Metabolomic Phenotype of Hepatic Steatosis and Fibrosis in Mexican Children Living with Obesity.

Background and Objectives: Metabolic-dysfunction-associated steatotic liver disease or MASLD is the main cause of chronic liver diseases in children, and it is estimated to affect 35% of children living with obesity. This study aimed to identify metabolic phenotypes associated with two advanced stages of MASLD (hepatic steatosis and hepatic steatosis plus fibrosis) in Mexican children with obesity. Materials and Methods: This is a cross-sectional analysis derived from a randomized clinical trial conducted in children and adolescents with obesity aged 8 to 16 years. Anthropometric and biochemical data were measured, and targeted metabolomic analyses were carried out using mass spectrometry. Liver steatosis and fibrosis were estimated using transient elastography (Fibroscan® Echosens, Paris, France). Three groups were studied: a non-MASLD group, an MASLD group, and a group for MASLD + fibrosis. A partial least squares discriminant analysis (PLS-DA) was performed to identify the discrimination between the study groups and to visualize the differences between their heatmaps; also, Variable Importance Projection (VIP) plots were graphed. A VIP score of >1.5 was considered to establish the importance of metabolites and biochemical parameters that characterized each group. Logistic regression models were constructed considering VIP scores of >1.5, and the receiver operating characteristic (ROC) curves were estimated to evaluate different combinations of variables. Results: The metabolic MASLD phenotype was associated with increased concentrations of ALT and decreased arginine, glycine, and acylcarnitine (AC) AC5:1, while MASLD + fibrosis, an advanced stage of MASLD, was associated with a phenotype characterized by increased concentrations of ALT, proline, and alanine and a decreased Matsuda Index. Conclusions: The metabolic MASLD phenotype changes as this metabolic dysfunction progresses. Understanding metabolic disturbances in MASLD would allow for early identification and the development of intervention strategies focused on limiting the progression of liver damage in children and adolescents.

Comparison of Carotid Intima-Media Thickness in Children and Adults With and Without Obesity: A Hysteresis Model.

OBJECTIVE: To describe a third-degree polynomial function (hysteresis) of the effect size of age, obesity, and insulin sensitivity over the carotid intima-media thickness (c-IMT), in the pediatric and adult groups. METHODS: A quasi-experimental study with fixed factor analysis of age (children aged 8-12 years, n = 73; adults aged 21-45 years, n = 82) and obesity (yes, n = 76; no, n = 79) was conducted to analyze the effect on the c-IMT and Matsuda insulin sensitivity index values. This quasi-experimental design was analyzed with robust regression modeling. RESULTS: The additive effect of obesity, independent of age, was evident in the case of the c-IMT values. There was no interaction effect, but a significant difference between participants with normal weight and those with obesity was found (P < .0001). The difference between adults and children was also significant, but the effect size was smaller. A model was created based on age, Tanner stage, and obesity using the c-IMT and Matsuda insulin sensitivity index values. A linear function fit as R2, and the cubic function estimated parameters like a polynomial model. CONCLUSION: This practical study design showed that children with obesity displayed the same levels of carotid intima-media abnormalities as adults with obesity. The polynomial shape of the model suggests potentially poor outcomes that resemble the hysteresis process and may predict chronic cardiometabolic events during early adulthood.

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness.

OBJECTIVE: Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. METHODS: Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg-1•day-1; ZOSV); Group 3: valsartan (31 mg•kg-1•day-1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg-1•day-1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. RESULTS: Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. CONCLUSIONS: These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

Gender-specific differences in clinical and metabolic variables associated with NAFLD in a Mexican pediatric population.

INTRODUCTION AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and it is more prevalent in Hispanic males. The gender differences can be explained by body fat distribution, lifestyle, or sex hormone metabolism. We evaluated anthropometric and metabolic differences by gender in children with and without NAFLD. METHODS: We included 194 participants (eutrophic, overweight, and individuals with obesity). The presence of NAFLD was determined using ultrasonography, and we evaluated the association between this disease with metabolic and anthropometric variables by gender. RESULTS: The mean age was 10.64±2.54 years. The frequency of NAFLD in boys was 24.51% and in girls was 11.96% (OR=2.39; 95%CI=1.10-5.19; p=0.025). For girls, NAFLD was significantly associated with triglycerides (p=0.012), homeostatic model assessment of insulin resistance (HOMA-IR) (p=0.048), and the visceral adiposity index (VAI) (p=0.024). The variables related to NAFLD in a gender-specific manner were body mass index (BMI) (p=0.001), waist circumference (WC) (p<0.001), HDL cholesterol (p=0.021), alanine aminotransferase (ALT) (p<0.001), and aspartate aminotransferase (AST) (p=0.002). CONCLUSIONS: In our study NAFLD is more frequent in boys, only ALT, and no other clinical or metabolic variables, were associated with NAFLD in these patients. HOMA-IR, VAI, triglyceride levels, and ALT were associated with NAFLD only in girls. The ALT cut-off points for the development of NAFLD in our study were 28.5U/L in females and 27.5U/L in males. Our findings showed that NAFLD should be intentionally screened in patients with obesity, particularly in boys.

The effects of resistance exercise and oral nutritional supplementation during hemodialysis on indicators of nutritional status and quality of life.

BACKGROUND: Protein-energy wasting (PEW) is common in patients undergoing hemodialysis (HD). Studies have assessed the positive effect of oral nutritional supplementation (ONS) or resistance exercise (RE) on nutritional status (NS) markers in patients undergoing HD. METHODS: The aim of this study was to assess the effect of ONS and RE on NS and the quality of life (QOL) of 36 patients undergoing HD. In a randomized clinical trial, patients were divided into the following two groups: a control group (ONS) that received a can of ONS during their HD sessions and an intervention group (ONS + RE) that received a can of ONS and underwent a 40-min session of RE during their HD sessions. Both interventions lasted 12 weeks. The patients' anthropometric, biochemical, dietetic and bioelectrical impedance measurements as well as their QOL, evaluated using the Kidney Disease Quality of Life Short Form, were recorded. RESULTS: At baseline, 55.5% of patients presented with PEW according to International Society of Renal Nutrition and Metabolism criteria (20 patients). We found statistically significant changes from baseline in both groups, such as increases in body weight, body mass index, midarm circumference, midarm muscle circumference, triceps skinfold thickness, fat mass percentage, handgrip strength, phase angle and serum albumin. A decrease in the prevalence of PEW was observed in both groups at the end of the intervention. A delta comparison between groups showed no statistically significant differences in the anthropometric and biochemical parameters. No significant improvement was observed in QOL and body composition measured by bioimpedance vector analysis. Dietary energy and protein intake increased significantly during the study period for all patients. CONCLUSION: Oral nutritional supplementation during HD improves NS. The addition of RE during HD does not seem to augment the acute anabolic effects of intradialytic ONS on NS.

Effect of Resistance Exercises on the Indicators of Muscle Reserves and Handgrip Strength in Adult Patients on Hemodialysis.

OBJECTIVE: Although resistance exercise has been associated with improvement in the muscle reserves, muscle strength and quality of life in end-stage renal disease patients, the objective of this paper is to evaluate the effect of resistance exercise performed during hemodialysis sessions on the anthropometric indicators of muscle reserve and handgrip strength in sedentary malnourished patients with end-stage renal disease. METHODS: Patients were randomized to perform resistance exercise during hemodialysis sessions with ankle weights and resistance bands. The exercises were performed twice a week over the course of 12 weeks. The control group underwent a hemodialysis session alone. The outcomes measures were the following anthropometric measurements: arm muscle circumference and arm muscle area. Dynamometry was used to measure the handgrip strength. RESULTS: Sixty-one sedentary patients with a median age of 29 years (interquartile range [IQR] 21-39 years), and 83% presenting with some grade of malnutrition were equally randomized to either the intervention or control group. In the resistance exercise group, there was an increase in the arm muscle circumference from 233.6 (IQR 202-254) mm to 241.4 (IQR 203-264) mm (P= .001), arm muscle area from 35.9 (26-41) cm(2) to 36.6 (IQR 26-46) cm(2) (P= .002), and handgrip strength from 19.6 (IQR 11-28) kg to 21.2 (IQR 13-32) kg between the basal and final measurements (P < .05). The tolerance to exercise was adequate, and no adverse events were reported during the practical exercise. CONCLUSIONS: Resistance exercise at least twice a week is safe and represents an opportunity for improving the muscle mass and strength in adult patients who are on hemodialysis, including in those with malnutrition.

[Metformin increases serum concentration of high molecular weight (HMW-adiponectin) in nondiabetic obese subjects]. / La metformina incrementa la concentración sérica de adiponectina de alto peso molecular (adiponectina-HMW) en obesos no diabéticos.

INTRODUCTION: Obesity is associated with low-intensity chronic systemic inflammation. OBJECTIVE: To evaluate the efficacy of two different doses of metformin in comparison with placebo on increased serum levels of high molecular weight (HMW) adiponectin. MATERIAL AND METHODS: An experimental design was developed with a crossover complete treatment and balanced design; 28 female and eight male nondiabetic obese adults participated. All participants received, during a week and in randomized order: placebo or metformin 500 or 850 mg twice daily; there was a week washout period between each treatment. The HMW adiponectin serum concentration (0 and 120 minutes) at the end of each treatment was measured. Analyses of variance (ANOVA), Bonferroni test, and size effect calculations were performed. RESULTS: Differences in concentrations of HMW adiponectin (t0', t120') were measured for each treatment by ANOVA, having values of p = 0.03 and 0.002, respectively. The post hoc analysis reported differences favoring treatment with metformin 850 mg (p = 0.025). The sizes of the effect at times t0 and t120 for metformin 500 mg were 34 and 35%, and for metformin 850 mg, 65 and 84%, respectively.

Antioxidant supplementation has a positive effect on oxidative stress and hematological toxicity during oncology treatment in cervical cancer patients.

BACKGROUND AND AIM: Hematological toxicity and oxidative stress are common in cancer patients. Antioxidant supplementation has been shown to decrease oxidative stress, but there is still controversy on this topic. The aim of this study was to determine the effect of antioxidant supplementation on oxidative stress, hematological toxicity, and quality of life (QoL) in cervical cancer patients. METHODS: Randomized, single-blinded controlled trial in women with cervical cancer treated with radiotherapy and chemotherapy with cisplatin. Subjects were randomly assigned to receive antioxidant supplement or placebo supplement. Plasma concentrations of malondialdehyde, free carbonyls, and blood biometry were measured. EORTC quality of life questionnaire was applied before and after oncology treatment. Student's t test for independent samples and X (2) for categorical variables were performed. RESULTS: One hundred three patients were randomly assigned to receive treatment with antioxidants 49 (48 %) or placebo 54 (52.40 %). At the end of the oncology treatment, hemoglobin levels were maintained, and global QoL was better only in the supplemented group (p < 0.025). CONCLUSIONS: Antioxidant supplementation in patients treated with chemotherapy and radiotherapy apparently decreased oxidative stress, maintained hemoglobin levels, and improved QoL; however, more studies are needed to study the long-term effect of this intervention.

IL-10 and TNF-alpha polymorphisms in subjects with irritable bowel syndrome in Mexico.

BACKGROUND: there has been recent evidence of an alteration in irritable bowel syndrome (IBS) immune regulation, as well as variations in cytokine polymorphisms. AIMS: to determine the frequency of the IL-10 (-1082G/A) and TNF-alpha (-308G/A) polymorphisms in subjects with IBS in Mexico. METHODS: volunteers answered the Rome II Questionnaire and were classified as IBS (n = 45) and controls (n = 92). The IBS subjects were then categorized as IBS-D: 22.2%, IBS-C: 28.9%, and IBS-A/M: 48.9%. The polymorphism frequency among groups was compared. RESULTS: there were no differences between IBS vs. controls in the frequency of the high (8.9 vs. 18.5%), intermediate (60.0 vs. 57.6%), or low (23.9 vs. 38.9%) producer IL-10 genotypes, p = 0.315. Neither were there differences in the high (0 vs. 1.1%), intermediate (55.4 vs. 43.2%), or low (43.5 vs. 56.8%) producer TNF-alpha genotypes, p = 0.296. However the low producer of IL-10 was more frequent in IBS-D vs. IBS-C vs. IBS-A/M (63.6 vs. 7.1 vs. 33,3%) p = 0.023. CONCLUSIONS: in this group of volunteers in Mexico, the frequency of the IL-10 (-1082G/A) and TNF-alpha (-308G/A) genotypes was similar in IBS and controls. However, there was a greater frequency of the low producer of IL-10 in those subjects with IBS-D, suggesting a genetic predisposition to abnormal immune regulation due to a lower anti-inflammatory component in this subgroup.

Commentary on Metabolic Health Disparities Affecting the Rio Grande Valley Mexican American Population: Seeking Answers Using Animal Models.

Mexican Americans living in the Rio Grande Valley (RGV) have a high prevalence of type 2 diabetes (T2D). The US-Mexico border frontier has a unique blended culture of American lifestyle and Mexican traditions. Some examples of the cultural traditions are the food and the use of herbal medicine, but these traditions are in danger of disappearing after a very short number of generations living in the United States. This article describes the use of animal models under experimental conditions to solve practical questions (etiology or treatment). We performed studies with murine (ie, mouse and rat) models to elucidate the characteristics of medicinal plants that modulate glucose metabolism and inflammation and protect from bone loss, complications related to T2D. The University of Texas Rio Grande Valley researchers also have collaborated with the University of Texas Health Science Center at San Antonio researchers in performing studies in nonhuman primates (NHP) (ie, baboon) to understand the effect of T2D and diets on organs and tissues. With the new knowledge gained from the use of animal models (murine and NHP), new therapies are discovered for the prevention and treatment of T2D and its related complications, such as bone loss and nonalcoholic fatty liver disease, all of which the Mexican American and other human populations are at high risk of developing.

Functional characterization of the disease-associated CCL2 rs1024611G-rs13900T haplotype: The role of the RNA-binding protein HuR.

CC-chemokine ligand 2 (CCL2) is involved in the pathogenesis of several diseases associated with monocyte/macrophage recruitment, such as HIV-associated neurocognitive disorder (HAND), tuberculosis, and atherosclerosis. The rs1024611 (alleles:A>G; G is the risk allele) polymorphism in the CCL2 cis-regulatory region is associated with increased CCL2 expression in vitro and ex vivo, leukocyte mobilization in vivo, and deleterious disease outcomes. However, the molecular basis for the rs1024611-associated differential CCL2 expression remains poorly characterized. It is conceivable that genetic variant(s) in linkage disequilibrium (LD) with rs1024611 could mediate such effects. Previously, we used rs13900 (alleles:_C>T) in the CCL2 3' untranslated region (3' UTR) that is in perfect LD with rs1024611 to demonstrate allelic expression imbalance (AEI) of CCL2 in heterozygous individuals. Here we tested the hypothesis that the rs13900 could modulate CCL2 expression by altering mRNA turnover and/or translatability. The rs13900 T allele conferred greater stability to the CCL2 transcript when compared to the rs13900 C allele. The rs13900 T allele also had increased binding to Human Antigen R (HuR), an RNA-binding protein, in vitro and ex vivo. The rs13900 alleles imparted differential activity to reporter vectors and influenced the translatability of the reporter transcript. We further demonstrated a role for HuR in mediating allele-specific effects on CCL2 expression in overexpression and silencing studies. The presence of the rs1024611G-rs13900T conferred a distinct transcriptomic signature related to inflammation and immunity. Our studies suggest that the differential interactions of HuR with rs13900 could modulate CCL2 expression and explain the interindividual differences in CCL2-mediated disease susceptibility.

Lower serum IL-10 is an independent predictor of IBS among volunteers in Mexico.

OBJECTIVES: Studies suggest that altered immune activation, manifested by an imbalance in anti- and pro-inflammatory cytokine levels, exists in a subgroup of irritable bowel syndrome (IBS) patients. However, similar studies have not been conducted in Latin populations. The objective of this study was to measure serum levels of interleukin (IL)-10 and tumor necrosis factor (TNF)-α in subjects fulfilling symptom criteria for IBS and controls. METHODS: Volunteers (n=178) from a university population in Mexico City, participated in the study. Of the sample, 34.8% met Rome II criteria for IBS and 65.2% were designated as controls. Serum cytokines were measured by enzyme-linked immunoabsorbent assay. Analysis of covariance models were used to test main effects between gender, IBS symptoms, and bowel habit subtype to explain the cytokine serum levels. Statistical models were tested using body mass index as a covariate. RESULTS: IL-10 levels were significantly lower in IBS vs. controls (mean (95% confidence interval): 15.6 (14.8, 16.3) vs. 18.6 (17.9, 19.4) pg/ml, P<0.001), while TNF-α levels were higher in IBS (20.9 (19.1, 23.0) vs. 17.9 (16.7, 19.3) pg/ml, P=0.010). IBS and female gender were independent predictors for IL-10 (P<0.05). In contrast, female gender was an independent predictor for TNF-α. In addition, women with IBS-D had the lowest IL-10 (P<0.001) and highest TNF-α (P=0.021) vs. other subtypes. CONCLUSIONS: The lower serum IL-10 in our subjects fulfilling IBS Rome II symptom criteria suggests an altered immune regulation. Further studies are needed to elucidate if a lower serum IL-10 may be useful as a biomarker for IBS in the Mexican population, especially for women with IBS-D.

Proton pump inhibitors in gastroesophageal reflux disease: "a custom-tailored therapeutic regimen".

The Montreal Definition and Classification divides Gastroesophageal Reflux Disease (GERD) into esophageal symptomatic syndromes (and with mucosal damage) and extraesophageal syndromes (with acid established association and proposed association). In typical GERD symptoms, an 8-week treatment with PPIs is satisfactory in most cases (> 90%). Response rates to PPIs in GERD are highly variable, as they also rely on an appropriate clinical diagnosis of the disease; endoscopy differentiates the macroscopic GERD phenotype. The non-erosive variety (50-70% prevalence) has a different symptomatic response rate, as gastric acid is not the sole etiology of symptoms. The possible explanations of treatment failure include treatment adherence, PPI metabolism alterations and characteristics, and inadequate diagnosis. Refractory symptoms are related to gastric content neutralization by the chronic use of PPIs.Extraesophageal manifestations are associated with other pathophysiological mechanisms where an autonomic nervous system disturbance gives rise to symptoms. In these clinical entities, the relationship between symptoms and acid needs to be established in order to determine the use of PPIs, or consider other drugs. In other words, so as to "custom-tailor the best-fitting therapy" we need to answer the questions for whom, for what, how and for how long. Finally, PPI safety and tolerability are factors to be considered in elderly patients requiring chronic PPI use, who usually have chronic concomitant illnesses.

Factors of Poor Prognosis Associated with Chronic Kidney Disease by Stage in Ambulatory Patients: A Cross-sectional Study.

BACKGROUND: Mexico has a high prevalence of chronic kidney disease (CKD) but limited information about the early stages of CKD and their clusters of poor prognosis factors (PPF) such as hyperuricemia, electrolyte abnormalities or comorbidities. OBJECTIVE: To assess the prevalence of PPF by CKD stages in ambulatory patients. METHODS: A cross-sectional study with 1772 adult patients with CKD that attended the Nephrology Outpatient Clinic. PPF data is reported as adjusted OR (95% confidence interval) (CI). RESULTS: Mean age was 56.2 ± 15.8 years. Kidney Replacement Therapy (KRT) was reported in 12% of the patients. Type 2 diabetes mellitus (T2DM), age >50 years and male gender were the PPF associated with all CKD stages. The PPF in CKD 2 and 3a hyperuricemia OR 3.4 (2.02,6.0) and 4.4 (2.5,7.6), and hypertension OR 1.8 (1.01,3.4) and 2.3 (1.2,4.3) respectively. In CKD 3b were hyperuricemia OR 5.1 (3.1,8.6), hypertension OR 2.7 (1.5,4.9) and hyperkalemia OR 3.4 (1.5,7.6). For CKD 4, 5 without KRT and 5 were hyperuricemia OR 7.02 (4.1,11.8), 13.5 (7.4,24.6), 3.9 (2.2-6.9), hypertension OR 3.4 (1.9,6.1), 3.4 (1.9,6.1), 3.8 (2.1,7.1), and hyperkalemia 2.9 (1.3,6.3), 7.9 (3.6,17.3), 8.7 (3.9,19.3), respectively. Anemia was important for CKD 5 without KRT and 5 with OR of 5.7 (3.09,10.6) and 8 (4.2,15), respectively. CONCLUSIONS: This is the largest study of Mexican patients with CKD; most of them without KRT. Patients had multiple modifiable PPF. Early and comprehensive management of PPF could prevent or delay progression to KRT. Treatment of associated PPF should be a priority, as it could make a significant difference both for CKD progression and its subsequent cardiovascular risk.

The CCR2+ Monocyte Subsets Increase in Obese Boys but Not Girls with Abnormally High Carotid Intima-Media Thickness: A Pilot Study.

The differential contribution of monocyte subsets expressing the C-C chemokine receptor 2 (CCR2) to subclinical atherosclerosis in girls and boys is unclear. In this pilot study, we compared classical, intermediate, and nonclassical monocyte subsets expressing CCR2 in 33 obese children of both sexes aged 8 to 16 divided by carotid intima-media thickness (IMT), considering values above the 75th percentile (p75) as abnormally high IMT. Obesity was defined as body mass index above the 95th percentile according to age and sex. Flow cytometry analyses revealed that boys but not girls with IMT ≥ p75 displayed increased CCR2+ cell percentage and CCR2 expression in the three monocyte subsets, compared to boys with IMT < p75. The CCR2+ cell percentage and CCR2 expression in the three monocyte subsets significantly correlated with increased IMT and insulin resistance in boys but not girls, where the CCR2+ nonclassical monocyte percentage had the strongest associations (r = 0.73 and r = 0.72, respectively). The role of CCR2+ monocyte subpopulations in identifying an abnormally high IMT shows a marked sexual dimorphism, where boys seem to be at higher subclinical atherosclerosis risk than girls.

Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium.

To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ≤ 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits.

Neuropsychiatric Symptoms Among Hispanics: Results of the Maracaibo Aging Study.

BACKGROUND: Neuropsychiatric symptoms play an important role in diagnosing and clinical follow-up of cognitive impairment and dementia. OBJECTIVE: We investigated the relationship between neuropsychiatric symptoms, cognitive impairment, and dementia in Hispanics. METHODS: We included 529 participants (age ≥40 years) from the Maracaibo Aging Study with standardized neuropsychiatric assessments, including the Neuropsychiatric Inventory (NPI). Based on the Clinical Dementia Rating and the Mini-Mental State Examination scores, participants' cognitive status was categorized into normal cognition, mild/moderate, and severe cognitive impairment. Diagnosis of dementia was established in a consensus conference. Statistical analyses included multivariable logistic regression models and area under the curve (AUC). RESULTS: The mean age of participants was 59.3 years, and 71.8%were women. The proportion of dementia was 6.8%. Disturbed sleep, anxiety, and depression were the most common neuropsychiatric symptoms in the study sample. In crude analyses, the proportions of hallucinations, aberrant motor behavior, agitation/aggression, apathy, delusions, irritability, eating disturbance, depression, and euphoria were differently distributed among cognitive status groups (p < 0.05). After accounting for confounders, aberrant motor behavior and agitation/aggression remained significantly associated with cognitive impairment and dementia (p < 0.05). The inclusion of the NPI domains significantly improved the AUC to discriminate severe cognitive impairment and dementia compared to a basic model that included sex, age, education, alcohol, obesity, serum glucose, total cholesterol, hypertension, and stroke. CONCLUSION: Neuropsychiatric symptoms are associated with severe cognitive impairment and dementia. The addition of NPI items to the global cognitive assessment might help early detection of dementia in primary care settings.

Association of HIV-1 Infection and Antiretroviral Therapy With Type 2 Diabetes in the Hispanic Population of the Rio Grande Valley, Texas, USA.

The Rio Grande Valley (RGV) in South Texas has one of the highest prevalence of obesity and type 2 diabetes (T2D) in the United States (US). We report for the first time the T2D prevalence in persons with HIV (PWH) in the RGV and the interrelationship between T2D, cardiometabolic risk factors, HIV-related indices, and antiretroviral therapies (ART). The PWH in this study received medical care at Valley AIDS Council (VAC) clinic sites located in Harlingen and McAllen, Texas. Henceforth, this cohort will be referred to as Valley AIDS Council Cohort (VACC). Cross-sectional analyses were conducted using retrospective data obtained from 1,827 registries. It included demographic and anthropometric variables, cardiometabolic traits, and HIV-related virological and immunological indices. For descriptive statistics, we used mean values of the quantitative variables from unbalanced visits across 20 months. Robust regression methods were used to determine the associations. For comparisons, we used cardiometabolic trait data obtained from HIV-uninfected San Antonio Mexican American Family Studies (SAMAFS; N = 2,498), and the Mexican American population in the National Health and Nutrition Examination Survey (HHANES; N = 5,989). The prevalence of T2D in VACC was 51% compared to 27% in SAMAFS and 19% in HHANES, respectively. The PWH with T2D in VACC were younger (4.7 years) and had lower BMI (BMI 2.43 units less) when compared to SAMAFS individuals. In contrast, VACC individuals had increased blood pressure and dyslipidemia. The increased T2D prevalence in VACC was independent of BMI. Within the VACC, ART was associated with viral load and CD4+ T cell counts but not with metabolic dysfunction. Notably, we found that individuals with any INSTI combination had higher T2D risk: OR 2.08 (95%CI 1.67, 2.6; p < 0.001). In summary, our results suggest that VACC individuals may develop T2D at younger ages independent of obesity. The high burden of T2D in these individuals necessitates rigorously designed longitudinal studies to draw potential causal inferences and develop better treatment regimens.

Serum carotenoids and Pediatric Metabolic Index predict insulin sensitivity in Mexican American children.

High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and ß-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and ß-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and ß-cryptoxanthin were highly heritable [h2 = 0.98, P = 7 × 10-18 and h2 = 0.58, P = 1 × 10-7]. We found significant (P ≤ 0.05) negative phenotypic correlations between ß-cryptoxanthin and five CMTs: body mass index (- 0.22), waist circumference (- 0.25), triglycerides (- 0.18), fat mass (- 0.23), fasting glucose (- 0.09), and positive correlations with HDL cholesterol (0.29). In contrast, lycopene only showed a significant negative correlation with fasting glucose (- 0.08) and a positive correlation with HDL cholesterol (0.18). Importantly, we found that common genetic influences significantly contributed to the observed phenotypic correlations. RSM showed that increased serum concentrations of α- and ß-carotenoids rather than that of ß-cryptoxanthin or lycopene had maximal effects on ISI. In summary, our findings suggest that the serum carotenoids are under strong additive genetic influences and may have differential effects on susceptibility to CMTs in children.

Further evidence supporting a potential role for ADH1B in obesity.

Insulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m-2) or obese (BMI ≥ 30 kg m-2) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.