Liver Fat Reduction After Gastric Banding and Associations with Changes in Insulin Sensitivity and ß-Cell Function.

OBJECTIVE: The aim of this study was to examine the relationship between changes in liver fat and changes in insulin sensitivity and ß-cell function 2 years after gastric banding surgery. METHODS: Data included 23 adults with the surgery who had prediabetes or type 2 diabetes for less than 1 year and BMI 30 to 40 kg/m2 at baseline. Body adiposity measures including liver fat content (LFC), insulin sensitivity (M/I), and ß-cell responses (acute, steady-state, and arginine-stimulated maximum C-peptide) were assessed at baseline and 2 years after surgery. Regression models were used to assess associations adjusted for age and sex. RESULTS: Two years after surgery, all measures of body adiposity, LFC, fasting and 2-hour glucose, and hemoglobin A1c significantly decreased; M/I significantly increased; and ß-cell responses adjusted for M/I did not change significantly. Among adiposity measures, reduction in LFC had the strongest association with M/I increase (r = -0.61, P = 0.003). Among ß-cell measures, change in LFC was associated with change in acute C-peptide response to arginine at maximal glycemic potentiation adjusted for M/I (r = 0.66, P = 0.007). Significant reductions in glycemic measures and increase in M/I were observed in individuals with LFC loss >2.5%. CONCLUSIONS: Reduction in LFC after gastric banding surgery appears to be an important factor associated with long-term improvements in insulin sensitivity and glycemic profiles in adults with obesity and prediabetes or early type 2 diabetes.

Impact of Gastric Banding Versus Metformin on ß-Cell Function in Adults With Impaired Glucose Tolerance or Mild Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes (T2D) results from progressive loss of ß-cell function. The BetaFat study compared gastric banding and metformin for their impact on ß-cell function in adults with moderate obesity and impaired glucose tolerance (IGT) or recently diagnosed, mild T2D. RESEARCH DESIGN AND METHODS: Eighty-eight people aged 21-65 years, BMI 30-40 kg/m2, with IGT or diabetes known for <1 year, were randomized to gastric banding or metformin for 2 years. Hyperglycemic clamps (11.1 mmol/L) followed by arginine injection at maximally potentiating glycemia (>25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I). RESULTS: At 24 months, the band group lost 10.7 kg; the metformin group lost 1.7 kg (P < 0.01). Insulin sensitivity increased 45% in the band group and 25% in the metformin group (P = 0.30 between groups). SSCP adjusted for insulin sensitivity fell slightly but not significantly in each group (P = 0.34 between groups). ACPRmax adjusted for insulin sensitivity fell significantly in the metformin group (P = 0.002) but not in the band group (P = 0.25 between groups). HbA1c fell at 12 and 24 months in the band group (P < 0.004) but only at 12 months (P < 0.01) in the metformin group (P > 0.14 between groups). Normoglycemia was present in 22% and 15% of band and metformin groups, respectively, at 24 months (P = 0.66 between groups). CONCLUSIONS: Gastric banding and metformin had similar effects to preserve ß-cell function and stabilize or improve glycemia over a 2-year period in moderately obese adults with IGT or recently diagnosed, mild T2D.

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 ß-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.

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.

Genetic variation in MTNR1B is associated with gestational diabetes mellitus and contributes only to the absolute level of beta cell compensation in Mexican Americans.

AIMS/HYPOTHESIS: MTNR1B is a type 2 diabetes susceptibility locus associated with cross-sectional measures of insulin secretion. We hypothesised that variation in MTNR1B contributes to the absolute level of a diabetes-related trait, temporal rate of change in that trait, or both. METHODS: We tested rs10830963 for association with cross-sectional diabetes-related traits in up to 1,383 individuals or with rate of change in the same phenotypes over a 3-5 year follow-up in up to 374 individuals from the family-based BetaGene study of Mexican Americans. RESULTS: rs10830963 was associated cross-sectionally with fasting glucose (p = 0.0069), acute insulin response (AIR; p = 0.0013), disposition index (p = 0.00078), glucose effectiveness (p = 0.018) and gestational diabetes mellitus (OR 1.48; p = 0.012), but not with OGTT 30 min Δinsulin (the difference between the 30 min and fasting plasma insulin concentration) or 30 min insulin-based disposition index. rs10830963 was also associated with rate of change in fasting glucose (p = 0.043), OGTT 30 min Δinsulin (p = 0.01) and AIR (p = 0.037). There was no evidence for an association with the rate of change in beta cell compensation for insulin resistance. CONCLUSIONS/INTERPRETATION: We conclude that variation in MTNR1B contributes to the absolute level of insulin secretion but not to differences in the temporal rate of change in insulin secretion. The observed association with the rate of change in insulin secretion reflects the natural physiological response to changes in underlying insulin sensitivity and is not a direct effect of the variant.

Longitudinal changes in insulin sensitivity and beta cell function between women with and without a history of gestational diabetes mellitus.

AIMS/HYPOTHESIS: The aim of the study was to compare longitudinal changes in insulin sensitivity (SI) and beta cell function between women with and without a history of gestational diabetes mellitus (GDM). METHODS: The prospective follow-up cohort included 235 parous non-diabetic Mexican-American women, 93 with and 142 without a history of GDM. The participants underwent dual-energy x-ray absorptiometry, OGTTs and IVGTTs at baseline and at a median of 4.1 years follow-up. The baseline values and rates of change of metabolic measures were compared between groups. RESULTS: At baseline, women with prior GDM (mean age 36.3 years) had similar values of SI but higher percentages of body fat and trunk fat (p ≤ 0.02), a lower acute insulin response and poorer beta cell compensation (disposition index [DI]) (p < 0.0001) than women without GDM (mean age 37.9 years). During the follow-up, women with GDM had a faster decline in SI (p = 0.02) and DI (p = 0.02) than their counterparts without GDM, with no significant differences in changes of weight or fat (p > 0.50). Adjustment for baseline age, adiposity, calorie intake, physical activity, age at first pregnancy, additional pregnancies and changes in adiposity during follow-up increased the between-group differences in the rates of change of SI and DI (p ≤ 0.003). CONCLUSIONS/INTERPRETATION: Mexican-American women with recent GDM had a faster deterioration in insulin sensitivity and beta cell compensation than their parous counterparts without GDM. The differences were not explained by differences in adiposity, suggesting more deleterious effects of existing fat and/or reduced beta cell robustness in women with GDM.

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.

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 ß-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 ß-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.

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 ß-cell compensation for insulin resistance were independently associated with development of diabetes. During follow-up, weight and fat gain and rates of decline in ß-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 ß-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.

Declining beta-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.

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 beta-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' Deltainsulin, 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' Deltainsulin (corrected P = 0.027). This additive association was replicated in METSIM (fasting glucose, P = 3.5 x 10(-10) 30' Deltainsulin, P = 0.028). When we examined the relationship between fasting glucose and 30' Deltainsulin 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.

Evidence for sex-specific associations between variation in acid phosphatase locus 1 (ACP1) and insulin sensitivity in Mexican-Americans.

CONTEXT: Acid phosphatase locus 1 (ACP1) is a low molecular weight tyrosine phosphatase that has been shown to be an important regulator of insulin receptor signaling. OBJECTIVE: We tested whether variation in ACP1 is associated with type 2 diabetes-related traits in 1035 individuals in 339 Mexican-American families of probands with or without a previous diagnosis of gestational diabetes mellitus (GDM). DESIGN: Study participants were phenotyped by oral glucose tolerance test (for glucose and insulin level) and iv glucose tolerance test (for insulin sensitivity and acute insulin response) and had dual-energy x-ray absorptiometry scans to assess body composition. Six tag single nucleotide polymorphisms (SNPs) were identified from among 15 SNPs genotyped across the ACP1 region. SNPs were tested for association with phenotypes using a likelihood ratio test under a variance components framework. RESULTS: After Bonferroni correction, none of the SNPs were associated with type 2 diabetes mellitus-related phenotypes. However, we observed a significant sex-specific effect of rs3828329. Among males, rs3828329 was significantly associated with fasting insulin (Bonferroni P = 0.007) and insulin sensitivity (Bonferroni P = 0.019) and marginally associated with 2-h insulin (Bonferroni P = 0.058) and percentage body fat (Bonferroni P = 0.09). CONCLUSIONS: There were no significant associations in females. We conclude that variation in ACP1 is associated with fasting insulin and insulin sensitivity in a sex-specific manner.

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 (P(ACT) = 0.041) with body fat decreasing approximately 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.

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.

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' Deltainsulin (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' Deltainsulin 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 beta-cell compensation for insulin resistance based on 30' Deltainsulin 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.

Coordinate changes in plasma glucose and pancreatic beta-cell function in Latino women at high risk for type 2 diabetes.

The purpose of this study was to examine longitudinally the relationship among glucose levels, pancreatic beta-cell function, and insulin resistance in women at high risk for type 2 diabetes. Oral glucose tolerance tests (OGTTs) and intravenous glucose tolerance tests (IVGTTs) were performed at 15-month intervals for up to 5 years or until fasting plasma glucose exceeded 140 mg/dl in Hispanic women with recent gestational diabetes. Data were analyzed 1) to compare changes in insulin sensitivity, beta-cell function, and glucose levels between women who had diabetes at one or more visits and women who remained diabetes free and 2) to determine longitudinal patterns of change in glucose levels and acute beta-cell compensation for insulin resistance. Seventy-one women provided data from a total of 280 paired OGTTs and IVGTTs during a median follow-up of 46 months. Compared with the 47 women who remained free of diabetes, the 24 who either had diabetes (n = 9) or developed it during follow-up (n = 15) had higher baseline glucose levels and lower acute beta-cell compensation for insulin resistance. Baseline insulin sensitivity was low in both groups and did not change significantly during follow-up. Fasting and 2-h glucose levels increased more rapidly in the diabetic group despite a decline in acute beta-cell compensation that was significantly slower than the decline in women who did not develop diabetes. This paradox was explained by an accelerated rise in glucose levels for any decline in beta-cell compensation when beta-cell compensation reached approximately 10% of normal, a level that was reached in the women who had or developed diabetes but not in the women who remained diabetes free. These findings define a pathogenesis for type 2 diabetes in one high-risk group that is characterized by a relatively long-term decline in acute beta-cell compensation for chronic insulin resistance that is attended by slowly rising glucose levels. Only relatively late in this process do glucose levels rise rapidly and into the diabetic range.