Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim2)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether microbiome modulation and an experimental reduction in plasma LPS concentration improve inflammation and insulin action in insulin resistant (obese and T2DM) subjects.

Detailed Description
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In this Aim we will test the hypothesis that lowering lipopolysaccharide (LPS) concentration in the circulation will improve systemic (muscle) inflammation and glucose metabolism in insulin resistant (obese and T2DM) subjects by protecting the intestinal barrier with a synbiotic (Bifidobacterium longum R0175 and oligofructose) or by sequestering LPS in the gastrointestinal lumen with sevelamer.

Official Title
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Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim2)

Conditions
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Insulin Sensitivity

Intervention / Treatment
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* Drug: Maltodextrin
* Drug: Synbiotic
* Drug: Sevelamer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Both genders (50%, male). 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 results of 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. Exclusion 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Type2 Diabetes Mellitus - Placebo<br>Type 2 Diabetes Mellitus subjects will receive maltodextrin (placebo) | Drug: Maltodextrin<br>* Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks.<br>|
| Placebo Comparator: Obese with NGT - Placebo<br>Obese (BMI = 30-37 kg/m2) normal glucose tolerant (NGT) subjects will receive maltodextrin (placebo) | Drug: Maltodextrin<br>* Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks.<br>|
| Placebo Comparator: Lean with NGT -Placebo<br>Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive maltodextrin (placebo) | Drug: Maltodextrin<br>* Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks.<br>|
| Active Comparator: Type2 Diabetes Mellitus - Synbiotic<br>Type 2 Diabetic subjects will receive synbiotic | Drug: Synbiotic<br>* Synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks.<br>|
| Active Comparator: Type2 Diabetes Mellitus - Sevelamer<br>Type 2 Diabetic subjects will receive sevelamer | Drug: Sevelamer<br>* Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks<br>* Other names: Renvela;|
| Active Comparator: Obese with NGT - Synbiotic<br>Obese (BMI = 30-37 kg/m2) normal glucose tolerant subjects (NGT) will receive Synbiotic | Drug: Synbiotic<br>* Synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks.<br>|
| Active Comparator: Obese with NGT - Sevelamer<br>Obese subjects (BMI = 30-37 kg/m2) normal glucose tolerant (NGT) will receive Sevelamer | Drug: Sevelamer<br>* Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks<br>* Other names: Renvela;|
| Active Comparator: Lean with NGT - Synbiotic<br>Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive Synbiotic | Drug: Synbiotic<br>* Synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks.<br>|
| Active Comparator: Lean with NGT - Sevelamer<br>Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive Sevelamer | Drug: Sevelamer<br>* Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks<br>* Other names: Renvela;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Insulin sensitivity in skeletal muscle (M value) as measured by hyperinsulinemic euglycemic clamp study. The clamp study tests the ability of peripheral tissues such as skeletal muscle to uptake glucose in response to a constant insulin stimulus, which give a measure of sensitivity to insulin action. 60 mU/m2*min insulin was infused into subjects for 180 minutes with concomitant adjustment of glucose infusion rate using D20 glucose to maintain a clamped plasma glucose concentration of 100 mg/dL. When the glucose infusion rate equals the rate of glucose uptake and the targeted glucose concentration is achieved, the clamp is at steady-state equilibrium. Steady-state glucose infusion rate at 150min-180mins was used as the measure to calculate the M value. | Change from baseline insulin sensitivity at 28 days of the intervention. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Endotoxin Level and Its Panel. | Plasma Lipopolysaccharide (LPS) after intervention period | Change from baseline plasma endotoxin level and its panel during 28 days. | 
| Gut Permeability | urine lactulose: mannitol ratio. | Change from baseline gut permeability at 24 days of the intervention. |