Association Analyses of Variants in the DIO2 Gene with Early-Onset Type 2 Diabetes Mellitus in Pima Indians

Background: The type 2 deiodinase gene (DIO2) encodes a deiodinase that converts the thyroid prohormone, thyroxine, to the biologically active triiodothyronine. Thyroid hormones regulate energy balance and may also influence glucose metabolism. Therefore, we hypothesized that variations in DIO2 could contribute to obesity or type 2 diabetes mellitus (T2DM) in Pima Indians. Methods: Sequencing of the DIO2 gene in DNA from 83 Pima Indians identified 12 single-nucleotide polymorphisms (SNPs). Several of these SNPs were in perfect genotypic concordance among the 83 samples that were sequenced, and all 12 could be divided into five linkage disequilibrium groups. One representative SNP from each group (Thr92Ala, rs225011, rs225015, rs6574549, and a rare 5¢ flanking SNP) was selected for further genotyping for association analyses. In this study, the five selected variants in DIO2, as described above, were genotyped in three groups of Pima Indians: (i) a case (n = 150)/control (n = 150) group for early-onset T2DM (onset age \u3c 25 years); (ii) a case (n = 362)/control (n = 127) group for obesity; (iii) a large (n = 1,311, cases n = 810/ controls n = 501) family-based group, of which 256 nondiabetic subjects had undergone detailed metabolic phenotyping. Results: The Thr92Ala variant common in Pima Indians, rs225011, and rs225015 were modestly associated with early-onset T2DM ( p = 0.01–0.04) in the case–control study, but were not associated with obesity in the obesity case–control study, nor associated with T2DM (at any age) or body–mass index (BMI; as a quantitative trait) in the family-based analysis. Thr92Ala, rs225011, rs225015, and rs6574549 were also nominally associated with hepatic glucose output ( p = 0.02). rs6574549 was associated with fasting insulin ( p = 0.02), insulin action ( p = 0.04), and energy expenditure ( p = 0.02). None of these nominal associations remained statistically significant after corrections for multiple testing. Conclusions: We propose that variation in DIO2 may have a subtle role in altering metabolic processes that lead to early-onset T2DM, but this gene does not have a large impact on T2DM at older ages, nor does DIO2 influence BMI in the Pima Indian population. Introductio

Influence of Diet on Metabolic Physiology in People with and without a Family History of Type 2 Diabetes

Type 2 diabetes (T2D) prevalence in the Rio Grande Valley is ~27% versus the 9% national average. Simply having a family history (FH+) of type 2 diabetes (T2D) increases T2D prevalence by ~40 over those with no family history (FH-). We have shown that FH+ display early markers of cardiometabolic impairment vs FH-, such as blunted microvascular reactivity, and impaired metabolic flexibility. What is not yet known is the degree to which environment vs genetics may contribute to these impairments. PURPOSE: This pilot study seeks to examine normal dietary patterns between FH groups to identify potential patterns in macro- and micro-nutrient consumption that may help explain differences in metabolic function. METHODS: Thirty-three healthy individuals, including 10 FH+ and 23 FH- (26 ± 7; 24 ± 5 yrs respectively) participated in this study. Anthropometrics were assessed at rest. One-way ANOVA was used to determine group differences. Three-day food questionnaires were given to subjects prior to testing. Amino acid, Vitamin B3 & B6, water, and caffeine levels were measured. RESULTS: Compared to FH-, FH+ had higher (p\u3c0.05) consumption of caffeine (151.54 ± 44.0mg vs 34.83 ± 11.63mg), water (1264.76 ± 713.30g vs 770.08 ± 504.16g), Vitamin B3 (30.35 ± 22.35mg vs 19.99 ± 12.92mg), B6 (2.43 ± 1.45mg), Histidine (2.56 ± 2.18g), Lysine (6.60 ± 5.84 vs 3.72 ± 2.72g), and Methionine (2.18 ± 1.77 vs 1.33 ± 0.94 compared to FH-, with no differences noted in total energy intake between groups. CONCLUSION: Differing nutritional intake noted between FH groups is a potential confounding factor in the development of T2D in FH+ of the RGV and warrants further study

Lifestyle Factors Affecting Android Fat in Hispanic Residents of The RGV

ABSTRACT Approximately 79% of the Hispanic population in the Rio Grande Valley (HPRGV) are overweight or obese. As such, this population also have ~3x the type 2 diabetes (T2D) rates than the US average. Distribution of adipose tissue, affected largely by genetics and lifestyle (diet and physical activity, has been identified as a key-marker for T2D risk among apparently healthy individuals. However, the relationship of lifestyle factors such as diet and physical activity on android fat in healthy young Hispanics of the RGV has not been completely explored. Purpose: The purpose of this study was to determine whether there is a relationship between android fat, and lifestyle factors such as diet and physical activity in HPRGV. Methods: 23 healthy people from the RGV were recruited and matched for weight, BMI, and age. Android fat was assessed by a Dual-energy X-ray Absorptiometry (DEXA), dietary habits were determined by 3-day nutrition log, from which macro and micronutrients were gathered via a web-based micronutrient calculator (Cronometer), and physical activity was determined using the International Physical Activity Questionnaire. Results: Overall, there was significant variation between participants for time spent (minutes per week) in vigorous (318.9 ± 50.1 mean ± SEM), and moderate activity (62323.8 ± 38291.8 mean ± SEM), and time sitting (246366.7 ± 134104.2 mean ± SEM), with no correlations for any physical activity variable noted with android fat. However, there were numerous macro- and micronutrients displaying significant inverse 2-tailed correlations with android fat, which include: Total energy (r=-.56, p\u3c0.005), B1 (r=-.73, p\u3c0.001), B5 (r=-.57, p\u3c0.001), folate (r=-.54, p\u3c0.001), calcium (r=-.65, p\u3c0.001), selenium (r=-.61, p\u3c0.001), CHO (r=-.54, p\u3c0.001), Omega 3 (r=-.54, p\u3c0.001), Omega 6 (r=.61, p\u3c0.001), and threonine (r=.56, p\u3c0.001). There were no direct relationships between diet and android fat. Conclusion: Overnutrition in the RGV appears to be driving abdominal obesity in HPRGV, and likely largely contributing to T2D incidence in the region, more than physical activity, which has significant variation

Microvascular Blood Flow Changes in RGV Hispanics in Response to a Mixed Meal Challenge

Type 2 diabetes rates in the Rio Grande Valley (RGV) are 3x higher than the national average, with etiologies being multifactorial. Impaired postprandial skeletal muscle microvascular blood flow (MBF) is one of the earliest T2D pathophysiologies noted in Caucasians. However, MBF responses are unknown in the Hispanic population of the RGV. PURPOSE: Our goal in this study was to determine whether normoglycemic Hispanic individuals in the RGV exhibit impaired skeletal muscle MBF responses compared with healthy Caucasian individuals from a previous study. METHODS: 15 Hispanic individuals from the RGV with no family history of T2D (FH-), and 13 with a family history of T2D (FH+) were recruited to determine skeletal muscle MBF responses to a mixed-meal challenge (MMC). MBF was measured via contrast-enhanced ultrasound while fasting, and again one hour after consuming the MMC. RESULTS: We previously reported that in Caucasian individuals, MBF increases postprandially in both FH+ (pCONCLUSION: Apparently healthy Hispanic individuals of the RGV display impaired skeletal muscle MBF responses compared with healthy Caucasian individuals. Further, there were no differences in skeletal muscle MBF responses between FH groups in Hispanic individuals of the RGV. Further research is needed to determine why this population displays early microvascular impairments

P1 Height in Hispanics With and Without Family History of Type 2 Diabetes

Coronary heart disease (CHD) is the world’s leading cause of death, with type 2 diabetes (T2D) increasing that risk ~3-fold. T2D incidence in Hispanics of the Rio Grande Valley (RGV) is \u3e27% vs 9% noted nationwide. Further, having a family history of T2D (FH+) increases risk by ~40%. PURPOSE: To determine if specific aspects of macrovascular function may precede overt hypertension and T2D in FH+ people in the RGV. METHODS: Thirty-three healthy individuals, including 10 FH+ and 23 FH- (26 ± 7; 24 ± 5 yrs respectively), participated in this study. Hemodynamics and large artery function were assessed at rest. One-way ANOVA was used to determine group differences. Pearson correlation was used to determine relationships between significant variables. RESULTS: P1 Height, a measure of forward vascular pressure generated by ventricular contraction, was higher (pCONCLUSIONS: P1 Height is elevated in FH+ individuals and is related to some variables of positive health status, such as triglycerides and lower body fat. More studies are warranted to determine if P1 height is cardioprotective, or a pathophysiological precedent to hypertension

Host susceptibility to tuberculosis: insights from a longitudinal study of gene expression in diabetes

Tuberculosis (TB) remains a major global disease, and diabetes which is documented to increase susceptibility to TB threefold, is also becoming pandemic. This susceptibility has been attracting extensive research interest. The increased risk of TB in diabetes may serve as a unique model to understand host susceptibility to specific pathogens in humans. To examine this rationale, we investigated expression of reported TB candidate genes in a longitudinal diabetes study. Two genes HK2 and CD28 emerged as potential culprits in diabetes-increased TB susceptibility

Updated Genes, Lifestyles, and their Interactions for Human Longevity

Healthy aging is the prolonging of optimal wellbeing during the progressive decline in physiological functions that are necessary for survival. Two important components of aging include an individual’s genetic makeup and lifestyle choices such as diet and exercise. Genetic factors are responsible for the functional physiology of the body including cell maintenance, metabolism and apoptosis. The individual effects of genes and lifestyle choices on aging are reported mainly in Caucasian populations, with very limited studies in minority populations. In this review, we included the effects of genes and environment and the interaction between them on aging in Hispanic population in addition to other populations. Our systematic review focuses on exploring present findings that assess the involvement of genes and lifestyles with healthy aging, as well as the interactions between the two. The purpose of the review is to update current findings of longevity as it pertains to the genetic composition of humans and the lifestyle choices people make. We were specifically looking for research conducted in the US Hispanic population and/or other minority populations. We searched through PubMed to identify reliable and relevant research articles involving ‘genes’, ‘lifestyle’, ‘longevity’, and ‘healthy aging’. We filtered the articles for those that pertain towards humans and are in the English language. We searched most updated top longevity-associated genes, lifestyles, and their interactions. We found that the biological and environmental factors (e.g., lifestyle) involved in aging are important factors that attribute towards attainment of longevity. The individual’s genetic composition and lifestyle choices significantly impact the aging process and longevity

Decreased expression of ATP6V1H in type 2 diabetes: a pilot report on the diabetes risk study in Mexican Americans

Objective: Previous studies in mice and humans observed down-regulation of the gene expression of ATP6V1H associated with type 2 diabetes. This study identified prospectively changes in ATP6V1H expression before and after overt diabetes. Methods: Expression of ATP6V1H in peripheral blood was compared pre and post development of diabetes in nine individuals. Results: Considerable variation of ATP6V1H mRNA levels was observed between different individuals. However, within each individual the decrease in expression of ATP6V1H with the development of diabetes was highly statistically significant. Conclusions: ATP6V1H may represent a critical molecular mechanism involved in the development of type 2 diabetes and its compilations through its important regulatory effect on vacuolar-ATPase activity

Association of a serotonin transporter gene (SLC6A4) 5-HTTLPR polymorphism with body mass index categories but not type 2 diabetes mellitus in Mexicans

The serotonergic system has been hypothesized to contribute to the biological susceptibility to type 2 diabetes mellitus (T2DM) and body-mass index (BMI) categories. We investigate a possible association of 5-HTTLPR polymorphism (L and S alleles) in the promoter region of the serotonin transporter gene (SLC6A4) with the development of T2DM and/or higher BMI by analyzing a sample of 138 individuals diagnosed with T2DM and 172 unrelated controls from the Mexican general population. In the total sample genotypes were distributed according to Hardy-Weinberg equilibrium, and S allele frequency was 0.58. There was no statistical association between 5-HTTLPR polymorphism and the development of T2DM in this Mexican population sample (p = 0.12). Nevertheless, logistic regression analysis of the L allele and increased BMI disclosed an association, after adjusting for age, sex and T2DM (p = 0.02, OR 1.74, 95% CI: 1.079-2.808)

Association Study of Candidate Gene Polymorphisms and Obesity in a Young Mexican-American Population from South Texas

Background and Aims Obesity is increasingly a health problem and a risk factor for diabetes in young Mexican-American populations. Genetic association studies in older, mostly non-Hispanic populations have reported that polymorphisms in the candidate genes HSD11B1, CRP, ADIPOQ, PPARG, ANKK1, ABCC8 and SERPINF1 are associated with obesity or diabetes. We analyzed the polymorphisms rs846910, rs1205, rs1501299, rs1801282, rs1800497, rs757110 and rs1136287in these candidate genes, for association with obesity and metabolic traits in a young Mexican-American population from south Texas. Methods Genotyping of the seven common SNPs were performed by allelic discrimination assays in 448 unrelated Mexican Americans (median age = 16 years) from south Texas. χ2 tests and regression analyses using additive models were used for genetic association analyses adjusting for covariates; p values were corrected for multiple testing by permutation analyses. Results rs1800497 (ANKK1) shows association with waist circumference (p = 0.009) and retains the association (p = 0.03) after permutation testing. Analysis of metabolic quantitative traits shows that rs846910 (HSD11B1) was associated with HOMA-IR (p = 0.04) and triglycerides (p = 0.03), and rs1205 (CRP) with HOMA-IR (p = 0.03) and fasting glucose levels (p = 0.007). However, the quantitative traits associations are not maintained after permutation analysis. None of the other SNPs in this study showed associations with obesity or metabolic traits in this young Mexican-American population. Conclusions We report a potential association between rs1800497 (linked to changes in brain dopamine receptor levels) and central obesity in a young Mexican-American population