Enrique Trigo

Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes mellitus and interacts with adiposity to alter insulin secretion in Mexican Americans.

OBJECTIVE— Variation in transcription factor 7-like 2 (TCF7L2) gene has been shown to be associated with type 2 diabetes and diabetes-related quantitative traits. We examined variation in a 0.1-Mb region surrounding marker DG10S478 for association with diabetes-related quantitative traits in 132 Mexican-American families of a proband with previous gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS— Study participants were phenotyped by an oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test and by a dual-energy X-ray absorptiometry scan for percentage of body fat. Of the 42 tag single nucleotide polymorphisms (SNPs) genotyped, 15 were identified. RESULTS— On univariate analysis, none of the SNPs showed association with diabetes-related quantitative traits. However, rs12255372 showed association with 30′ Δinsulin (OGTT 30′ min fasting insulin) in an interaction with percentage of body fat (Bonferroni-corrected P = 0.027). The effect of adiposity to increase 30′ Δinsulin was greater in subjects with the T allele. This interaction was not associated with acute insulin response to intravenous glucose. rs12255372 also showed an association with β-cell compensation for insulin resistance based on 30′ Δinsulin in an interaction with percentage of body fat (Bonferroni-corrected P = 0.014). rs12255372 was also associated with GDM (odds ratio [OR] 2.49 [95% CI 1.17–5.31]; P = 0.018) in our case-control sample. CONCLUSIONS— We conclude that variation in TCF7L2 is associated with GDM and interacts with adiposity to alter insulin secretion in Mexican Americans. Our observations partly explain the increased ORs observed in previous associated studies when analyses were restricted to lean subjects and the variability in quantitative trait association results.

Detailed Physiological Characterization of the Development of Type 2 Diabetes in Hispanic Women With Prior Gestational Diabetes Mellitus

OBJECTIVE To identify physiological and clinical variables associated with development of type 2 diabetes up to 12 years after pregnancies complicated by gestational diabetes. RESEARCH DESIGN AND METHODS Seventy-two islet cell antibody–negative nondiabetic Hispanic women had oral (oGTT) and intravenous (ivGTT) glucose tolerance tests, glucose clamps, and body composition assessed between 15 and 30 months after pregnancies complicated by gestational diabetes mellitus (GDM). They returned for oGTTs at 15-month intervals until they dropped out, developed diabetes, or reached 12 years postpartum. Cox regression analysis was used to identify baseline predictors and changes during follow-up that were associated with development of type 2 diabetes. RESULTS At baseline, relatively low insulin sensitivity, insulin response, and β-cell compensation for insulin resistance were independently associated with development of diabetes. During follow-up, weight and fat gain and rates of decline in β-cell compensation were significantly associated with diabetes, while additional pregnancy and use of progestin-only contraception were marginally associated with diabetes risk. CONCLUSIONS In Hispanic women, GDM represents detection of a chronic disease process characterized by falling β-cell compensation for chronic insulin resistance. Women who are farthest along at diagnosis and/or deteriorating most rapidly are most likely to develop type 2 diabetes within 12 years after the index pregnancy. Weight gain, additional pregnancy, and progestin-only contraception are potential modifiable factors that increase diabetes risk.

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 (SI) (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 SI compared with individuals with at least one G allele. SI did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for SI 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 SI 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.

Declining β-Cell Compensation for Insulin Resistance in Hispanic Women With Recent Gestational Diabetes Mellitus: Association with changes in weight, adiponectin, and C-reactive protein

OBJECTIVE To identify factors associated with declining beta-cell compensation for insulin resistance. RESEARCH DESIGN AND METHODS In a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining beta-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on beta-cell compensation decline. RESULTS A total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance. CONCLUSIONS These results identify weight gain as the strongest factor associated with declining beta-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance.OBJECTIVE To identify factors associated with declining β-cell compensation for insulin resistance. RESEARCH DESIGN AND METHODS In a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining β-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on β-cell compensation decline. RESULTS A total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance. CONCLUSIONS These results identify weight gain as the strongest factor associated with declining β-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance.

Variation in IGF2BP2 interacts with adiposity to alter insulin sensitivity in Mexican Americans.

Genome‐wide association studies showed variation in insulin‐like growth factor‐2 binding protein 2 (IGF2BP2) to be associated with type 2 diabetes mellitus (T2DM). We examined a 20‐kb region of IGF2BP2 for association with T2DM‐related quantitative traits in Mexican American families of a proband with gestational diabetes mellitus (GDM) from the BetaGene study. We genotyped 14 single‐nucleotide polymorphisms (SNPs) in 717 individuals from 146 families phenotyped by oral glucose tolerance test (OGTT), intravenous glucose tolerance tests (IVGTTs) with minimal model analysis, and dual‐energy X‐ray absorptiometry scan for percent body fat. Three SNPs and one SNP combination that captured the majority of the variation in the region were tested for association with T2DM‐related quantitative traits using a variance components framework. After correction for multiple testing, rs11705701 showed association with percent body fat (PACT = 0.041) with body fat decreasing ∼1.5–2% per copy of the A allele. We next tested whether the interaction between rs11705701 and body fat was associated with T2DM‐relative quantitative traits. rs11705701 was significantly associated with insulin sensitivity (Bonferroni P = 0.028) and marginally associated with OGTT 2‐h insulin (Bonferroni P = 0.066) and disposition index (DI) (Bonferroni P = 0.072). We conclude that rs11705701 in IGF2BP2 is associated with body fat and this effect on body fat influences insulin resistance which may contribute to T2DM risk.

ADDITIVE EFFECTS OF GENETIC VARIATION IN GCK AND G6PC2 ON INSULIN SECRETION AND FASTING GLUCOSE

OBJECTIVE Glucokinase (GCK) and glucose-6-phosphatase catalytic subunit 2 (G6PC2) regulate the glucose-cycling step in pancreatic β-cells and may regulate insulin secretion. GCK rs1799884 and G6PC2 rs560887 have been independently associated with fasting glucose, but their interaction on glucose-insulin relationships is not well characterized. RESEARCH DESIGN AND METHODS We tested whether these variants are associated with diabetes-related quantitative traits in Mexican Americans from the BetaGene Study and attempted to replicate our findings in Finnish men from the METabolic Syndrome in Men (METSIM) Study. RESULTS rs1799884 was not associated with any quantitative trait (corrected P > 0.1), whereas rs560887 was significantly associated with the oral glucose tolerance test 30-min incremental insulin response (30′ Δinsulin, corrected P = 0.021). We found no association between quantitative traits and the multiplicative interaction between rs1799884 and rs560887 (P > 0.26). However, the additive effect of these single nucleotide polymorphisms was associated with fasting glucose (corrected P = 0.03) and 30′ Δinsulin (corrected P = 0.027). This additive association was replicated in METSIM (fasting glucose, P = 3.5 × 10−10 30′ Δinsulin, P = 0.028). When we examined the relationship between fasting glucose and 30′ Δinsulin stratified by GCK and G6PC2, we noted divergent changes in these quantitative traits for GCK but parallel changes for G6PC2. We observed a similar pattern in METSIM. CONCLUSIONS Our data suggest that variation in GCK and G6PC2 have additive effects on both fasting glucose and insulin secretion.

Ambient Air Pollutants Have Adverse Effects on Insulin and Glucose Homeostasis in Mexican Americans

OBJECTIVE Recent studies suggest that air pollution plays a role in type 2 diabetes (T2D) incidence and mortality. The underlying physiological mechanisms have yet to be established. We hypothesized that air pollution adversely affects insulin sensitivity and secretion and serum lipid levels. RESEARCH DESIGN AND METHODS Participants were selected from BetaGene (n = 1,023), a study of insulin resistance and pancreatic β-cell function in Mexican Americans. All participants underwent DXA and oral and intravenous glucose tolerance tests and completed dietary and physical activity questionnaires. Ambient air pollutant concentrations (NO2, O3, and PM2.5) for short- and long-term periods were assigned by spatial interpolation (maximum interpolation radius of 50 km) of data from air quality monitors. Traffic-related air pollution from freeways (TRAP) was estimated using the dispersion model as NOx. Variance component models were used to analyze individual and multiple air pollutant associations with metabolic traits. RESULTS Short-term (up to 58 days cumulative lagged averages) exposure to PM2.5 was associated with lower insulin sensitivity and HDL-to-LDL cholesterol ratio and higher fasting glucose and insulin, HOMA-IR, total cholesterol, and LDL cholesterol (LDL-C) (all P ≤ 0.036). Annual average PM2.5 was associated with higher fasting glucose, HOMA-IR, and LDL-C (P ≤ 0.043). The effects of short-term PM2.5 exposure on insulin sensitivity were largest among obese participants. No statistically significant associations were found between TRAP and metabolic outcomes. CONCLUSIONS Exposure to ambient air pollutants adversely affects glucose tolerance, insulin sensitivity, and blood lipid concentrations. Our findings suggest that ambient air pollutants may contribute to the pathophysiology in the development of T2D and related sequelae.

Deterioration in cardiometabolic risk markers in obese women during depot medroxyprogesterone acetate use

BACKGROUND Highly effective contraception is essential in obese women, but it should not increase their risk of developing or worsening obesity-related cardiometabolic illness. The purpose of this 18-week prospective experimental study was to compare the impact of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) on cardiometabolic markers in obese and normal-weight women. METHODS Normal-weight [body mass index (BMI) 18.5-24.9 kg/m(2)] and obese (BMI≥30 kg/m(2)) women received injections of 104 mg DMPA-SC at baseline and 12 weeks later. Markers of cardiometabolic risk measured at baseline and 18 weeks after the first injection included body morphometry, fasting blood tests, and oral and frequently sampled intravenous glucose tolerance tests (FSIGT). RESULTS At baseline, median gravidity, BMI, abdominal circumference, and acute insulin response to intravenous glucose were higher and high-density lipoprotein (HDL) cholesterol and insulin sensitivity (S(I) from FSIGTs) were lower in the 10 obese participants than the five normal-weight women (p≤.05 for each). While there was no significant difference between median baseline and follow-up values among normal-weight women, the difference between median baseline and follow-up among the obese cohort was significantly higher for BMI and lower for HDL cholesterol and insulin sensitivity (S(I)) (p≤.05 for each). The absolute changes for routinely measured clinical laboratory values of metabolic decline were no different among the normal-weight vs. obese women. The difference in absolute change in β-cell compensation for insulin resistance [disposition index (DI)] was significant between the two groups at follow-up, with the normal-weight group experiencing an increase in DI while the obese group experienced a decline in DI (188.5 vs. -286, p=.04). CONCLUSIONS Obese women have an increased baseline cardiometabolic risk when compared with normal-weight women at baseline. There was a significantly greater decline in β-cell compensation for insulin resistance in obese women on DMPA. Our data suggest potential deleterious effects of DMPA on glucose regulation in obese women. Further studies should elucidate the long-term cardiometabolic consequences of DMPA use in obese women.

Self-Reported Physical Activity Is Associated With β-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/m2, 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 β-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 β-cell function that is not explained by differences in BMI or percent body fat. Our results suggest that PA can be beneficial to β-cell function and glucose regulation independent of obesity.

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 β-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 β-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 β-cell function in Mexican Americans at risk for T2DM.