| 1. |
- Cropano, Catrina, et al.
(author)
-
The rs7903146 variant in the tcf7l2 gene increases the risk of prediabetes/type 2 diabetes in obese adolescents by impairing b-cell function and hepatic insulin sensitivity
- 2017
-
In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 40:8, s. 1082-1089
-
Journal article (peer-reviewed)abstract
- OBJECTIVE In this study, we aimed to explore the mechanism by which TCF7L2 rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents. RESEARCH DESIGN AND METHODS The rs7903146 variant in the TCF7L2 gene was genotyped in a multiethnic cohort of 955 youths. All subjects underwent an oral glucose tolerance test with the use of the Oral Minimal Model to assess insulin secretion, and 33 subjects underwent a hyperinsulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 6 2.36 years. RESULTS The TCF7L2 rs7903146 risk allele was associated with higher 2-h glucose levels in Caucasians (P = 0.006) and African Americans (P = 0.009), and a trendwas seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased b-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose productionwas lower in subjects with the risk variant (P = 0.006). Finally, the odds of showing IGT/T2D at follow-up were higher in subjects carrying the minor allele (odds ratio 2.224; 95% CI 1.370-3.612; P = 0.0012). CONCLUSIONS The rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing b-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.
|
|
| 2. |
- Galderisi, Alfonso, et al.
(author)
-
Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths : A Longitudinal Study
- 2020
-
In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 105:2
-
Journal article (peer-reviewed)abstract
- CONTEXT: The time-to-glucose-peak following the oral glucose tolerance test (OGTT) is a highly reproducible marker for diabetes risk. In obese youths, we lack evidence for the mechanisms underlying the effects of the TCF7L2 rs7903146 variant on glucose peak. METHODS: We analyzed the metabolic phenotype and the genotype for the TCF7L2 rs7903146 in 630 obese youths with normal (NGT) and impaired (IGT) glucose tolerance. Participants underwent a 3-hour, 9-point OGTT to estimate, using the oral minimal model, the disposition index (DI), the static (φstatic) and dynamic (φdynamic) components β-cell responsiveness and insulin sensitivity (SI). In a subgroup (n = 241) longitudinally followed for 2 years, we estimated the effect of time-to-glucose-peak on glucose tolerance change. RESULTS: Participants were grouped into early (<30 minutes) and late (≥30 minutes) glucose peakers. A delayed glucose peak was featured by a decline in φstatic (P < .001) in the absence of a difference in φdynamic. The prevalence of T-risk allele for TCF7L2 rs7903146 variant significantly increased in the late peak group. A lower DI was correlated with higher glucose concentration at 1 and 2 hours, whereas SI was inversely associated with 1-hour glucose. Glucose peak <30 minutes was protective toward worsening of glucose tolerance overtime (odds ratio 0.35 [0.15-0.82]; P = .015), with no subjects progressing to NGT or persisting IGT, in contrast to the 40% of progressor in those with late glucose peak. CONCLUSION: The prevalence of T-risk allele for the TCF7L2 rs7903146 prevailed in the late time-to-glucose peak group, which in turn is associated with impaired β-cell responsiveness to glucose (φ), thereby predisposing to prediabetes and diabetes in obese youths.
|
|
| 3. |
- Giannini, Cosimo, et al.
(author)
-
Co-occurrence of Risk Alleles in or Near Genes Modulating Insulin Secretion Predisposes Obese Youth to Prediabetes
- 2014
-
In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 37:2, s. 475-482
-
Journal article (peer-reviewed)abstract
- OBJECTIVEParalleling the rise of pediatric obesity, the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) is increasing among youth. In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents.RESEARCH DESIGN AND METHODSWe studied 714 obese subjects (290 boys and 424 girls; mean age 13.6 3.1 years; mean z score BMI 2.2 0.4) and evaluated the insulin secretion by using the oral minimal model and, in a subgroup of 37 subjects, the hyperglycemic clamp. Also, 203 subjects were followed up for a mean of 2.1 years.RESULTSWe observed that the increase of risk alleles was associated with a progressive worsening of insulin secretion (P < 0.001) mainly due to an impairment of the dynamic phase of insulin secretion (P = 0.004); the higher the number of the risk alleles, the higher the chance of progression from normal glucose tolerance (NGT) to IGT/T2D (P = 0.022). Also, for those who were IGT at baseline, a higher risk score was associated with a lower odds to revert to NGT (P = 0.026).CONCLUSIONSObese children and adolescents developing IGT/T2D have a higher genetic predisposition than those who do not show these diseases, and this predisposition is mainly related to gene variants modulating the early phase of insulin secretion. Although these data are very interesting, they need to be replicated in other cohorts.
|
|
| 4. |
- Hagman, Emilia, et al.
(author)
-
Predictors of responses to clinic-based childhood obesity care
- 2018
-
In: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 19:8, s. 1351-1356
-
Journal article (peer-reviewed)abstract
- Background/Objective: Lifestyle modification is the therapy of choice for childhood obesity, yet the response rate is variable and may be affected by genetic factors. We aimed to investigate predictors of poor response to lifestyle modification obesity treatment in children. Methods: A prospective cohort study of 434 youths (64.5% females) between 4 and 20 years of age undergoing a standard care of lifestyle modification obesity management for 35.9 ± 20.8 months at Yale Childhood Obesity Clinic, USA. The primary outcome was a “poor response,” defined as the quintile with the largest increase in BMI Z-score over time. The secondary outcome was the endpoint BMI Z-score. Covariates investigated were sex, baseline pubertal status and degree of obesity, race, biochemical profile, and family history of overweight. A subsample (n = 214) had FTO genotyping (SNP rs8050136) tested. Results: Males (hazard ratio [HR] = 5.35, 95% confidence interval [CI] [3.32-8.61], P < 0.0001) and pubertal adolescents (HR = 2.78, [1.40-5.50], P = 0.003) compared to prepubertal children were more prone to respond poorly. Baseline degree of obesity was associated with relative protection from responding poorly (HR per BMI Z-score unit = 0.32, [0.17-0.61], P = 0.0006). Carriers of the FTO obesity-predisposing allele (AA genotype) were protected from responding poorly compared to non-carriers (CC genotype) (HR = 0.33, [0.12-0.88], P = 0.028). Conclusions: Boys and pubertal adolescents are more prone to respond poorly to standard obesity care while those with greater baseline degree of obesity and carriers of the FTO obesity-predisposing allele are not.
|
|
| 5. |
- Johnson, Calvin W., et al.
(author)
-
White paper: From bound states to the continuum
- 2020
-
In: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 47:12
-
Research review (peer-reviewed)abstract
- This white paper reports on the discussions of the 2018 Facility for Rare Isotope Beams Theory Alliance (FRIB-TA) topical program ‘From bound states to the continuum: Connecting bound state calculations with scattering and reaction theory’. One of the biggest and most important frontiers in nuclear theory today is to construct better and stronger bridges between bound state calculations and calculations in the continuum, especially scattering and reaction theory, as well as teasing out the influence of the continuum on states near threshold. This is particularly challenging as many-body structure calculations typically use a bound state basis, while reaction calculations more commonly utilize few-body continuum approaches. The many-body bound state and few-body continuum methods use different language and emphasize different properties. To build better foundations for these bridges, we present an overview of several bound state and continuum methods and, where possible, point to current and possible future connections.
|
|
| 6. |
- Nowicka, Paulina, 1974-, et al.
(author)
-
Utility of Hemoglobin A1c for Diagnosing Prediabetes and Diabetes in Obese Children and Adolescents
- 2011
-
In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 34:6, s. 1306-1311
-
Journal article (peer-reviewed)abstract
- OBJECTIVE—Hemoglobin A1c (A1C) has emerged as a recommended diagnostic tool for identifying diabetes and subjects at risk for the disease. This recommendation is based on data in adults showing the relationship between A1C with future development of diabetes and microvascular complications. However, studies in the pediatric population are lacking.RESEARCH DESIGN AND METHODS—We studied a multiethnic cohort of 1,156 obese children and adolescents without a diagnosis of diabetes (male, 40%/female, 60%). All subjects underwent an oral glucose tolerance test (OGTT) and A1C measurement. These tests were repeated after a follow-up time of ;2 years in 218 subjects.RESULTS—At baseline, subjects were stratified according to A1C categories: 77% with normal glucose tolerance (A1C,5.7%), 21% at risk for diabetes (A1C 5.7–6.4%), and 1% with diabetes (A1C .6.5%). In the at risk for diabetes category, 47% were classified with prediabetes or diabetes, and in the diabetes category, 62% were classified with type 2 diabetes by the OGTT. The area under the curve receiver operating characteristic for A1C was 0.81 (95%CI 0.70–0.92). The threshold for identifying type 2 diabetes was 5.8%, with 78% specificity and 68% sensitivity. In the subgroup with repeated measures, a multivariate analysis showed that the strongest predictors of 2-h glucose at follow-up were baseline A1C and 2-h glucose, independently of age, ethnicity, sex, fasting glucose, and follow-up time.CONCLUSIONS—The American Diabetes Association suggested that an A1C of 6.5% underestimates the prevalence of prediabetes and diabetes in obese children and adolescents. Given the low sensitivity and specificity, the use of A1C by itself represents a poor diagnostic tool for prediabetes and type 2 diabetes in obese children and adolescents.
|
|
| 7. |
- Santoro, Nicola, et al.
(author)
-
Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents
- 2012
-
In: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 55:3, s. 781-789
-
Journal article (peer-reviewed)abstract
- Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein (GCKR), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (VLDL) (Caucasians P = 0.001; African Americans, P = 0.03), and with fatty liver (Caucasians P = 0.034; African Americans P = 0.00002; and Hispanics P = 0.016). The PNPLA3, but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians (P = 0.00161), 39.0% in African Americans (P = 0.00000496), and 15% in Hispanics (P = 0.00342). Conclusion: The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths. (Hepatology 2012)
|
|
| 8. |
- Savoye, Mary, et al.
(author)
-
Long-term Results of an Obesity Program in an Ethnically Diverse Pediatric Population
- 2011
-
In: Pediatrics. - : American Academy of Pediatrics (AAP). - 0031-4005 .- 1098-4275. ; 127, s. 402-410
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To determine if beneficial effects of a weight-management program could be sustained for up to 24 months in a randomized trial in an ethnically diverse obese population.PATIENTS AND METHODS: There were 209 obese children (BMI95th percentile), ages 8 to 16 of mixed ethnic backgrounds randomly assigned to the intensive lifestyle intervention or clinic control group. The control group received counseling every 6 months, and the intervention group received a family-based program, which included exercise, nutrition, and behavior modification. Lifestyle intervention sessions occurred twice weekly for the first 6 months, then twice monthly for the second 6 months; for the last 12 months there was no active intervention. There were 174 children who completed the 12 months of the randomized trial. Follow-up data were available for 76 of these children at 24 months. There were no statistical differences in dropout rates among ethnic groups or in any other aspects.RESULTS: Treatment effect was sustained at 24 months in the intervention versus control group for BMI z score (0.16 [95% confidence interval: 0.23 to 0.09]), BMI (2.8 kg/m2 [95% confidence interval: 4.0 –1.6 kg/m2]), percent body fat (4.2% [95% confidence interval: 6.4% to 2.0%]), total body fat mass (5.8 kg [95% confidence interval: 9.1 kg to 2.6 kg]), total cholesterol (13.0 mg/dL [95% confidence interval:21.7 mg/dL to4.2 mg/dL]), low-density lipoprotein cholesterol (10.4 mg/dL [95% confidence interval: 18.3 mg/dL to 2.4 mg/dL]), and homeostasis model assessment of insulin resistance (2.05 [95% confidence interval: 2.48 to 1.75]).CONCLUSIONS: This study, unprecedented because of the high degree of obesity and ethnically diverse backgrounds of children, reveals that benefits of an intensive lifestyle program can be sustained 12 months after completing the active intervention phase
|
|
| 9. |
- Savoye, Mary, et al.
(author)
-
Reversal of Early Abnormalities in Glucose Metabolism in Obese Youth: Results of an Intensive Lifestyle Randomized Controlled Trial
- 2014
-
In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 37, s. 317-324
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: The childhood obesity epidemic has been accompanied by an increasing prevalence of type 2 diabetes (T2D), particularly in minority children. Twenty to thirty percent of obese youth have “prediabetes,” a precursor to diabetes marked by insulin resistance, b-cell dysfunction, and impaired glucose tolerance. The Diabetes Prevention Programdemonstrated that T2D could be prevented/delayed by intensive lifestyle modification in adults with prediabetes, but efficacy of similar interventions in youth has not been established. Therefore, we evaluated the effects of the Bright Bodies (BB) Healthy Lifestyle Program on 2-h oral glucose tolerance test (OGTT) glucose in comparison with adolescents receiving standard of care.RESEARCH DESIGN AND METHODS: A parallel-group randomized controlled trial comparing BB with standard clinical care (CC) in obese adolescents (10–16 years old, Tanner stage >2) with elevated OGTT 2-h blood glucose (130–199 mg/dL) from a racially/ethnically diverse population. OGTTs, including cardiovascular and anthropometric assessments, were conducted at baseline and 6 months. Children attended BB twice per week for exercise and nutrition/behavior modification, and the CC group received CC from their pediatrician. Primary outcome was change in 2-h OGTT glucose and percentage conversion from elevated 2-h blood glucose to nonelevated (,130 mg/dL) 2-h blood glucose. Changes in outcomes were compared between groups using an ANCOVA, with adjustment for baseline outcome and multiple imputation for missing data.RESULTS: Reductions in 2-h glucose weremore favorable in BB compared with CC (227.2 vs. 210.1 mg/dL; difference = 217.1, 95% CI; P = 0.005). Moreover, greater conversion to ,130 mg/dL 2-h glucose occurred in BB than CC (P = 0.003), and other insulin sensitivity indices were significantly improved.CONCLUSIONS: Compared with standard of care, the Yale BB Program is amore effective means of reducing the risk of T2D in obese adolescents with elevated 2-h glucose levels.
|
|
| 10. |
- Teo, Kevin, et al.
(author)
-
rs641738C>T near MBOAT7 is associated with liver fat, ALT, and fibrosis in NAFLD: a meta-analysis.
- 2021
-
In: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 74:1, s. 20-30
-
Journal article (peer-reviewed)abstract
- A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and characterize its role in the regulation of related metabolic phenotypes through meta-analysis.We performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed random effects meta-analysis using recessive, additive, and dominant genetic models.Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI: 0.02 - 0.05], pz=4.8x10-5) and diagnosis of NAFLD (OR 1.17 [95% CI 1.05 - 1.3], pz=0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI: 1.03 - 1.45], pz=0.021) in Caucasian adults using a recessive model of inheritance (CC+CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz=0.002) and lower serum triglycerides (pz=1.5x10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.
|
|
| 11. |
- Trico, Domenico, et al.
(author)
-
Mechanistic Insights Into the Heterogeneity of Glucose Response Classes in Youths With Obesity : A Latent Class Trajectory Approach
- 2022
-
In: Diabetes Care. - : American Diabetes Association. - 0149-5992. ; 45:8, s. 1841-1851
-
Journal article (peer-reviewed)abstract
- In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS Latent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and b-cell function were estimated by glucose, insulin, and C-peptide modeling. RESULTS Four latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and b-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and b-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in b-cell glucose sensitivity. CONCLUSIONS We identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by b-cell glucose sensitivity.
|
|
| 12. |
- Tuomi, Tiinamaija, et al.
(author)
-
The many faces of diabetes: a disease with increasing heterogeneity
- 2014
-
In: The Lancet. - 1474-547X. ; 383:9922, s. 1084-1094
-
Research review (peer-reviewed)abstract
- Diabetes is a much more heterogeneous disease than the present subdivision into types 1 and 2 assumes; type 1 and type 2 diabetes probably represent extremes on a range of diabetic disorders. Both type 1 and type 2 diabetes seem to result from a collision between genes and environment. Although genetic predisposition establishes susceptibility, rapid changes in the environment (ie, lifestyle factors) are the most probable explanation for the increase in incidence of both forms of diabetes. Many patients have genetic predispositions to both forms of diabetes, resulting in hybrid forms of diabetes (eg, latent autoimmune diabetes in adults). Obesity is a strong modifi er of diabetes risk, and can account for not only a large proportion of the epidemic of type 2 diabetes in Asia but also the ever-increasing number of adolescents with type 2 diabetes. With improved characterisation of patients with diabetes, the range of diabetic subgroups will become even more diverse in the future.
|
|
| 13. |
- Zheng, Chao, et al.
(author)
-
A Common Variant in the MTNR1B Gene Is Associated with Increased Risk of Impaired Fasting Glucose (IFG) in Youth with Obesity
- 2015
-
In: Obesity. - : Wiley. - 1930-739X .- 1930-7381. ; 23:5, s. 1022-1029
-
Journal article (peer-reviewed)abstract
- Objective: To explore the role of MTNR1B rs10830963 and G6PC2 rs560887 variants in the pathogenesis of impaired fasting glucose (IFG) in obese adolescents. Methods: A total of 346 Caucasians, 218 African-Americans, and 217 Hispanics obese children and adolescents underwent an oral glucose tolerance test (OGTT) and 518 underwent the evaluation of insulin secretion by the oral minimal model (OMM). Also, 274 subjects underwent a second OGTT after 3.0 -/+ 2.1years. Results: The MTNR1B rs10830963 variant was associated with higher fasting glucose levels and lower dynamic beta-cell response in Caucasians and Hispanics (P<0.05) and conferred an increased risk of showing IFG to Caucasians (P=0.05), African-Americans (P=0.0066), and Hispanics (P=0.024). Despite the association between the G6PC2 rs560887 and higher fasting glucose levels (P<0.05), there was no association between this variant and IFG at baseline or at follow-up (all P > 0.10). Conclusions: It has been shown for the first time in obese youth that the MTNR1B variant is associated with an increased risk of IFG.
|
|
