential, oxygen consumption and MPO levels. The velocity of leukocytes rolling over endothelial cells increased in PMNs from GLP-1 RA-treated patients, whereas rolling and adhesion were diminished. ICAM-1, VCAM-1, IL-6, TNFα and IL-12 protein levels also decreased in the GLP-1 RA-treated group, while IL-10 increased. CIMT was lower in GLP-1 RA-treated T2D patients than in T2D patients without GLP-1 RA treatment. CONCLUSIONS: GLP-1 RA treatment improves the redox state and mitochondrial respiration, and reduces leukocyte-endothelial interactions, inflammation and CIMT in T2D patients, thereby potentially diminishing the risk of atherosclerosis and CVDs.
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Aterosclerose , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Endoteliais , Receptor do Peptídeo Semelhante ao Glucagon 1 , Espessura Intima-Media Carotídea , Espécies Reativas de Oxigênio , Aterosclerose/tratamento farmacológico , Inflamação/tratamento farmacológico , Leucócitos , Endotélio , Peptídeo 1 Semelhante ao GlucagonRESUMO
Extremely variable prevalence rates of atherogenic dyslipidaemia (AD) in type 2 diabetes (T2DM) subjects have been reported. The primary aim was to assess AD prevalence in Spanish T2DM subjects. Secondary objectives were to evaluate the differential clinical characteristics between T2DM subjects with and without AD, to describe lipid profile evolution and use of lipid-lowering treatment in clinical practice by the Spanish Lipid Units. Data was obtained from the National Registry of Dyslipidaemias of the Spanish Atherosclerosis Society, from a multicentric sub-study focused on AD prevalence in T2DM subjects (PREDISAT study). The inclusion criteria were subjects diagnosed of T2DM with age ≥18 years old. A total of 385 T2DM subjects with a mean age of 61 years and 246 (64%) men were included. The mean follow-up was 22 ± 7.4 months. At baseline, 41.3% of the T2DM subjects presented AD, this percentage decreasing to 34.8% with therapeutic intervention. AD prevalence varied in different age groups and appeared to be more prevalent in younger T2DM subjects. Those with AD had a more atherogenic lipid profile at baseline, with higher total cholesterol, triglyceride and non-(high-density lipoprotein) HDL cholesterol levels at baseline, together with lower HDL cholesterol concentrations, without achieving lipid subfraction goals during follow-up. Although almost 90% of the AD subjects were under lipid-lowering treatment, most were receiving only one drug, being statins the most used treatmentA high AD prevalence in T2DM subjects was observed, being age a determinant factor, with a modest decline during follow-up. Although almost 90% of the AD subjects were under lipid-lowering drugs, most were only receiving monotherapy with statins.
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Aterosclerose , Diabetes Mellitus Tipo 2 , Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases , Masculino , Humanos , Pessoa de Meia-Idade , Adolescente , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , HDL-Colesterol , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Dislipidemias/complicações , Aterosclerose/tratamento farmacológico , Aterosclerose/epidemiologiaRESUMO
AIMS AND OBJECTIVES: To evaluate perceived stress, concern about hypoglycaemia and the level of knowledge of management of the disease in patients with type 1 diabetes mellitus and their relationship with glycaemic control, gender and age. BACKGROUND: Perceived stress and concern about hypoglycaemia are significant obstacles to achieving adequate glycaemic control in patients with type 1 diabetes mellitus, and notably influence management of the disease itself. MATERIAL AND METHODS: A cross-sectional study was carried out in 193 adult patients with type 1 diabetes mellitus. Study quality was scored using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cohort studies. Glycaemic control was evaluated by number and type of hypoglycaemic event and glycosylated haemoglobin. Questionnaires about hypoglycaemia concern (HFS II), perceived stress (PSS), unrecognised hypoglycaemia (Clarke Test) and level of knowledge of the disease were completed. RESULTS: Perceived stress was significantly associated with glycosylated haemoglobin (p < 0.001) and concern about hypoglycaemia (p < 0.037). With respect to level of knowledge, we observed that an advanced level was associated with lower glycosylated haemoglobin (p < 0.001), number (p < 0.001) and type (p < 0.001) of hypoglycaemic episode, and less perceived stress (p = 0.006). In addition, age was negatively correlated with perceived stress (p < 0.030) and positively correlated with the number of unrecognised hypoglycaemic episodes (p < 0.002), which was associated, in turn, with a higher number of daily glycaemia tests (p < 0.037) and concern about hypoglycaemia (p < 0.006). CONCLUSION: In type 1 diabetes mellitus, perceived stress can negatively influence glycaemic control and concern about hypoglycaemia, and level of knowledge about the condition has a bearing on glycosylated haemoglobin levels, perceived stress and number and type of hypoglycaemic events. In addition, higher age is associated with more frequent unrecognised hypoglycaemic events. RELEVANCE TO CLINICAL PRACTICE: It is essential to identify and address the psychological needs of patients with type 1 diabetes mellitus with the aim of achieving an adequate management of the disease itself and generating a change in future intervention strategies.
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Diabetes Mellitus Tipo 1 , Hipoglicemia , Adulto , Humanos , Hemoglobinas Glicadas , Controle Glicêmico , Estudos Transversais , Hipoglicemiantes , Estresse Psicológico , InsulinaRESUMO
Gold-ceria nanoparticles (Au/CeO2) are known to have antioxidant properties. However, whether these nanoparticles can provide benefits in type 2 diabetes mellitus (T2D) remains unknown. This work aimed to study the effects of Au/CeO2 nanoparticles at different rates of gold purity (10, 4.4, 1.79 and 0.82) on leukocyte-endothelium interactions and inflammation in T2D patients. Anthropometric and metabolic parameters, leukocyte-endothelium interactions, ROS production and NF-κB expression were assessed in 57 T2D patients and 51 healthy subjects. T2D patients displayed higher Body Mass Index (BMI) and characteristic alterations in carbohydrate and lipid metabolism. ROS production was increased in leukocytes of T2D patients and decreased by Au/CeO2 at 0.82% gold. Interestingly, Au/CeO2 0.82% modulated leukocyte-endothelium interactions (the first step in the atherosclerotic process) by increasing leukocyte rolling velocity and decreasing rolling flux and adhesion in T2D. A static adhesion assay also revealed diminished leukocyte-endothelium interactions by Au/CeO2 0.82% treatment. NF-κB (p65) levels increased in T2D patients and were reduced by Au/CeO2 treatment. Cell proliferation, viability, and apoptosis assays demonstrated no toxicity produced by Au/CeO2 nanoparticles. These results demonstrate that Au/CeO2 nanoparticles at 0.82% exert antioxidant and anti-inflammatory actions in the leukocyte-endothelium interaction of T2D patients, suggesting a protective role against the appearance of atherosclerosis and cardiovascular diseases when this condition exists.
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The chronic low-grade inflammation widely associated with obesity can lead to a prooxidant status that triggers mitochondrial dysfunction. To date, Roux-en-Y gastric bypass (RYGB) is considered the most effective strategy for obese patients. However, little is known about its molecular mechanisms. This interventional study aimed to investigate whether RYGB modulates oxidative stress, inflammation and mitochondrial dynamics in the leukocytes of 47 obese women at one year follow-up. We evaluated biochemical parameters and serum inflammatory cytokines -TNFα, IL6 and IL1ß- to assess systemic status. Total superoxide production -dHe-, mitochondrial membrane potential -TMRM-, leucocyte protein expression of inflammation mediators -MCP1 and NF-kB-, antioxidant defence -GPX1-, mitochondrial regulation-PGC1α, TFAM, OXPHOS and MIEAP- and dynamics -MFN2, MNF1, OPA1, FIS1 and p-DRP1- were also determined. After RYGB, a significant reduction in superoxide and mitochondrial membrane potential was evident, while GPX1 content was significantly increased. Likewise, a marked upregulation of the transcription factors PGC1α and TFAM, complexes of the oxidative phosphorylation chain (I-V) and MIEAP and MFN1 was observed. We conclude that women undergoing RYGB benefit from an amelioration of their prooxidant and inflammatory status and an improvement in mitochondrial dynamics of their leukocytes, which is likely to have a positive effect on clinical outcome.
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Type 2 diabetes is a chronic metabolic disease that affects mitochondrial function. In this context, the rescue mechanisms of mitochondrial health, such as mitophagy and mitochondrial biogenesis, are of crucial importance. The gold standard for the treatment of type 2 diabetes is metformin, which has a beneficial impact on the mitochondrial metabolism. In this study, we set out to describe the effect of metformin treatment on mitochondrial function and mitophagy in peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients. We performed a preliminary cross-sectional observational study complying with CONSORT requirements, for which we recruited 242 subjects, divided into 101 healthy volunteers, 93 metformin-treated type 2 diabetic patients and 48 non-metformin-treated type 2 diabetic patients. Mitochondria from the type 2 diabetic patients not treated with metformin displayed more reactive oxygen species (ROS) than those from healthy or metformin-treated subjects. Protein expression of the electron transport chain (ETC) complexes was lower in PBMCs from type 2 diabetic patients without metformin treatment than in those from the other two groups. Mitophagy was altered in type 2 diabetic patients, evident in a decrease in the protein levels of PINK1 and Parkin in parallel to that of the mitochondrial biogenesis protein PGC1α, both of which effects were reversed by metformin. Analysis of AMPK phosphorylation revealed that its activation was decreased in the PBMCs of type 2 diabetic patients, an effect which was reversed, once again, by metformin. In addition, there was an increase in the serum levels of TNFα and IL-6 in type 2 diabetic patients and this was reversed with metformin treatment. These results demonstrate that metformin improves mitochondrial function, restores the levels of ETC complexes, and enhances AMPK activation and mitophagy, suggesting beneficial clinical implications in the treatment of type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Metformina , Proteínas Quinases Ativadas por AMP/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia , Espécies Reativas de Oxigênio/metabolismoRESUMO
AIM: To validate the psychometric properties of a questionnaire to measure adherence to treatment among people with type 1 diabetes mellitus and to evaluate its relationship with metabolic control. DESIGN: A cross-sectional study of 167 adult people with type 1 diabetes mellitus recruited from the Endocrinology Service of University Hospital Doctor Peset (Spain). METHODS: The validity of the content, construct and reliability of the instrument were evaluated and the results correlated with levels of glycosylated haemoglobin. RESULTS: The questionnaire was composed of 25 items and 5 dimensions, with a score of 25-150 points and an internal consistency of 0.92, according to Cronbach's coefficient α. The content of validity ratio and the construct (exploratory functional analysis, Kaiser-Meyer-Olkin index and Barlett's spherical test) were adequate. We observed a significant correlation between glycosylated haemoglobin levels and treatment adherence. CONCLUSION: The questionnaire to measure adherence to treatment in type 1 diabetes mellitus is consistent, reliable and valid, showing an excellent association with degree of metabolic control.
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Diabetes Mellitus Tipo 1 , Adulto , Estudos Transversais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas , Humanos , Psicometria , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Dapagliflozin is a selective sodium-glucose cotransporter 2 inhibitor (SGLT2i) indicated for the treatment of type 2 diabetes mellitus (T2DM), heart failure (HF) with reduced ejection fraction (EF) and chronic kidney disease (CKD). In monotherapy or as an additive therapy, dapagliflozin aids glycaemic control, is associated with reductions in blood pressure and weight, and promotes a favourable lipid profile. In this review, we address the impact of dapagliflozin on cardiovascular risk factors and common microangiopathic complications such as kidney disease and retinopathy in patients with T2DM. Furthermore, we evaluate its potential beneficial effects on other less frequent complications of diabetes, such as macular oedema, cognitive impairment, non-alcoholic fatty liver disease and respiratory disorders during sleep. Moreover, the underuse of SGLT2i in clinical practice is discussed. Our goal is to help translate this evidence into clinical practice.
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Obesity is characterized by low-grade chronic inflammation, metabolic overload, and impaired endothelial and cardiovascular function. Roux-en-Y gastric bypass (RYGB) results in amelioration of the pro-oxidant status of leukocytes and the metabolic profile. Nevertheless, little is known about the precise mechanism that drives systemic and metabolic improvements following bariatric surgery. In this cohort study, we investigated the effect of RYGB on molecular pathways involving energy homeostasis in leukocytes in 43 obese subjects one year after surgery. In addition to clinical and biochemical parameters, we determined protein expression of systemic proinflammatory cytokines by Luminex®, different markers of inflammation, endoplasmic reticulum (ER) stress, autophagy/mitophagy by western blot, and mitochondrial membrane potential by fluorescence imaging. Bariatric surgery induced an improvement in metabolic outcomes that was accompanied by a systemic drop in hsCRP, IL6, and IL1ß levels, and a slowing down of intracellular inflammatory pathways in leukocytes (NF-κB and MCP-1), an increase in AMPK content, a reduction of ER stress (ATF6 and CHOP), augmented autophagy/mitophagy markers (Beclin 1, ATG5, LC3-I, LC3-II, NBR1, and PINK1), and a decrease of mitochondrial membrane potential. These findings shed light on the specific molecular mechanisms by which RYGB facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis as key mediators of these outcomes. In addition, since leukocytes are particularly exposed to physiological changes, they could be used in routine clinical practice as a good sensor of the whole body's responses.
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Sodium-glucose co-transporter 2 inhibitors (iSGLT2) have been linked to cardiovascular risk reduction in patients with type 2 diabetes (T2D). However, their underlying molecular mechanisms remain unclear. This study aimed to evaluate the effects of empagliflozin, a novel potent and selective iSGLT-2, on anthropometric and endocrine parameters, leukocyte-endothelium interactions, adhesion molecules, ROS production, and NFkB-p65 transcription factor expression. According to standard clinical protocols, sixteen T2D patients receiving 10 mg/day of empagliflozin were followed-up for 24 weeks. Anthropometric and analytical measurements were performed at baseline, 12 weeks, and 24 weeks. Interactions between polymorphonuclear leukocytes and human umbilical vein endothelial cells (HUVECs), serum levels of adhesion molecules (P-Selectin, VCAM-1 and ICAM-1) and pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), mitochondrial ROS levels, antioxidant enzymes (SOD1 and GPX1), and NFkB-p65 were measured. We observed a decrease in body weight, BMI, and HbA1C levels from 12 weeks of treatment, which became more pronounced at 24 weeks and was accompanied by a significant reduction in waist circumference and glucose. Leukocyte-endothelium interactions were reduced due to an enhancement in the leukocyte rolling velocity from 12 weeks onwards, together with a significant decrease in leukocyte rolling flux and adhesion at 24 weeks. Accordingly, a significant decrease in ICAM-1 levels, mitochondrial ROS levels, and IL-6 and NFkB-p65 expression was observed, as well as an increase in SOD1. This pilot study provides evidence of the anti-inflammatory and antioxidant properties of empagliflozin treatment in humans, properties which may underlie its beneficial cardiovascular effects.
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The prevalence of type 2 diabetes mellitus worldwide stands at nearly 9.3% and it is estimated that 20-40% of these patients will develop diabetic kidney disease (DKD). DKD is the leading cause of chronic kidney disease (CKD), and these patients often present high morbidity and mortality rates, particularly in those patients with poorly controlled risk factors. Furthermore, many are overweight or obese, due primarily to insulin compensation resulting from insulin resistance. In the last decade, treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have been shown to be beneficial in renal and cardiovascular targets; however, in patients with CKD, the previous guidelines recommended the use of drugs such as repaglinide or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), plus insulin therapy. However, new guidelines have paved the way for new treatments, such as SGLT2i or GLP1-RA in patients with CKD. Currently, the new evidence supports the use of GLP1-RA in patients with an estimated glomerular filtration rate (eGFR) of up to 15 mL/min/1.73 m2 and an SGLT2i should be started with an eGFR > 60 mL/min/1.73 m2. Regarding those patients in advanced stages of CKD, the usual approach is to switch to insulin. Thus, the add-on of GLP1-RA and/or SGLT2i to insulin therapy can reduce the dose of insulin, or even allow for its withdrawal, as well as achieve a good glycaemic control with no weight gain and reduced risk of hypoglycaemia, with the added advantage of cardiorenal benefits.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêuticoRESUMO
Obese individuals without metabolic comorbidities are categorized as metabolically healthy obese (MHO). MicroRNAs (miRNAs) may be implicated in MHO. This cross-sectional study explores the link between circulating miRNAs and the main components of metabolic syndrome (MetS) in the context of obesity. We also examine oxidative stress biomarkers in MHO vs. metabolically unhealthy obesity (MUO). We analysed 3536 serum miRNAs in 20 middle-aged obese individuals: 10 MHO and 10 MUO. A total of 159 miRNAs were differentially expressed, of which, 72 miRNAs (45.2%) were higher and 87 miRNAs (54.7%) were lower in the MUO group. In addition, miRNAs related to insulin signalling and lipid metabolism pathways were upregulated in the MUO group. Among these miRNAs, hsa-miR-6796-5p and hsa-miR-4697-3p, which regulate oxidative stress, showed significant correlations with glucose, triglycerides, HbA1c and HDLc. Our results provide evidence of a pattern of differentially expressed miRNAs in obesity according to MetS, and identify those related to insulin resistance and lipid metabolism pathways.
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The authors have requested that the following changes be made to their paper [...].
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Metformin is an effective drug against type 2 diabetes (T2D), a pathogenesis in which mitochondrial dysfunction is one of the main players. Thus, our first aim was to describe the effect of metformin on mitochondrial function in an outpatient population with T2D. For analyzing this hypothesis, we performed a preliminary cross-sectional study complying with the STROBE requirements. We studied leukocytes from 139 healthy controls, 39 T2D patients without metformin treatment, and 81 T2D patients who had been on said treatment for at least 1 year. Leukocytes from T2D patients displayed higher total and mitochondrial reactive oxygen species levels, lower mitochondrial membrane potential, and lower oxygen consumption. Moreover, their mitochondria expressed lower mRNA and protein levels of fusion proteins mitofusin-1 (MFN1), mitofusin-2 (MFN2), and optic atrophy 1 (OPA1), and higher protein and gene expression levels of mitochondrial fission protein 1 (FIS1) and dynamin-related protein 1 (DRP-1). In addition, we observed enhanced leukocyte/endothelial interactions in T2D patients. Metformin reversed most of these effects, ameliorating mitochondrial function and dynamics, and reducing the leukocyte/endothelial interactions observed in T2D patients. These results raise the question of whether metformin tackles T2D by improving mitochondrial dysfunction and regulating mitochondrial dynamics. Furthermore, it would seem that metformin modulates the alteration of interactions between leukocytes and the endothelium, a subclinical marker of early atherosclerosis. Antioxid. Redox Signal. 35, 377-385.