Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim 1)

We will test the hypothesis that a high fat diet given to lean, normal glucose tolerant
subjects will modify gut microbiome composition and enhance intestinal permeability, which
will increase plasma LPS concentration, induce an inflammatory response in peripheral tissues
(skeletal muscle), and impair insulin signaling and sensitivity. 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.

Inclusion Criteria:

- 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.

Exclusion Criteria:

- 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.