Insulin Sensitivity
Conditions
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.
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.
Interventions
DRUGMaltodextrin
Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks.
DRUGSynbiotic
Synbiotic \[5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks.
DRUGSevelamer
Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks
Sponsors
American Diabetes Association
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | 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
| Measure | Time frame | Description |
|---|---|---|
| Plasma Endotoxin Level and Its Panel. | Change from baseline plasma endotoxin level and its panel during 28 days. | Plasma Lipopolysaccharide (LPS) after intervention period |
| Gut Permeability | Change from baseline gut permeability at 24 days of the intervention. | urine lactulose: mannitol ratio. |
Countries
United States
Participant flow
Pre-assignment details
69 participants were screened, 8 were screen failures, so not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Lean With NGT-Placebo Lean (BMI\< 26 kg/m2) normal glucose tolerant Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks. | 6 |
| Lean With NGT-Sevelamer Lean (BMI\< 26 kg/m2) normal glucose tolerant Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks | 8 |
| Lean With NGT-Synbiotic Lean (BMI\< 26 kg/m2) normal glucose tolerant Synbiotic \[5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks. | 8 |
| Obese With NGT-Placebo Obese (BMI = 30-37 kg/m2) normal glucose tolerant. Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks. | 10 |
| Obese With NGT-Sevelamer Obese (BMI = 30-37 kg/m2) normal glucose tolerant. Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks | 9 |
| Obese With NGT-Synbiotic Obese (BMI = 30-37 kg/m2) normal glucose tolerant. Synbiotic \[5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks. | 9 |
| Type 2 Diabetes-Placebo Type 2 Diabetics Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks. | 2 |
| Type 2 Diabetes-Sevelamer Type 2 Diabetics Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks | 0 |
| Type 2 Diabetes-Synbiotic Type 2 Diabetics Synbiotic \[5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks. | 1 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Lean With NGT-Placebo | Lean With NGT-Sevelamer | Lean With NGT-Synbiotic | Obese With NGT-Placebo | Obese With NGT-Sevelamer | Obese With NGT-Synbiotic | Type 2 Diabetes-Placebo | Type 2 Diabetes-Sevelamer | Type 2 Diabetes-Synbiotic | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 7 Participants | 8 Participants | 10 Participants | 8 Participants | 9 Participants | 2 Participants | 0 Participants | 1 Participants | 51 Participants |
| Age, Continuous | 38.8 years STANDARD_DEVIATION 14.3 | 46.9 years STANDARD_DEVIATION 15.7 | 48.8 years STANDARD_DEVIATION 12.7 | 51.6 years STANDARD_DEVIATION 9.5 | 51.7 years STANDARD_DEVIATION 12.4 | 50.3 years STANDARD_DEVIATION 8.4 | 61.0 years STANDARD_DEVIATION 1.4 | — | 52.0 years STANDARD_DEVIATION 0 | 49.2 years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 4 Participants | 6 Participants | 6 Participants | 6 Participants | 0 Participants | 0 Participants | 1 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 6 participants | 8 participants | 8 participants | 10 participants | 9 participants | 9 participants | 2 participants | — | 1 participants | 53 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 6 Participants | 8 Participants | 6 Participants | 6 Participants | 1 Participants | 0 Participants | 1 Participants | 37 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 9 | 0 / 9 | 0 / 2 | 0 / 0 | 0 / 1 |
| other Total, other adverse events | 4 / 6 | 3 / 8 | 4 / 8 | 6 / 10 | 3 / 9 | 4 / 9 | 1 / 2 | 0 / 0 | 0 / 1 |
| serious Total, serious adverse events | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 9 | 0 / 9 | 0 / 2 | 0 / 0 | 0 / 1 |
Outcome results
Primary
Insulin Sensitivity
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.
Time frame: Change from baseline insulin sensitivity at 28 days of the intervention.
Population: Enrollment and completion for Type 2 diabetes mellitus group was low due to exclusionary criteria that prevented most diabetes medications from being used while in the study. Lean with NGT and Obese with NGT groups completed 6 control, 8 sevelamer, 8 synbiotic subjects for Lean group and 10 control, 9 sevelamer and 9 synbiotic for Obese group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lean With NGT-Placebo | Insulin Sensitivity | 10.16 M Value (mg/kg/min) | Standard Deviation 3.78 |
| Lean With NGT-Sevelamer | Insulin Sensitivity | 8.45 M Value (mg/kg/min) | Standard Deviation 2.25 |
| Lean With NGT-Synbiotic | Insulin Sensitivity | 9.47 M Value (mg/kg/min) | Standard Deviation 2.59 |
| Obese With NGT-Placebo | Insulin Sensitivity | 5.96 M Value (mg/kg/min) | Standard Deviation 2.24 |
| Obese With NGT-Sevelamer | Insulin Sensitivity | 8.14 M Value (mg/kg/min) | Standard Deviation 2.138 |
| Obese With NGT-Synbiotic | Insulin Sensitivity | 5.45 M Value (mg/kg/min) | Standard Deviation 1.88 |
| Type 2 Diabetes-Placebo | Insulin Sensitivity | 3.81 M Value (mg/kg/min) | Standard Deviation 0.386 |
| Type 2 Diabetes-Synbiotic | Insulin Sensitivity | 1.42 M Value (mg/kg/min) | — |
Comparison: Null hypothesis is that Sevelamer treated Obese subjects with normal glucose tolerance will show no post-treatment change in insulin sensitivity compared to placebo treated subjects.p-value: <0.025Generalized Estimating Equation
Comparison: Null hypothesis is that Synbiotic treated Obese subjects with normal glucose tolerance will show no post-treatment change in insulin sensitivity compared to placebo treated subjects.p-value: >0.05Generalized Estimating Equation
Secondary
Gut Permeability
urine lactulose: mannitol ratio.
Time frame: Change from baseline gut permeability at 24 days of the intervention.
Population: One obese sevelamer subject was not able to complete their baseline Lactulose: Mannitol ratio assay, thus cannot evaluate pre-post effect from their study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lean With NGT-Placebo | Gut Permeability | 0.02262 ratio | Standard Deviation 0.006856 |
| Lean With NGT-Sevelamer | Gut Permeability | 0.02164 ratio | Standard Deviation 0.008943 |
| Lean With NGT-Synbiotic | Gut Permeability | 0.02349 ratio | Standard Deviation 0.00868 |
| Obese With NGT-Placebo | Gut Permeability | 0.02055 ratio | Standard Deviation 0.01018 |
| Obese With NGT-Sevelamer | Gut Permeability | 0.01635 ratio | Standard Deviation 0.006882 |
| Obese With NGT-Synbiotic | Gut Permeability | 0.01952 ratio | Standard Deviation 0.004869 |
| Type 2 Diabetes-Placebo | Gut Permeability | 0.02662 ratio | Standard Deviation 0.004186 |
| Type 2 Diabetes-Synbiotic | Gut Permeability | 0.01979 ratio | — |
Comparison: Null hypothesis is that Sevelamer treated Obese subjects with normal glucose tolerance will show no post-treatment change in Lactulose:Mannitol ratio compared to placebo treated subjects.p-value: >0.05Generalized Estimating Equation
Comparison: Null hypothesis is that Synbiotic treated Obese subjects with normal glucose tolerance will show no post-treatment change in Lactulose:Mannitol ratio compared to placebo treated subjects.p-value: >0.05Generalized Estimating Equation
Secondary
Plasma Endotoxin Level and Its Panel.
Plasma Lipopolysaccharide (LPS) after intervention period
Time frame: Change from baseline plasma endotoxin level and its panel during 28 days.
Population: Poor recruitment for type 2 diabetic group means few subjects analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lean With NGT-Placebo | Plasma Endotoxin Level and Its Panel. | 0.4452 Endotoxin units/mL | Standard Deviation 0.1987 |
| Lean With NGT-Sevelamer | Plasma Endotoxin Level and Its Panel. | 0.5634 Endotoxin units/mL | Standard Deviation 0.1713 |
| Lean With NGT-Synbiotic | Plasma Endotoxin Level and Its Panel. | 0.6925 Endotoxin units/mL | Standard Deviation 0.5907 |
| Obese With NGT-Placebo | Plasma Endotoxin Level and Its Panel. | 0.6230 Endotoxin units/mL | Standard Deviation 0.1976 |
| Obese With NGT-Sevelamer | Plasma Endotoxin Level and Its Panel. | 0.8012 Endotoxin units/mL | Standard Deviation 0.4187 |
| Obese With NGT-Synbiotic | Plasma Endotoxin Level and Its Panel. | 0.7195 Endotoxin units/mL | Standard Deviation 0.2905 |
| Type 2 Diabetes-Placebo | Plasma Endotoxin Level and Its Panel. | 0.2961 Endotoxin units/mL | — |
| Type 2 Diabetes-Synbiotic | Plasma Endotoxin Level and Its Panel. | 0.4062 Endotoxin units/mL | — |
Comparison: Null hypothesis is that Sevelamer treated Obese subjects with normal glucose tolerance will show no post-treatment change in insulin sensitivity compared to placebo treated subjects.p-value: >0.05Generalized Estimating Equation
Comparison: Null hypothesis is that Synbiotic treated Obese subjects with normal glucose tolerance will show no post-treatment change in insulin sensitivity compared to placebo treated subjects.p-value: >0.05Generalized Estimating Equation