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

• Sponsor: The University of Texas Health Science Center at San Antonio (Other)
• Overall Status: Completed
• CT.gov ID: NCT02124759
• Collaborator: American Diabetes Association (Other)
• Enrollment: 20
• Location: 1
• Arms: 3
• Actual Duration (Months): 71.9
• Patients Per Site Per Month: 0.3

Study Details

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
• 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: Apr 2, 2014
• Actual Primary Completion Date: Feb 23, 2018
• Actual Study Completion Date: Mar 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Isocaloric low fat (normal) diet

Outcome Measures

Primary Outcome Measures

1. Insulin Sensitivity Low Fat Diet [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol and Statistical Analysis Plan - Aug 16, 2013

More Information

Publications

None provided.

• Responsible Party: The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT02124759
• Other Study ID Numbers: HSC20130459H; IRB #20130458H
• First Posted: Apr 28, 2014
• Last Update Posted: Oct 15, 2021
• Last Verified: Sep 1, 2021

• Additional relevant MeSH terms: Insulin Resistance; Sevelamer

Study Results

Participant Flow

Pre-assignment Detail	Subjects were initially screened by BMI and glucose tolerance via OGTT. Qualified Study participants were then assigned to begin a low or high isocaloric diet and then randomized to one of the 3 arms for 4 weeks. After a 10-12 week washout, subjects are changed over to the other diet and remain in the same arm of the study that they were in previously.

Arm/Group Title	Placebo	Sevelamer	Synbiotic
Arm/Group Description	placebo, maltodextrin, 6 g three times a day during diet This is a control group.	Sevelamer: 1.6 g sevelamer + 4.4 g maltodextrin three times a day during diet	5g Oligofructose + 4x1010 Bifidobacterium longum CFU 3x daily during diet
Period Title: Overall Study
STARTED	6	7	7
Subjects Randomized to Intervention	4	5	4
Low Fat Diet	4	4	4
High Fat Diet	2	5	4
COMPLETED	1	4	3
NOT COMPLETED	5	3	4

Baseline Characteristics

Arm/Group Title	Placebo	Sevelamer	Synbiotic	Total
Arm/Group Description	placebo, maltodextrin, 6 g three times a day	Sevelamer: 1.6 g sevelamer + 4.4 g maltodextrin three times a day	*synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion CFU/g)three times a day]	Total of all reporting groups
Overall Participants	1	4	3	8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (0)	40.5 (22.0)	59 (3.8)	50.6 (18.1)
Sex: Female, Male (Count of Participants)
Female	1 100%	3 75%	3 100%	7 87.5%
Male	0 0%	1 25%	0 0%	1 12.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	3 75%	1 33.3%	4 50%
Not Hispanic or Latino	1 100%	1 25%	2 66.7%	4 50%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	1 100%	2 50%	2 66.7%	5 62.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 50%	1 33.3%	3 37.5%
Region of Enrollment (participants) [Number]
United States	1 100%	4 100%	3 100%	8 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sevelamer	Synbiotic
Arm/Group Description	placebo, maltodextrin, 6 g three times a day	Sevelamer: 1.6 g sevelamer + 4.4 g maltodextrin three times a day	*synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion CFU/g)three times a day]
Measure Participants	1	4	3
Mean (Standard Deviation) [M value (mg/kg/min]	6.5 (0)	8.2 (2.4)	9.8 (0.6)

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sevelamer	Synbiotic
Arm/Group Description	Maltodextrin: This is a control group. Maltodextrin, 6 g three times a day	Sevelamer: 1.6 g sevelamer + 4.4 g maltodextrin three times a day	Synbiotic: 5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.
Measure Participants	1	4	3
Mean (Standard Deviation) [M Value (mg/kg/min)]	6.8 (0)	8.5 (1.87)	8.8 (1.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sevelamer, Synbiotic
	Comments	Null hypothesis is that high fat diet will have no effect on M value, the measure of insulin sensitivity for each intervention as assessed by clamp.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 2 sided
	Comments	Paired T-test

3. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Plasma Endotoxin levels not analyzed after study completed enrollment due to low subject enrollment and limited ability to compare between subjects (max n=3 per group)

Arm/Group Title	Placebo	Sevelamer	Synbiotic
Arm/Group Description	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 Maltodextrin: This is a control group. Maltodextrin, 6 g three times a day	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 Sevelamer: 1.6 g sevelamer + 4.4 g maltodextrin three times a day	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 Synbiotic: 5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.
Measure Participants	0	0	0

4. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Gut permeability not analyzed after study completed enrollment due to low subject enrollment and limited ability to compare between subjects (max n=3 per group)

Arm/Group Title	Placebo	Sevelamer	Synbiotic
Arm/Group Description	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 Maltodextrin: This is a control group. Maltodextrin, 6 g three times a day	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 Sevelamer: 1.6 g sevelamer + 4.4 g maltodextrin three times a day	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 Synbiotic: 5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.
Measure Participants	0	0	0

Adverse Events

Time Frame	Adverse Event Data was collected over the course of the study intervention period, beginning with subject's enrollment into study and ending once they completed all visits. This period takes approximately 6 months from screening to completion of all visits.
Adverse Event Reporting Description	Adverse events were collected per arm of the study, for placebo, sevelamer and synbiotic, rather than by arm and low or high fat diet. Each arm reports adverse events to include the participant assignment to either low or high fat diets.
Arm/Group Title	Placebo		Sevelamer		Synbiotic
Arm/Group Description	Maltodextrin: This is a control group that were fed both low and high fat diets. Maltodextrin, 6 g three times a day		Sevelamer: 1.6 g sevelamer + 4.4 g maltodextrin three times a day that were fed either a low fat or high fat diet, followed by the other type of diet.		Synbiotic: 5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day that were fed either a low fat or high fat diet, followed by the other type of diet.
All Cause Mortality
	Placebo		Sevelamer		Synbiotic
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/7 (0%)		0/7 (0%)
Serious Adverse Events
	Placebo		Sevelamer		Synbiotic
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Sevelamer		Synbiotic
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		3/7 (42.9%)		4/7 (57.1%)
Ear and labyrinth disorders
Ear Itching	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Gastrointestinal disorders
Nausea	1/6 (16.7%)	1	1/7 (14.3%)	1	0/7 (0%)	0
Diarrhea	1/6 (16.7%)	3	0/7 (0%)	0	0/7 (0%)	0
Mouth Ulcers	1/6 (16.7%)	1	1/7 (14.3%)	1	0/7 (0%)	0
Abdominal Bloating/Flatulence	0/6 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	2
Gum Infection	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
General disorders
Dehydration	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Nervous system disorders
Headache	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Surgical and medical procedures
Hematoma	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Vasovagal Syncope	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Vascular disorders
Hypertension	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1

Limitations/Caveats

Despite continued recruitment efforts, we had difficulty with subjects fully completing the study due to dissatisfaction with the diets. Evaluable subjects completed both low and high fat diet while randomized to one of the three interventions, and only insulin sensitivity was captured for both the low fat and high fat diets due to the low completion numbers.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.