Association of weight gain and fifteen adipokines with declining beta-cell function in Mexican Americans.

Obesity and adipokines are associated with development of type 2 diabetes. However, limited longitudinal studies have examined their roles on declining ß-cell function over time. This report assessed three adiposity measures (BMI, percent body fat, trunk fat), insulin resistance, and fifteen adipokines in relationship to longitudinal change in ß-cell function measured by disposition index (DI) from frequently-sampled-intravenous-glucose-tolerance testing. The results showed that three factors were significantly and independently associated with rate of change in DI over time: rate of change in BMI (negative), rate of change in IL-6 (negative), and baseline adiponectin (positive). The association was the strongest for changing BMI and was largely explained by changing insulin resistance; the association with changing IL-6 was also largely explained by changing insulin resistance. Baseline adiponectin remained positively associated after adjustment for changing insulin resistance, suggesting an independent effect of adiponectin to preserve or improve ß-cell function. These findings provide evidence and potential mechanisms for the role of obesity in promoting ß-cell dysfunction, highlighting the potential importance of mitigating obesity and its metabolic effects in preventing and treating type 2 diabetes.

Longitudinal Increases in Adiposity Contribute to Worsening Adipokine Profile over Time in Mexican Americans.

OBJECTIVE: Limited studies have assessed the relationship between longitudinal changes in adiposity and changes in multiple adipokines over time. This study examined changes in BMI, total body fat, and trunk fat associated with changes in 16 circulating adipokines in Mexican Americans at risk for type 2 diabetes. METHODS: Participants included 1,213 individuals with cross-sectional data and a subset of 368 individuals with follow-up measures (mean 4.6 ± 1.5 years from baseline). Joint multivariate associations between 3 adiposity measures and 16 adipokines were assessed by canonical correlation analysis. RESULTS: Longitudinal increases in adiposity were most strongly associated with increasing leptin, C-reactive protein (CRP), and interleukin 1 receptor antagonist (IL-1Ra) and decreasing adiponectin and secreted frizzled protein 5 (SFRP5) over time. Participants with BMI ≥ 30 kg/m2 at baseline had greater increases in leptin, CRP, IL-1Ra, and interleukin 6 (IL-6) and greater decreases in adiponectin and SFRP5, associated with increasing adiposity over follow-up, than those with BMI < 30 kg/m2 . Associations between adiposity and adipokines were most accounted for by leptin; adjustment for leptin greatly reduced the magnitude of all associations between adiposity and remaining adipokines. CONCLUSIONS: Increasing adiposity contributes to a worsening imbalance of pro- and anti-inflammatory adipokines over time, in which leptin may have an important role as a key mediator of metabolic disease risk in Mexican Americans.

Variation in PPARG is associated with longitudinal change in insulin resistance in Mexican Americans at risk for type 2 diabetes.

CONTEXT: Peroxisome proliferator-activated receptor gamma (PPARG) is a susceptibility locus for type 2 diabetes mellitus (T2DM). Although cross-sectional associations have been reported, primarily for Pro12Ala, few longitudinal studies in nondiabetic populations have been conducted. OBJECTIVE: This study aimed to examine whether and to what extent variation in PPARG is associated with longitudinal changes in anthropometric and metabolic traits in Mexican Americans at risk for T2DM. SETTING AND DESIGN: Subjects were participants of BetaGene, a family-based study of obesity, insulin resistance, and ß-cell function, who completed a baseline and follow-up study visit (n = 378; mean followup, 4.6 ± 1.5 y). Phenotypes included body fat assessed by dual-energy x-ray absorptiometry; insulin sensitivity (SI), acute insulin response, and ß-cell function (disposition index; DI) were estimated from iv glucose tolerance tests with Minimal Model analysis. Eighteen tag single nucleotide polymorphisms (SNPs) capturing variation in a 156-kb region surrounding PPARG were tested for association with changes in longitudinal traits. P-values were Bonferroni-corrected for multiple testing. RESULTS: Six SNPs (rs2972164, rs11128598, rs17793951, rs1151996, rs1175541, rs3856806) were significantly associated with rate of change in SI after adjustment for age, sex, and body fat percentage, but not with changes in adiposity. rs17793951 also had a significant effect on change in DI over time. Association between rs1175541 and change in SI varied by changes in adiposity such that only carriers of the minor allele who reduced body fat over followup improved SI. rs1306470 (captured Pro12Ala, r(2) = 0.9) was not associated with rates of change in any traits and its effects were not modified by changes in adiposity. CONCLUSIONS: Variation in PPARG, but not Pro12Ala, contributes to declining SI and concomitant deterioration in ß-cell function in Mexican Americans at risk for T2DM.

High-fat diet is associated with obesity-mediated insulin resistance and ß-cell dysfunction in Mexican Americans.

Consumption of energy-dense, nutrient-poor foods has contributed to the rising incidence of obesity and may underlie insulin resistance and ß-cell dysfunction. Macronutrient intake patterns were examined in relation to anthropometric and metabolic traits in participants of BetaGene, a family-based study of obesity, insulin resistance, and ß-cell dysfunction in Mexican Americans. Dietary intake, body composition, insulin sensitivity (SI), and ß-cell function [Disposition Index (DI)] were assessed by food-frequency questionnaires, dual-energy X-ray absorptiometry, and intravenous glucose-tolerance tests, respectively. Patterns of macronutrient intake were identified by using a K-means model based on the proportion of total energy intake per day attributable to carbohydrate, fat, and protein and were tested for association with anthropometric and metabolic traits. Among 1150 subjects aged 18-65 y (73% female), tertiles of fat intake were associated with greater adiposity and lower SI, after adjustment for age, sex, and daily energy intake. Moreover, 3 distinct dietary patterns were identified: "high fat" (35% fat, 44% carbohydrate, 21% protein; n = 238), "moderate fat" (28% fat, 54% carbohydrate, 18% protein; n = 520), and "low fat" (20% fat, 65% carbohydrate, 15% protein; n = 392). Compared with the low-fat group, the high-fat group had higher age- and sex-adjusted mean body mass index, body fat percentage, and trunk fat and lower SI and DI. Further adjustment for daily energy intake by matching individuals across dietary pattern groups yielded similar results. None of the observed associations were altered after adjustment for physical activity; however, associations with SI and DI were attenuated after adjustment for adiposity. These findings suggest that high-fat diets may contribute to increased adiposity and concomitant insulin resistance and ß-cell dysfunction in Mexican Americans.

Self-reported physical activity is associated with ß-cell function in Mexican American adults.

OBJECTIVE: To examine the association between self-reported physical activity (PA) and diabetes-related quantitative traits. RESEARCH DESIGN AND METHODS: The observational cohort was 1,152 Mexican American adults with dual-energy X-ray absorptiometry, oral and intravenous glucose tolerance tests, and self-reported dietary and PA questionnaires. PA was categorized into three mutually exclusive groups according to the U.S. Department of Health and Human Services PA guidelines for Americans: low (vigorous <75 min/week and moderate <150 min/week), moderate (vigorous ≥75 min/week or moderate ≥150 min/week), and high (vigorous ≥75 min/week and moderate ≥150 min/week). Trends in PA groups were tested for association with metabolic traits in a cross-sectional analysis. RESULTS: The participants' mean age was 35 years (range, 18-66 years), mean BMI was 29.6 kg/m(2), and 73% were female. Among them, 501 (43%), 448 (39%), and 203 (18%) were classified as having low, moderate, and high PA, respectively. After adjustment for age, a higher PA was significantly associated with lower 2-h glucose, fasting insulin, and 2-h insulin and greater ß-cell function (P = 0.001, 0.0003, 0.0001, and 0.004, respectively). The association did not differ significantly by sex. Results were similar after further adjustment for age, sex, BMI, or percent body fat. CONCLUSIONS: An increasing level of PA is associated with a better glucose and insulin profile and enhanced ß-cell function that is not explained by differences in BMI or percent body fat. Our results suggest that PA can be beneficial to ß-cell function and glucose regulation independent of obesity.

Metabolic syndrome is linked to chromosome 7q21 and associated with genetic variants in CD36 and GNAT3 in Mexican Americans.

The prevalence of metabolic syndrome (MS) has been rising alarmingly worldwide, including in the United States, but knowledge on specific genetic determinants of MS is very limited. Therefore, we planned to identify the genetic determinants of MS as defined by National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria. We performed linkage screen for MS using data from 692 Mexican Americans, who participated in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS). We found strong evidence for linkage of MS on chromosome 7q (LOD = 3.6, empirical P = 6.0 × 10(-5)), between markers D7S2212 and D7S821. In addition, six chromosomal regions exhibited potential evidence for linkage (LOD ≥1.2) with MS. Furthermore, we examined 29 single-nucleotide polymorphisms (SNPs) from the fatty acid translocase (FAT or CD36, 18 SNPs) gene and guanine nucleotide binding protein, α transducing 3 (GNAT3, 11 SNPs) gene, located within the 1-LOD support interval region for their association with MS and its related traits. Several SNPs were associated with MS and its related traits. Remarkably, rs11760281 in GNAT3 and rs1194197 near CD36 exhibited the strongest associations with MS (P = 0.0003, relative risk (RR) = 1.6 and P = 0.004, RR = 1.7, respectively) and several other related traits. These two variants explained ~18% of the MS linkage evidence on chromosome 7q21, and together conferred approximately threefold increase in MS risk (RR = 2.7). In conclusion, our linkage and subsequent association studies implicate a region on chromosome 7q21 to influence MS in Mexican Americans.

Demographic and clinical correlates of diabetes-related quality of life among youth with type 1 diabetes.

OBJECTIVES: To evaluate the reliability and cluster structure of the Pediatric Quality of Life Inventory Type 1 Diabetes Module 3.0 (PedsQL-T1DM) and associated subscales and to explore the associations between PedsQL-T1DM total score and demographic and clinical characteristics and clinical indicators among a large racially/ethnically diverse cohort of youth with type 1 diabetes. STUDY DESIGN: Principal components analysis was conducted on responses from the PedsQL-T1DM child self-report forms completed by SEARCH for Diabetes in Youth study participants aged ≥ 5 years. Multivariate linear regression models were fit to examine the associations among PedsQL-T1DM total score, demographic and clinical characteristics, and clinical indicators. RESULTS: The sample comprised 2602 youth with a mean age of 13.6 ± 4.1 years and a mean T1DM duration of 62.1 ± 47.0 months. Principal components analysis did not support the 5 existing PedsQL-T1DM subscales. In multivariate analyses, the PedsQL-T1DM total score was negatively and significantly associated with younger age (5-7 years), female sex, receiving insulin by injection (vs pump), having parents without a college degree, Medicaid/Medicare insurance, and having a comorbid medical condition. Youth with poor glycemic control based on their age-specific hemoglobin A1c target values and those with depressive symptoms had significantly lower PedsQL-T1DM scores than their counterparts with good control and no or limited depressive symptoms. CONCLUSION: This study has identified sociodemographic and clinical characteristics of youth with T1DM more likely to experience poor diabetes-specific quality of life. The association of lower PedsQL-T1DM scores with depressive symptoms and poor glycemic control is especially concerning and may be the focus of future interventions and studies.

The association of psoriasis and elevated blood lipids in overweight and obese children.

OBJECTIVE: To investigate whether obesity and cardiovascular risk factors are associated with psoriasis in children and adolescents. STUDY DESIGN: For this population-based, cross-sectional study, measured weight and height, laboratory data, and psoriasis diagnoses were extracted from electronic medical records of 710,949 patients age 2 to 19 years enrolled in an integrated health plan. Weight class was assigned on the basis of body mass index-for-age. RESULTS: The OR for psoriasis was 0.68, 1.00, 1.31, 1.39, and 1.78 (95% CI, 1.49 to 2.14) for underweight, normal-weight, overweight, moderately obese, and extremely obese children, respectively (P for trend < .001). The OR for psoriasis treated with systemic therapy or phototherapy as an indicator of severe or widespread psoriasis was 0.00, 1.00, 2.78, 2.93, and 4.19 (95% CI, 1.81 to 9.68) for underweight, normal-weight, overweight, moderately obese, and extremely obese children, respectively (P for trend < .003). In adolescents, mean total cholesterol, low-density lipoprotein cholesterol, triglycerides, and alanine aminotransferase were significantly higher in children with psoriasis compared with children without psoriasis after adjustment for body mass index. CONCLUSION: Overweight and obesity are associated with higher odds of psoriasis in youths. Independent of body weight, adolescent patients with psoriasis have higher blood lipids. These data suggest that pediatricians and dermatologists should screen youths with psoriasis for cardiovascular disease risk factors.

Evidence of interaction between PPARG2 and HNF4A contributing to variation in insulin sensitivity in Mexican Americans.

OBJECTIVE: We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes-related quantitative traits in Mexican-American families of a proband with previous gestational diabetes. RESEARCH DESIGN AND METHODS: The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests. RESULTS: Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes-related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (S(I)) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher S(I) compared with individuals with at least one G allele. S(I) did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for S(I) was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher S(I) compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401). CONCLUSIONS: Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes.

The phase I trial

Los objetivos del estudio del estudio Fase 1 en el desarrollo de drogas anticancer son: determinar la dósis más alta tolerada, programas de administración, patrones de toxicidad, propiedades farmacoquinéticas, y si fuera posible, potencial terapéutico. Su diseño depende grandemente de datos obtenidos en el desarrollo preclínico. Muchos protocolos requieren una dósis inicial a nivel de 1/10 de la dósis letal en ratones (en mg/m2), escalando por etapas, siguiendo un esquema tipo Fibonacci, y administrando la droga una vez o diariamente por cinco días cada tres o cuatro semanas. Los estudios Fase 1 se limitan a pacientes con función hepática y renal relativametne buena y con neoplasias clínicamente estables que han sido confirmadas histológicamente y son resistentes a teapia convencional. Los hallazgos correlacionados dósis/programa con niveles plasmáticos/toxicidad son incorporados en el diseño de estudios terapéuticos subsiguientes