Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim 1) (MicroB1)

• ClinicalTrials.gov Identifier: NCT02124759
• Recruitment Status: Active, not recruiting
• First Posted: April 28, 2014
• Last Update Posted: February 7, 2019
• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborator: American Diabetes Association
• Information provided by (Responsible Party): Nicolas Musi, The University of Texas Health Science Center at San Antonio

Study Description

Brief Summary:

The purpose of this study is to determine the effect of high fat consumption on the intestinal microbiome, metabolic endotoxemia, and insulin action, in lean normal glucose tolerant subjects.

Condition or disease	Intervention/treatment	Phase
Insulin Sensitivity	Drug: Sevelamer; Drug: Synbiotic; Drug: Maltodextrin	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim 1)
• Actual Study Start Date: April 2, 2014
• Estimated Primary Completion Date: April 2019
• Estimated Study Completion Date: December 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: High fat diet; The high fat diet will provide 60% of energy from fat (of which 50% from saturated fat), 15% of energy as CHO and 25% from protein. subjects will be randomized to receive, in a double-blind fashion; placebo, maltodextrin, 6 g three times a day; synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion CFU/g)three times a day]; sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day)	Drug: Sevelamer; 1.6 g sevelamer + 4.4 g maltodextrin three times a day; Other Name: Renvela; Drug: Synbiotic; 5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.; Drug: Maltodextrin; This is a control group. Maltodextrin, 6 g three times a day
Active Comparator: Low fat diet; The low fat diet will provide 55% of energy from CHO, 20% from fat, and 25% from protein. subjects will be randomized to receive, in a double-blind fashion; placebo, maltodextrin, 6 g three times a day; synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion CFU/g)three times a day]; sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day)	Drug: Sevelamer; 1.6 g sevelamer + 4.4 g maltodextrin three times a day; Other Name: Renvela; Drug: Synbiotic; 5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.; Drug: Maltodextrin; This is a control group. Maltodextrin, 6 g three times a day

Outcome Measures

Primary Outcome Measures :

1. Insulin sensitivity [ Time Frame: At day 28th after put the intervention. ]

Secondary Outcome Measures :

1. Plasma endotoxin levels [ Time Frame: At baseline, on day 3, and 28 of the intervention. ]
2. Gut permeability [ Time Frame: on Day 24 of the intervention. ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

United States, Texas

Audie L. Murphy VA Hospital, STVHCS

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

The University of Texas Health Science Center at San Antonio

American Diabetes Association

Investigators

• Principal Investigator: Nicolas Musi, MD.; The University of Texas Health Science Center at San Antonio

More Information

• Responsible Party: Nicolas Musi, Nicolas Musi, MD, The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT02124759
• Other Study ID Numbers: HSC20130459H; IRB #20130458H ( Other Grant/Funding Number: American Diabetes Association )
• First Posted: April 28, 2014
• Last Update Posted: February 7, 2019
• Last Verified: February 2019

Additional relevant MeSH terms:

Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Sevelamer; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action