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Human Beta-2 Adrenergic Stimulation and Muscle Glucose Uptake

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ClinicalTrials.gov Identifier: NCT03800290
Recruitment Status : Not yet recruiting
First Posted : January 11, 2019
Last Update Posted : January 11, 2019
Sponsor:
Information provided by (Responsible Party):
Maastricht University

Brief Summary:
Type 2 diabetes mellitus (T2DM) and its associated cardiovascular comorbidities have developed into a leading cause of death in western countries. Medical and non-medical treatments have failed to counter this 'diabesity' epidemic, fostering the need for novel therapies. In this context, we have recently demonstrated robust improvements in insulin sensitivity in T2DM patients upon 10 days of mild cold acclimatisation, which proved to be primarily mediated through an increased skeletal muscle glucose uptake and occurred independent of improvements in classical regulatory pathways (i.e. insulin signalling or AMPK activation). Given this background, it was recently shown that skeletal muscle glucose uptake can also be mediated through an alternative novel pathway involving β2-adrenergic receptors, through activation of mTORC2. Thus, animal studies showed robust improvements in glucose homeostasis in diabetic rodents upon prolonged treatment with a low-dose of the selective β2-agonist clenbuterol. This project aims to investigate the human relevance of this novel β2-mTORC2 pathway and intents to investigate if prolonged supplementation with the selective β2-adrenergic agonist clenbuterol improves glucose disposal in healthy, lean male individuals. As such, this study serves as a proof-of-principle to identify if this novel pathway could potentially be used as a novel treatment target to improve glucose homeostasis T2DM patients.

Condition or disease Intervention/treatment Phase
Healthy Drug: Clenbuterol Hydrochloride Drug: Placebos Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomized, double-blinded, placebo-controlled, cross-over, single-center study
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Targeting the Beta-2-adrenergic Pathway to Improve Skeletal Muscle Glucose Uptake in Healthy Humans
Estimated Study Start Date : February 1, 2019
Estimated Primary Completion Date : October 31, 2019
Estimated Study Completion Date : May 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Clenbuterol hydrochloride

Subjects will ingest clenbuterol hydrochloride capsules (20 microgram/each) twice daily (40 microgram/day) for a maximum of 14 days.

Subjects that received the clenbuterol hydrochloride capsules (at random) in the first study period will receive the placebo capsules during the second study period.

Drug: Clenbuterol Hydrochloride
Daily ingestion of clenbuterol hydrochloride capsules (40 microgram/day) for a total period of 14 days with a wash-out period of 4 weeks.

Placebo Comparator: Placebos

Subjects will ingest placebo capsules matching the clenbuterol hydrochloride capsules one time per day for a maximum of 14 days.

Subjects that received the placebo capsules (at random) in the first study period will receive the clenbuterol hydrochloride capsules during the second study period.

Drug: Placebos
Daily ingestion of placebo capsules for a total period of 14 days with a wash-out period of 4 weeks.




Primary Outcome Measures :
  1. Insulin-stimulated peripheral glucose disposal (Rd) [ Time Frame: 2 weeks ]
    Comparison between prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on insulin-stimulated peripheral glucose disposal (Rd) during the high-insulin infusion step during the two-step hyperinsulinemic-euglycemic clamp.


Secondary Outcome Measures :
  1. Skeletal muscle GLUT4 translocation [ Time Frame: acute (4 hours) and long-term (2 weeks) ]
    Comparison between acute (4h) and prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on skeletal muscle GLUT4 translocation as assessed by means of wide-field microscopy in skeletal muscle biopsies

  2. Body weight/composition [ Time Frame: 2 weeks ]
    Comparison between prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on body weight and composition as assessed by means of a Bodpod measurement.

  3. Plasma substrates [ Time Frame: Acute (4 hours) and long-term (1 and 2 weeks) ]
    Comparison between acute (4h) and prolonged (1 and 2 weeks) clenbuterol hydrochloride or placebo supplementation on plasma substrate concentrations, including insulin, glucose, free fatty acids and TAGs.

  4. Heart rate [ Time Frame: Acute (4 hours) and long-term (1 and 2 weeks) ]
    Comparison between acute (4h) and prolonged (1 and 2 weeks) clenbuterol hydrochloride or placebo supplementation on heart rate as measured by means of an automated cuff.

  5. Blood pressure [ Time Frame: Acute (4 hours) and long-term (1 and 2 weeks) ]
    Comparison between acute (4h) and prolonged (1 and 2 weeks) clenbuterol hydrochloride or placebo supplementation on blood pressure (systolic and diastolic) as measured by means of an automated cuff.

  6. Insulin-mediated suppression of hepatic glucose production [ Time Frame: 2 weeks ]
    Comparison between prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on hepatic glucose production as assessed during the two-step hyperinsulinemic-euglycemic clamp.

  7. Energy expenditure and substrate oxidation [ Time Frame: Acute (4 hours) and long-term (2 weeks) ]
    Comparison between acute (4h) and prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on energy expenditure and substrate oxidation as assessed by means of indirect calorimetry.

  8. Sleeping energy expenditure and substrate oxidation [ Time Frame: 2-weeks ]
    Comparison between prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on sleeping energy expenditure and substrate oxidation as assessed by means of a metabolic chamber (indirect calorimetry).

  9. Skeletal muscle glycogen [ Time Frame: 2 weeks ]
    Comparison between prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on skeletal muscle glycogen as assessed in muscle biopsies.

  10. Skeletal muscle lipid content [ Time Frame: 2 weeks ]
    Comparison between prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on skeletal muscle lipid content as assessed in muscle biopsies.

  11. Skeletal muscle gene expression [ Time Frame: Acute (4 hours) and long-term (1 and 2 weeks) ]
    Comparison between acute (4h) and prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on skeletal muscle gene expression of specific pathways as determined in muscle biopsies by means of RT-qPCR

  12. Skeletal muscle protein expression [ Time Frame: Acute (4 hours) and long-term (1 and 2 weeks) ]
    Comparison between acute (4h) and prolonged (2 weeks) clenbuterol hydrochloride or placebo supplementation on skeletal muscle protein expression of specific pathways as determined in muscle biopsies as determined by means of Western Blotting



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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Caucasian;
  2. Male sex;
  3. Age: 18-30
  4. BMI: 18-25 kg/m2;
  5. Normal physical activity levels;

Exclusion Criteria:

  1. Not meeting all inclusion criteria
  2. Cardiovascular diseases (determined by means of questionnaires, heart rate/blood pressure measurements)
  3. Respiratory diseases (including asthma, bronchitis and COPD);
  4. Unstable body weight (weight gain or loss > 5 kg in the last three months);
  5. Intention to lose or gain body weight (e.g. with caloric restriction or physical activity)
  6. Excessive alcohol and/or drug abuse;
  7. Hypokalaemia;
  8. Hb < 8.4 mmol/L;
  9. Epilepsy;
  10. Smoking;
  11. Renal and/or liver insufficiency;
  12. Participation in another biomedical study within 1 month before the first study visit, possibly interfering with the study results;
  13. Medication use known to hamper subject's safety during the study procedures;
  14. Subjects who do not want to be informed about unexpected medical findings;
  15. Subjects who do not want that their treating physician to be informed;
  16. Inability to participate and/or complete the required measurements;
  17. Participation in organised or structured physical exercise;
  18. Any condition, disease or abnormal laboratory test result that, in the opinion of the Investigator, would interfere with the study outcome, affect trial participation or put the subject at undue risk;
  19. Hyperthyroidism

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): NCT03800290


Contacts
Contact: Sten van Beek, Msc 0031 043 3884254 sten.vanbeek@maastrichtuniversity.nl
Contact: Joris Hoeks, PhD 0031 043 3881507 J.hoeks@maastrichtuniversity.nl

Locations
Netherlands
Maastricht University Not yet recruiting
Maastricht, Limburg, Netherlands, 6229ER
Sponsors and Collaborators
Maastricht University
Investigators
Principal Investigator: Joris Hoeks, PhD Principle Investigator

Responsible Party: Maastricht University
ClinicalTrials.gov Identifier: NCT03800290     History of Changes
Other Study ID Numbers: NL67646.068.18
First Posted: January 11, 2019    Key Record Dates
Last Update Posted: January 11, 2019
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Maastricht University:
Beta-2 adrenergic agonist
Glucose homeostasis
Skeletal muscle
Human

Additional relevant MeSH terms:
Adrenergic Agents
Clenbuterol
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic beta-Agonists
Adrenergic Agonists
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Sympathomimetics