There are 5 clinical trials
Type 2 Diabetes (T2D) in obese youth is often preceded by a prediabetic state called: Impaired Glucose Tolerance (IGT), which is associated with a pre-existing defect in insulin secretion. This study intends to determine if genetic factors are associated with defects in insulin secretion, the incretin system and hepatic insulin resistance in obese adolescents. The long-term goal of this study is to generate information on both the genetics as well as the pathophysiology of Type 2 Diabetes in Youth, which ultimately might guide the investigators towards better preventive and treatment avenues.
To delineate the effects of TCF7L2 rs7903146 on functional Beta-Cell Capacity in obese adolescents with Impaired Glucose Tolerance (IGT) and pre-IGT.
Aim 2. To examine the functional effect of the rs7903146 variant in the TCF7L2 gene on a) incretin effect in obese adolescents with IGT and pre-IGT.
Aim 3. To determine the functional effects of TCF7L2 rs7903146 SNP on hepatic glucose fluxes in obese adolescents with IGT and pre-IGT.
Description: An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects are pre-IGT or IGT
Measure: Glucose tolerance status Time: BaselineDescription: DNA screening to measure whether subject is CC or TT genotype
Measure: Genotype Time: BaselineDescription: AIRmax stimulation test during the hyperglycemic clamp to ascertain the maximal acute insulin response (AIR) to arginine, which is a measure of functional beta cell capacity.
Measure: Beta cell capacity Time: BaselineDescription: Subjects will undergo the IsoIVGT test with GLP-1 measurements to measure the incretin effect
Measure: Incretin effect Time: 3weeks to 1 month post Baseline testingDescription: The AIRmax stimulation test during the hyperglycemic clamp will be repeated at 2 years to determine if genotype TCF7L2 contributes to worsening in beta cell function longitudinally
Measure: Beta cell function (longitudinally) Time: 2 years post BaselineDescription: Measurements from the Hyperinsulinemic Euglycemic Clamp/ 2H20 Study will be used to assess insulin effects on hepatic glucose production and glycerol kinetics isotopes and the deuterium enrichment at carbons 2 and 5 (C2 and C5) of plasma glucose providing information on glucose fluxes
Measure: Hepatic glucose fluxes Time: 2 months post baseline testingNutrients and chemicals in food are able to regulate expression of genetic elements. Gene-nutrient interaction in response specific diets can increase an individual's risk, shifting the individual from health toward the development of chronic disease. The Transcription Factor 7 Like 2 (TCF7L2) gene may either put individuals at risk for or protect from Type 2 diabetes mellitus in the presence of certain foods. The main purpose of this four-week study is to examine diet-induced gene-nutrient interaction, with a focus on glucose, insulin, inflammation (CRP) and the plasma metabolome in individuals who have either the CC or the TT form of the rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene. The (2) one-week study diets, one Mediterranean diet (MedDiet) based and the other low-fat based will be separated by a (1) week return to a regular habitual diet.
The main purpose of this four-week study is to examine diet-induced gene-nutrient interaction, with a focus on glucose, insulin, inflammation (CRP) and the plasma metabolome in individuals who have either the CC or the TT form of the rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene.
Plasma glucose levels (mg/dl) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP.
Fasting plasma insulin levels (pmol/l) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP.
The response of plasma metabolites to the Mediterranean and low-fat diets diet) will be measured using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP.
Fasting plasma concentrations of VLDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP.
Fasting plasma concentrations of LDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP.
Fasting plasma concentrations of HDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP.
Plasma C-reactive protein (mg/dl) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP.
The rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene is the most replicated T2D-associated SNP.
For this purpose, a four-week study will be conducted to examine diet-induced gene-nutrient interaction, with a focus on glucose, insulin, and inflammation (CRP) in individuals who have either the CC or the TT form of the rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene.
Description: Plasma glucose levels (mg/dl) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Measure: Glucose Time: 1 week per intervention armDescription: Fasting plasma insulin levels (pmol/l) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Measure: Insulin Time: 1 week per intervention armDescription: The response of plasma metabolites to the Mediterranean and low-fat diets diet) will be measured using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Measure: Metabolomics Time: 1 week per intervention armDescription: Fasting plasma concentrations of VLDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Measure: Very low density lipoproteins (VLDL) Time: 1 week per intervention armDescription: Fasting plasma concentrations of LDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Measure: Low-density lipoproteins (LDL) Time: 1 week per intervention armDescription: Fasting plasma concentrations of HDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Measure: High-density lipoproteins (HDL) Time: 1 week per intervention armDescription: Plasma C-reactive protein (mg/dl) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Measure: CRP Time: 1 week per intervention armCystic fibrosis related diabetes (CFRD) is associated with worse CF-relevant outcomes. The mechanisms underlying CFRD development are not fully understood, but recent evidence suggests Type 2 Diabetes Mellitus (T2DM) mechanisms may be involved and may involve incretins (gut secreted hormones that augment insulin secretion in response to a nutrient load). This study will examine the prevalence of Genome wide association study (GWAS)-implicated T2DM alleles (including TCF7L2) across the spectrum of glucose abnormalities in CF and will use this information to compare incretin and insulin secretion in non-diabetic children and adults with high risk and low risk alleles.
SECOND PHASE OF STUDY: Inclusion Criteria 1. Subjects age >8y 2. Diagnosis of Cystic Fibrosis 3. pancreatic insufficient 4. negative urine pregnancy test at enrollment 5. TCF7L2 rs7903146 genotype of T/T or C/C 6.
Description: To examine the prevalence of GWAS-implicated T2DM alleles (including TCF7L2) across the spectrum of glucose abnormalities in children and adults with CF.
Measure: Blood sample for DNA to genotype TCF7L2 and about 10 other GWAS-implicated T2DM genes. Time: 1 dayDescription: Pancreatic ß-cell function will be evaluated using the GPA test which can be used to measure β-cell secretory capacity and sensitivity to glucose.
Measure: Glucose-Potentiated Arginine Stimulation Test (GPA test) Time: 1 dayDescription: Incretin and insulin secretion as well as glucose tolerance will be assessed using the MMTT.
Measure: Mixed Meal Tolerance Testing (MMTT) Time: 1 dayThis is a phase I placebo-controlled study to assess safety, tolerability, pharmacokinetics and pharmacodynamics of Globalagliatin Hydrochloride (SY-004) after Multiple Ascending Doses in patients with Type 2 Diabetes Mellitus (T2DM).
Compared with placebo, the mean changes of post-prandial blood glucose from baseline at D7，D14，D21 and D28.. genetic: TCF7L2 ( Transcription factor 7-like 2) rs7903146 and GCKR (glucokinase regulatory protein) rs780094 ).
The genetic（TCF7L2 rs7903146 and GCKR rs780094）effects on response of SY-004 in T2DM patients.. the changes of GA (Glycated albumin) from baseline.
Description: Compared with placebo, the mean change in glucose AUC from baseline at D28.
Measure: the mean change in glucose area under curve (AUC) from baseline. Time: 28 daysDescription: Compared with placebo, the fasting plasma glucose from baseline at D7，D14，D21 and D28.
Measure: the fasting plasma glucose from baseline Time: 7, 14, 21, 28 daysDescription: Compared with placebo, the changes of MMTT (mixed-meal tolerance test) results from baseline at D28
Measure: the changes of MMTT (mixed-meal tolerance test) results from baseline Time: 28 daysDescription: Compared with placebo, the mean changes of average 7-points blood glucose profiles from baseline at D7，D14，D21 and D28.
Measure: the mean changes of average 7-points blood glucose profiles from baseline Time: 7, 14, 21, 28 daysDescription: Compared with placebo, the mean changes of average 14-points blood glucose profiles from baseline at D7，D14，D21 and D28.
Measure: the mean changes of average 14-points blood glucose profiles from baseline Time: 7, 14, 21, 28 daysDescription: Compared with placebo, the mean changes of post-prandial blood glucose from baseline at D7，D14，D21 and D28.
Measure: the mean changes of post-prandial blood glucose from baseline Time: 7, 14, 21, 28 daysDescription: The genetic（TCF7L2 rs7903146 and GCKR rs780094）effects on response of SY-004 in T2DM patients.
Measure: genetic: TCF7L2 ( Transcription factor 7-like 2) rs7903146 and GCKR (glucokinase regulatory protein) rs780094 ) Time: 28 daysDescription: Compared with placebo, the changes of GA (Glycated albumin) from baseline at D28.
Measure: the changes of GA (Glycated albumin) from baseline Time: 28 daysIn the present study the investigators will measure the extent of coronary artery disease via coronary angiography and the correlating risk factors.
The incidence, extent and clinical manifestation of coronary artery disease and the circulating levels of hs-CRP, adipokines and RAGEs.. To associate the incidence, extent and clinical manifestation of coronary artery disease with systemic inflammatory status assessed by hs-CRP levels, circulating adipokines (adiponectin, resistin) and the receptors of advanced glycation end products (sRAGE and esRAGE).. TCF7L2 gene polymorphims and the incidence and extent of coronary artery disease.. To associate the incidence, extent and clinical manifestation of coronary artery disease with the rs7903146 single nucleotide polymorphism of TCF7L2 gene, that has been strongly associated with diabetes mellitus development.. Inclusion Criteria: - Any subject eligible for coronary angiography with or without known CV disease for clinical reasons.
Description: We will investigate the incidence, extent and clinical manifestation of coronary artery disease in diabetics and non-diabetics undergoing coronary angiography for clinical reasons.
Measure: The incidence and extent of coronary artery disease between diabetics and non-diabetic patients. Time: Up to four years on average.Description: To associate the incidence, extent and clinical manifestation of coronary artery disease with classic demographic risk factors (such as smoking, alcohol consumption, physical exercise, arterial hypertension, family history of diabetes mellitus or coronary artery disease) and common biochemical risk factors (such as fasting glucose levels, urea, creatinine, HbA1c%, uric acid, total cholesterol, HDL, LDL, triglycerides, VLDL, glomerular filtration rate - GFR).
Measure: The incidence and extent of coronary artery disease via coronary angiography scores and related biochemical and demographical risk factors. Time: Up to 4 years on average.Description: To associate the incidence, extent and clinical manifestation of coronary artery disease with systemic inflammatory status assessed by hs-CRP levels, circulating adipokines (adiponectin, resistin) and the receptors of advanced glycation end products (sRAGE and esRAGE).
Measure: The incidence, extent and clinical manifestation of coronary artery disease and the circulating levels of hs-CRP, adipokines and RAGEs. Time: Up to 4 years on average.Description: To associate the incidence, extent and clinical manifestation of coronary artery disease with the rs7903146 single nucleotide polymorphism of TCF7L2 gene, that has been strongly associated with diabetes mellitus development.
Measure: TCF7L2 gene polymorphims and the incidence and extent of coronary artery disease. Time: Within a maximum period of 4 years.