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

• ClinicalTrials.gov Identifier: NCT02124759
• Recruitment Status: Completed
• First Posted: April 28, 2014
• Results First Posted: October 15, 2021
• Last Update Posted: October 15, 2021
• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborator: American Diabetes Association
• Information provided by (Responsible Party): The University of Texas Health Science Center at San Antonio

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)

Condition or disease	Intervention/treatment	Phase
Insulin Sensitivity	Drug: Sevelamer; Drug: Synbiotic; Drug: Maltodextrin; Other: High Fat diet; Other: Low Fat diet	Phase 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel 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
• Actual Primary Completion Date: February 23, 2018
• Actual Study Completion Date: March 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo: maltodextrin, 6 g three times a day	Drug: Maltodextrin; This is a control group. Maltodextrin, 6 g three times a day; Other: 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.; Other Name: Isocaloric high fat diet; Other: Low Fat diet; The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.; Other Name: Isocaloric low fat (normal) diet
Active Comparator: Sevelamer; 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; Other: 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.; Other Name: Isocaloric high fat diet; Other: Low Fat diet; The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.; Other Name: Isocaloric low fat (normal) diet
Active Comparator: Synbiotic; Synbiotic: 5g Oligofructose + 4x1010 Bifidobacterium longum CFU 3x daily during diet	Drug: Synbiotic; 5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.; Other: 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.; Other Name: Isocaloric high fat diet; Other: Low Fat diet; The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.; Other Name: Isocaloric low fat (normal) diet

Outcome Measures

Primary Outcome Measures :

1. Insulin Sensitivity Low Fat Diet [ Time Frame: Day 28 ]
   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.
2. Insulin Sensitivity High Fat Diet [ Time Frame: Day 28 ]
   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 :

1. Plasma Endotoxin Levels [ Time Frame: At baseline, on day 3, and 28 of the intervention. ]
   Endotoxin is a bacterially derived product that we hypothesized would impact insulin sensitivity through pro inflammatory pathways.
2. Gut Permeability [ Time Frame: on Day 24 of the intervention. ]
   Gut permeability is measured using a lactulose/mannitol ingestion assay where urine samples are collected to analyse the ratio of excreted lactulose:mannitol.

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

  Study Documents (Full-Text)

Documents provided by The University of Texas Health Science Center at San Antonio:

Study Protocol and Statistical Analysis Plan  [PDF] August 16, 2013

More Information

• Responsible Party: 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
• Results First Posted: October 15, 2021
• Last Update Posted: October 15, 2021
• Last Verified: September 2021

Additional relevant MeSH terms:

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