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

Phase 2

Completed

Brief Summary: 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: 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.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Type2 Diabetes Mellitus - Sevelamer	Sevelamer	Type 2 Diabetic subjects will receive sevelamer
Lean with NGT -Placebo	Maltodextrin	Lean (BMI\< 26 kg/m2) normal glucose tolerant (NGT) will receive maltodextrin (placebo)
Type2 Diabetes Mellitus - Synbiotic	Synbiotic	Type 2 Diabetic subjects will receive synbiotic
Obese with NGT - Placebo	Maltodextrin	Obese (BMI = 30-37 kg/m2) normal glucose tolerant (NGT) subjects will receive maltodextrin (placebo)
Obese with NGT - Synbiotic	Synbiotic	Obese (BMI = 30-37 kg/m2) normal glucose tolerant subjects (NGT) will receive Synbiotic
Type2 Diabetes Mellitus - Placebo	Maltodextrin	Type 2 Diabetes Mellitus subjects will receive maltodextrin (placebo)
Obese with NGT - Sevelamer	Sevelamer	Obese subjects (BMI = 30-37 kg/m2) normal glucose tolerant (NGT) will receive Sevelamer
Lean with NGT - Synbiotic	Synbiotic	Lean (BMI\< 26 kg/m2) normal glucose tolerant (NGT) will receive Synbiotic
Lean with NGT - Sevelamer	Sevelamer	Lean (BMI\< 26 kg/m2) normal glucose tolerant (NGT) will receive Sevelamer

Primary Outcome Measures

Name	Time	Method
Insulin Sensitivity	Change from baseline insulin sensitivity at 28 days of the intervention.	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.

Secondary Outcome Measures

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