Insulin Sensitivity
Conditions
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.
Interventions
DRUGSevelamer
1.6 g sevelamer + 4.4 g maltodextrin three times a day
DRUGSynbiotic
5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming units (CFU)/g) three times a day.
DRUGMaltodextrin
This is a control group. Maltodextrin, 6 g three times a day
OTHERHigh 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.
OTHERLow Fat diet
The isocaloric low fat diet will provide 55% energy from carbohydrates, 20% from fat and 25% from protein.
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. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo placebo, maltodextrin, 6 g three times a day | 1 |
| Sevelamer Sevelamer: 1.6 g sevelamer + 4.4 g maltodextrin three times a day | 4 |
| Synbiotic \*synbiotic \[5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion CFU/g)three times a day\] | 3 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Screen Fail | 2 | 2 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Synbiotic | Sevelamer |
|---|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 0 | 50.6 years STANDARD_DEVIATION 18.1 | 59 years STANDARD_DEVIATION 3.8 | 40.5 years STANDARD_DEVIATION 22 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 4 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 4 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 1 Participants | 5 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 1 participants | 8 participants | 3 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 3 / 6 | 3 / 7 | 4 / 7 |
| serious Total, serious adverse events | 0 / 6 | 0 / 7 | 0 / 7 |
Outcome results
Primary
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.
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Insulin Sensitivity High Fat Diet | 6.8 M Value (mg/kg/min) | Standard Deviation 0 |
| Sevelamer | Insulin Sensitivity High Fat Diet | 8.5 M Value (mg/kg/min) | Standard Deviation 1.87 |
| Synbiotic | Insulin Sensitivity High Fat Diet | 8.8 M Value (mg/kg/min) | Standard Deviation 1.63 |
Comparison: 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.p-value: >0.05t-test, 2 sided
Primary
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.
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Insulin Sensitivity Low Fat Diet | 6.5 M value (mg/kg/min | Standard Deviation 0 |
| Sevelamer | Insulin Sensitivity Low Fat Diet | 8.2 M value (mg/kg/min | Standard Deviation 2.4 |
| Synbiotic | Insulin Sensitivity Low Fat Diet | 9.8 M value (mg/kg/min | Standard Deviation 0.6 |
Secondary
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.
Time frame: on Day 24 of the intervention.
Population: 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)
Secondary
Plasma Endotoxin Levels
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.
Population: 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)