Enrique Torres-Rasgado

Serum Levels of Glutathione Peroxidase 3 in Overweight and Obese Subjects from Central Mexico

BACKGROUND AND AIMS Overweight and obesity are considered complex entities in which there are alterations in the concentration of antioxidant enzymes. It has been reported that glutathione peroxidase 3 (GPx3), an extracellular enzyme involved in the reduction of both hydro- and lipoperoxides, shows changes both in gene expression and protein concentration in animal models for type 2 diabetes (T2D) and obesity, but the variability of GPx3 levels in different human populations and under different health conditions are currently unclear. We undertook this study to determine the GPx3 levels in overweight and obese subjects from central Mexico. METHODS Biochemical profile (serum glucose, insulin and lipid profile) and GPx3 concentrations were determined in 28 healthy subjects (control) and 133 subjects who were overweight or obese (OW-OB). RESULTS The OW-OB group had a higher concentration of triacylglycerides (TAG) compared with the control group (201.2 ± 88.7 vs. 100.3 ± 46.4 mg/dL, p <0.05) and the TAG/high density lipoprotein-cholesterol (HDL-C) index (5.6 ± 2.8 vs. 2.1 ± 1.2, p <0.05), whereas the concentration of HDL-C decreased (38.2 ± 8.7 vs. 50.1 ± 14.5 mg/dL, p <0.05). Serum GPx3 was significantly higher in the OW-OB group than in the control group (175.4 ± 25.4 vs. 143.5 ± 23.1 ng/dL). GPx3 concentration correlated with insulin sensitivity (IS) and the TAG/HDL-C index (Rho = -0.2336 and Rho = 0.2275) (p <0.01). CONCLUSIONS The TAG/HDL-C index and serum GPx3 concentration increased in the OW-OB group. In addition, GPx3 had a significant correlation with IS, weight, and the TAG/HDL-C index.

Obese First-Degree Relatives of Patients with Type 2 Diabetes with Elevated Triglyceride Levels Exhibit Increased β-Cell Function

BACKGROUND Type 2 diabetes mellitus (T2DM) is characterized as a disease continuum that is marked by metabolic changes that are present for several years, sometimes well before frank diagnosis of T2DM. Genetic predisposition, ethnicity, geography, alterations in BMI, and lipid profile are considered important markers for the pathogenesis of T2DM through mechanisms that remain unresolved and controversial. The aim of this study was to investigate the relationship between triglycerides (TGs) and β-cell function, insulin resistance (IR), and insulin sensitivity (IS) in obese first-degree relatives of patients with T2DM (FDR-T2DM) among subjects from central Mexico with normal glucose tolerance (NGT). METHODS We studied 372 FDR-T2DM subjects (ages,18-65) and determined body mass index (BMI), fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), insulin, and TGs levels. Subjects were categorized based on glycemic control [NGT, prediabetes (PT2DM), or T2DM]. NGT subjects were further categorized by BMI [normal weight (Ob-) or obese (Ob+)] and TGs levels (TG-, <150 mg/dL, or TG+, ≥150 mg/dL). β-cell function, IR, and IS were determined by the homeostasis model assessment of β-cell function (HOMA2-β), homeostasis model assessment of insulin resistance (HOMA2-IR), and Quantitative Insulin Sensitivity Check Index (QUICKI) indices, respectively. RESULTS The obese subjects with elevated TGs levels had 21%-60% increased β-cell function when compared to all groups (P<0.05). In addition, this group had insulin levels, IS, and IR similar to PT2DM. Furthermore, only in obese subjects did TGs correlate with β-cell function (ρ=0.502, P<0.001). CONCLUSION We characterized FDR-T2DM subjects from central Mexico with NGT and revealed a class of obese subjects with elevated TGs and β-cell function, which may precede PT2DM.

Glutathione Peroxidase 3 Serum Levels and GPX3 Gene Polymorphisms in Subjects with Metabolic Syndrome

BACKGROUND AND AIMS Glutathione peroxidase 3 (GPx3) plays a main role in removing hydro- and lipoperoxides from the body. Changes in concentration and several single-nucleotide polymorphisms (SNP) at the GPX3 gene have been associated with vascular diseases, but the relationship of GPx3 with metabolic syndrome (MetS) remains unexplored. We undertook this study to determine the association of GPx3 serum levels and several GPX3 SNPs with the presence of MetS in Mexican subjects. METHODS Clinical, biochemical, and anthropometric evaluation were conducted in 426 subjects assigned to three groups: control (n = 42); risk group (RG, n = 200), and MetS group (n = 184). Insulin sensitivity (IS) and cardiovascular risk were determined by the QUICKI and TG/HDL-C index, respectively. Serum GPx3 was determined by enzyme immunoassay and polymorphisms within GPX3 gene were identified by nucleotide sequencing. RESULTS MetS group showed low IS and increased cardiovascular risk with respect to controls as well as higher GPx3 serum levels (172.9 ± 32.2 vs. 145.6 ± 24.8 ng/dL; p <0.05). Only three of the ten GPX3 SNPs screened were polymorphic with two haplotypes observed (CCT and TTA-rs8177404, rs8177406, and rs8177409), indicating tight linkage disequilibrium in this genetic region. No differences for either genotype or allele frequencies among groups were observed, but rs8177409 (allele T) was associated with cardiovascular risk (odds ratio [OR], 4.5; p = 0.0125). CONCLUSION This study shows that serum levels of GPx3 are increased in subjects with MetS and that rs8177409 SNP was associated with cardiovascular risk in a Mexican population.

c.+62G>A and g.-420C>G RETN Polymorphisms and the Risk of Developing Type 2 Diabetes and Obesity: Original Research on a Mexican Population and Meta-analysis

Objective: To determine the association between the c.+62G>A and g.-420C>G polymorphisms and Type 2 Diabetes (T2D) or obesity susceptibility for Mexicans. Additionally, we examined their overall effect across different populations by a systematic review. Methods: 164 Mexicans were classified as Healthy, Obese, or T2D. Genotypes were determined and associated risk for the heterozygous, homozygous, dominant, recessive, and allelic genetic models were determined by calculating the Odds Ratios (OR). For the meta-analysis, original publications that had determined RETN polymorphisms in T2D or obese subjects were searched for in PubMed, Scopus, EBSCO, Ovid, and Wiley databases until November 2015, using the search terms: T2D, obesity, RETN, and polymorphism. Pooled ORs were computed using a random-effects or fixed-effects models. Results: For our cohort, no associations were observed between the polymorphisms and obesity or T2D. The metaanalysis indicates an increased risk of obesity among carriers of the g.-420G allele for the heterozygous and dominant models (OR=1.33 and OR=1.30, p<0.05, respectively). By regional assessment, Africans were associated with an elevated risk of developing T2D (OR=2.35-7.17, p<0.05) and obesity (OR=1.54-2.13, p<0.05). North Americans had an increased risk of developing obesity for the heterozygous and dominant models (OR=1.49and OR=1.42, p<0.05, respectively). No associations were determined between the c.+62 polymorphism and obesity or T2D. Conclusion: For Mexicans, none of the polymorphisms were associated with a risk of developing obesity or T2D. However, there is an increased risk of developing obesity for the whole population for subjects who carry the g.-420G allele.

Low Prevalence of Interleukin-6 Haplotypes Associated with a Decreased Risk of Type 2 Diabetes in Mexican Subjects with a Family History of Type 2 Diabetes

BACKGROUND AND AIMS There is evidence that family history of type 2 diabetes (FHT2D) and single nucleotide polymorphisms (SNP) on the IL-6 gene promoter region are separately associated with the risk of developing type 2 diabetes. However the relationship between adult Mexican subjects with FHT2D and genotypes/haplotypes for IL-6 gene has not been explored. The aim of the present work was to study the prevalence of IL-6 -598G>A-572G>C-174G>C haplotypes among subjects with FHT2D and to determine whether their presence influences the relationship between FHT2D and risk factors for diabetes. METHODS Two hundred fifty eight nondiabetic subjects participated in this study; 153 with and 105 without FHT2D. Polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) was used for genotyping. Logistic regression analysis was employed to assess the impact of IL-6 haplotypes on FHT2D per se and hyperinsulinemia and insulin resistance as risk factors for diabetes. RESULTS Subjects with FHT2D showed a higher prevalence of hyperinsulinemia and insulin resistance (IR) than those without FHT2D (14.4 vs. 5.7%, p = 0.029, and 14.2 vs. 7.0% p = 0.050, respectively). Lower prevalence of -598 -572-174 (AGC)-haplotype (19%) in subjects with FHT2D was observed as well as a lower prevalence of hyperinsulinemia and IR among AGC haplotype carriers (12 and 14%, respectively). The relationship between FHT2D and IR was modified by the presence of AGC haplotype (from OR, 2.70; 95% CI, 0.99-7.36; p = 0.050 OR, 30.08; 95% CI, 0.58-1,568.06; p = 0.092). CONCLUSIONS IL-6 -598/-572/-174 (AGC) haplotype has a low prevalence among first-degree relatives of subjects with type 2 diabetes. Our results suggest that this haplotype is associated with decreased risk of type 2 diabetes in Mexican subjects with FHT2D.

Serum Amylin Indicates Hypertriglyceridemia in Pre-diabetics

Background: Hypertriglyceridemia is associated with increased insulin secretion and the incidence of Type 2 Diabetes. Studies in rodents and obese children have proposed a relationship between hypertriglyceridemia and elevated plasma amylin levels. However, there are limited data regarding serum amylin and triglyceride levels in adult human subjects with impaired glucose tolerance. In this study, we evaluated the association between serum triglycerides with circulating amylin levels in adult subjects with and without impaired glucose tolerance. Methods: Glucose, insulin, Hemoglobin A1c, triglycerides, total amylin and unreduced amylin levels were determined in 80 non-pregnant females and 60 males enrolled in a cross-sectional study. Subjects were allocated according to their glucose tolerance status into normal glucose tolerance (n=81) and impaired glucose tolerance (n=59). Subjects with Type 2 Diabetes, endocrine diseases, chronic inflammation or inflammatory diseases, as well as alcoholism were excluded. Correlation and sensitivity between triglycerides and amylin was investigated using Pearson’s correlation coefficient (r) and Receiver-Operating Characteristics (ROC) curve, respectively. Results: Serum triglycerides strongly correlated with only total amylin (r=0.470, p<0.05) in the impaired glucose tolerance group and not the normal glucose tolerance group. No correlation between triglycerides and unreduced amylin was observed in neither group. The area under the ROC curve (AUC) was only significant for hypertriglyceridemia and total amylin in the impaired glucose tolerance group (AUC=0.731, 95% CI: 0.600-0.838, p<0.05). Conclusion: Our results suggest that serum triglycerides and total amylin levels are significantly associated in impaired glucose tolerance subjects.

Serum resistin levels inversely associated with cardiovascular risk indices in type 2 diabetics from central Mexico

AIMS Since, resistin has been associated with coronary heart disease and with the progression of Type 2 Diabetes (T2D), our objective was to determine the correlation between resistin and cardiovascular risk (CVR) in subjects with increasing degrees of hyperglycemia. METHODS Using a cross-sectional study design, the anthropometric and biochemical profiles were collected from 180 subjects from Puebla, Mexico. Subjects were separated into Normoglycemic (NGT), pre-diabetic (PT2D), or T2D. CVR was determined by the Atherosclerosis Coefficient ((total cholesterol-high-density lipoprotein)/high-density lipoprotein), Castelli 1 index (total cholesterol/high-density lipoprotein), Castelli 2 index (low-density lipoprotein/high-density lipoprotein), Framingham risk score (https://www.mdcalc.com/framingham-coronary-heart-disease-risk-score#next-steps), and the CVR index (CVRI=triglyceride/high-density lipoprotein). Differences between groups were determined using ANOVA. Partial correlation assessed the association between resistin and CVR indices. Logistic regression was used to determine the risk [Odds ratio (OR)] between resistin and CVR. RESULTS Serum Resistin levels were similar between NGT, PT2D, and T2D. No correlation was observed between resistin and CVR indices for the NGT and PT2D. However, T2D demonstrated a strong negative association between the Framingham (r=-0.34, p=0.01), the Castelli 1 index (r=-0.29, p<0.01), and the CVRI (r=-0.38, p<0.05), when adjusted for sex and taking treatment for T2D. For T2D, when the subjects were separated by resistin into tertiles, elevated resistin was associated with a benefit for the Castelli 1 index (T1 v T3: OR=0.15, 95% CI: 0.03-0.070) and the CVRI (T1 v T3: OR=0.13, 95% CI: 0.03-0.66). CONCLUSIONS Here, we demonstrate that, for T2D, elevated resistin levels lowered the CVR in Mexicans.

Low serum uric acid concentration augments insulin effects on the prevalence of metabolic syndrome

AIM Insulin and uric acid were shown affect the prevalence of Metabolic Syndrome (MetS), but no studies examine their interaction. Therefore, we conducted this study to determine their biological interaction in subjects from central Mexico. METHODS 433 subjects were enrolled for a cross-sectional study. MetS was defined according to the Harmonizing Definition. Hyperuricemia was defined as ≥7.0 mg/dL in males and ≥5.8 mg/dL in females. Hyperinsulinemia was defined as ≥11.0 μU/mL. Pearson correlation coefficient (r) was calculated to determine the association between uric acid or insulin and MetS. Logistic regression was used to determine the risk (odds ratio) of developing MetS. Biological interactions were determined by the PROCESS Macro and Andersons method. RESULTS Insulin and uric acid levels were elevated in MetS positive group (p < .05) and correlated with the number of MetS components (r = 0.276 and r = 0.166, p < .001, respectively). The interaction between uric acid and insulin was associated with the number of MetS components (PROCESS Model 1, interaction coefficient = -0.009, 95%CI: -0.017 to -0.001, p = .036). Johnson-Neyman analysis suggests the interaction is lost when uric acid concentration increased >7.0 mg/dL. When the cohort was separated by hyperinsulinemia and hyperuricemia, there was a significant risk of developing MetS for subjects with hyperuricemia (odds ratio = 2.3; 95%CI: 1.1-4.8, p < .05), hyperinsulinemia (odds ratio = 3.1; 95%CI: 1.9-4.9, p < .05), or both (odds ratio = 7.4; 95%CI: 3.2-17.2, p < .05); however, there was no multiplicative or additive interaction. CONCLUSION Here, we show that uric acid and insulin augments the prevalence of MetS; however, no biological interaction was determined for hyperuricemia and hyperinsulinemia.

The impact of parental history of type 2 diabetes on hyperinsulinemia and insulin resistance in subjects from central Mexico

AIMS Hyperinsulinemia and insulin resistance are both associated with the development of Type 2 Diabetes and other pathologies; however, the influence of parental history of Type 2 diabetes (PH-T2D) has yet to be investigated. Therefore, this study was conducted to determine the effect of PH-T2D has on the risk of developing hyperinsulinemia and IR. MATERIALS AND METHODS 1092 subjects (703 non-pregnant females and 389 males) were enrolled for a cross-sectional study. Clinical and biochemical parameters were collected. Subjects were allocated according to their PH-T2D: no parents, one parent, or both parents. Insulin resistance was calculated using the HOMA1 equation (HOMA1-IR). Logistic regression was used to determine the association (odds ratio) between PH-T2D and hyperinsulinemia or insulin resistance. RESULTS Increasing degrees of PH-T2D were associated with significant increases in fasting plasma glucose, insulin, and HOMA1-IR (p <0.05). Subjects having one or both parents were associated with an increase risk of developing hyperinsulinemia (odds ratio=1.53, 95%CI: 1.12-2.09, and odds ratio=1.92, 95%CI: 1.21-3.06, respectively) and insulin resistance (odds ratio=1.47, 95%CI: 1.08-2.00 and odds ratio=1.77, 95%CI: 1.09-2.87, respectively), when adjusting for age, sex, BMI, fasting plasma glucose, and triglycerides. CONCLUSION The presences of PH-T2D significantly increased the risk of developing hyperinsulinemia and insulin resistance.

Metallothionein-1 and nitric oxide expression are inversely correlated in a murine model of Chagas disease

Chagas disease, caused by Trypanosoma cruzi, represents an endemic among Latin America countries. The participation of free radicals, especially nitric oxide (NO), has been demonstrated in the pathophysiology of seropositive individuals with T. cruzi. In Chagas disease, increased NO contributes to the development of cardiomyopathy and megacolon. Metallothioneins (MTs) are efficient free radicals scavengers of NO in vitro and in vivo. Here, we developed a murine model of the chronic phase of Chagas disease using endemic T. cruzi RyCH1 in BALB/c mice, which were divided into four groups: infected non-treated (Inf), infected N-monomethyl-L-arginine treated (Inf L-NAME), non-infected L-NAME treated and non-infected vehicle-treated. We determined blood parasitaemia and NO levels, the extent of parasite nests in tissues and liver MT-I expression levels. It was observed that NO levels were increasing in Inf mice in a time-dependent manner. Inf L-NAME mice had fewer T. cruzi nests in cardiac and skeletal muscle with decreased blood NO levels at day 135 post infection. This affect was negatively correlated with an increase of MT-I expression (r = -0.8462, p < 0.0001). In conclusion, we determined that in Chagas disease, an unknown inhibitory mechanism reduces MT-I expression, allowing augmented NO levels.