ABCA1 variant rs9282541 is associated with metabolic syndrome in Maya children.

INTRODUCTION: Metabolic syndrome (MetS) is a metabolic disorder encompassing risk factors for cardiovascular disease and type 2 diabetes (T2D). In Mexico, the MetS is a national health problem in adults and children. Environmental and genetic factors condition the MetS. However, studies to elucidate the contribution of genetic factors to MetS in Mexico are scarce. A recent study showed that variant rs9282541 (A-allele) in ATP-binding cassette transporter A1 (ABCA1) was associated with T2D in the Maya population in addition to low levels of high-density lipoprotein cholesterol (HDL-C). Thus, this study aimed to determine whether the genetic variant of ABCA1 A-allele (rs9282541, NM_005502.4:c.688C > T, NP_005493.2:p.Arg230Cys) is associated with MetS and its components in Mexican Maya children. METHODS: The study was conducted in 508 children aged 9-13 from the Yucatán Peninsula. MetS was identified according to the de Ferranti criteria. Genotyping was performed using TaqMan assay by real-time PCR. Evaluation of genetic ancestry group was included. RESULTS: The frequency of MetS and overweight-obesity was 45.9% and 41.6%, respectively. The genetic variant rs9282541 was associated with low HDL-C and high glucose concentrations. Remarkably, for the first time, this study showed the association of ABCA1 rs9282541 with MetS in Maya children with an OR of 3.076 (95% CI = 1.16-8.13 p = 0.023). Finally, this study reveals a high prevalence of MetS and suggests that variant rs9282541 of the ABCA1 gene plays an important role in the developing risk of MetS in Maya children.

(-)-Epicatechin improves body composition of male rats descendant of obese mothers postnatally fed with a high-fat diet.

A combination of maternal obesity and high-fat diet (HFD) in offspring postnatal life has deleterious effects, and (-)-epicatechin (Epi) treatment can reverse these adverse effects. To investigate whether Epi administration can modify fat mass, muscle mass, and bone mass in male rats descended from obese mothers, fed postnatally on an HFD. Male offspring of mothers fed with control diet formed the control group (C), control group with high-fat diet (CHF), and control group with high-fat diet + epicatechin (CHF + Epi). Male offspring of maternal obesity formed the group with control diet (MO), maternal obesity group with high-fat diet (MOHF), and maternal obesity group with high-fat diet + epicatechin (MOHF + Epi). We measured total fat and weight of visceral adipose tissue by dissection and by dual-energy x-ray absorptiometry scanning body composition. Epicatechin diminished total and visceral pads fat of male offspring of CHF + Epi and MOHF + Epi groups versus to male offspring of CHF and MOHF groups. Besides, epicatechin increased lean mass in CHF + Epi and MOHF + Epi groups, but these changes were not significant. Total body mineral density of the male offspring of CHF, MOHF, and MOHF + Epi groups was significantly higher versus male offspring of C and MO groups. Obesity programming model plus a high-fat postnatal diet presents higher visceral adipose tissue, decreased lean mass, and modified body mineral density when compared with a direct obesity model and its controls. Epicatechin treatment improved body composition; however, it was not able to induce similar values as presented by the controls.

High Prevalence of Hypocitraturia in Stone Formers from the Maya Region of Yucatan, Mexico.

BACKGROUND: Urinary Stone Disease (USD) arises from an interaction of genetic and environmental factors. Urinary metabolic abnormalities are well described as risk factors. In Mexico, the Maya region holds the highest prevalence of USD. Treatment of these abnormalities lowers the risk of recurrences. AIM: Assess the underlying metabolic abnormalities of patients with USD to provide a rationale to lead further prevention strategies. METHODS: Clinical and demographical data from patients coming to the Stone Clinic were prospectively collected along with a 24 h urinary panel to identify metabolic abnormalities. All participants signed consent and the study was approved by the hospital's institutional review board. RESULTS: A total of 126 patients were included, with a mean age of 47.2 ± 13 years, 75.4% were female. A positive family history of stones was observed in 40 and 87.3% were overweight/obese. The frequency of hypocitraturia, hypercalciuria, hypomagnesuria, hyperoxaluria, and hyperuricosuria was 91.3, 68.5, 42.1, 36.5, and 26.6%, respectively. Median urinary citrate was 79.5 (37.5-160) mg/24 h and was inversely correlated to glycemia. Urine Calcium/Creatinine index was correlated with Hounsfield units (HU) (p = 0.01). Oxalate was correlated with HU and stone burden. Interestingly, dietary distribution of macro- and micronutrients were similar between groups. Patients with a single kidney had lower citrate and higher urinary calcium. CONCLUSIONS: Interestingly, a shortage of inhibitors such as citrate and magnesium are highly prevalent in patients with USD from the Maya region and seems to be influenced by other metabolic conditions as malnutrition next to the genetic component.

Risk factors associated with diabetic neuropathy in Mexican patients.

INTRODUCTION: Diabetic neuropathy (DN) is one of the most common complications of type 2 diabetes (T2D) and is a leading cause of lower limb amputation. The aim of the present study was to evaluate the risk factors contributing to DN in Mexican patients through the comparison of T2D patients with and without DN. MATERIALS AND METHODS: This cross-sectional study consisted of 509 subjects from Mexico who were classified as with DN and without DN. DN was assessed according to Douleur Neuropathique 4 questionnaire. Logistic regression analysis was performed to analyze risk factors contributing to DN. RESULTS: The prevalence of DN in the studied population was 28.3%. The risk factors associated with DN were T2D duration (odds ratio [OR]: 2.51; 95% confidence interval [CI] 1.36-4.65), glycemic exposure index (OR: 1.82; 95% CI 1.01-3.64), low- and high-density lipoprotein levels (OR: 1.53; 95% CI 1.02-2.31), metformin treatment (OR: 2.08; 95% CI 1.11-3.91), diabetic retinopathy (OR: 1.65; 95% CI 1.07-2.54), and smoking (OR: 1.51; 95% CI 1.00-2.26). CONCLUSIONS: Therefore, the early identification of risk factors for DN development in Mexican population would allow implementing personalized strategies to improve the overall T2D patients' quality of life and reduce healthcare costs in our country.

ANTECEDENTES: La neuropatía diabética (ND) es una de las complicaciones más comunes de la diabetes tipo 2 (DT2). ­. OBJETIVO: Investigar los factores de riesgo que contribuyen al desarrollo de ND en población mexicana con DT2, comparando pacientes diabéticos con y sin ND. MÉTODO: Estudio transversal con 509 pacientes mexicanos con DT2, clasificados en dos grupos, con y sin ND. La ND fue diagnosticada con el cuestionario DN4. La identificación de los factores de riesgo de ND se realizó mediante un análisis de regresión logística. RESULTADOS: La prevalencia de ND en la población de estudio fue del 28.3%. Los factores de riesgo asociados a ND fueron la duración de la DT2 (odds ratio [OR]: 2.51; intervalo de confianza del 95% [IC 95%]: 1.36-4.65), el índice glucémico (OR: 1.82; IC 95%: 1.01-3.64), las concentraciones bajas de colesterol unido a lipoproteínas de alta densidad (OR: 1.53; IC 95%: 1.02-2.31), el tratamiento con metformina (OR: 2.08; IC 95%: 1.11-3.91), la retinopatía diabética (OR: 1.65; IC 95%: 1.07-2.54) y el tabaquismo (OR: 1.51; IC 95%: 1.00-2.26). CONCLUSIONES: La identificación temprana de los factores de riesgo para el desarrollo de ND en población mexicana permitirá implementar estrategias personalizadas para mejorar la calidad de vida de los pacientes con DT2 y disminuir el gasto del sector salud originado por esta complicación.

Maternal interventions to prevent adverse fetal programming outcomes due to maternal malnutrition: Evidence in animal models.

Animal studies indicate that suboptimal conditions during pregnancy adversely impact both maternal health and offspring phenotype, predisposing offspring to development of later-life diseases including obesity, diabetes, cardiovascular diseases, and behavioral and reproductive dysfunction. Effective interventions during pregnancy and/or lactation are needed to improve both maternal and offspring health. This review addresses the relationship between adverse perinatal insults and its negative impact on offspring development and presents some maternal intervention studies in animal models, such as maternal nutrition (diet modification, antioxidants, omega-3-6 (n-3-6), probiotics) or physical activity, which can prevent or alleviate negative outcomes in both mother and offspring.

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.

Strengths and validity of three methods for assessing rat body fat across the life course.

There are several different methods available for the determination of body fat composition. Two current methods requiring special instrumentation are magnetic resonance imaging (MRI) and dual energy x-ray absorptiometry (DXA). The use of these techniques is very limited despite desirable properties, due to their high costs. Dissection of all fat depots (DF) requires no special instrumentation and allows examination and evaluation of each fat depot in more detail. MRI, DXA, and DF each have their unique advantages and disadvantages when they are applied to animal models. Most studies have determined body fat in young animals, and few studies have been performed in aging models. The aim of this study was to compare MRI, DXA, and DF data in offspring (F1) of mothers fed with control and high-fat diet. We studied rats that varied by age, sex, and maternal diet. The relationships between the three methods were determined via linear regression methods (using log-transformed values to accommodate relativity in the relationships), incorporating when useful age, sex, or diet of the animal. We conclude that the three methods are comparable for measuring body fat, but that direct equivalence gets masked by age, sex, and sometimes dietary group. Depending on the equipment available, the budget of the laboratory, and the nature of the research questions, different approaches may often suggest themselves as the best one.

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.

Demographic history and biologically relevant genetic variation of Native Mexicans inferred from whole-genome sequencing.

Understanding the genetic structure of Native American populations is important to clarify their diversity, demographic history, and to identify genetic factors relevant for biomedical traits. Here, we show a demographic history reconstruction from 12 Native American whole genomes belonging to six distinct ethnic groups representing the three main described genetic clusters of Mexico (Northern, Southern, and Maya). Effective population size estimates of all Native American groups remained below 2,000 individuals for up to 10,000 years ago. The proportion of missense variants predicted as damaging is higher for undescribed (~ 30%) than for previously reported variants (~ 15%). Several variants previously associated with biological traits are highly frequent in the Native American genomes. These findings suggest that the demographic and adaptive processes that occurred in these groups shaped their genetic architecture and could have implications in biological processes of the Native Americans and Mestizos of today.

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.

Genetic Component of Type 2 Diabetes in a Mexican Population.

Type 2 diabetes (T2D) is a complex disease caused by the interaction of genetic and environmental factors. In this regard, it has been demonstrated that Hispanics have a greater susceptibility to developing complex diseases like T2D, which has been attributed to their Amerindian component. Mexico has a wide population variety as a result of Amerindian (56-69%), European (26-41.8%) and African (1.8-6%) ancestral components. The stratification of the population has made difficult the study of T2D in the Mexican population. Despite advances, in Mexico the studies in this field are scarce; 9 of 88 loci associated with type 2 diabetes by genome-wide association studies (GWAS) in Caucasian populations have been replicated in the Mexican population. Currently, only 19 common variants and two variants of low frequency have been associated with T2D in Mexico. With respect to the private genetic variation in Mexican population, only one haplotype and two genetic variants have been described. This confirms the existence of new genetic variants not yet described, exclusive to the Mexican population, which suggests most likely, that there are more genetic variants to discover. Thus, in the present review we aim to bring together in one place all the studies about T2D in Mexico to understand the contribution of the genetic factors in the susceptibility to developing T2D in a Mexican population.

PNPLA3 I148M polymorphism is associated with elevated alanine transaminase levels in Mexican Indigenous and Mestizo populations.

The patatin like phospholipase domain-containing (PNPLA3) I148M variant is the strongest genetic factor associated with elevated alanine transaminase (ALT) levels in different populations, particularly in Hispanics who have the highest 148M risk allele frequency reported to date. It has been suggested that Indigenous ancestry is associated with higher ALT levels in Mexicans. The aim of the present study was to assess the frequency of the PNPLA3 148M risk allele in Mexican indigenous and Mestizo individuals, and to examine its association with serum ALT levels. The study included a total of 1624 Mexican individuals: 919 Indigenous subjects from five different native groups and 705 Mexican Mestizo individuals (141 cases with ALT levels ≥ 40 U/L and 564 controls with ALT <40 U/L). The I148M polymorphism was genotyped by TaqMan assays. The frequency of elevated ALT levels in Indigenous populations was 18.7%, and varied according to obesity status: 14.4% in normal weight, 19.9% in overweight and 24.5% in obese individuals. The Mexican indigenous populations showed the highest reported frequency of the PNPLA3 148M risk allele (mean 0.73). The M148M genotype was significantly associated with elevated ALT levels in indigenous individuals (OR = 3.15, 95 % CI 1.91-5.20; P = 7.1 × 10(-6)) and this association was confirmed in Mexican Mestizos (OR = 2.24, 95% CI 1.50-3.33; P = 8.1 × 10(-5)). This is the first study reporting the association between M148M genotype and elevated ALT levels in Indigenous Mexican populations. The 148M allele risk may be considered an important risk factor for liver damage in Mexican indigenous and Mestizo populations.

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.

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.

It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

Rosiglitazone modifies HDL structure and increases HDL-apo AI synthesis and catabolic rates.

BACKGROUND: Rosiglitazone is an agonist of the peroxisome proliferator-activated receptor (PPAR) gamma that may modify HDL metabolism in humans, but this effect has not been completely elucidated. Therefore, we determined the effect of rosiglitazone on apo AI turnover, HDL structure, and PON1 plasma activity. METHODS: Kinetic studies of HDL-apo AI radiolabeled with (125)I were performed in 7 chow-fed, male, New Zealand white rabbits after 6 weeks of 0.32 mg/kg/d rosiglitazone-treatment vs. vehicle-treated rabbits (n=11). HDL size distribution was determined by polyacrylamide gradient electrophoresis and paraoxonase-1 (PON1); plasma activity was assessed spectrophotometrically using phenylacetate as substrate. RESULTS: Fractional catabolic rate (FCR) of HDL apo AI was higher in the rosiglitazone-treated group than in the control group (0.031+/-0.004 vs. 0.025+/-0.006 pools/h, respectively, p<0.05). The mean apo AI production rate (PR) was 62% higher in the rosiglitazone group as compared to controls (0.918+/-0.238 vs. 0.564+/-0.160 mg/kg/h, p<0.01). Accordingly, apo AI plasma levels in rosiglitazone-treated animals were about 37% higher than in the control group. Rosiglitazone-induced changes in apo AI turnover appeared concomitantly with a significant increase of phospholipids and a decrease in colesteryl esters content of the HDL. Compositional changes resulted in a relative increase of the HDL3b and HDL3c subfractions and a significant enhancement of the plasma PON1 activity (488.5+/-138.2 vs. 595.2+/-179.4 micromol/min/ml, p<0.05). CONCLUSIONS: Rosiglitazone increased apo AI plasma concentrations, resulting from an enhancement of apo AI synthesis, and induced the synthesis of smaller HDL particles with a concomitant increase of plasma PON1 activity. These modifications may contribute to the anti-atherogenic potential of rosiglitazone.