Effect of Prolonged PDE-5 Inhibition on Insulin Signaling in Skeletal Muscle.

Renin- Angiotensin and Fibrinolysis Interaction in Humans: Effect of Long-term PDE-5 Inhibition on Glucose Homeostasis. Sub-study

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.

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome
• Intervention / Treatment: Drug: Sildenafil citrate; Drug: Placebo Oral Capsule

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6602
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sildenafil citrate; In the parent study, subjects are randomized to sildenafil 25 mg tid.	Drug: Sildenafil citrate; Sildenafil citrate 25 mg, 1 capsule three times a day for 3 months; Other Names: Viagra
Placebo Comparator: placebo oral capsule; In the parent study, subjects are randomized to matching placebo	Drug: Placebo Oral Capsule; placebo capsules, 1 capsule po three times a day for 3 months; Other Names: placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 months

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: April 30, 2014
• First Submitted That Met QC Criteria: April 30, 2014
• First Posted (Estimate): May 2, 2014

Study Record Updates

• Last Update Posted (Actual): April 19, 2017
• Last Update Submitted That Met QC Criteria: March 7, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Insulin Resistance; Hyperinsulinism; Metabolic Syndrome; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 110206-substudy

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO