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

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.

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.