Role of secreted frizzled-related protein 4 in prediabetes and type 2 diabetes: a cross sectional study.

BACKGROUND: Type 2 diabetes (T2D) has become an epidemic. Delays in diagnosis and as a consequent late treatment has resulted in high prevalence of complications and mortality. Secreted frizzled-related protein 4 (SFRP4), has been recently identified as a potential early biomarker of T2D related to obesity, due to its association with low grade inflammation in adipose tissue and impaired glucose metabolism. We aimed to evaluate the role of SFRP4 in prediabetes and T2D in a Mexican population. METHODS: This was a cross-sectional study that included 80 subjects with T2D, 50 subjects with prediabetes and 50 healthy individuals. Fasting SFRP4 and insulin concentrations were measured by ELISA. Human serum IL-10, IL-6, IL-1ß and IL-8 levels were quantified by flow cytometry. Genotyping was performed by TaqMan® probes. RESULTS: Prediabetes and T2D patients had significantly higher SFRP4 levels than controls (P < 0.05). In turn, prediabetes subjects had higher SFRP4 concentrations than control subjects (P < 0.05). Additionally, the prediabetes and T2D groups had higher concentrations of proinflammatory molecules such as IL-6, IL-1ß and IL-8, and lower concentrations of IL-10, an anti-inflammatory cytokine, than controls (P < 0.001). The serum SFRP4 concentrations were positively correlated with parameters that are elevated in prediabetes and T2D states, such as, HbA1c and homeostasis model assessment insulin resistance (HOMA-IR), (r = 0.168 and 0.248, respectively, P < 0.05). Also, serum SFRP4 concentrations were positively correlated with concentrations of pro-inflammatory molecules (CRP, IL-6, IL-1ß and IL-8) and negatively correlated with the anti-inflammatory molecule IL-10, even after adjusting for body mass index and age (P < 0.001). The genetic variant rs4720265 was correlated with low HDL concentrations in T2D (P < 0.05). CONCLUSIONS: SFRP4 correlates positively with the stage of prediabetes, suggesting that it may be an early biomarker to predict the risk of developing diabetes in people with high serum concentrations of SFRP4, although further longitudinal studies are required.

Association of the T130I Variant of the HNF4A Gene with Metabolic Syndrome and Its Components in Mexican Children.

Background: Metabolic syndrome (MetS), a cluster of risk factors, leads to cardiovascular disease (CVD) and type 2 diabetes (T2D). The second leading cause of mortality in Mexico is T2D. Genetic factors participate in the pathogenesis of MetS. The HNFA gene encodes a transcription factor that plays a crucial role in energy homeostasis by regulating the metabolism of glucose and lipids. This study aimed to investigate the association of the T130I variant of the HNF4A gene in Mexican children with MetS and its constituent components. Methods: The study was performed in 477 children from elementary schools. MetS was classified according to the de Ferranti definition. Biochemical parameters were measured and genotyping was performed. Logistic regression under a dominant genetic model was used to analyze the association of the T130I variant of the HNF4A gene with MetS and with its components separately. Results: The prevalence of MetS was 25.4%, and 18.9% in children who presented insulin resistance. Interestingly, this is the first time that a significant association between the T130I variant of the HNF4A gene and MetS has been reported [odds ratios (OR) = 2.31; 95% confidence interval (CI) 1.10-4.83; P = 0.026]. Moreover, carriers of the risk allele show higher abdominal obesity (OR = 1.20; 95% CI 1.09-4.50; P = 0.029). These findings highlight the active role of genetic variants in the pathogenesis of MetS in Mexican children. Conclusions: The high prevalence of children with MetS and insulin resistance places this population at an elevated risk of early CVD and T2D. The Clinical Trial Registration Number is HJM2315/14C.

Pharmacogenetic Evaluation of Metformin and Sulphonylurea Response in Mexican Mestizos with Type 2 Diabetes.

BACKGROUND: In Mexico, approximately 25% of patients with type 2 diabetes (T2D) have adequate glycemic control. Polymorphisms in pharmacogenetic genes have been shown to have clinical consequences resulting in drug toxicity or therapeutic inefficacy. OBJECTIVE: The study aimed to evaluate the impact of variants in genes known to be involved in response to oral hypoglycemic drugs, such as CYP2C9, OCT, MATE, ABCA1 and C11orf65, in the Mexican Mestizo population of T2D patients. METHODS: In this study, 265 patients with T2D were enrolled from the Hospital Juárez de México, Mexico City. Genotyping was performed by TaqMan® assays. SNP-SNP interactions were analyzed using the multifactor dimensionality reduction (MDR) method. RESULTS: Carriers of the del allele of rs72552763 could achieve better glycemic control than noncarriers. There was a significant difference in plasma glucose and HbA1c levels among rs622342 genotypes. The results suggested an SNP-SNP interaction between rs72552763 and rs622342 OCT1 and rs12943590 MATE2. CONCLUSION: The interaction between rs72552763 and rs622342 in OCT1, and rs12943590 in MATE2 suggested an important role of these polymorphisms in metformin response in T2D Mexican Mestizo population.

Corrigendum: Altered Gut Microbiota and Compositional Changes in Firmicutes and Proteobacteria in Mexican Undernourished and Obese Children.

[This corrects the article DOI: 10.3389/fmicb.2018.02494.].

Altered Gut Microbiota and Compositional Changes in Firmicutes and Proteobacteria in Mexican Undernourished and Obese Children.

Mexico is experiencing an epidemiological and nutritional transition period, and Mexican children are often affected by the double burden of malnutrition, which includes undernutrition (15.3% of children) and obesity (13.6%). The gut microbiome is a complex and metabolically active community of organisms that influences the host phenotype. Although previous studies have shown alterations in the gut microbiota in undernourished children, the affected bacterial communities remain unknown. The present study investigated and compared the bacterial richness and diversity of the fecal microbiota in groups of undernourished (n = 12), obese (n = 12), and normal-weight (control) (n = 12) Mexican school-age children. We used next-generation sequencing to analyze the V3-V4 region of the bacterial 16S rRNA gene, and we also investigated whether there were correlations between diet and relevant bacteria. The undernourished and obese groups showed lower bacterial richness and diversity than the normal-weight group. Enterotype 1 correlated positively with dietary fat intake in the obese group and with carbohydrate intake in the undernourished group. The results showed that undernourished children had significantly higher levels of bacteria in the Firmicutes phylum and in the Lachnospiraceae family than obese children, while the Proteobacteria phylum was overrepresented in the obese group. The level of Lachnospiraceae correlated negatively with energy consumption and positively with leptin level. This is the first study to examine the gut microbial community structure in undernourished and obese Mexican children living in low-income neighborhoods. Our analysis revealed distinct taxonomic profiles for undernourished and obese children.

Whole-exome sequencing in maya indigenous families: variant in PPP1R3A is associated with type 2 diabetes.

It has been presumed that increased susceptibility in Mexicans to type 2 diabetes (T2D) is attributed to the Native American genetic ancestry. Nonetheless, it is not known if there are private genetic variants that confer susceptibility to develop T2D in our population. The Maya indigenous group has the highest proportion of Native American ancestry (98%) which makes it a representative group of the original peoples of Mexico. Thus, the aim of the present study is to identify new genetic variants associated with T2D in Maya families. Whole-exome sequencing was performed on DNA samples from Maya families with a third-generation family history of T2D only in one parental line. Four variants were identified for APOB, PPP1R3A, TPPP2, and GPR1 genes, and were further tested for association with T2D in 600 unrelated Maya in a case-control study. For the first time, rs1799999 in PPP1R3A was associated with risk of T2D in Mayan Mexican individuals (OR = 1.625, P = 0.014). Interestingly, carriers of rs1799999 presented increased values of HOMA-IR. In addition, rs1801702 in APOB was associated with total cholesterol and LDL-C (P = 0.019 and P = 0.020, respectively) in normoglycemic individuals; rs3732083 in GPR1 with HOMA-IR (P = 0.016) and rs9624 in TPPP2 with total cholesterol and triglycerides (P = 0.002 and P = 0.005, respectively) in T2D subjects. Overall, these findings support the idea that there are other genetic variants yet to be described, involved in T2D development in Maya population, being insulin resistance and lipid metabolism the main mechanisms implicated. Thus, these results can contribute to the understanding of diabetes genetic background in Mexican population.

Síndrome metabólico en niños mexicanos: poca efectividad de las definiciones diagnósticas / Metabolic syndrome in Mexican children: Low effectiveness of diagnostic definitions

Antecedentes: La identificación oportuna de niños con síndrome metabólico (SM) es la clave para disminuir el riesgo de desarrollar diabetes y enfermedad cardiovascular en la vida adulta, sin embargo, su detección representa un gran reto debido a las diversas definiciones para su diagnóstico dejando excluidos niños con factores de riesgo a los cuales no se les brindarán medidas preventivas. El objetivo es comparar la prevalencia de SM según las definiciones de la IDF, NCEP-ATP-III, Cook, de Ferranti y Weiss e incluir marcadores de resistencia a la insulina (RI) como el HOMA-IR y/o índice metabólico (IM). Metodología: Estudio transversal en 508 niños mexicanos de 9 a 13 años. Se registraron medidas somatométricas y evaluaron parámetros bioquímicos y hormonales. Resultados: La frecuencia de SM fue de 2,4-45,9% dependiendo de la definición utilizada. La RI en los niños sin diagnóstico de SM fue del 12,4-25,2% con HOMA-IR y 4,0-16,3% con IM. Al incluir el HOMA-IR o IM en cada una de las definiciones la frecuencia de SM fue 8,5-50,2% y 7,7-46,9% respectivamente. El valor de Kappa incluyendo HOMA-IR e IM fue mayor a 0,8. Conclusiones: Este trabajo revela la poca efectividad de las definiciones diagnósticas de SM empleadas actualmente, evidenciada por la variabilidad entre ellas y por la presencia de RI en niños que escapan al diagnóstico de SM. Incluir al HOMA-IR y/o IM en las definiciones, disminuye la probabilidad de excluir niños con SM y aumenta la concordancia entre ellas haciendo posible la comparación de la prevalencia de SM entre las poblaciones (AU)

Background: Early identification of children with metabolic syndrome (MS) is essential to decrease the risk of developing diabetes and cardiovascular disease in adulthood. Detection of MS is however challenging because of the different definitions for diagnosis; as a result, preventive actions are not taken in some children at risk. The study objective was therefore to compare prevalence of MS in children according to the IDF, NCEP-ATP-III, Cook, de Ferranti and Weiss definitions, considering insulin resistance (IR) markers such as HOMA-IR and/or metabolic index (MI). Methods: A total of 508 Mexican children (aged 9 to 13 years) from seven schools were enrolled in a cross-sectional study. Somatometric, biochemical, and hormonal measurements were evaluated. Results: Frequency of MS was 2.4-45.9% depending on the definition used. Frequency of IR in children not diagnosed with MS was 12.4-25.2% using HOMA-IR and 4.0-16.3% using MI. When HOMA-IR or MI was included in each of the definitions, frequency of MS was 8.5-50.2% and 7.7-46.9% respectively. The kappa value including HOMA-IR and/or MI was greater than 0.8. Conclusions: This study demonstrated the poor effectiveness of the current criteria used to diagnose MS in Mexican children, as shown by the variability in the definitions and by the presence of IR in children who not diagnosed with MS. Inclusion of HOMA-IR and/or MI in definitions of MS (thus increasing agreement between them) decreases the chance of excluding children at risk and allows for MS prevalence between populations (AU)

Metabolic syndrome in Mexican children: Low effectiveness of diagnostic definitions. / Síndrome metabólico en niños mexicanos: poca efectividad de las definiciones diagnósticas.

BACKGROUND: Early identification of children with metabolic syndrome (MS) is essential to decrease the risk of developing diabetes and cardiovascular disease in adulthood. Detection of MS is however challenging because of the different definitions for diagnosis; as a result, preventive actions are not taken in some children at risk. The study objective was therefore to compare prevalence of MS in children according to the IDF, NCEP-ATP-III, Cook, de Ferranti and Weiss definitions, considering insulin resistance (IR) markers such as HOMA-IR and/or metabolic index (MI). METHODS: A total of 508 Mexican children (aged 9 to 13 years) from seven schools were enrolled in a cross-sectional study. Somatometric, biochemical, and hormonal measurements were evaluated. RESULTS: Frequency of MS was 2.4-45.9% depending on the definition used. Frequency of IR in children not diagnosed with MS was 12.4-25.2% using HOMA-IR and 4.0-16.3% using MI. When HOMA-IR or MI was included in each of the definitions, frequency of MS was 8.5-50.2% and 7.7-46.9% respectively. The kappa value including HOMA-IR and/or MI was greater than 0.8. CONCLUSIONS: This study demonstrated the poor effectiveness of the current criteria used to diagnose MS in Mexican children, as shown by the variability in the definitions and by the presence of IR in children who not diagnosed with MS. Inclusion of HOMA-IR and/or MI in definitions of MS (thus increasing agreement between them) decreases the chance of excluding children at risk and allows for MS prevalence between populations.

Genetic variability of CYP2C9*2 and CYP2C9*3 in seven indigenous groups from Mexico.

AIM: CYP2C9 is one of the major drug metabolizing enzymes, however, little is known about polymorphisms in CYP2C9 gene and pharmacological implications in Mexican indigenous populations. Thus, frequencies of CYP2C9*2 and CYP2C9*3 alleles were evaluated in indigenous groups located in northwest (Cora), center (Mazahua and Teenek), south (Chatino and Mixteco) and southeast (Chontal and Maya) regions Mexico. MATERIALS & METHODS: Allelic discrimination was performed by real-time PCR. RESULTS: CYP2C9*2 allele was found only in Chontal and Maya groups, despite the low contribution of Caucasian component in these populations. CYP2C9*3 allele was present in all populations except in Mazahua, showing a wide genetic variability in the studied populations. Interestingly, we found significant differences between indigenous groups in CYP2C9*3 allele, even in groups located at the same region and belonging to the same linguistic family. CONCLUSION: These results contribute to laying the pharmacogenetic bases in Mexico, in addition to improving treatment, taking into account the genetic interethnic differences.

[Micronutrients and diabetes, the case of minerals]. / Micronutrientes y diabetes, el caso de los minerales.

Minerals are essential nutrients for the body, are of inorganic nature which gives them the characteristic of being resistant to heat, are involved in a lot of chemical reactions in metabolism, regulating electrolyte balance, in maintaining bone, in the process of blood clotting and the transmission of nerve impulses, particularly its role as enzyme cofactors confers a key role in various physiological processes. Glucose homeostasis involves a fine coordination of events where hormonal control by insulin plays a key role. However, the role of minerals like magnesium, zinc, chromium, iron and selenium in the diabetes is less obvious and in some cases may be controversial. This review shows the knowledge of these five elements and their correlation with diabetes.

Los minerales son nutrientes esenciales para el organismo, de naturaleza inorgánica que les confiere, entre otras características, ser resistentes al calor, participan en diversas reacciones químicas del metabolismo en donde regulan el equilibrio hidroelectrolítico, el mantenimiento óseo, en la trasmisión de los impulsos nerviosos, y durante el proceso de coagulación sanguínea, particularmente por su función como cofactores enzimáticos, tienen un papel clave en varios procesos fisiológicos. La homeostasis de la glucosa involucra una fina coordinación de eventos en donde el control hormonal por la insulina tiene un papel primordial. Sin embargo, la función de los minerales, como el magnesio, el zinc, el cromo, el hierro y el selenio en la diabetes es menos evidente y puede ser, en algún caso, controversial. Esta revisión muestra el conocimiento acerca de estos cinco elementos y su correlación con la diabetes.

Developmental programming of neonatal pancreatic ß-cells by a maternal low-protein diet in rats involves a switch from proliferation to differentiation.

Maternal low-protein diets (LP) impair pancreatic ß-cell development, resulting in later-life failure and susceptibility to type 2 diabetes (T2D). We hypothesized that intrauterine and/or postnatal developmental programming seen in this situation involve altered ß-cell structure and relative time course of expression of genes critical to ß-cell differentiation and growth. Pregnant Wistar rats were fed either control (C) 20% or restricted (R) 6% protein diets during pregnancy (1st letter) and/or lactation (2nd letter) in four groups: CC, RR, RC, and CR. At postnatal days 7 and 21, we measured male offspring ß-cell fraction, mass, proliferation, aggregate number, and size as well as mRNA level for 13 key genes regulating ß-cell development and function in isolated islets. Compared with CC, pre- and postnatal LP (RR) decreased ß-cell fraction, mass, proliferation, aggregate size, and number and increased Hnf1a, Hnf4a, Pdx1, Isl1, Rfx6, and Slc2a2 mRNA levels. LP only in pregnancy (RC) also decreased ß-cell fraction, mass, proliferation, aggregate size, and number and increased Hnf1a, Hnf4a, Pdx1, Rfx6, and Ins mRNA levels. Postnatal LP offspring (CR) showed decreased ß-cell mass but increased ß-cell fraction, aggregate number, and Hnf1a, Hnf4a, Rfx6, and Slc2a2 mRNA levels. We conclude that LP in pregnancy sets the trajectory of postnatal ß-cell growth and differentiation, whereas LP in lactation has smaller effects. We propose that LP promotes differentiation through upregulation of transcription factors that stimulate differentiation at the expense of proliferation. This results in a decreased ß-cell reserve, which can contribute to later-life predisposition to T2D.

LOC387761 polymorphism is associated with type 2 diabetes in the Mexican population.

Worldwide researchers have invested time, effort, and money during the last years to find new genes associated with diabetes susceptibility, such as LOC387761, HHEX, EXT2, and SLC30A8. The aim of the present study was to evaluate whether single-nucleotide polymorphisms (SNPs) of these genes are associated with type 2 diabetes (T2D) and metabolic traits in the Mexican population. We also assessed these SNPs in Mexican indigenous groups to identify a possible inherited susceptibility. Seven SNPs were analyzed in 789 Mexicans (234 control subjects, 455 type 2 diabetic patients, and 100 of indigenous origin), using the KASPar assay (KBioscience Company). Analysis of the data showed an association of the LOC387761 SNP rs7480010 with T2D (p = 0.019). The risk allele A of rs7480010 increased body mass index in diabetic patients (p = 0.01). In addition, there was no association between T2D and the SNPs of HHEX, EXT2, and SLC30A8. Our findings suggest that the SNP rs7480010 (LOC387761) can contribute to a failure in insulin secretion, thus increasing the susceptibility to T2D in Mexicans.

Dynamic tests and FSH biological activity in female rats with acute nephrotic syndrome.

To investigate the pituitary-ovarian status during the acute state of the nephrotic syndrome, a sequence of experiments were undertaken in adult female rats after a single dose of the puromycin aminonucleoside (PAN). The functional condition of the hypophyseal-ovarian unit was determined in control and nephrotic rats by two dynamic tests. In the first one, 10 days after PAN or placebo administration female rats were stimulated with LHRH (300 ng/100 g body wt) and samples were collected at 0, 20, 40, 60 and 80 min after releasing factor administration. The second dynamic test, which was performed in control and nephrotic rats, consists of one (day 10 after PAN) or four (between days 7-10 after PAN) doses of hCG (8 UI), respectively. In all cases, serum samples were collected on day 10. In addition, the relative in vitro biological activity of FSH from control and nephrotic rats before and after LHRH stimulus was determined. The results reveal that after a stimulatory dose of LHRH the secretion of LH was significantly diminished in nephrotic rats at all registered times. By contrast, normal response was observed in terms of FSH secretion in nephrotic females. On the other hand, no ovarian response, in terms of progesterone or estradiol synthesis, was observed in nephrotic rats after either one or four stimuli with hCG Interestingly, in spite of the normal or high concentrations of FSH, the biological activity of FSH was totally abolished in nephrotic rats. On the whole, the results from this study indicate that the nephrotic syndrome had a harmful effect on the pituitary-ovarian unit, and strongly suggest that the endocrine dysfunction could be initiated at the hypophysial level; even though a specific ovarian damage is also predictable.