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

NCT ID: NCT02124759

Last Updated: 2021-10-15

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-04-02

Study Completion Date

2020-03-30

Brief Summary

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The purpose of this study is to determine insulin sensitivity in individuals that are lean normal glucose tolerant subjects after consumption of a normal low fat diet and after a high fat diet and to explore the effects of high fat consumption on the intestinal microbiome, and metabolic endotoxemia.( Aim 1 of the protocol, a separate record is available for Aim 2)

Detailed Description

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

All subjects are fed both a low fat diet (considered a normal diet) and high fat diet, first one and then the other in no particular sequence. After a washout period participants are fed the other type of high or low fat diet, depending on which diet they were first assigned to in order to compare the effects of the intervention on insulin sensitivity during each diet.

Conditions

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Insulin Sensitivity

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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Placebo

Placebo: maltodextrin, 6 g three times a day

Group Type PLACEBO_COMPARATOR

Maltodextrin

Intervention Type DRUG

This is a control group. Maltodextrin, 6 g three times a day

High Fat diet

Intervention Type OTHER

The High Fat diet consists of 60% energy from fat (50% saturated), 15% of energy as carbohydrate and 25% from protein consumed while study intervention is being administered.

Low Fat diet

Intervention Type OTHER

The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.

Sevelamer

Sevelamer: (1.6 g sevelamer + 4.4 g maltodextrin three times a day)

Group Type ACTIVE_COMPARATOR

Sevelamer

Intervention Type DRUG

1.6 g sevelamer + 4.4 g maltodextrin three times a day

High Fat diet

Intervention Type OTHER

The High Fat diet consists of 60% energy from fat (50% saturated), 15% of energy as carbohydrate and 25% from protein consumed while study intervention is being administered.

Low Fat diet

Intervention Type OTHER

The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.

Synbiotic

Synbiotic: 5g Oligofructose + 4x1010 Bifidobacterium longum CFU 3x daily during diet

Group Type ACTIVE_COMPARATOR

Synbiotic

Intervention Type DRUG

5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.

High Fat diet

Intervention Type OTHER

The High Fat diet consists of 60% energy from fat (50% saturated), 15% of energy as carbohydrate and 25% from protein consumed while study intervention is being administered.

Low Fat diet

Intervention Type OTHER

The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.

Interventions

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Sevelamer

1.6 g sevelamer + 4.4 g maltodextrin three times a day

Intervention Type DRUG

Synbiotic

5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.

Intervention Type DRUG

Maltodextrin

This is a control group. Maltodextrin, 6 g three times a day

Intervention Type DRUG

High Fat diet

The High Fat diet consists of 60% energy from fat (50% saturated), 15% of energy as carbohydrate and 25% from protein consumed while study intervention is being administered.

Intervention Type OTHER

Low Fat diet

The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.

Intervention Type OTHER

Other Intervention Names

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Renvela Isocaloric high fat diet Isocaloric low fat (normal) diet

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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American Diabetes Association

OTHER

Sponsor Role collaborator

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Nicolas Musi, MD.

Role: PRINCIPAL_INVESTIGATOR

The University of Texas Health Science Center at San Antonio

Locations

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Audie L. Murphy VA Hospital, STVHCS

San Antonio, Texas, United States

Site Status

Countries

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United States

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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IRB #20130458H

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

HSC20130459H

Identifier Type: -

Identifier Source: org_study_id