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

Primary Purpose

Insulin Sensitivity

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sevelamer
Synbiotic
Maltodextrin
High Fat diet
Low Fat diet
Sponsored by
The University of Texas Health Science Center at San Antonio
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Insulin Sensitivity

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Audie L. Murphy VA Hospital, STVHCS

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Active Comparator

Active Comparator

Arm Label

Placebo

Sevelamer

Synbiotic

Arm Description

Placebo: maltodextrin, 6 g three times a day

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

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

Outcomes

Primary Outcome Measures

Insulin Sensitivity Low Fat Diet
Skeletal muscle insulin sensitivity measured after 28 days of low fat diet and drug intervention. The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.
Insulin Sensitivity High Fat Diet
Skeletal muscle insulin sensitivity measured after 28 days of 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.

Secondary Outcome Measures

Plasma Endotoxin Levels
Endotoxin is a bacterially derived product that we hypothesized would impact insulin sensitivity through pro inflammatory pathways.
Gut Permeability
Gut permeability is measured using a lactulose/mannitol ingestion assay where urine samples are collected to analyse the ratio of excreted lactulose:mannitol.

Full Information

First Posted
April 24, 2014
Last Updated
September 15, 2021
Sponsor
The University of Texas Health Science Center at San Antonio
Collaborators
American Diabetes Association
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1. Study Identification

Unique Protocol Identification Number
NCT02124759
Brief Title
Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim 1)
Acronym
MicroB1
Official Title
Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim 1)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
April 2, 2014 (Actual)
Primary Completion Date
February 23, 2018 (Actual)
Study Completion Date
March 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The University of Texas Health Science Center at San Antonio
Collaborators
American Diabetes Association

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Insulin Sensitivity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo: maltodextrin, 6 g three times a day
Arm Title
Sevelamer
Arm Type
Active Comparator
Arm Description
Sevelamer: (1.6 g sevelamer + 4.4 g maltodextrin three times a day)
Arm Title
Synbiotic
Arm Type
Active Comparator
Arm Description
Synbiotic: 5g Oligofructose + 4x1010 Bifidobacterium longum CFU 3x daily during diet
Intervention Type
Drug
Intervention Name(s)
Sevelamer
Other Intervention Name(s)
Renvela
Intervention Description
1.6 g sevelamer + 4.4 g maltodextrin three times a day
Intervention Type
Drug
Intervention Name(s)
Synbiotic
Intervention Description
5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.
Intervention Type
Drug
Intervention Name(s)
Maltodextrin
Intervention Description
This is a control group. Maltodextrin, 6 g three times a day
Intervention Type
Other
Intervention Name(s)
High Fat diet
Other Intervention Name(s)
Isocaloric high fat diet
Intervention Description
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
Intervention Name(s)
Low Fat diet
Other Intervention Name(s)
Isocaloric low fat (normal) diet
Intervention Description
The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.
Primary Outcome Measure Information:
Title
Insulin Sensitivity Low Fat Diet
Description
Skeletal muscle insulin sensitivity measured after 28 days of low fat diet and drug intervention. The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.
Time Frame
Day 28
Title
Insulin Sensitivity High Fat Diet
Description
Skeletal muscle insulin sensitivity measured after 28 days of 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.
Time Frame
Day 28
Secondary Outcome Measure Information:
Title
Plasma Endotoxin Levels
Description
Endotoxin is a bacterially derived product that we hypothesized would impact insulin sensitivity through pro inflammatory pathways.
Time Frame
At baseline, on day 3, and 28 of the intervention.
Title
Gut Permeability
Description
Gut permeability is measured using a lactulose/mannitol ingestion assay where urine samples are collected to analyse the ratio of excreted lactulose:mannitol.
Time Frame
on Day 24 of the intervention.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicolas Musi, MD.
Organizational Affiliation
The University of Texas Health Science Center at San Antonio
Official's Role
Principal Investigator
Facility Information:
Facility Name
Audie L. Murphy VA Hospital, STVHCS
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States

12. IPD Sharing Statement

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

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