Obese Human Beta-2-adrenergic Stimulation and Muscle Glucose Uptake

Targeting the Beta-2-adrenergic Pathway to Improve Skeletal Muscle Glucose Uptake in Obese Humans

The purpose of this study is to investigate the effect of four weeks clenbuterol/placebo supplementation on skeletal muscle glucose disposal in overweight/obese male and (postmenopausal) female volunteers.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Clenbuterol Hydrochloride; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands
    • Maastricht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Caucasian;
2. Male or (postmenopausal; defined as 1 year after the last cycle) female;
3. Age between 40-70 years;
4. BMI: 27-35 kg/m2;

Exclusion Criteria:

1. Not meeting all inclusion criteria
2. Cardiovascular disease (determined by means of questionnaires, heart rate/blood pressure measurements and an ECG)
3. Respiratory diseases (including asthma, bronchitis and COPD);
4. Unstable body weight (weight gain or loss > 3 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. Hyperthyroidism
9. Anaemia;
10. Epilepsy;
11. Smoking;
12. Renal and/or liver insufficiency;
13. Diagnosed with type 1 or type 2 diabetes mellitus;

14. Any contra-indications to MRI scanning. These contra-indications include patients with:

    1. Electronic implants such as pacemakers, defibrillators or neurostimulators
    2. Central nervous system aneurysm clip
    3. Some hearing aids (such as cochlear implant) and artificial (heart) valves which are contraindicated for MRI/MRS
    4. Iron containing corpora aliena in the eye or brains
    5. Claustrophobia
15. Participation in another biomedical study within 1 month before the first study visit, possibly interfering with the study results;
16. Medication use known to hamper subject's safety during the study procedures;
17. Subjects who do not want to be informed about unexpected medical findings;
18. Subjects who do not want that their treating physician to be informed;
19. Inability to participate and/or complete the required measurements;
20. Participation in organised or structured physical exercise (>2h per week);
21. 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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clenbuterol hydrochloride; Subjects will ingest clenbuterol hydrochloride capsules (20 microgram/each) twice daily (40 microgram/day) for a maximum of 28 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 28 days with a wash-out period of at least 6-8 weeks.
Placebo Comparator: Placebo; Subjects will ingest placebo capsules matching the clenbuterol hydrochloride capsules one time per day for a maximum of 28 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: Placebo; Daily ingestion of placebo capsules for a total period of 28 days with a wash-out period of at least 6-8 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin-stimulated fluorodeoxyglucose (18F-FDG) uptake in quadriceps muscle.	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on insulin-stimulated 18F-FDG uptake in quadriceps muscle as assessed using radio-active labelled tracer (18F-FDG) in positron emission tomogaphy magnetic resonance imaging (PET-MRI).	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin-stimulated 18F-FDG uptake in BAT	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on insulin-stimulated 18F-FDG uptake in BAT as assessed using radio-active labelled tracer (18F-FDG) in PET-MRI.	4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body weight	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on body weight	4 weeks
Lean mass	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on lean mass as assessed by Bodpod measurement	4 weeks
Fat mass	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on fat mass as assessed by Bodpod measurement	4 weeks
Glucose infusion rate (GIR)	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on glucose-infusion rate (GIR) during a one-step hyperinsulinemic-euglycemic clamp	4 weeks
Plasma insulin concentrations	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on plasma insulin concentrations	4 weeks
Plasma glucose concentrations	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on plasma glucose concentrations	4 weeks
Plasma free fatty acid (FFA) concentrations	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on plasma FFA concentrations	4 weeks
Plasma triacylglycerol (TAG) concentrations	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on plasma (TAG) concentrations	4 weeks
Heart rate	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on heart rate as assessed by means of an automated cuff	4 weeks
Blood pressure	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on blood pressure (systolic and diastolic blood pressure) as assessed by means of an automated cuff	4 weeks
Energy expenditure	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on energy expenditure as measured by indirect calorimetry	4 weeks
Substrate oxidation	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on substrate oxidation as measured by indirect calorimetry	4 weeks
Sleeping energy expenditure	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on sleeping energy expenditure as assessed by means of whole-room indirect calorimetry	4 weeks
Substrate oxidation during sleep	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on substrate oxidation during sleep as assessed by means of whole-room indirect calorimetry	4 weeks
Skeletal muscle gene expression	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on skeletal muscle gene expression of insulin signalling and beta-adrenergic pathways as determined in muscle biopsies by means of RT-qPCR	4 weeks
Skeletal muscle protein expression	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on skeletal muscle protein expression of insulin signalling and adrenergic signalling pathways as determined in muscle biopsies by means of Western blot	4 weeks
Femoral artery flow mediated dilation	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on FMD as assessed by means of echo-doppler	4 weeks
skeletal muscle GLUT4 translocation	Comparison between prolonged (4 weeks) clenbuterol hydrochloride or placebo supplementation on skeletal muscle GLUT4 translocation as assessed by means of wide-field microscopy in skeletal muscle biopsies	4 weeks

Collaborators and Investigators

• Sponsor: Maastricht University
• Collaborators: Eurostars

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2022
• Primary Completion (Actual): March 1, 2024
• Study Completion (Actual): March 1, 2024

Study Registration Dates

• First Submitted: May 25, 2021
• First Submitted That Met QC Criteria: June 2, 2021
• First Posted (Actual): June 10, 2021

Study Record Updates

• Last Update Posted (Actual): May 7, 2024
• Last Update Submitted That Met QC Criteria: May 6, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-Agonists; Sympathomimetics; Clenbuterol
• Other Study ID Numbers: NL76746.068.21

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No