Impaired Glucose Tolerance, Insulin Resistance, Obesity, Pre-diabetes
Conditions
Keywords
Obesity, Insulin resistance, Impaired glucose tolerance, pre-diabetes
Brief summary
A study of 12 weeks' treatment with losartan or placebo, to test the hypothesis that RAS inhibition will improve insulin' vascular actions and therefore improve insulin sensitivity in skeletal muscle.
Detailed description
Recent studies suggesting an effect of cardiovascular therapies to prevent diabetes remain unexplained. We hypothesize that these therapies improve vascular endothelial function allowing improved actions of insulin in the vasculature, which comprise a significant portion of insulin's metabolic action. We therefore propose to measure insulin-mediated glucose disposal and insulin-mediated vasodilation before and after 12 weeks' therapy with Losartan (an angiotensin receptor blocker) or placebo, in a randomized design. Subjects will include 28 subjects with impaired glucose tolerance, which is generally accompanied by both insulin resistance and impaired vascular function. With this number of participants we have a 90% chance of showing a statistically significant and clinically meaningful effect of insulin on leg vascular resistance, and an even higher chance of showing a difference in insulin's metabolic effects. Exclusion criteria will include frank hypertension, diabetes, or hypercholesterolemia, and biochemical or other contraindications to losartan therapy. The primary endpoint for statistical analysis will be the invasive measure of insulin-stimulated endothelial function. We anticipate an improvement in both vascular and metabolic measures of insulin action following Losartan therapy but no change from untreated baseline following placebo.
Interventions
DRUGLosartan
Tablet, 100mg, once per day for 3 months
Sponsors
Indiana University School of Medicine
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy * Age 20-55 * Male and female * Obese, defined as Males: BMI \>28 or \> 30% fat by DEXA scan or Bod Pod; Females: BMI \>30 or \> 33% fat by DEXA scan or Bod Pod * Weight stable over at least 4 months
Exclusion criteria
* Diabetes mellitus (ADA criteria) * Age \<20 or \> 55 yrs * Blood pressure \>160/90 or \< 90/65 mmHg * Total cholesterol \>240 or LDL cholesterol \>160 mg/dL * Baseline elevations in AST or ALT \> 3X ULN * Baseline elevation in creatinine \>1.6 ng/mL * Unexplained baseline elevation in creatine kinase \> 3X ULN * Concurrent significant chronic medical illness including, but not limited to, human immunodeficiency virus infection, Syphilis, hepatitis B infection, or hepatitis C infection * Pregnancy * Known hypersensitivity or intolerance to the study agents
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Leg Blood Flow Response to Insulin | 3 months |
| Insulin-stimulated Leg Glucose Uptake | 3 months |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited by word of mouth and flyers posted in key locations on campus.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Treatment with 100mg of losartan daily or placebo. Outcomes measured before and after 3 months of treatment. | 9 |
| Placebo Placebo | 8 |
| Total | 17 |
Baseline characteristics
| Characteristic | Placebo | Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 9 Participants | 17 Participants |
| Age Continuous | 36.5 years STANDARD_DEVIATION 10.1 | 41.0 years STANDARD_DEVIATION 8.7 | 38.8 years STANDARD_DEVIATION 9.4 |
| Region of Enrollment United States | 8 participants | 9 participants | 17 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 8 |
| serious Total, serious adverse events | 0 / 9 | 0 / 8 |
Outcome results
Primary
Insulin-stimulated Leg Glucose Uptake
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Insulin-stimulated Leg Glucose Uptake | 0.42 mmol/min | Standard Deviation 0.08 |
| Placebo | Insulin-stimulated Leg Glucose Uptake | 0.30 mmol/min | Standard Deviation 0.09 |
Primary
Leg Blood Flow Response to Insulin
Time frame: 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Leg Blood Flow Response to Insulin | Baseline Leg Blood Flow | 0.24 Liters/minute | Standard Deviation 0.05 |
| Treatment | Leg Blood Flow Response to Insulin | Insulin stimulated leg blood flow | 0.353 Liters/minute | Standard Deviation 0.327 |
| Placebo | Leg Blood Flow Response to Insulin | Baseline Leg Blood Flow | 0.26 Liters/minute | Standard Deviation 0.05 |
| Placebo | Leg Blood Flow Response to Insulin | Insulin stimulated leg blood flow | 0.046 Liters/minute | Standard Deviation 0.049 |