The Effect of Obesity-induced Cytokine Elevation on the Molecular Regulation of Protein Turnover and Carbohydrate Metabolism in Human Skeletal Muscle
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Change in muscle protein synthesis response to simulated feeding with data reported as % fractional synthetic rate per hour.
研究概览
简要总结
Obesity in humans has been shown to result in the increased release of small inflammatory-inducing proteins, called cytokines, from the fat cells of the body. The investigators are interested in the effects of these cytokines on the mechanisms that control muscle mass and metabolism in the obese human. Previous research from work in cells and animals has shown the cytokines reduce the synthesis of muscle proteins and simultaneously enhance their rate of breakdown, resulting in a loss of muscle mass. Furthermore, research suggests that the same cytokines may inhibit carbohydrate oxidation, a pivotal step in muscle metabolism. However, despite these potential negative consequences for skeletal muscle function, the effect of low-level and persistent inflammation as seen in obese humans, remains largely unknown.
In the current study, the investigators plan to measure the rates of synthesis and breakdown of muscle proteins in conjunction with rates of carbohydrate oxidation in obese older participants, and compare them to rates determined in healthy non-obese individuals. Furthermore, participants will undergo a 12-week course of either pioglitazone, an insulin sensitiser often prescribed to type II diabetics, or a placebo. Pioglitazone has been shown previously to normalise the levels of cytokines in the blood of chronically inflamed individuals. By repeating after the 12-week intervention period the initial measurements described above, and by accurately determining the levels of the cytokines, the identification of the negative effects of obesity-induced inflammation in older adults on muscle metabolism will be determined.
详细描述
Recruitment of subjects:
24 obese (but otherwise healthy) participants with elevated cytokine levels and 24 non-obese subjects with normal cytokine levels will be recruited. Following the first experimental visit (see below), participants will be divided in a double-blind fashion into four groups (n=12). In previous studies utilising similar low-grade inflammatory states where thiazolidinediones have been administered, significant differences (P<0.05) in processes under investigation have been observed with group sizes of 10. Therefore group sizes of 12 have been selected to accommodate for the anticipated 15% dropout seen in long-term studies. Participants will be male, age matched (>55 years), non-smoking, live a sedentary lifestyle and non-vegetarian. Before taking part in the study, all subjects will undergo medical screening and complete a general health questionnaire. This will include measures of blood pressure, heart rate, 12-lead electrocardiogram (ECG), blood biochemistry and a blood clotting profile. For non-control subjects, inclusion into the study will be determined by measures of waist circumference (>100 cm), and inflammatory status (non-obese subjects with C-reactive proteins (CRP) plasma levels <1.35 μg.ml-1 and tumor necrosis factor-alpha (TNFα) plasma levels <3.3 pg.ml-1 and obese subjects with a CRP >1.35 μg.ml-1 and TNFα >4.1 pg.ml-1). Following an explanation of the study and associated procedures, written consent will be obtained and subjects made aware that they are free to withdraw at any point. Subjects will be recruited via press advertisements from the local population.
Experimental trials:
At the start of a 12-week long study, muscle protein synthesis and leg protein breakdown will be determined in all subjects via the administration of stable-isotopes of leucine and phenylalanine concomitant to a two-stage insulin clamp to simulate going from the fasted to fed state. This will establish the baseline values for these measures prior to the 12-week intervention period. These measures will be achieved in a single visit with the execution of an established protocol for the determination of muscle protein synthesis and leg protein breakdown. In summary, to achieve this the following will be performed: a basal muscle biopsy from the thigh will be obtained after which serum insulin concentrations will be held at fasting levels and a further muscle biopsy obtained; once taken serum insulin concentrations will be elevated and mixed amino acids administered to simulate feeding followed by the taking of a third and final muscle biopsy. The taking of biopsies will allow for the determination of isotope incorporation and thereby the determination of muscle protein synthesis and leg protein breakdown rates.
Following the first experimental visit, subjects will start a 12 week treatment period of either pioglitazone (30 mg•day-1) or a placebo, administered in a double-blind fashion. Subjects will be monitored at intervals throughout the period to ensure compliance and report unwanted side effects. After 12 weeks of drug or placebo administration, subjects will return to the laboratory for a repeat of the measurements determined in the first experimental visit (muscle protein synthesis and leg protein breakdown in response to simulated feeding). Circulating levels of select cytokines will be additionally examined in blood samples collected from subjects at the start of the two experimental visits (pre- and post- 12-week drug intervention period), thus allowing an assessment of any associated changes between systemic cytokine concentrations and muscle protein synthesis and leg protein breakdown.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 75 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •55-75 years old
- •Body Mass Index 20-25 or >30 kg/m2
- •Residing in Nottinghamshire area
排除标准
- •Taking statin medication
- •Clotting disorders of previous central venous access (CVA) / thrombosis-inducing activity (TIA)/ deep vein thrombosis (DVT)
- •Metabolic disease e.g. diabetes, thyroid dysfunction
- •Inflammatory conditions e.g. Rheumatoid Arthritis, Crohn's Disease
- •Tobacco smoker in previous 3 years
- •Lower limb circulation problems e.g. Claudication
- •Renal pathology
- •Respiratory problems including asthma
研究组 & 干预措施
Placebo
Placebo tablet taken once daily for 12 weeks.
For study visits performed pre- and post 12-week placebo treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Insulin (Drug)
Placebo
Placebo tablet taken once daily for 12 weeks.
For study visits performed pre- and post 12-week placebo treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Octreotide (Drug)
Placebo
Placebo tablet taken once daily for 12 weeks.
For study visits performed pre- and post 12-week placebo treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Glucose (Drug)
Placebo
Placebo tablet taken once daily for 12 weeks.
For study visits performed pre- and post 12-week placebo treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Mixed Amino Acids (Drug)
Placebo
Placebo tablet taken once daily for 12 weeks.
For study visits performed pre- and post 12-week placebo treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: [2H5]phenylalanine (Other)
Placebo
Placebo tablet taken once daily for 12 weeks.
For study visits performed pre- and post 12-week placebo treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: [1-13C]leucine (Other)
Pioglitazone
30mg pioglitazone encapsulated and taken once daily for 12 weeks.
For study visits performed pre- and post 12-week pioglitazone treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Pioglitazone (Drug)
Pioglitazone
30mg pioglitazone encapsulated and taken once daily for 12 weeks.
For study visits performed pre- and post 12-week pioglitazone treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Insulin (Drug)
Pioglitazone
30mg pioglitazone encapsulated and taken once daily for 12 weeks.
For study visits performed pre- and post 12-week pioglitazone treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Octreotide (Drug)
Pioglitazone
30mg pioglitazone encapsulated and taken once daily for 12 weeks.
For study visits performed pre- and post 12-week pioglitazone treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Glucose (Drug)
Pioglitazone
30mg pioglitazone encapsulated and taken once daily for 12 weeks.
For study visits performed pre- and post 12-week pioglitazone treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: Mixed Amino Acids (Drug)
Pioglitazone
30mg pioglitazone encapsulated and taken once daily for 12 weeks.
For study visits performed pre- and post 12-week pioglitazone treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: [2H5]phenylalanine (Other)
Pioglitazone
30mg pioglitazone encapsulated and taken once daily for 12 weeks.
For study visits performed pre- and post 12-week pioglitazone treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, [2H5]phenylalanine and [1-13C]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.
干预措施: [1-13C]leucine (Other)
结局指标
主要结局
Change in muscle protein synthesis response to simulated feeding with data reported as % fractional synthetic rate per hour.
时间窗: Assessed at study visits pre and post 90 day drug intervention period
次要结局
- Change in leg protein breakdown response to simulated feeding with data reported as nmol/min/100g leg mass.(Assessed at study visits pre and post 90 day drug intervention period)
- Change in respiratory exchange ratio response to simulated feeding with data reported as the ratio between the volume of CO2 produced and O2 consumed in air breathed.(Assessed at study visits pre and post 90 day drug intervention period)
- Change in plasma concentration of pro-inflammatory cytokines with data reported as picograms per ml of plasma.(Assessed pre- and post- 90 day drug intervention period)