Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim2) (MicroB2)

• ClinicalTrials.gov Identifier: NCT02127125
• Recruitment Status: Completed
• First Posted: April 30, 2014
• Results First Posted: September 11, 2020
• Last Update Posted: September 11, 2020
• 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 whether microbiome modulation and an experimental reduction in plasma LPS concentration improve inflammation and insulin action in insulin resistant (obese and T2DM) subjects.

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

Detailed Description:

In this Aim we will test the hypothesis that lowering lipopolysaccharide (LPS) concentration in the circulation will improve systemic (muscle) inflammation and glucose metabolism in insulin resistant (obese and T2DM) subjects by protecting the intestinal barrier with a synbiotic (Bifidobacterium longum R0175 and oligofructose) or by sequestering LPS in the gastrointestinal lumen with sevelamer.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 69 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 (Aim2)
• Actual Study Start Date: April 10, 2014
• Actual Primary Completion Date: September 2018
• Actual Study Completion Date: September 10, 2018

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Type2 Diabetes Mellitus - Placebo; Type 2 Diabetes Mellitus subjects will receive maltodextrin (placebo)	Drug: Maltodextrin; Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks.
Placebo Comparator: Obese with NGT - Placebo; Obese (BMI = 30-37 kg/m2) normal glucose tolerant (NGT) subjects will receive maltodextrin (placebo)	Drug: Maltodextrin; Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks.
Placebo Comparator: Lean with NGT -Placebo; Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive maltodextrin (placebo)	Drug: Maltodextrin; Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks.
Active Comparator: Type2 Diabetes Mellitus - Synbiotic; Type 2 Diabetic subjects will receive synbiotic	Drug: Synbiotic; Synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks.
Active Comparator: Type2 Diabetes Mellitus - Sevelamer; Type 2 Diabetic subjects will receive sevelamer	Drug: Sevelamer; Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks; Other Name: Renvela
Active Comparator: Obese with NGT - Synbiotic; Obese (BMI = 30-37 kg/m2) normal glucose tolerant subjects (NGT) will receive Synbiotic	Drug: Synbiotic; Synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks.
Active Comparator: Obese with NGT - Sevelamer; Obese subjects (BMI = 30-37 kg/m2) normal glucose tolerant (NGT) will receive Sevelamer	Drug: Sevelamer; Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks; Other Name: Renvela
Active Comparator: Lean with NGT - Synbiotic; Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive Synbiotic	Drug: Synbiotic; Synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks.
Active Comparator: Lean with NGT - Sevelamer; Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive Sevelamer	Drug: Sevelamer; Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks; Other Name: Renvela

Outcome Measures

Primary Outcome Measures :

1. Insulin Sensitivity [ Time Frame: Change from baseline insulin sensitivity at 28 days of the intervention. ]
   Insulin sensitivity in skeletal muscle (M value) as measured by hyperinsulinemic euglycemic clamp study. The clamp study tests the ability of peripheral tissues such as skeletal muscle to uptake glucose in response to a constant insulin stimulus, which give a measure of sensitivity to insulin action. 60 mU/m2*min insulin was infused into subjects for 180 minutes with concomitant adjustment of glucose infusion rate using D20 glucose to maintain a clamped plasma glucose concentration of 100 mg/dL. When the glucose infusion rate equals the rate of glucose uptake and the targeted glucose concentration is achieved, the clamp is at steady-state equilibrium. Steady-state glucose infusion rate at 150min-180mins was used as the measure to calculate the M value.

Secondary Outcome Measures :

1. Plasma Endotoxin Level and Its Panel. [ Time Frame: Change from baseline plasma endotoxin level and its panel during 28 days. ]
   Plasma Lipopolysaccharide (LPS) after intervention period
2. Gut Permeability [ Time Frame: Change from baseline gut permeability at 24 days of the intervention. ]
   urine lactulose: mannitol ratio.

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 (50%, male). 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 results of 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:

• 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.
• 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] March 12, 2019

More Information

• Responsible Party: The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT02127125
• Other Study ID Numbers: HSC20130458H
• First Posted: April 30, 2014
• Results First Posted: September 11, 2020
• Last Update Posted: September 11, 2020
• Last Verified: August 2020

Additional relevant MeSH terms:

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