Dataset Information

Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths: A Longitudinal Study.

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 (?static) and dynamic (?dynamic) components ?-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 ?static (P < .001) in the absence of a difference in ?dynamic. 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 ?-cell responsiveness to glucose (?), thereby predisposing to prediabetes and diabetes in obese youths.

SUBMITTER: Galderisi A

PROVIDER: S-EPMC6977541 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths: A Longitudinal Study.

Galderisi Alfonso A Tricò Domenico D Dalla Man Chiara C Santoro Nicola N Pierpont Bridget B Groop Leif L Cobelli Claudio C Caprio Sonia S

The Journal of clinical endocrinology and metabolism 20200201 2

<h4>Context</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 31972003

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Project description:BACKGROUND:Type 2 diabetes is preceded by a prediabetic stage of impaired glucose tolerance that affects 10-23% of youth and is expected to double over the next decade. The natural history of impaired glucose tolerance and the determinants of ?-cell dynamic response have never been investigated longitudinally in young people. We aimed to investigate the clinical and metabolic determinants of longitudinal glucose tolerance changes and ?-cell function in a multiethnic cohort of obese youth. METHODS:We followed up prospectively a multiethnic cohort of overweight and obese (body-mass index >85th percentile) adolescents with baseline normal glucose tolerance (plasma glucose <140 mg/dL) or impaired glucose tolerance (plasma glucose 140-199 mg/dL) at the Yale Pediatric Obesity Clinic (CT, USA). All participants underwent a 3-h oral glucose tolerance test at baseline and after 2 years to estimate insulin secretion (oral disposition index) in the context of body insulin sensitivity. As part of standard care at the clinic, all participants received dietary advice and underwent dietary assessment every 5-6 months. No structured lifestyle or pharmacological intervention was administered. FINDINGS:Between January, 2010, and December, 2016, 526 adolescents (mean age 12·7 years, range 10·6-14·2) were enrolled to our study. At baseline, 364 had normal and 162 had impaired glucose tolerance. Median follow-up was 2·9 years (IQR 2·7-3·1). 105 (65%) of 162 with impaired glucose tolerance at baseline reverted to normal glucose tolerance at follow-up, 44 (27%) had persistent impaired glucose tolerance, and 13 (8%) progressed to type 2 diabetes. A feature of reversion to normal glucose tolerance was a roughly four-fold increase in the oral disposition index (from median 0·94 [IQR 0·68-1·35] at baseline to 3·90 [2·58-6·08] at follow-up; p<0·0001) and a significantly higher oral disposition index at follow-up compared with participants who maintained normal glucose tolerance across the study period (median 3·90 [IQR 2·58-6·08] vs 1·59 [1·12-2·23]; p<0·0001). By contrast, a decrease in insulin secretion was seen in participants who had persistent impaired glucose tolerance (median 1·31 [IQR 1·01-1·85]; p<0·0001) or who progressed to type 2 diabetes (0·20 [0·12-0·58]; p<0·0001), compared with participants who maintained normal glucose tolerance across the study period. Non-Hispanic white ethnic origin conferred five times the odds of reversion to normal glucose tolerance compared with non-Hispanic black ethnic origin (OR 5·06, 95% CI 1·86-13·76; p=0·001), with a two times greater annual increase in the oral disposition index (? 2·32, 95% CI 0·05-4·60; p=0·045). INTERPRETATION:Impaired glucose tolerance is highly reversible in obese adolescents. Ethnic origin is the main clinical modifier of the dynamic ?-cell response to prediabetic hyperglycaemia and, thus, determines the reversibility of impaired glucose tolerance, or its persistence. Therapeutic interventions for impaired glucose tolerance should target the specific mechanisms underpinning glucose tolerance changes in high-risk ethnic groups. FUNDING:National Institutes of Health (National Institute of Child Health and Human Development, National Center for Research Resources, and National Institute of Diabetes and Digestive and Kidney Diseases), American Diabetes Association, International Society for Pediatric and Adolescent Diabetes, Robert Leet Patterson and Clara Guthrie Patterson Trust, European Society for Pediatric Endocrinology, American Heart Association, and the Allen Foundation.

Project description:AIM:The oral glucose tolerance test (OGTT), widely used as a gold standard for gestational diabetes mellitus (GDM) diagnosis, provides a broad view of glucose pathophysiology in response to a glucose challenge. We conducted the present study to evaluate metabolite changes before and after an oral glucose challenge in pregnancy; and to examine the extent to which metabolites may serve to predict GDM diagnosis in pregnant women. METHODS:Peruvian pregnant women (n=100) attending prenatal clinics (mean gestation 25 weeks) participated in the study with 23% of them having GDM diagnosis. Serum samples were collected immediately prior to and 2-hours after administration of a 75-g OGTT. Targeted metabolic profiling was performed using a LC-MS based metabolomics platform. Changes in metabolite levels were evaluated using paired Student's t-tests and the change patterns were examined at the level of pathways. Multivariate regression procedures were used to examine metabolite pairwise differences associated with subsequent GDM diagnosis. RESULTS:Of the 306 metabolites detected, the relative concentration of 127 metabolites were statistically significantly increased or decreased 2-hours after the oral glucose load (false discovery rate [FDR] corrected P-value<0.001). We identified relative decreases in metabolites in acylcarnitines, fatty acids, and diacylglycerols while relative increases were noted among bile acids. In addition, we found that C58:10 triacylglycerol (?=-0.08, SE=0.04), C58:9 triacylglycerol (?=-0.07, SE=0.03), adenosine (?=0.70, SE=0.32), methionine sulfoxide (?=0.36, SE=0.13) were significantly associated with GDM diagnosis even after adjusting for age and body mass index. CONCLUSIONS:We identified alterations in maternal serum metabolites, representing distinct cellular and metabolic pathways including fatty acid metabolism, in response to an oral glucose challenge. These findings offer novel perspectives on the pathophysiological mechanisms underlying GDM.

Dataset Information

Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths: A Longitudinal Study.

Context

Methods

Results

Conclusion

Publications

Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths: A Longitudinal Study.

Similar Datasets

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