Pirfenidone use in fibrotic diseases: What do we know so far?

BACKGROUND: Pirfenidone has demonstrated significant anti-inflammatory and antifibrotic effects in both animal models and some clinical trials. Its potential for antifibrotic activity positions it as a promising candidate for the treatment of various fibrotic diseases. Pirfenidone exerts several pleiotropic and anti-inflammatory effects through different molecular pathways, attenuating multiple inflammatory processes, including the secretion of pro-inflammatory cytokines, apoptosis, and fibroblast activation. OBJECTIVE: To present the current evidence of pirfenidone's effects on several fibrotic diseases, with a focus on its potential as a therapeutic option for managing chronic fibrotic conditions. FINDINGS: Pirfenidone has been extensively studied for idiopathic pulmonary fibrosis, showing a favorable impact and forming part of the current treatment regimen for this disease. Additionally, pirfenidone appears to have beneficial effects on similar fibrotic diseases such as interstitial lung disease, myocardial fibrosis, glomerulopathies, aberrant skin scarring, chronic liver disease, and other fibrotic disorders. CONCLUSION: Given the increasing incidence of chronic fibrotic conditions, pirfenidone emerges as a potential therapeutic option for these patients. However, further clinical trials are necessary to confirm its therapeutic efficacy in various fibrotic diseases. This review aims to highlight the current evidence of pirfenidone's effects in multiple fibrotic conditions.

Detection of sudomotor alterations evaluated by Sudoscan in patients with recently diagnosed type 2 diabetes.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) causes morbidity and affects the quality of life. Before diabetes diagnosis, neuropathic damage may be present. Sudoscan provides accurate measurement of the sudomotor function. This study aimed to assess the abnormalities detected by Sudoscan, offered estimates of DPN prevalence, and investigated the relationship between metabolic and clinical parameters. Additionally, we evaluated the diagnostic accuracy of the Sudoscan compared with monofilament and tuning fork tests for detecting DPN. RESEARCH DESIGN AND METHODS: Cross-sectional descriptive study including patients with type 2 diabetes for <5 years since diagnosis. We investigated the presence of DPN using a 128 Hz tuning fork test, the 10 g monofilament, and the sudomotor dysfunction in feet using Sudoscan. We compared patients with and without alterations in the Sudoscan. A logistic regression model analyzed variables independently associated with sudomotor dysfunction. RESULTS: From 2013 to 2020, 2243 patients were included, 55.1% women, age 51.8 years, and 17.1% with normal weight. Monofilament tests and/or tuning fork examination were abnormal in 29% (95% CI 0.23% to 0.27%) and 619 patients (27.6%, 0.25% to 0.29%) had sudomotor alterations. In logistic regression analysis, age (ß=1.01, 0.005-1.02), diastolic blood pressure (ß=0.98, 0.96-0.99), heart rate (ß=1.01, 1.00-1.02), glucose (ß=1.00, 1.00-1.03), albuminuria (ß=1.001, 1.000-1.001), beta-blockers=1.98, 1.21-3.24) and fibrate use=0.61, 0.43-0.87) were associated with sudomotor dysfunction. The AUC (area under the curve) for Sudoscan was 0.495 (0.469-0.522), with sensitivity and specificity of 24% and 71%, respectively. CONCLUSION: The Sudoscan identified an important proportion of patients with dysfunction, allowing prompt intervention to decrease the risk for complications. TRIAL REGISTRATION NUMBER: NCT02836808.

Metabolomic markers of glucose regulation after a lifestyle intervention in prediabetes.

INTRODUCTION: Disentangling the specific factors that regulate glycemia from prediabetes to normoglycemia could improve type 2 diabetes prevention strategies. Metabolomics provides substantial insights into the biological understanding of environmental factors such as diet. This study aimed to identify metabolomic markers of regression to normoglycemia in the context of a lifestyle intervention (LSI) in individuals with prediabetes. RESEARCH DESIGN AND METHODS: We conducted a single-arm intervention study with 24 weeks of follow-up. Eligible study participants had at least one prediabetes criteria according to the American Diabetes Association guidelines, and body mass index between 25 and 45 kg/m2. LSI refers to a hypocaloric diet and >150 min of physical activity per week. Regression to normoglycemia (RNGR) was defined as achieving hemoglobin A1c (HbA1c) <5.5% in the final visit. Baseline and postintervention plasma metabolomic profiles were measured using liquid chromatography-tandem mass spectrometry. To select metabolites associated with RNGR, we conducted the least absolute shrinkage and selection operator-penalized regressions. RESULTS: The final sample was composed of 82 study participants. Changes in three metabolites were significantly associated with regression to normoglycemia; N-acetyl-D-galactosamine (OR=0.54; 95% CI 0.32 to 0.82), putrescine (OR=0.90, 95% CI 0.81 to 0.98), and 7-methylguanine (OR=1.06; 95% CI 1.02 to 1.17), independent of HbA1c and weight loss. In addition, metabolomic perturbations due to LSI displayed enrichment of taurine and hypotaurine metabolism pathway (p=0.03) compatible with biomarkers of protein consumption, lower red meat and animal fats and higher seafood and vegetables. CONCLUSIONS: Evidence from this study suggests that specific metabolomic markers have an influence on glucose regulation in individuals with prediabetes after 24 weeks of LSI independently of other treatment effects such as weight loss.

Cost-effectiveness of a self-management and comprehensive training intervention in patients with type 2 diabetes up to 5 years of diagnosis in a specialized hospital in Mexico City.

INTRODUCTION: To assess the cost-effectiveness of a multidisciplinary and comprehensive innovative diabetes care program (CAIPaDi) versus usual treatment in public health institutions. RESEARCH DESIGN AND METHODS: Using a cost-effectiveness analysis, we compared the CAIPaDi program versus usual treatment given in Mexican public health institutions. The analysis was based on the IQVIA Core Diabetes Model, a validated simulation model used to estimate long-term clinical outcomes. Data were prospectively obtained from the CAIPaDi program and from public databases and published papers. Health outcomes were expressed in terms of life-years gained and quality-adjusted life years (QALYs). Health and economic outcomes were estimated from a public perspective and discounted at 5% per year over a 20-year horizon. Costs are reported in US dollars (US$) of 2019. A probabilistic sensitivity analysis was performed using life-years gained and QALYs. RESULTS: The CAIPaDi costs on average US$559 (95% CI: -$879 to -$239) less than the usual treatment (95% CI: -$879 to -$239) and produced a difference in mean life-years gained (0.48, 95% CI: 0.45 to 0.52) and mean QALYs (1.43, 95% CI: 1.40 to 1.46). The cost-effectiveness ratio resulted in a saving per life-year gained of -US$1155 (95% CI: -$1962 to -$460). Mean differences in QALYs resulted in a saving per QALY of -US$735 (95% CI: -$1193 to -$305). Probabilistic sensitivity analysis proved the results are robust on both life-years gained and QALYs. CONCLUSIONS: CAIPaDi has a better cost-effectiveness ratio than the usual therapy in Mexican public health institutions.

Primary Barriers of Adherence to a Structured Nutritional Intervention in Patients with Dyslipidemia.

PURPOSE: To describe the primary barriers to adequately adhering to a structured nutritional intervention. PATIENTS AND METHODS: A total of 106 participants diagnosed with dyslipidemia and without a medical nutrition therapeutic plan were included in this two-year study conducted at the INCMNSZ dyslipidemia clinic in Mexico City. All patients were treated with the same structured strategies, including three face-to-face visits and two telephone follow-up visits. Diet plan adherence was evaluated at each site visit through a 3-day or 24-h food recall. RESULTS: Barriers to adhere to the nutritional intervention were: lack of time to prepare their meals (23%), eating outside the home (19%), unwillingness to change dietary patterns (14%), and lack of information about a correct diet for dyslipidemias (14%). All barriers decreased significantly at the end of the intervention. Female gender, current smoking, and following a plan of more than 1500 kcal (R2 = 0.18 and p-value = 0.004) were associated with good diet adherence. Participants showed good levels of adherence to total caloric intake at visit 2 and 3, reporting 104.7% and 95.4%, respectively. Adherence to macronutrient intake varied from 65.1% to 126%, with difficulties in adhering to recommended carbohydrate and fat consumption being more notable. CONCLUSION: The study findings confirm that a structured nutritional intervention is effective in reducing barriers and improving dietary adherence and metabolic control in patients with dyslipidemias. Health providers must identify barriers to adherence early on to design interventions that reduce these barriers and improve adherence.

Liver fibrosis in patients with metabolic associated fatty liver disease is a risk factor for adverse outcomes in COVID-19.

BACKGROUND: Metabolic diseases are risk factors for severe Coronavirus disease (COVID-19), which have a close relationship with metabolic dysfunction-associated fatty liver disease (MAFLD). AIMS: To evaluate the presence of MAFLD and fibrosis in patients with COVID-19 and its association with prognosis. METHODS: Retrospective cohort study. In hospitalized patients with COVID-19, the presence of liver steatosis was determined by computed tomography scan (CT). Liver fibrosis was assessed using the NAFLD fibrosis score (NFS score), and when altered, the AST to platelet ratio index (APRI) score. Mann-Whitney U, Student´s t-test, logistic regression analysis, Kaplan-Meier curves and Cox regression analysis were used. RESULTS: 432 patients were analyzed, finding steatosis in 40.6%. No differences in pulmonary involvement on CT scan, treatment, or number of days between the onset of symptoms and hospital admission were found between patients with and without MAFLD. The presence of liver fibrosis was associated with higher severity scores, higher levels of inflammatory markers, requirement of mechanical ventilation, incidence of acute kidney injury (AKI), and higher mortality than patients without fibrosis. CONCLUSION: The presence of fibrosis rather than the presence of MAFLD is associated with increased risk for mechanical ventilation, development of AKI, and higher mortality in COVID-19 patients.

Clinician prescription of lipid-lowering drugs and achievement of treatment goals in patients with newly diagnosed type 2 diabetes mellitus.

INTRODUCTION: Lipid control is essential in type 2 diabetes mellitus (T2DM). The aim of this study is to investigate factors associated with lipid therapy adherence and achievement of goals in real-life setting among patients with recently diagnosed T2DM. RESEARCH DESIGN AND METHODS: This is a longitudinal analysis in a center of comprehensive care for patients with diabetes. We include patients with T2DM, <5 years of diagnosis, without disabling complications (eg, amputation, myocardial infarct, stroke, proliferative retinopathy, glomerular filtration rate <60 mL/min/m2) and completed 2-year follow-up. The comprehensive diabetes care model includes 9 interventions in 4 initial visits and annual evaluations. Endocrinologists follow the clinic's guideline and adapt therapy to reach risk-based treatment goal. The main outcome measures were the proportion of patients meeting low-density lipoprotein cholesterol (c-LDL) (<100 mg/dL) and triglycerides (<150 mg/dL) and proportion of patients taking statin, fibrate or combination at baseline, 3 months and annual evaluations. RESULTS: We included 288 consecutive patients (54±9 years, 53.8% women), time since T2DM diagnosis 1 (0-5) year. Baseline, 10.8% patients were receiving statin therapy (46.5% moderate-intensity therapy and 4.6% high-intensity therapy), 8.3% fibrates and 4.2% combined treatment. The proportion of patients with combined treatment increased to 41.6% at 3 months, decreased to 20.8% at 1 year and increased to 38.9% at 2 years of evaluation. Patients receiving treatment met LDL and triglycerides goals at 3 months (17% vs 59.7%, relative ratio (RR)=0.89, 95% CI 0.71 to 1.12), at 1 year (17% vs 26.7%, RR=0.62, 95% CI 0.41 to 0.95) and at 2 years (17% vs 29.9%, RR=0.63, 95% CI 0.43 to 0.93). Main reasons for medication suspension: patient considered treatment was not important (37.5%) and other physician suspended treatment (31.3%). CONCLUSION: 88.2% of patients with T2DM required lipid-lowering drugs. Education for patients and physicians is critical to achieve and maintain diabetes goals. TRIAL REGISTRATION NUMBER: NCT02836808.

Impact of undiagnosed type 2 diabetes and pre-diabetes on severity and mortality for SARS-CoV-2 infection.

INTRODUCTION: Diabetes and hyperglycemia are risk factors for critical COVID-19 outcomes; however, the impact of pre-diabetes and previously unidentified cases of diabetes remains undefined. Here, we profiled hospitalized patients with undiagnosed type 2 diabetes and pre-diabetes to evaluate its impact on adverse COVID-19 outcomes. We also explored the role of de novo and intrahospital hyperglycemia in mediating critical COVID-19 outcomes. RESEARCH DESIGN AND METHODS: Prospective cohort of 317 hospitalized COVID-19 cases from a Mexico City reference center. Type 2 diabetes was defined as previous diagnosis or treatment with diabetes medication, undiagnosed diabetes and pre-diabetes using glycosylated hemoglobin (HbA1c) American Diabetes Association (ADA) criteria and de novo or intrahospital hyperglycemia as fasting plasma glucose (FPG) ≥140 mg/dL. Logistic and Cox proportional regression models were used to model risk for COVID-19 outcomes. RESULTS: Overall, 159 cases (50.2%) had type 2 diabetes and 125 had pre-diabetes (39.4%), while 31.4% of patients with type 2 diabetes were previously undiagnosed. Among 20.0% of pre-diabetes cases and 6.1% of normal-range HbA1c had de novo hyperglycemia. FPG was the better predictor for critical COVID-19 compared with HbA1c. Undiagnosed type 2 diabetes (OR: 5.76, 95% CI 1.46 to 27.11) and pre-diabetes (OR: 4.15, 95% CI 1.29 to 16.75) conferred increased risk of severe COVID-19. De novo/intrahospital hyperglycemia predicted critical COVID-19 outcomes independent of diabetes status. CONCLUSIONS: Undiagnosed type 2 diabetes, pre-diabetes and de novo hyperglycemia are risk factors for critical COVID-19. HbA1c must be measured early to adequately assess individual risk considering the large rates of undiagnosed type 2 diabetes in Mexico.

PCSK-9 Inhibitors in a Real-World Setting and a Comparison Between Alirocumab and Evolocumab in Heterozygous FH Patients.

A real-world setting study of familial hypercholesterolemia (FH) patients who received Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in a specialized referral center in Mexico City. Ten patients between the ages of 18 and 70 years, with a diagnosis of FH according to Dutch Lipid Clinic Network (DLCN) criteria, with failure to achieve their Low-density lipoprotein Cholesterol (LDL-C) goals, and with standard therapy between 2016 and 2017 enrolled in a simple randomization in which a group of 5 participants received alirocumab (75 mg every 2 weeks) and the remaining 5 patients received evolocumab (140 mg every 2 weeks). Comparative analysis was made, analyzing the means of LDL at baseline at 4, 6, and 12 weeks. The evolocumab group had an average initial LDL-C of 277 mg/dL, which, after 12 weeks of treatment, was significantly reduced to 116 mg/dL; P = 0.04 (95% confidence interval [CI]: 11.5-310.9). The alirocumab group with a mean initial LDL-C of 229 mg/dL showed a reduction of LDL-C levels at 12 weeks of treatment to 80 mg/dL; P = 0.008 (95% CI: 63.8-233.7). In conclusion, PCSK9 inhibitors are an excellent treatment option in patients with FH who do not reach their LDL-C goals with standard therapy or due to intolerance to the standard therapy. There is no difference in the lipid-lowering effect between both PSCK9 inhibitors.

Development and validation of a tool for predicting type 2 diabetes in Mexican women of reproductive age / Desarrollo y validación de una herramienta de predicción de diabetes tipo 2 en mujeres mexicanas en edad reproductiva

INTRODUCTION: Diabetes is a worldwide problem with a greater impact in developing countries, where many people are unaware of their risk. In Mexico, women show the greatest risk for T2D. Current risk scores have been developed and validated in predominantly older European cohorts. They are not the best option in Mexican women. The development of a risk model/score in this population would be useful. OBJECTIVE: To develop and validate a risk model and score that incorporates the most relevant risk factors for T2D in Mexican women of reproductive age. METHODS: The study was carried out in two phases, with the first phase being the development of the predictive model and the second phase the validation of the model in a separate independent population. A cohort of Mexican patients of reproductive age ("Derivation Cohort") was used to create the predictive model. It included data on 3161 women. Risk factors for identification were assessed using Cox proportional hazards regression. Finally a score with a range of 0 to 19 points was developed to identify the 2.4 year probability of developing DM2 in Mexican women of reproductive age. RESULTS: 147 new cases of T2D (4.6%) were identified in the Derivation Cohort model, 97 of 925 participants (10.48%) in the validation cohort. The risk factor predictors of T2D were: history of gestational diabetes (HR 2.69, 95% CI 1.10-6.58), BMI (HR 1.03, 95% CI 1.01-1.06), hypertriglyceridemia (HR 1.54, 95% CI 1.11-2.14) and fasting blood glucose (HR 1.06, 95% CI 1.05-1.08), with an AUC of 0.75. The AUC in the validation cohort was 0.91 (95% CI 0.87-0.94). The score had a sensitivity of 73% and specificity of 67% at a cutoff of ≥15. CONCLUSIONS: A predictive model and risk score was developed to detect cases at risk for incident T2D. It was generated using the characteristics of Mexican women of reproductive age. This risk score is a step forward in attempting to address the generational legacy that diabetes in pregnancy could have on women and their children

INTRODUCCIÓN: La diabetes es un problema mundial con mayor impacto en los países en desarrollo, donde muchas personas desconocen su riesgo. En México las mujeres muestran un mayor riesgo de diabetes tipo 2 (DT2). Las escalas de riesgo actuales se han desarrollado y validado principalmente en cohortes europeas de edad avanzada y no representan la mejor opción para las mujeres mexicanas. El desarrollo de un modelo/puntaje de riesgo en esta población sería útil. OBJETIVO: Desarrollar y validar un modelo y escala de riesgo que incorpore los factores de riesgo de la DT2 más relevantes en las mujeres mexicanas en edad reproductiva. MÉTODOS: El estudio se realizó en 2 fases, en la primera se desarrolló el modelo predictivo en una cohorte de 3.161 mujeres mexicanas en edad reproductiva (cohorte de derivación) y en la segunda se validó en una población independiente. Se utilizó una regresión de riesgos proporcionales de Cox. Finalmente se desarrolló una escala de riesgo de 0 a 19, para identificar la probabilidad de desarrollar DT2 en 2,4 años en las mujeres mexicanas en edad reproductiva. El punto de corte fue ≥15, con una sensibilidad del 73% y una especificidad del 67%. RESULTADOS: Se identificaron 147 (4,6%) casos nuevos de DT2 en la cohorte de derivación del modelo y 97 de 925 (10,48%) en la cohorte de validación. Los factores de riesgo predictivos de DT2 fueron: historia de diabetes gestacional (HR: 2,69; IC 95%: 1,10-6,58), IMC (HR: 1,03; IC 95%: 1,01-1,06), hipertrigliceridemia (HR: 1,54; IC 95%: 1,11-2,14) y glucosa de ayuno (HR: 1,06; IC 95%: 1,05-1,08), con AUC de 0,75 y 0,91 (IC 95%: 0,87-0,95) en la cohorte de validación. CONCLUSIONES: Se desarrolló un modelo y score de riesgo para detectar casos en riesgo de diabetes incidente. Esta herramienta fue generada empleando las características de las mujeres mexicanas en edad reproductiva. El score de riesgo es un paso adelante al tratar de abordar el legado generacional que la diabetes en el embarazo podría tener sobre las mujeres y sus hijos

The type 2 diabetes-specific dementia risk score (DSDRS) is associated with frailty, cognitive and functional status amongst Mexican community-dwelling older adults.

BACKGROUND: The type 2 diabetes (T2D) specific dementia-risk score (DSDRS) was developed to evaluate dementia risk in older adults with T2D. T2D-related factors have been shown increase the risk of age-related conditions, which might also increase dementia risk. Here, we investigate the associations of DSDRS with frailty, disability, quality of life (QoL) and cognition in community-dwelling older adults with T2D. METHODS: We included 257 community-dwelling older adults with T2D to evaluate the association between DSDRS and Mini-mental state examination (MMSE), Isaac's set-test (IST), clock drawing test (CDT), quality of life (SF-36), risk of malnutrition (Mini-Nutritional Assessment or MNA), as well as frailty, Katz' and Lawton-Brody scores. We also assessed the phenotype and correlates of high-estimated dementia risk by assessing individuals with DSDRS >75th age-specific percentiles. RESULTS: Mean age of participants was 78.0 ± 6.2 years. DSDRS showed a significant correlation with MMSE test, IST, CDT, SF-36, MNA, Lawton-Brody and Katz scores, and an increasing number of frailty components. DSDRS was higher among frail, pre-frail, and subjects with limited ADL and IADL (p < 0.001). Participants with DSDRS >75th age-specific percentiles had lower education, MMSE, IST, SF-36, MNA, Katz, Lawton-Brody, and higher frailty scores. High-estimated 10-year dementia risk was associated with ADL and IADL disability, frailty and risk of malnutrition. When assessing individual components of DSDRS, T2D-related microvascular complications were associated to all outcome measures. CONCLUSION: The DSDRS is associated with frailty, disability, malnutrition and lower cognitive performance. These findings support that T2D-related factors have significant burden on functional status, QoL, disability and dementia risk.

Clinical characterization of data-driven diabetes subgroups in Mexicans using a reproducible machine learning approach.

INTRODUCTION: Previous reports in European populations demonstrated the existence of five data-driven adult-onset diabetes subgroups. Here, we use self-normalizing neural networks (SNNN) to improve reproducibility of these data-driven diabetes subgroups in Mexican cohorts to extend its application to more diverse settings. RESEARCH DESIGN AND METHODS: We trained SNNN and compared it with k-means clustering to classify diabetes subgroups in a multiethnic and representative population-based National Health and Nutrition Examination Survey (NHANES) datasets with all available measures (training sample: NHANES-III, n=1132; validation sample: NHANES 1999-2006, n=626). SNNN models were then applied to four Mexican cohorts (SIGMA-UIEM, n=1521; Metabolic Syndrome cohort, n=6144; ENSANUT 2016, n=614 and CAIPaDi, n=1608) to characterize diabetes subgroups in Mexicans according to treatment response, risk for chronic complications and risk factors for the incidence of each subgroup. RESULTS: SNNN yielded four reproducible clinical profiles (obesity related, insulin deficient, insulin resistant, age related) in NHANES and Mexican cohorts even without C-peptide measurements. We observed in a population-based survey a high prevalence of the insulin-deficient form (41.25%, 95% CI 41.02% to 41.48%), followed by obesity-related (33.60%, 95% CI 33.40% to 33.79%), age-related (14.72%, 95% CI 14.63% to 14.82%) and severe insulin-resistant groups. A significant association was found between the SLC16A11 diabetes risk variant and the obesity-related subgroup (OR 1.42, 95% CI 1.10 to 1.83, p=0.008). Among incident cases, we observed a greater incidence of mild obesity-related diabetes (n=149, 45.0%). In a diabetes outpatient clinic cohort, we observed increased 1-year risk (HR 1.59, 95% CI 1.01 to 2.51) and 2-year risk (HR 1.94, 95% CI 1.13 to 3.31) for incident retinopathy in the insulin-deficient group and decreased 2-year diabetic retinopathy risk for the obesity-related subgroup (HR 0.49, 95% CI 0.27 to 0.89). CONCLUSIONS: Diabetes subgroup phenotypes are reproducible using SNNN; our algorithm is available as web-based tool. Application of these models allowed for better characterization of diabetes subgroups and risk factors in Mexicans that could have clinical applications.

Development and validation of a tool for predicting type 2 diabetes in Mexican women of reproductive age.

INTRODUCTION: Diabetes is a worldwide problem with a greater impact in developing countries, where many people are unaware of their risk. In Mexico, women show the greatest risk for T2D. Current risk scores have been developed and validated in predominantly older European cohorts. They are not the best option in Mexican women. The development of a risk model/score in this population would be useful. OBJECTIVE: To develop and validate a risk model and score that incorporates the most relevant risk factors for T2D in Mexican women of reproductive age. METHODS: The study was carried out in two phases, with the first phase being the development of the predictive model and the second phase the validation of the model in a separate independent population. A cohort of Mexican patients of reproductive age ("Derivation Cohort") was used to create the predictive model. It included data on 3161 women. Risk factors for identification were assessed using Cox proportional hazards regression. Finally a score with a range of 0 to 19 points was developed to identify the 2.4 year probability of developing DM2 in Mexican women of reproductive age. RESULTS: 147 new cases of T2D (4.6%) were identified in the Derivation Cohort model, 97 of 925 participants (10.48%) in the validation cohort. The risk factor predictors of T2D were: history of gestational diabetes (HR 2.69, 95% CI 1.10-6.58), BMI (HR 1.03, 95% CI 1.01-1.06), hypertriglyceridemia (HR 1.54, 95% CI 1.11-2.14) and fasting blood glucose (HR 1.06, 95% CI 1.05-1.08), with an AUC of 0.75. The AUC in the validation cohort was 0.91 (95% CI 0.87-0.94). The score had a sensitivity of 73% and specificity of 67% at a cutoff of ≥15. CONCLUSIONS: A predictive model and risk score was developed to detect cases at risk for incident T2D. It was generated using the characteristics of Mexican women of reproductive age. This risk score is a step forward in attempting to address the generational legacy that diabetes in pregnancy could have on women and their children.

Intermittent Fasting as Part of the Management for T2DM: from Animal Models to Human Clinical Studies.

PURPOSE OF REVIEW: Diet is a pillar of type 2 diabetes mellitus (T2DM) management. Intermittent fasting (IF) is postulated as a novel approach, able to improve glucose control and potentially capable of reversing some of the pathophysiological alterations of this condition. In this review, the molecular and clinical evidence of diets based on intermittent energy restriction (IER) in laboratory animal models and subjects with type 2 diabetes is discussed. The mechanisms through which IF are thought to improve glucose homeostasis and reverse ß cell failure are also reviewed. RECENT FINDINGS: Studies derived from murine models suggest that IER is associated with improvements in ß cell function and insulin resistance. Two main mechanisms have been demonstrated, one derived from the autophagy-lysosome pathway and, the other from an increase in neurogenin3 (Ngn3) levels (a marker for endocrine progenitor cells like ß cells during development). Notably, IER also promotes reconstruction of gut microbiota. In mice, all effects were independent of weight loss. By contrast, in human studies, outcomes are widely attributable to weight loss. The more consistent results are reductions in body weight, visceral fat, and glucose and insulin levels. Increases in HDL cholesterol levels are also frequently reported. The decrease in insulin levels observed in humans is in opposition with the increase reported in mice, suggesting that the main mechanism in humans is an improvement in peripheral insulin action. Recommending diets based on intermittent fasting in humans is based on the promising results found in animal models where an improvement in ß cell function has been recorded. ß cell function after IF has not been assessed in human subjects with T2DM. This review provides information regarding different protocols for the implementation of IF in diabetic persons and also provides important safety advice in order to avoid adverse effects. Clinical studies do not show an increased risk of hypoglycemia, and a recent case series reported reversal of T2DM.

[Impact of different front-of-pack nutrition labels on foods according to their nutritional quality: a comparative study in Mexico]. / Impacto de diferentes etiquetados frontales de alimentos según su calidad nutricional: estudio comparativo en México.

OBJECTIVE: This study aimed to compare consumers' objec- tive understanding of five FoPLs [Health Star Rating system (HSR), Multiple Traffic Lights (MTL), Nutri-Score, Reference Intakes (RIs), Warning Symbol] in Mexico. MATERIALS AND METHODS: 1 001 Mexican consumers were recruited and asked to rank three sets of label-free products according to their nutritional quality, via a survey. Upon completion of this task, participants were randomized to one of five FoPL condi- tions and were again asked to rank the same sets of products, this time with a FoPL displayed on pack. Change in ability to correctly rank products across the two tasks was assessed by FoPL using ordinal logistic regression. RESULTS: Nutri-Score and MTL performed best, followed Warning Symbol, HSR and RIs. CONCLUSIONS: Nutri-Score and MTL appear as efficient schemes to inform consumers on the nutritional quality of foods, in particular in Mexico, where it would be a helpful tool for consumers in purchasing situations.

OBJETIVO: Evaluar la comprensión objetiva de cinco tipos de etiquetados frontales de paquetes (EFP) (Sistema de Clasifi- cación de Estrellas de Salud, Semáforo Múltiple, Nutri-Score, Ingestas de Referencia y Símbolo de Advertencia) en México. MATERIAL Y MÉTODOS: Se reclutaron 1 001 consumidores mexicanos para clasificar tres productos de tres categorías de alimentos sin EFP, según su calidad nutricional. Se les asignó al azar uno de los cinco EFP para clasificar los mismos productos, esta vez con un EFP en el empaque. El cambio en la capacidad para clasificar correctamente los productos en las dos tareas fue evaluado por EFP, utilizando un modelo de regresión logística ordinal. RESULTADOS: Nutri-Score y Semáforo Múltiple obtuvieron un mejor desempeño, seguidos del Símbolo de Advertencia, Sistema de Clasificación de Estrellas de Salud e Ingestas de Referencia. CONCLUSIONES: Nutri-Score y el Semáforo Múltiple surgen como esquemas eficientes para informar a los consumidores sobre la calidad nutricional de los alimentos en México, donde podrían ser una herramienta útil para los consumidores en situación de compra.

Impacto de diferentes etiquetados frontales de alimentos según su calidad nutricional: estudio comparativo en México / Impact of different front-of-pack nutrition labels on foods according to their nutritional quality: a comparative study in Mexico

Resumen: Objetivo: Evaluar la comprensión objetiva de cinco tipos de etiquetados frontales de paquetes (EFP) (Sistema de Clasificación de Estrellas de Salud, Semáforo Múltiple, Nutri-Score, Ingestas de Referencia y Símbolo de Advertencia) en México. Material y métodos: Se reclutaron 1 001 consumidores mexicanos para clasificar tres productos de tres categorías de alimentos sin EFP, según su calidad nutricional. Se les asignó al azar uno de los cinco EFP para clasificar los mismos productos, esta vez con un EFP en el empaque. El cambio en la capacidad para clasificar correctamente los productos en las dos tareas fue evaluado por EFP, utilizando un modelo de regresión logística ordinal. Resultados: Nutri-Score y Semáforo Múltiple obtuvieron un mejor desempeño, seguidos del Símbolo de Advertencia, Sistema de Clasificación de Estrellas de Salud e Ingestas de Referencia. Conclusión: Nutri-Score y el Semáforo Múltiple surgen como esquemas eficientes para informar a los consumidores sobre la calidad nutricional de los alimentos en México, donde podrían ser una herramienta útil para los consumidores en situación de compra.

Abstract: Objective: This study aimed to compare consumers' objective understanding of five FoPLs [Health Star Rating system (HSR), Multiple Traffic Lights (MTL), Nutri-Score, Reference Intakes (RIs), Warning Symbol] in Mexico. Materials and methods: 1 001 Mexican consumers were recruited and asked to rank three sets of label-free products according to their nutritional quality, via a survey. Upon completion of this task, participants were randomized to one of five FoPL conditions and were again asked to rank the same sets of products, this time with a FoPL displayed on pack. Change in ability to correctly rank products across the two tasks was assessed by FoPL using ordinal logistic regression. Results: Nutri-Score and MTL performed best, followed Warning Symbol, HSR and RIs. Conclusion: Nutri-Score and MTL appear as efficient schemes to inform consumers on the nutritional quality of foods, in particular in Mexico, where it would be a helpful tool for consumers in purchasing situations.

Pathophysiological Mechanisms Linking Type 2 Diabetes and Dementia: Review of Evidence from Clinical, Translational and Epidemiological Research.

BACKGROUND: Type 2 diabetes represents an increasing health burden world-wide and its prevalence in particularly higher in elderly population. Consistent epidemiological evidence suggests an increased risk of dementia associated to type 2 diabetes; the mechanisms underlying these associations, however, remain unclear. OBJECTIVE: The study aims to review epidemiological, clinical and pre-clinical data that weigh on pathophysiological links, mechanisms of disease and associations between type 2 diabetes and dementia to identify areas of opportunity for future research. METHODS: We searched the following electronic bibliographic databases: PUBMED, EMBASE, SCIELO, MEDLINE and OVID for clinical, translational and epidemiological research literature that summarize diabetes-related risk factors for dementia, metabolic and neurological changes associated to T2D, evidence of therapeutic approaches in type 2 diabetes and its pathophysiological implications for dementia. RESULTS: Type 2 diabetes mellitus increases risk for all-cause dementia, vascular dementia and Alzheimer's disease. The most evaluated mechanisms linking both disorders in pre-clinical studies include an increase in neuronal insulin resistance, impaired insulin signaling, pro-inflammatory state, mitochondrial dysfunction and vascular damage which increase deposition of ß-amyloid, tau proteins and GSK3ß, leading to an earlier onset of dementia in individuals with impairment in the glucose metabolism. Neuroimaging and neuropathology evidence linking cerebrovascular lesions, neurodegeneration and particularly small-vessel disease in the onset of dementia is consistent with the increased risk of incident dementia in type 2 diabetes, but consistent evidence of AD-related pathology is scarce. Epidemiological data shows increased risk of dementia related to hypoglycemic episodes, glycemic control, metabolic syndrome, insulin resistance and genetic predisposition, but the evidence is not consistent and statistical analysis might be affected by inconsistent covariate controlling. Therapeutic approaches for T2D have shown inconsistent result in relation to dementia prevention and delay of cognitive decline; lifestyle intervention, particularly physical activity, is a promising alternative to ameliorate the impact of disability and frailty on T2D-related dementia. CONCLUSION: Vascular disease, inflammation and impaired brain insulin signaling might occur in T2D and contribute to dementia risk. Evidence from epidemiological studies has not consistently reported associations that could integrate a unified mechanism of disease in humans. Evaluation of the effect of antidiabetic medications and non-pharmacological interventions in dementia prevention in type 2 diabetes is promising but has thus far offered inconsistent results.

A panel of 32 AIMs suitable for population stratification correction and global ancestry estimation in Mexican mestizos.

BACKGROUND: Association studies are useful to unravel the genetic basis of common human diseases. However, the presence of undetected population structure can lead to both false positive results and failures to detect genuine associations. Even when most of the approaches to deal with population stratification require genome-wide data, the use of a well-selected panel of ancestry informative markers (AIMs) may appropriately correct for population stratification. Few panels of AIMs have been developed for Latino populations and most contain a high number of markers (> 100 AIMs). For some association studies such as candidate gene approaches, it may be unfeasible to genotype a numerous set of markers to avoid false positive results. In such cases, methods that use fewer AIMs may be appropriate. RESULTS: We validated an accurate and cost-effective panel of AIMs, for use in population stratification correction of association studies and global ancestry estimation in Mexicans, as well as in populations having large proportions of both European and Native American ancestries. Based on genome-wide data from 1953 Mexican individuals, we performed a PCA and SNP weights were calculated to select subsets of unlinked AIMs within percentiles 0.10 and 0.90, ensuring that all chromosomes were represented. Correlations between PC1 calculated using genome-wide data versus each subset of AIMs (16, 32, 48 and 64) were r2 = 0.923, 0.959, 0.972 and 0.978, respectively. When evaluating PCs performance as population stratification adjustment covariates, no correlation was found between P values obtained from uncorrected and genome-wide corrected association analyses (r2 = 0.141), highlighting that population stratification correction is compulsory for association analyses in admixed populations. In contrast, high correlations were found when adjusting for both PC1 and PC2 for either subset of AIMs (r2 > 0.900). After multiple validations, including an independent sample, we selected a minimal panel of 32 AIMs, which are highly informative of the major ancestral components of Mexican mestizos, namely European and Native American ancestries. Finally, the correlation between the global ancestry proportions calculated using genome-wide data and our panel of 32 AIMs was r2 = 0.972. CONCLUSIONS: Our panel of 32 AIMs accurately estimated global ancestry and corrected for population stratification in association studies in Mexican individuals.

FAMILIAL COMBINED HYPERLIPIDEMIA: CURRENT KNOWLEDGE, PERSPECTIVES, AND CONTROVERSIES.

Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hypertriglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review. (REV INVEST CLIN. 2018;70:224-36).

Optimization of kidney dysfunction prediction in diabetic kidney disease using targeted metabolomics.

AIMS: Metabolomics have been used to evaluate the role of small molecules in human disease. However, the cost and complexity of the methodology and interpretation of findings have limited the transference of knowledge to clinical practice. Here, we apply a targeted metabolomics approach using samples blotted in filter paper to develop clinical-metabolomics models to detect kidney dysfunction in diabetic kidney disease (DKD). METHODS: We included healthy controls and subjects with type 2 diabetes (T2D) with and without DKD and investigated the association between metabolite concentrations in blood and urine with eGFR and albuminuria. We also evaluated performance of clinical, biochemical and metabolomic models to improve kidney dysfunction prediction in DKD. RESULTS: Using clinical-metabolomics models, we identified associations of decreased eGFR with body mass index (BMI), uric acid and C10:2 levels; albuminuria was associated to years of T2D duration, A1C, uric acid, creatinine, protein intake and serum C0, C10:2 and urinary C12:1 levels. DKD was associated with age, A1C, uric acid, BMI, serum C0, C10:2, C8:1 and urinary C12:1. Inclusion of metabolomics increased the predictive and informative capacity of models composed of clinical variables by decreasing Akaike's information criterion, and was replicated both in training and validation datasets. CONCLUSIONS: Targeted metabolomics using blotted samples in filter paper is a simple, low-cost approach to identify outcomes associated with DKD; the inclusion of metabolomics improves predictive capacity of clinical models to identify kidney dysfunction and DKD-related outcomes.