Metabolic Syndrome
Conditions
Brief summary
Our research proposal will determine if PDE-5 inhibition exerts a favorable effect on insulin signaling pathways in skeletal muscle of subjects with impaired fasting glucose and/or impaired glucose tolerance.
Detailed description
Participants enrolled in the study titled Renin-angiotensin and fibrinolysis interaction in humans: effect of long-term PDE5 inhibition on glucose Homeostasis, (Specific aim 2) will be offered the opportunity to participate in this sub-study. We will obtain skeletal muscle biopsies from 16 subjects who are enrolled in specific aim 2. Eight subjects will be in the sildenafil group and 8 subjects will be in the placebo group.
Interventions
DRUGSildenafil citrate
Sildenafil citrate 25 mg, 1 capsule three times a day for 3 months
DRUGPlacebo Oral Capsule
placebo capsules, 1 capsule po three times a day for 3 months
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Age \> 18 years and BMI \> 25 kg/M2 (\> 23 kg/M2 among Asian Americans) and ≤40kg/m2 Impaired fasting glucose (100-125mg/dL) and/or impaired glucose tolerance (2-hr plasma glucose 140-199 mg/dL) and/or hemoglobin A1c 5.7-6.4%
Exclusion criteria
* Diabetes type 1 or type 2, as defined by a fasting glucose of 126 mg/dL or greater, a two-hour plasma glucose of 200 mg/dL or greater, or the use of anti-diabetic medication. * The use of nitrates or any disease that might require the use of nitrates. * The use of any potent CYP3A4 inhibitor. * Subjects who have participated in a weight-reduction program during the last 6 month or whose weight has increased or decreased more than 2 kg over the preceding 6 months. * Pregnancy. Women of child-bearing potential will be required to have undergone tubal ligation or to be using barrier or hormonal methods of birth control. * Breast-feeding. * Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure, deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy. * Treatment with anticoagulants. * Treatment with metformin. * History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack. * History or presence of immunological or hematological disorders. * Diagnosis of asthma on current inhaled corticosteroid therapy. * Clinically significant gastrointestinal impairment that could interfere with drug absorption. * Impaired hepatic function (aspartate amino transaminase and/or alanine amino transaminase \>1.5 x upper limit of normal range) * Impaired renal function (serum creatinine \>1.5 mg/dl). * Hematocrit \<35%. * Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult. * Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month). * Treatment with lithium salts. * History of alcohol or drug abuse. * Treatment with any investigational drug in the 1 month preceding the study. * Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study. * Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin-stimulated AKT Phosphorylation | 3 months | measured using Western blot for pAkt and for total Akt from muscle biopsies obtained at the end of the baseline hyperinsulinemic clamp and the three-month hyperglycemic clamp. The ratio of pAkt to Akt expression was calculated at each time point and the change in ratio from 0 to 3 months is presented. |
Countries
United States
Participant flow
Recruitment details
Subjects consented to give muscle biopsy
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Subjects consented for the biopsy substudy and randomized | 8 |
| Placebo Subjects consented for the biopsy substudy and randomized | 7 |
| Total | 15 |
Baseline characteristics
| Characteristic | Placebo | Total | Sildenafil |
|---|---|---|---|
| Age, Continuous | 47.3 years STANDARD_DEVIATION 12.4 | 47.4 years STANDARD_DEVIATION 12.1 | 47.5 years STANDARD_DEVIATION 12.8 |
| Body mass index | 34.5 mg/kg2 STANDARD_DEVIATION 5 | 32.9 mg/kg2 STANDARD_DEVIATION 4.7 | 31.5 mg/kg2 STANDARD_DEVIATION 4.1 |
| Fasting glucose | 91.4 mg/dL STANDARD_DEVIATION 13.4 | 94.5 mg/dL STANDARD_DEVIATION 11.7 | 97.2 mg/dL STANDARD_DEVIATION 10.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 12 Participants | 7 Participants |
| Region of Enrollment United States | 7 participants | 15 participants | 8 participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 3 Participants |
| Two-hour glucose | 134.3 mg/dL STANDARD_DEVIATION 37.9 | 128.0 mg/dL STANDARD_DEVIATION 41 | 122.6 mg/dL STANDARD_DEVIATION 45.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 8 | 3 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 7 |
Outcome results
Primary
Insulin-stimulated AKT Phosphorylation
measured using Western blot for pAkt and for total Akt from muscle biopsies obtained at the end of the baseline hyperinsulinemic clamp and the three-month hyperglycemic clamp. The ratio of pAkt to Akt expression was calculated at each time point and the change in ratio from 0 to 3 months is presented.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Insulin-stimulated AKT Phosphorylation | 0.065 change in ratio | Standard Deviation 0.16 |
| Placebo | Insulin-stimulated AKT Phosphorylation | -0.457 change in ratio | Standard Deviation 0.71 |