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Sildenafil Activates Browning of White Adipose and Improves Insulin Sensitivity

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ClinicalTrials.gov Identifier: NCT02524184
Recruitment Status : Unknown
Verified August 2016 by Xiang Guang-da, Wuhan General Hospital of Guangzhou Military Command.
Recruitment status was:  Recruiting
First Posted : August 14, 2015
Last Update Posted : September 2, 2016
Sponsor:
Information provided by (Responsible Party):
Xiang Guang-da, Wuhan General Hospital of Guangzhou Military Command

Study Description
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Brief Summary:
Obesity and metabolic disease result when energy intake consistently exceeds energy expenditure. One appealing new target for treatment is the activation of brown adipose tissue (BAT), an organ recently found to be functional in adult humans. Brown adipocytes selectively express uncoupling protein 1 (UCP1), which renders the inner membrane of mitochondria leaky, thereby diverting chemical energy from ATP generation to heat production. Interest in BAT has been spurred by the recognition that in addition to classical BAT depots, other brown-fat-like cells are present in the subcutaneous white adipose tissue (WAT) in animals and also in humans.These cells have structural and functional properties that resemble brown adipocytes, and they are referred to as beige or 'brite' (brown-in-white) adipocytes. Interestingly, browning of WAT can be induced in animals and humans by physiological stimuli such as cold exposure, which increases adrenergic tone, and by exercise, which selectively drives WAT browning through irisin, an exercise-induced myokine. In addition b-adrenergic drugs and other pharmacological agents,such as prostaglandins, can induce browning of white adipose tissue. More recently, one study showed that treatment of C57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 d caused 4.6-fold increase in uncoupling protein-1 expression and promoted establishment of a brown fat cell-like phenotype ("browning") of WAT in vivo. Therefore, the investigators hypothesized that sildenafil can promote browning of white adipose tissue and improves insulin sensitivity in human adults.

Condition or disease Intervention/treatment Phase
Obesity Drug: sildenafil Drug: placebo Phase 4

Detailed Description:

The study subjects will be taken placebo (first stage) and sildenafil (second stage) intervention for 7 days, respectively afterward.Subcutaneous fat tissue and muscle samples will be obtained by biopsy from some individuals and measure the browning of white adipose tissue and insulin signaling.The insulin sensitivity will be tested by insulin clamp assay before and after each intervention, respectively. In addition,blood samples for biochemical analysis will be obtained before and after each intervention, respectively.

The browning of white adipose tissue will be measured by the expressions of peroxisome proliferator-activated receptor-γ (PPARγ), PPARγcoactivator 1α (PGC-1α), uncoupling protein 1 (UCP-1), the second messenger cyclic guanosine-3', 5'-monophosphate (cGMP),PR domain containing 16 zinc finger transcription factor (Prdm16) and deiodinase, iodothyronine, type II (DIO2).The metabolic makers will be measured by blood pressure, heart rate, thyroid functions, resting metabolic rate, respiratory quotient, blood cGMP, blood insulin and blood glucose.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 11 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Sildenafil Activates Browning of White Adipose and Improves Insulin Sensitivity in Human Adults
Study Start Date : August 2015
Estimated Primary Completion Date : September 2016
Estimated Study Completion Date : September 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy

Arms and Interventions
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Arm Intervention/treatment
Experimental: Sildenafil
Eleven patients receive sildenafil 100mg/day (25 mg at 8 AM plus 25 mg at 4 PM plus 50 mg at 10 PM)for 7 days.
 Drug: sildenafil
sildenafil 100 mg per day for 7 days.
Placebo Comparator: Placebo group
An identical placebo for 7 days in placebo group.
 Drug: placebo
an identical placebo per day for 7 days


Outcome Measures
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Primary Outcome Measures :
  1. Browning of white adipose tissue [ Time Frame: 7 days ]
    The browning of white adipose tissue was measured by Western blot (including the expressions of peroxisome proliferator-activated receptor-γ (PPARγ), PPARγcoactivator 1α (PGC-1α), uncoupling protein 1 (UCP-1), the second messenger cyclic guanosine-3', 5'-monophosphate (cGMP),PR domain containing 16 zinc finger transcription factor (Prdm16) and deiodinase, iodothyronine, type II (DIO2)).


Secondary Outcome Measures :
  1. Improvement of insulin sensitivity [ Time Frame: 7days ]
    The insulin sensitivity will be tested by insulin clamp before and after each intervention,respectively.


Other Outcome Measures:
  1. Change of metabolic status [ Time Frame: 3 months ]
    The metabolic status including blood pressure, heart rate, thyroid functions, resting metabolic rate, respiratory quotient, blood cGMP, blood insulin and blood glucose will be measured before and after intervention in each group.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 30 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • overweight volunteers
  • 20-30 years old
  • body mass index >=25 kg/m2
  • normal glucose tolerance

Exclusion Criteria:

  • normal body mass index
  • abnormal cardiovascular status
  • women
  • history of any local or systemic infectious disease with fever or requiring antibiotic within four weeks of drug administration
  • current addiction to alcohol or substances of abuse
  • children
  • current addiction to alcohol or substances of abuse
  • mental incapacity
  • the use of any medication within four weeks
  • subjects with hyperthyroidism or hypothyroidism, hypertension (even if controlled with medications)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02524184


Contacts
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Contact: Guangda Xiang, MD 086 027 50772191 Guangda64@hotmail.com

Locations
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China, Hubei
Wuhan General Hospital Recruiting
Wuhan, Hubei, China, 430070
Contact: Guangda Xiang, MD    13517275283    Guangda64@hotmail.com   
Contact: Lin Xiang, MD    18627838901    xianglin832010@hotmail.com   
Sponsors and Collaborators
Xiang Guang-da
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Xiang Guang-da, Director of Endocrinol Dept., Wuhan General Hospital of Guangzhou Military Command
ClinicalTrials.gov Identifier: NCT02524184    
Other Study ID Numbers: Wze20150088
First Posted: August 14, 2015    Key Record Dates
Last Update Posted: September 2, 2016
Last Verified: August 2016
Additional relevant MeSH terms:
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Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Sildenafil Citrate
Vasodilator Agents
 Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents