Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim 1)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Insulin Sensitivity Low Fat Diet
研究概览
简要总结
The purpose of this study is to determine insulin sensitivity in individuals that are lean normal glucose tolerant subjects after consumption of a normal low fat diet and after a high fat diet and to explore the effects of high fat consumption on the intestinal microbiome, and metabolic endotoxemia.( Aim 1 of the protocol, a separate record is available for Aim 2)
详细描述
We will test the hypothesis that a high fat diet given to lean, normal glucose tolerant subjects will impair insulin signaling and sensitivity and modify gut microbiome composition and enhance intestinal permeability, which will increase plasma LPS concentration, induce an inflammatory response in peripheral tissues (skeletal muscle). Also we will test the hypothesis that the inflammatory response and insulin resistance caused by high fat ingestion can be ameliorated by administering
- a synbiotic (Bifidobacterium longum R0175 and oligofructose) which protects the intestinal epithelial barrier and decreases intestinal translocation of LPS; and
- sevelamer, an agent which sequesters lipopolysaccharide (LPS) in the gastrointestinal tract limiting its translocation into the circulation.
All subjects are fed both a low fat diet (considered a normal diet) and high fat diet, first one and then the other in no particular sequence. After a washout period participants are fed the other type of high or low fat diet, depending on which diet they were first assigned to in order to compare the effects of the intervention on insulin sensitivity during each diet.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Both genders. All races and ethnic groups.
- •Premenopausal women in the follicular phase, non-lactating, and with a negative pregnancy test. Postmenopausal women on stable dose of or not exposed to hormone replacement for ≥6 months.
- •Hematocrit (HCT)≥ 34%, serum creatinine ≤ 1.4 mg/dl, and normal serum electrolytes, urinalysis, and coagulation tests. Liver function tests (LFTs) up to 2 times normal.
- •Stable body weight (±2%) for ≥ 3 months
- •Two or less sessions of strenuous exercise/wk for last 6 months.
排除标准
- •Presence of diabetes or impaired glucose tolerance based on ADA criteria.
- •Current treatment with drugs known to affect glucose and lipid homeostasis. If the subject has been on a stable dose for the past 3 months, the following agents will be permitted: calcium channel blockers, β-blockers, ACE inhibitors, angiotensin receptor blockers, and statins
- •History of allergy to sevelamer.
- •History of Non-steroidal anti-inflammatory drugs or systemic steroid use for more than a week within 3 months.
- •Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be permitted if these can be held for seven days prior to the biopsy in accordance with the primary physician.
- •Use of agents that affect gut flora (e.g. antibiotics, colestyramine, lactulose, PEG) within 3 months.
- •History of heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the ECG), peripheral vascular disease, pulmonary disease, smokers.
- •Poorly controlled blood pressure (systolic BP>170, diastolic BP>95 mmHg).
- •Active inflammatory, autoimmune, hepatic, gastrointestinal, malignant, and psychiatric disease.
- •History of gastrointestinal surgery or gastrointestinal obstruction within two years.
研究组 & 干预措施
Placebo
Placebo: maltodextrin, 6 g three times a day
干预措施: Maltodextrin (Drug)
Placebo
Placebo: maltodextrin, 6 g three times a day
干预措施: High Fat diet (Other)
Placebo
Placebo: maltodextrin, 6 g three times a day
干预措施: Low Fat diet (Other)
Sevelamer
Sevelamer: (1.6 g sevelamer + 4.4 g maltodextrin three times a day)
干预措施: Sevelamer (Drug)
Sevelamer
Sevelamer: (1.6 g sevelamer + 4.4 g maltodextrin three times a day)
干预措施: High Fat diet (Other)
Sevelamer
Sevelamer: (1.6 g sevelamer + 4.4 g maltodextrin three times a day)
干预措施: Low Fat diet (Other)
Synbiotic
Synbiotic: 5g Oligofructose + 4x1010 Bifidobacterium longum CFU 3x daily during diet
干预措施: Synbiotic (Drug)
Synbiotic
Synbiotic: 5g Oligofructose + 4x1010 Bifidobacterium longum CFU 3x daily during diet
干预措施: High Fat diet (Other)
Synbiotic
Synbiotic: 5g Oligofructose + 4x1010 Bifidobacterium longum CFU 3x daily during diet
干预措施: Low Fat diet (Other)
结局指标
主要结局
Insulin Sensitivity Low Fat Diet
时间窗: Day 28
Skeletal muscle insulin sensitivity measured after 28 days of low fat diet and drug intervention. The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.
Insulin Sensitivity High Fat Diet
时间窗: Day 28
Skeletal muscle insulin sensitivity measured after 28 days of high fat diet. The High Fat diet consists of 60% energy from fat (50% saturated), 15% of energy as carbohydrate and 25% from protein consumed while study intervention is being administered.
次要结局
- Gut Permeability(on Day 24 of the intervention.)
- Plasma Endotoxin Levels(At baseline, on day 3, and 28 of the intervention.)