Metabolic Syndrome Components in Patients with Pituitary Adenoma.

Pituitary adenomas are benign tumors of the anterior portion of the pituitary gland (adenohypophysis), representing the 25% of all the tumor alterations. Pituitary adenomas are classified by the type of hormone secreted, cellularity, size, and structural alterations by the hormonal segregation. The diagnosis consists on the histopathological identification of cell types and the image-guided by magnetic resonance or tomography; the treatment can be both pharmacological and surgical. Metabolic Syndrome is the set of clinical conditions that increase the risk of cardiovascular diseases with an estimated prevalence of 25% worldwide. The alterations of metabolic syndrome are obesity, hypertension, dyslipidemia, insulin resistance, and diabetes mellitus type II. Pituitary adenomas and metabolic syndrome have an important relationship, hormone-secreting by pituitary adenomas affects a myriad of signaling pathways, which allows a favorable environment for the appearance of the metabolic syndrome. Moreover, patients with pituitary adenomas are shown to have an improvement in metabolic parameters after the medical/surgical treatment. The objective of this review is to explore the possible mechanisms through which PAs contributes to MetSx.

Maternal Consumption of Non-Nutritive Sweeteners during Pregnancy Is Associated with Alterations in the Colostrum Microbiota.

Non-nutritive sweeteners (NNSs) provide a sweet taste to foods and beverages without significantly adding calories. Still, their consumption has been linked to modifications in adult's and children's gut microbiota and the disruption of blood glucose control. Human milk microbiota are paramount in establishing infants' gut microbiota, but very little is known about whether the consumption of sweeteners can alter it. To address this question, we sequenced DNA extracted colostrum samples from a group of mothers, who had different levels of NNS consumption, using the Ion Torrent Platform. Our results show that the "core" of colostrum microbiota, composed of the genera Bifidobacterium, Blautia, Cutibacteium, Staphylococcus, and Streptococcus, remains practically unchanged with the consumption of NNS during pregnancy, but specific genera display significant alterations, such as Staphylococcus and Streptococcus. A significant increase in the unclassified archaea Methanobrevibacter spp. was observed as the consumption frequency of NNS increased. The increase in the abundance of this archaea has been previously linked to obesity in Mexican children. NNS consumption during pregnancy could be related to changes in colostrum microbiota and may affect infants' gut microbiota seeding and their future health.

Role of the renin-angiotensin system in the development of COVID-19-associated neurological manifestations.

SARS-CoV-2 causes COVID-19, which has claimed millions of lives. This virus can infect various cells and tissues, including the brain, for which numerous neurological symptoms have been reported, ranging from mild and non-life-threatening (e.g., headaches, anosmia, dysgeusia, and disorientation) to severe and life-threatening symptoms (e.g., meningitis, ischemic stroke, and cerebral thrombosis). The cellular receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), an enzyme that belongs to the renin-angiotensin system (RAS). RAS is an endocrine system that has been classically associated with regulating blood pressure and fluid and electrolyte balance; however, it is also involved in promoting inflammation, proliferation, fibrogenesis, and lipogenesis. Two pathways constitute the RAS with counter-balancing effects, which is the key to its regulation. The first axis (classical) is composed of angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and angiotensin type 1 receptor (AT1R) as the main effector, which -when activated- increases the production of aldosterone and antidiuretic hormone, sympathetic nervous system tone, blood pressure, vasoconstriction, fibrosis, inflammation, and reactive oxygen species (ROS) production. Both systemic and local classical RAS' within the brain are associated with cognitive impairment, cell death, and inflammation. The second axis (non-classical or alternative) includes ACE2, which converts Ang II to Ang-(1-7), a peptide molecule that activates Mas receptor (MasR) in charge of opposing Ang II/AT1R actions. Thus, the alternative RAS axis enhances cognition, synaptic remodeling, cell survival, cell signal transmission, and antioxidant/anti-inflammatory mechanisms in the brain. In a physiological state, both RAS axes remain balanced. However, some factors can dysregulate systemic and local RAS arms. The binding of SARS-CoV-2 to ACE2 causes the internalization and degradation of this enzyme, reducing its activity, and disrupting the balance of systemic and local RAS, which partially explain the appearance of some of the neurological symptoms associated with COVID-19. Therefore, this review aims to analyze the role of RAS in the development of the neurological effects due to SARS-CoV-2 infection. Moreover, we will discuss the RAS-molecular targets that could be used for therapeutic purposes to treat the short and long-term neurological COVID-19-related sequelae.

Blood-brain Barrier Damage is Pivotal for SARS-CoV-2 Infection to the Central Nervous System.

Transsynaptic transport is the most accepted proposal to explain the SARS-CoV-2 infection of the CNS. Nevertheless, emerging evidence shows that neurons do not express the SARS-CoV-2 receptor ACE2, which highlights the importance of the blood-brain barrier (BBB) in preventing virus entry to the brain. In this study, we examine the presence of SARS-CoV-2 messenger ribonucleic acid (mRNA) and the cytokine profile in cerebrospinal fluids (CSF) from two patients with a brain tumor and COVID-19. To determine the BBB damage, we evaluate the Q- albumin index, which is an indirect parameter to assess the permeability of this structure. The Q-albumin index of the patient with an intraventricular brain tumor suggests that the BBB is undamaged, preventing the passage of SARS-CoV-2 and pro-inflammatory molecules. The development of brain tumors that disrupt the BBB (measured by the Q-albumin index), in this case, a petroclival meningioma (Case 1), allows the free passage of the SARS-CoV-2 virus and probably lets the free transit of pro-inflammatory molecules to the CNS, which leads to a possible activation of the microglia (astrogliosis) and an exacerbated immune response represented by IL-13, IFN-γ, and IL-2 trying to inhibit both the infection and the carcinogenic process.

In Vitro Exposure of Primary Human T Cells and Monocytes to Polyclonal Stimuli Reveals a Basal Susceptibility to Display an Impaired Cellular Immune Response and Develop Severe COVID-19.

The contribution of the cellular immune response to the severity of coronavirus disease 2019 (COVID-19) is still uncertain because most evidence comes from patients receiving multiple drugs able to change immune function. Herein, we conducted a prospective cohort study and obtained blood samples from 128 unvaccinated healthy volunteers to examine the in vitro response pattern of CD4+ and CD8+ T cells and monocyte subsets to polyclonal stimuli, including anti-CD3, anti-CD28, poly I:C, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) recombinant spike S1 protein, and lipopolysaccharide. Then, we started a six-month follow-up and registered 12 participants who got SARS-CoV-2 infection, from whom we retrospectively analyzed the basal immune response pattern of T cells and monocytes. Of the 12 participants infected, six participants developed mild COVID-19 with self-limiting symptoms such as fever, headache, and anosmia. Conversely, six other participants developed severe COVID-19 with pneumonia, respiratory distress, and hypoxia. Two severe COVID-19 cases required invasive mechanical ventilation. There were no differences between mild and severe cases for demographic, clinical, and biochemical baseline characteristics. In response to polyclonal stimuli, basal production of interleukin-2 (IL-2) and interferon (IFN-) gamma significantly decreased, and the programmed cell death protein 1 (PD-1) increased in CD4+ and CD8+ T cells from participants who posteriorly developed severe COVID-19 compared to mild cases. Likewise, CD14++CD16- classical and CD14+CD16+ non-classical monocytes lost their ability to produce IFN-alpha in response to polyclonal stimuli in participants who developed severe COVID-19 compared to mild cases. Of note, neither the total immunoglobulin G serum titers against the virus nor their neutralizing ability differed between mild and severe cases after a month of clinical recovery. In conclusion, using in vitro polyclonal stimuli, we found a basal immune response pattern associated with a predisposition to developing severe COVID-19, where high PD-1 expression and low IL-2 and IFN-gamma production in CD4+ and CD8+ T cells, and poor IFN-alpha expression in classical and non-classical monocytes are linked to disease worsening. Since antibody titers did not differ between mild and severe cases, these findings suggest cellular immunity may play a more crucial role than humoral immunity in preventing COVID-19 progression.

High Incidence Rate of SARS-CoV-2 Infection in Health Care Workers at a Dedicated COVID-19 Hospital: Experiences of the Pandemic from a Large Mexican Hospital.

Health care workers (HCW) are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The incidence of SARS-CoV-2 infection in HCW has been examined in cross-sectional studies by quantitative polymerase chain reaction (qPCR) tests, which may lead to underestimating exact incidence rates. We thus investigated the incidence of SARS-CoV-2 infection in a group of HCW at a dedicated coronavirus disease 2019 (COVID-19) hospital in a six-month follow-up period. We conducted a prospective cohort study on 109 participants of both sexes working in areas of high, moderate, and low SARS-CoV-2 exposure. qPCR tests in nasopharyngeal swabs and anti-SARS-CoV-2 IgG serum antibodies were assessed at the beginning and six months later. Demographic, clinical, and laboratory parameters were analyzed according to IgG seropositivity by paired Student's T-test or the chi-square test. The incidence rate of SARS-CoV-2 infection was considerably high in our cohort of HCW (58%), among whom 67% were asymptomatic carriers. No baseline risk factors contributed to the infection rate, including the workplace. It is still necessary to increase hospital safety procedures to prevent virus transmissibility from HCW to relatives and non-COVID-19 patients during the upcoming waves of contagion.

Ten-Week Sucralose Consumption Induces Gut Dysbiosis and Altered Glucose and Insulin Levels in Healthy Young Adults.

Sucralose consumption alters microbiome and carbohydrate metabolism in mouse models. However, there are no conclusive studies in humans. Our goals were to examine the effect of sucralose consumption on the intestinal abundance of bacterial species belonging to Actinobacteria, Bacteroidetes, and Firmicutes and explore potential associations between microbiome profiles and glucose and insulin blood levels in healthy young adults. In this open-label clinical trial, volunteers randomly drank water, as a control (n = 20), or 48 mg sucralose (n = 20), every day for ten weeks. At the beginning and the end of the study, participants were subjected to an oral glucose tolerance test (OGTT) to measure serum glucose and insulin every 15 min for 3 h and provided fecal samples to assess gut microbiota using a quantitative polymerase chain reaction. Sucralose intake altered the abundance of Firmicutes without affecting Actinobacteria or Bacteroidetes. Two-way ANOVA revealed that volunteers drinking sucralose for ten weeks showed a 3-fold increase in Blautia coccoides and a 0.66-fold decrease in Lactobacillus acidophilus compared to the controls. Sucralose consumption increased serum insulin and the area under the glucose curve compared to water. Long-term sucralose ingestion induces gut dysbiosis associated with altered insulin and glucose levels during an OGTT.

Incidence of neurosurgical pathology of the spine in population of Mexico City.

BACKGROUND: Spine pathologies have been increased in the past years worldwide being important cause of disability which represents significant economic losses. OBJECTIVE: The objective of the study was to establish the incidence of spinal neurosurgical pathology in a national reference hospital in Mexico City (General Hospital of Mexico "Dr. Eduardo Liceaga"). MATERIALS AND METHODS: A descriptive, observational, retrospective, and cross-sectional study was carried out, using the database of all patients that were undergoing spinal surgery from January 2015 to January 2020. Measures of central tendency and percentages, demographic variables, diagnosis, and affected segment were assessed. RESULTS: A total of 341 cases were analyzed, the group of patients with degenerative disease represents the main cause of care followed by neoplasms; trauma and special cases of congenital type and reoperations were the less frequent pathologies between the groups. In general, the most affected age group was 51-60 years. CONCLUSIONS: Within the study population, a wide range of diseases that affect the spine were treated, ranging from degenerative diseases, neoplasms, trauma, congenital, and infectious diseases.

ANTECEDENTES: La incidencia de enfermedades de la columna ha ido en incremento en los últimos años a nivel mundial, las cuales representan una importante causa de incapacidad laboral e importantes pérdidas económicas. OBJETIVO: Establecer la incidencia de enfermedades neuroquirúrgicas de la columna en un hospital nacional de referencia de la Ciudad de México (Hospital General de México "Dr. Eduardo Liceaga"). MATERIALES Y MÉTODOS: Se llevó a cabo un estudio descriptivo, observacional, retrospectivo y transversal utilizando la base de datos de los pacientes que se sometieron a una cirugía de columna de enero del 2015 a enero del 2020. Se evaluaron medidas de tendencia central y porcentajes, variables demográficas, diagnóstico y segmento afectado. RESULTADOS: Se analizaron un total de 341 casos, la enfermedad degenerativa representa la principal causa de atención seguida de las neoplasias y los traumatismos; los casos especiales de tipo congénito y las reintervenciones fueron las patologías menos frecuentes. El grupo de edad más afectado fue de entre 51 a 60 años. CONCLUSIONES: Dentro de la población de estudio se trataron una amplia gama de enfermedades que afectan a la columna, que van desde enfermedades degenerativas, neoplasias, traumatismos, enfermedades congénitas e infecciosas.

The Combined Use of Cytokine Serum Values with Laboratory Parameters Improves Mortality Prediction of COVID-19 Patients: The Interleukin-15-to-Albumin Ratio.

Laboratory parameters display limited accuracy in predicting mortality in coronavirus disease 2019 (COVID-19) patients, as with serum albumin. Emerging evidence suggests that cytokine serum values may enhance the predictive capacity of albumin, especially interleukin (IL)-15. We thus investigated whether the use of the IL-15-to-albumin ratio enables improving mortality prediction at hospital admission in a large group of COVID-19 patients. In this prospective cross-sectional study, we enrolled and followed up three hundred and seventy-eight patients with a COVID-19 diagnosis until hospital discharge or death. Two hundred and fifty-five patients survived, whereas one hundred and twenty-three died. Student's T-test revealed that non-survivors had a significant two-fold increase in the IL-15-to-albumin ratio compared to survivors (167.3 ± 63.8 versus 74.2 ± 28.5), a difference that was more evident than that found for IL-15 or albumin separately. Likewise, mortality prediction considerably improved when using the IL-15-to-albumin ratio with a cut-off point > 105.4, exhibiting an area under the receiver operating characteristic curve of 0.841 (95% Confidence Interval, 0.725-0.922, p < 0.001). As we outlined here, this is the first study showing that combining IL-15 serum values with albumin improves mortality prediction in COVID-19 patients.

Native Low-Density Lipoproteins Act in Synergy with Lipopolysaccharide to Alter the Balance of Human Monocyte Subsets and Their Ability to Produce IL-1 Beta, CCR2, and CX3CR1 In Vitro and In Vivo: Implications in Atherogenesis.

Increasing evidence has demonstrated that oxidized low-density lipoproteins (oxLDL) and lipopolysaccharide (LPS) enhance accumulation of interleukin (IL)-1 beta-producing macrophages in atherosclerotic lesions. However, the potential synergistic effect of native LDL (nLDL) and LPS on the inflammatory ability and migration pattern of monocyte subpopulations remains elusive and is examined here. In vitro, whole blood cells from healthy donors (n = 20) were incubated with 100 µg/mL nLDL, 10 ng/mL LPS, or nLDL + LPS for 9 h. Flow cytometry assays revealed that nLDL significantly decreases the classical monocyte (CM) percentage and increases the non-classical monocyte (NCM) subset. While nLDL + LPS significantly increased the number of NCMs expressing IL-1 beta and the C-C chemokine receptor type 2 (CCR2), the amount of NCMs expressing the CX3C chemokine receptor 1 (CX3CR1) decreased. In vivo, patients (n = 85) with serum LDL-cholesterol (LDL-C) >100 mg/dL showed an increase in NCM, IL-1 beta, LPS-binding protein (LBP), and Castelli's atherogenic risk index as compared to controls (n = 65) with optimal LDL-C concentrations (≤100 mg/dL). This work demonstrates for the first time that nLDL acts in synergy with LPS to alter the balance of human monocyte subsets and their ability to produce inflammatory cytokines and chemokine receptors with prominent roles in atherogenesis.

High Levels of IL-8 and MCP-1 in Cerebrospinal Fluid of COVID-19 Patients with Cerebrovascular Disease.

The coronavirus family has tropism for the Central Nervous System (CNS), however, there is no solid evidence demonstrating that the neurological effects of COVID-19 result from direct viral infection or systemic inflammation. The goals of this study were to examine the cytokine profile and the presence of SARS-CoV-2 messenger ribonucleic acid (mRNA) in cerebrospinal fluids (CSF) from two patients with cerebrovascular disease and COVID-19. Although the SARS-CoV-2 mRNA was not detected in CSF of both patients, we found abnormally high levels of numerous proinflammatory cytokines and chemokines, especially IL-8 and MCP-1. Since these chemokines mediate activation and recruitment of neutrophils, monocytes, and macrophages, it is feasible that cerebrovascular disease related-neuroinflammation found in both patients results from an exacerbated inflammatory response instead of SARS-CoV-2 direct invasion to CNS. These results suggest that neuroinflammation plays a key role in cerebrovascular disease and COVID-19.

The Neutrophil-to-Monocyte Ratio and Lymphocyte-to-Neutrophil Ratio at Admission Predict In-Hospital Mortality in Mexican Patients with Severe SARS-CoV-2 Infection (Covid-19).

There is a deep need for mortality predictors that allow clinicians to quickly triage patients with severe coronavirus disease 2019 (Covid-19) into intensive care units at the time of hospital admission. Thus, we examined the efficacy of the lymphocyte-to-neutrophil ratio (LNR) and neutrophil-to-monocyte ratio (NMR) as predictors of in-hospital death at admission in patients with severe Covid-19. A total of 54 Mexican adult patients with Covid-19 that met hospitalization criteria were retrospectively enrolled, followed-up daily until hospital discharge or death, and then assigned to survival or non-survival groups. Clinical, demographic, and laboratory parameters were recorded at admission. A total of 20 patients with severe Covid-19 died, and 75% of them were men older than 62.90 ± 14.18 years on average. Type 2 diabetes, hypertension, and coronary heart disease were more prevalent in non-survivors. As compared to survivors, LNR was significantly fourfold decreased while NMR was twofold increased. LNR ≤ 0.088 predicted in-hospital mortality with a sensitivity of 85.00% and a specificity of 74.19%. NMR ≥ 17.75 was a better independent risk factor for mortality with a sensitivity of 89.47% and a specificity of 80.00%. This study demonstrates for the first time that NMR and LNR are accurate predictors of in-hospital mortality at admission in patients with severe Covid-19.

Growth hormone ameliorates high glucose-induced steatosis on in vitro cultured human HepG2 hepatocytes by inhibiting de novo lipogenesis via ChREBP and FAS suppression.

OBJECTIVE: Growth hormone (GH) deficiency has been associated with increased steatosis but the molecular mechanism has not been fully elucidated. We investigated the effect of GH on lipid accumulation of HepG2 cells cultured on an in vitro steatosis model and examined the potential involvement of insulin-like growth factor 1 (IGF-1) as well as lipogenic and lipolytic molecules. METHODS: Control and steatosis conditions were induced by culturing HepG2 cells with 5.5 or 25 mmol/l glucose for 24 h, respectively. Afterward, cells were exposed to 0, 5, 10 or 20 ng/ml GH for another 24 h. Lipid content was quantified as well as mRNA and protein levels of IGF-1, carbohydrate responsive element-binding protein (ChREBP), sterol regulatory element-binding protein 1c (SREBP1c), fatty acid synthase (FAS), carnitine palmitoyltransferase 1A (CPT1A), and peroxisome proliferator-activated receptor alpha (PPAR-alpha) by qPCR and western blot, respectively. Data were analyzed by one-way ANOVA and the Games-Howell post-hoc test. RESULTS: In the steatosis model, HepG2 hepatocytes showed a significant 2-fold increase in lipid amount as compared to control cells. IGF-1 mRNA and protein levels were significantly increased in control cells exposed to 10 ng/ml GH, whereas high glucose abolished this effect. High glucose also significantly increased both mRNA and protein of ChREBP and FAS without having effect on SREBP1c, CPT1A and PPAR-alpha. However, GH inhibited ChREBP and FAS production, even in HepG2 hepatocytes cultured under steatosis conditions. CONCLUSIONS: Growth hormone ameliorates high glucose-induced steatosis in HepG2 cells by suppressing de novo lipogenesis via ChREBP and FAS down-regulation.

Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1.

The relationship of uric acid with macrophages has not been fully elucidated. We investigated the effect of uric acid on the proinflammatory ability of human macrophages and then examined the possible molecular mechanism involved. Primary human monocytes were differentiated into macrophages for subsequent exposure to 0, 0.23, 0.45, or 0.9 mmol/L uric acid for 12 h, in the presence or absence of 1 mmol/L probenecid. Flow cytometry was used to measure proinflammatory marker production and phagocytic activity that was quantified as a percentage of GFP-labeled Escherichia coli positive macrophages. qPCR was used to measure the macrophage expression of the urate anion transporter 1 (URAT1). As compared to control cells, the production of tumor necrosis factor-alpha (TNF-alpha), toll-like receptor 4 (TLR4), and cluster of differentiation (CD) 11c was significantly increased by uric acid. In contrast, macrophages expressing CD206, CX3C-motif chemokine receptor 1 (CX3CR1), and C-C chemokine receptor type 2 (CCR2) were significantly reduced. Uric acid progressively increased macrophage phagocytic activity and downregulated URAT1 expression. Probenecid-a non-specific blocker of URAT1-dependent uric acid transport-inhibited both proinflammatory cytokine production and phagocytic activity in macrophages that were exposed to uric acid. These results suggest that uric acid has direct proinflammatory effects on macrophages possibly via URAT1.

Low Serum Interleukin-6 Is a Differential Marker of Obesity-Related Metabolic Dysfunction in Women and Men.

There is scant information regarding the role of interleukin (IL)-6 in obesity-related metabolic dysfunction in humans. Thus, we studied the serum levels of IL-6 in normal weight, overweight, and obese subjects, and examined associations of IL-6 with hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation. One hundred three women and men were included in the study. Anthropometric parameters, blood glucose, insulin, total cholesterol, and triglycerides were measured. Serum levels of tumor necrosis factor-alpha (TNF-alpha), IL-10, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). One-way analysis of variance (ANOVA) showed a 2.5-fold significant decrease in serum IL-6 in overweight and obese individuals when compared with normal weight controls. Serum IL-6 exhibited significant inverse correlations with body mass index (r = -0.39/P < 0.0001), waist circumference (r = -0.42/P < 0.001), blood glucose (r = -0.40/P < 0.0001), triglycerides (r = -0.34/P < 0.0001), and TNF-alpha (r = -0.48/P < 0.0001), whereas a strongly positive correlation was found with IL-10 (r = 0.77/P < 0.0001). Multiple linear regression analysis revealed that behavior of IL-6 was mainly influenced by IL-10 (beta = 0.28/P = 1.95 × 10-6), TNF-alpha (beta = -0.67/P = 0.0017), and body fat percentage (beta = -5.95/P = 7.67 × 10-5) in women. In contrast, IL-10 (beta = 0.37/P = 1.34 × 10-9), TNF-alpha (beta = -0.85/P = 0.0005), and triglycerides (beta = 1.07/P = 0.0007) were major influencing factors of IL-6 in men. This study demonstrates that IL-6 is a marker of metabolic dysfunction that is differentially regulated in obese women and men. [Figure: see text].

M2 macrophage immunotherapy abolishes glucose intolerance by increasing IL-10 expression and AKT activation.

Aim: Glucose intolerance associates with M1/M2 macrophage unbalance. We thus wanted to examine the effect of M2 macrophage administration on mouse model of glucose intolerance. Materials & methods: C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks and then received thrice 20 mg/kg streptozotocin (HFD-GI). Bone marrow-derived stem cells were collected from donor mice and differentiated/activated into M2 macrophages for intraperitoneal administration into HFD-GI mice. Results: M2 macrophage treatment abolished glucose intolerance independently of obesity. M2 macrophage administration increased IL-10 in visceral adipose tissue and serum, but showed no effect on serum insulin. While nitric oxide synthase-2 and arginase-1 remained unaltered, M2 macrophage treatment restored AKT phosphorylation in visceral adipose tissue. Conclusion: M2 macrophage treatment abolishes glucose intolerance by increasing IL-10 and phosphorylated AKT.

A Single 48 mg Sucralose Sip Unbalances Monocyte Subpopulations and Stimulates Insulin Secretion in Healthy Young Adults.

Sucralose is a noncaloric artificial sweetener that is widely consumed worldwide and has been associated with alteration in glucose and insulin homeostasis. Unbalance in monocyte subpopulations expressing CD11c and CD206 hallmarks metabolic dysfunction but has not yet been studied in response to sucralose. Our goal was to examine the effect of a single sucralose sip on serum insulin and blood glucose and the percentages of classical, intermediate, and nonclassical monocytes in healthy young adults subjected to an oral glucose tolerance test (OGTT). This study was a randomized, placebo-controlled clinical trial. Volunteers randomly received 60 mL water as placebo (n = 20) or 48 mg sucralose dissolved in 60 mL water (n = 25), fifteen minutes prior to an OGTT. Blood samples were individually drawn every 15 minutes for 180 minutes for quantifying glucose and insulin concentrations. Monocyte subsets expressing CD11c and CD206 were measured at -15 and 180 minutes by flow cytometry. As compared to controls, volunteers receiving sucralose exhibited significant increases in serum insulin at 30, 45, and 180 minutes, whereas blood glucose values showed no significant differences. Sucralose consumption caused a significant 7% increase in classical monocytes and 63% decrease in nonclassical monocytes with respect to placebo controls. Pearson's correlation models revealed a strong association of insulin with sucralose-induced monocyte subpopulation unbalance whereas glucose values did not show significant correlations. Sucralose ingestion decreased CD11c expression in all monocyte subsets and reduced CD206 expression in nonclassical monocytes suggesting that sucralose does not only unbalance monocyte subpopulations but also alter their expression pattern of cell surface molecules. This work demonstrates for the first time that a 48 mg sucralose sip increases serum insulin and unbalances monocyte subpopulations expressing CD11c and CD206 in noninsulin-resistant healthy young adults subjected to an OGTT. The apparently innocuous consumption of sucralose should be reexamined in light of these results.

Infliximab ameliorates tumor necrosis factor-alpha-induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro.

Insulin resistance is the inability to respond to insulin and is considered a key pathophysiological factor in the development of type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha) can directly contribute to insulin resistance by disrupting the insulin signalling pathway via protein-tyrosine phosphatase 1B (PTP1B) activation, especially in adipocytes. Infliximab (Remicade® ) is a TNF-alpha-neutralizing antibody that has not been fully studied in insulin resistance. We investigated the effect of infliximab on TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro, and examined the possible molecular mechanisms involved. Once differentiated, adipocytes were cultured with 5 mmol L-1 2-deoxy-D-glucose-3 H and stimulated twice with 2 µmol L-1 insulin, in the presence or absence of 5 ng/mL TNF-alpha and/or 10 ng/mL infliximab. Glucose uptake was measured every 20 minutes for 2 hour, and phosphorylated forms of insulin receptor (IR), insulin receptor substrate-2 (IRS-2), protein kinase B (AKT) and PTP1B were determined by Western blotting. TNF-alpha-treated adipocytes showed a significant 64% decrease in insulin-stimulated glucose uptake as compared with control cells, whereas infliximab reversed TNF-alpha actions by significantly improving glucose incorporation. Although IR phosphorylation remained unaltered, TNF-alpha was able to increase PTP1B activation and decrease phosphorylation of IRS-2 and AKT. Notably, infliximab restored phosphorylation of IRS-2 and AKT by attenuating PTP1B activation. This work demonstrates for the first time that infliximab ameliorates TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro by restoring the insulin signalling pathway via PTP1B inhibition. Further clinical research is needed to determine the potential benefit of using infliximab for treating insulin resistance in patients.