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Preliminary report: No association between TCF7L2 rs7903146 and euglycemic-clamp-derived insulin sensitivity in a mixed-age cohort.

ABSTRACT: There are conflicting reports about the significance of TCF7L2 single nucleotide polymorphism rs7903146, a single nucleotide polymorphism found to be associated with type 2 diabetes mellitus in several genomewide association studies, and insulin sensitivity. The association of rs7903146 and euglycemic-clamp-derived insulin sensitivity was tested in a cohort of children and their parents. Four hundred seventy whites (from 226 families) and 89 African Americans (from 48 families) were included in the analysis. No significant associations were seen between rs7903146 and insulin sensitivity. Adjusted genotype means were consistent across races and generational subgroups.

SUBMITTER: Rasmussen-Torvik LJ

PROVIDER: S-EPMC2748141 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Preliminary report: No association between TCF7L2 rs7903146 and euglycemic-clamp-derived insulin sensitivity in a mixed-age cohort.

Rasmussen-Torvik Laura J LJ Pankow James S JS Jacobs David R DR Sinaiko Alan R AR

Metabolism: clinical and experimental 20090701 10

There are conflicting reports about the significance of TCF7L2 single nucleotide polymorphism rs7903146, a single nucleotide polymorphism found to be associated with type 2 diabetes mellitus in several genomewide association studies, and insulin sensitivity. The association of rs7903146 and euglycemic-clamp-derived insulin sensitivity was tested in a cohort of children and their parents. Four hundred seventy whites (from 226 families) and 89 African Americans (from 48 families) were included in ...[more]

PMID: 19573884

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Differential insulin sensitivity of NMR-based metabolomic measures in a two-step hyperinsulinemic euglycemic clamp study.

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| S-EPMC8190027 | biostudies-literature

The metabolic footprint of compromised insulin sensitivity under fasting and hyperinsulinemic-euglycemic clamp conditions in an Arab population.

Project description:Metabolic pathways that are corrupted at early stages of insulin resistance (IR) remain elusive. This study investigates changes in body metabolism in clinically healthy and otherwise asymptomatic subjects that may become apparent already under compromised insulin sensitivity (IS) and prior to IR. 47 clinically healthy Arab male subjects with a broad range of IS, determined by hyperinsulinemic-euglycemic clamp (HIEC), were investigated. Untargeted metabolomics and complex lipidomics were conducted on serum samples collected under fasting and HIEC conditions. Linear models were used to identify associations between metabolites concentrations and IS levels. Among 1896 identified metabolites, 551 showed significant differences between fasting and HIEC, reflecting the metabolic switch in energy utilization. At fasting, 336 metabolites, predominantly di- and tri-acylglycerols, showed significant differences between subjects with low and high levels of IS. Changes in amino acid, carbohydrate and fatty acid metabolism in response to insulin were impaired in subjects with low IS. Association of altered mannose and amino acids with IS was also replicated in an independent cohort of T2D patients. We identified metabolic phenotypes that characterize clinically healthy Arab subjects with low levels of IS at their fasting state. Our study is providing further insights into the metabolic pathways that precede IR.

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TCF7L2 correlation in both insulin secretion and postprandial insulin sensitivity.

Project description:Background:The TCF7L2 rs7903146 variant is strongly associated with type 2 diabetes mellitus (T2DM). However, the mechanisms involved in this association remain unknown and may include extrapancreatic effects. The aim of this study was to perform a metabolic characterization of T2DM patients with and without the TCF7L2 rs7903146 risk T allele and analyze some influences of the TCF7L2 genotype on glucose metabolism. Methods:Patients with T2DM (n?=?162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism. Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C, HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon. Additional secondary assessments included determination of insulinogenic index (IGI30), and insulin sensitivity (%S) and resistance (IR) by Homeostatic model assessment (HOMA). Results:Patients with the CT/TT genotype showed lower baseline plasma concentrations of C-peptide when compared with those with the CC genotype. Of the 56 individuals who participated in the mixed-meal test, 26 and 30 had the CC and CT/TT genotypes, respectively. CT/TT subjects, compared with CC individuals, had higher post prandial plasma levels of insulin and C-peptide at 30-120 min (p?<?0.05) and proinsulin at 45-240 min (p?<?0.05). Interestingly CT/TT individuals presented at baseline higher %S (p?=?0.021), and lower IR (p?=?0.020) than CC individuals. No significant differences in IGI30 values were observed between groups. Conclusions:The T2DM individuals carrying the rs7903146 T allele of the TCF7L2 gene presented higher IR pattern in response to a mix-meal test, different of beta cell function at baseline assessed by C-peptide levels which was lower, and Homa-IR was lower when comparing with non-carriers.

| S-EPMC5922313 | biostudies-literature

Transcriptomic profiles of skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in insulin-resistant obese subjects.

Project description:Insulin resistance in skeletal muscle is an early phenomenon in the pathogenesis of type 2 diabetes. Muscle is mainly responsible for insulin-stimulated glucose clearance from the bloodstream. Thus, regulation of gene expression in muscle tissue may be involved in the pathogenesis of insulin resistance. The objective was to investigate gene expression and metabolic pathways alterations in skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in obese insulin-resistant subjects. We carried out a transcriptome comparison of skeletal muscle tissue before and after a 3-h euglycemic-hyperinsulinemic clamp following 8-week supplementation with n-3 polyunsaturated fatty acid (PUFA) (1.8 g/day) with or without a supplement of fish gelatin (FG) (25 % of daily protein intake) in 16 obese insulin-resistant subjects. Results indicate that approximately 5 % (1932) of expressed transcripts were significantly changed after the clamp in both n-3 PUFA and n-3 PUFA + FG supplementation periods. Of these differentially expressed transcripts, 1394 genes associated with enzymes, transcription and translation regulators, transporters, G protein-coupled receptors, cytokines, and ligand-dependent nuclear receptors were modified. Metabolic pathways that were significantly modified included liver X receptor/retinoid X receptors (RXR) activation, vitamin D receptor/RXR activation, interleukin (IL)-8, acute phase response, IL10, triggering receptor expressed on myeloid cells 1, peroxisome proliferator-activated receptor, G-beta/gamma and hepatocyte growth factor and IL6 signaling. Taken together, results suggest that mainly inflammatory and transcription factors are modified following clamp in obese insulin-resistant subjects. Overall, understanding the changes in metabolic pathways due to insulin may be a potential target for the management of insulin resistance.

| S-EPMC3534998 | biostudies-literature

TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population.

Project description:BACKGROUND: In adults, the TCF7L2 rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance. METHODS: The present association study aimed at analyzing the contribution of the rs7903146 SNP to smallness for gestational age (SGA) and metabolic profiles in subjects with SGA or appropriate for gestational age birth weight (AGA). Two groups of French Caucasian subjects were selected on birth data: SGA (birth weight < 10th percentile; n = 764), and AGA (25th < birth weight < 75th percentile; n = 627). Family-based association tests were also performed in 3,012 subjects from 628 SGA and AGA pedigrees. RESULTS: The rs7903146 genotypic distributions between AGA (30.7%) and SGA (29.0%) were not statistically different (allelic OR = 0.92 [0.78-1.09], p = 0.34). Family association-based studies did not show a distortion of T allele transmission in SGA subjects (p = 0.52). No significant effect of the T allele was detected on any of the metabolic parameters in the SGA group. However, in the AGA group, trends towards a lower insulin secretion (p = 0.03) and a higher fasting glycaemia (p = 0.002) were detected in carriers of the T allele. CONCLUSION: The TCF7L2 rs7903146 variant neither increases the risk for SGA nor modulates birth weight and young adulthood glucose homeostasis in French Caucasian subjects born with SGA.

| S-EPMC1920504 | biostudies-literature

The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing ?-Cell Function and Hepatic Insulin Sensitivity.

Project description: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 ± 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 trend was seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased ?-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose production was 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 ?-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.

| S-EPMC5521977 | biostudies-literature

Evaluation of insulin sensitivity by hyperinsulinemic-euglycemic clamps using stable isotope-labeled glucose.

Project description: Not available

| S-EPMC5902507 | biostudies-literature

Serotonin is elevated in risk-genotype carriers of TCF7L2 - rs7903146.

Project description:The transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146 is known to be tightly associated with an elevated risk for type 2 diabetes, whereas the molecular mechanisms remain elusive. We evaluated the metabolic profile of a total of 394 patients' serum samples with respect to their rs7903146 genotype using targeted metabolomics in a discovery (n = 154) and a validation (n = 240) study. We have identified serotonin as the top metabolite being increased in carriers of the risk allele. Serotonin was significantly associated with the rs7903146 genotype after full adjustment including type 2 diabetes and further top ranked metabolites. Given the role of peripheral serotonin in metabolic homeostasis and type 2 diabetes, this finding provides a first hint that the well-known impact of the TCF7L2 polymorphism on type 2 diabetes risk may involve a serotonin-dependent pathway.

| S-EPMC6731216 | biostudies-literature

Relation of cardiac function to insulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis in individuals with type 2 diabetes.

Project description:AimsWhereas homeostasis model assessment of insulin resistance (HOMA-IR), an easily measured but limited index of insulin resistance, has been shown to correlate with impairment of cardiac function in individuals without diabetes, the pathological relevance of insulin resistance to the development of cardiac dysfunction in individuals with type 2 diabetes has remained unclear. Here we investigated the relation between left ventricular (LV) function as assessed by echocardiography and insulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis, the gold standard for measurement of this parameter, in individuals with type 2 diabetes.MethodsThis retrospective study included 34 individuals with type 2 diabetes who underwent both hyperinsulinemic-euglycemic clamp analysis and echocardiography. Both the insulin sensitivity index (ISI) as determined by glucose clamp analysis as well as HOMA-IR were determined as measures of insulin resistance. The ratio of the peak early- to late-diastolic mitral inflow velocities (E/A) and the LV ejection fraction (LVEF) were determined as measures of diastolic and systolic function, respectively.ResultsThe ISI was significantly correlated with both the E/A ratio and LVEF (correlation coefficients of 0.480 and 0.360, respectively), whereas HOMA-IR was not correlated with either cardiac parameter. Multivariate analysis revealed that ISI was an independent predictor for both a high log [E/A] (P = 0.031) and a high LVEF (P = 0.045).ConclusionsInsulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis may be causally related to LV diastolic and systolic dysfunction in individuals with type 2 diabetes.

| S-EPMC8668073 | biostudies-literature

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