The Role of TBC1D4 in Exercise- and Insulin-induced Glucose Metabolism in Human Skeletal Muscle
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Changes in leg glucose uptake
研究概览
简要总结
Recently a common Greenlandic nonsense p.Arg684erTer variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 was discovered. The variant has an allele frequency of 17%. Homozygous carriers of this TBC1D4 variant have impaired glucose tolerance and a 10-fold enhanced risk of developing type 2 diabetes (T2D). The investigators propose to carry out comprehensive metabolic phenotyping of adult Inuits carrying zero or two alleles of the TBC1D4 variant. The investigators hypothesise that regulation of TBC1D4 in skeletal muscle is pivotal in regulating glucose uptake during exercise, during physiological insulin stimulation, and for the ability of an acute bout of exercise to improve insulin sensitivity to regulate glucose metabolism in humans.
The overall aims in the present project are to:
- Determine whether the TBC1D4 p.Arg684Ter variant affects the regulation of glucose uptake in skeletal muscle during exercise and during physiological insulin stimulation.
- Determine the effect of the TBC1D4 p.Arg684Ter variant for the ability of acute exercise to insulin sensitize skeletal muscle to regulate glucose metabolism.
- Define the metabolic pathways affected by the p.Arg684Ter variant in order to identify causal factors responsible for the diabetic phenotype of Inuit carriers.
The knowledge generated will contribute to additional explanatory clues to the increased frequency of T2D in the carriers.
详细描述
Recently a common Greenlandic nonsense p.Arg684erTer variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 was discovered. The variant has an allele frequency of 17%. Homozygous carriers of this TBC1D4 variant have impaired glucose tolerance and a 10-fold enhanced risk of T2D. The investigators propose to carry out comprehensive metabolic phenotyping of adult Inuits carrying zero or two alleles of the TBC1D4 variant. The investigators hypothesise that regulation of TBC1D4 in skeletal muscle is pivotal in regulating glucose uptake during exercise, during physiological insulin stimulation, and for the ability of an acute bout of exercise to improve insulin sensitivity to regulate glucose metabolism in humans.
Our overall aims in the present project are to:
- Determine whether the TBC1D4 p.Arg684Ter variant affects the regulation of glucose uptake in skeletal muscle during exercise and during physiological insulin stimulation.
- Determine the effect of the TBC1D4 p.Arg684Ter variant for the ability of acute exercise to insulin sensitize skeletal muscle to regulate glucose metabolism.
- Define the metabolic pathways affected by the p.Arg684Ter variant in order to identify causal factors responsible for the diabetic phenotype of Inuit carriers.
The knowledge generated will contribute to additional explanatory clues to the increased frequency of T2D in the carriers.
Study population:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Homozygote carriers of a pArg684T gene-variant (cases) and matched non carriers (controls)
- •BMI between 20-35 kg/m2
排除标准
- •Medical treated type 2 diabetes patients
研究组 & 干预措施
Exercise and vivo insulin stimulation in TBC1D4 gene-variants
Acute exercise and in vivo insulin stimulation in homozygote carriers of a p.ARg684T TBC1D4 gene-variant.
干预措施: Acute exercise (Other)
Exercise and vivo insulin stimulation in matched controls
Acute exercise and in vivo stimulation in none carriers (matched controls) of the p.Arg684T TBC1D4 gene-variant.
干预措施: Acute exercise (Other)
结局指标
主要结局
Changes in leg glucose uptake
时间窗: Measured 14 times during the experimental day (dispersed over 6 hours)
Leg glucose uptake is calculated by the arterial-venous difference i blood glucose concentration multiplied with leg blood flow. Sampling of artery and venous blood samples for blood glucose measurements. Measures of artery blood flow by Ultrasound Doppler technique allows a final calculation of glucose uptake across the legs before exercise, during exercise, in recovery from exercise and with insulin stimulation.
Changes in whole body insulin sensitivity sensitivity.
时间窗: 6 times (each 20 minutes) during 2 hours insulin stimulation.
Insulin stimulated glucose uptake at whole body level (glucose infusion rate)
Proteome and phosphoproteome.
时间窗: At 4 times points: Before exercise, immediately after exercise, 3 hours after exercise and after 2 hours of insulin stimulation.
Proteomics and targeted phosphoproteomic to identify changes in skeletal muscle.
Metabolome.
时间窗: At 4 times points: Before exercise, immediately after exercise, 3 hours after exercise and after 2 hours of insulin stimulation.
Metabolomic analyses to map changes in biochemical pathways in skeletal muscle.
Transcriptome.
时间窗: At 4 times points: Before exercise, immediately after exercise, 3 hours after exercise and after 2 hours of insulin stimulation.
Transcriptome sequencing in skeletal muscle.
Changes in the TBC1D4 interactome.
时间窗: At 4 times points: Before exercise, immediately after exercise, 3 hours after exercise and after 2 hours of insulin stimulation.
TBC1D4 interactome analyses, to identify TBC1D4 signaling partners
Changes in phosphorylation and glycosylation signatures of TBC1D4
时间窗: At 4 times points: Before exercise, immediately after exercise, 3 hours after exercise and after 2 hours of insulin stimulation.
Phosphorylation and glycosylation signatures of the TBC1D4 protein by western blotting to describe regulation of TBC1D4.
Changes of canonical intermediates in insulin- and exercise-induced signaling
时间窗: At 4 times points: Before exercise, immediately after exercise, 3 hours after exercise and after 2 hours of insulin stimulation.
Expression and/or activity of canonical intermediates in insulin- and exercise-induced signaling and metabolic pathways.
Changes in leg substrate utilization
时间窗: At 4 times points: Before exercise, immediately after exercise, 3 hours after exercise and after 2 hours of insulin stimulation.
Throughout the study day sampling of artery and venous blood/plasma samples allow estimation of substrate utilization based on the respiratory quotient (RQ).
次要结局
- Substrate metabolism in primary myotubes from TBC1D4 p.Arg684 variant carriers and controls(At two conditions: With and without insulin.)
- Activities of key enzymes in glucose and fat metabolism(at 2 time points: Before and after 2 hours of insulin stimulation.)
研究者
Professor Jorgen FP Wojtaszewski
Professor
University of Copenhagen