Effect of Obesity-derived Cytokines on Protein Turnover and Carbohydrate Metabolism in Human Skeletal Muscle

NCT02305069 | Completed

• 1 other identifier: RIS33323
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

Obesity in humans has been shown to result in the increased release of small inflammatory-inducing proteins, called cytokines, from the fat cells of the body. The investigators are interested in the effects of these cytokines on the mechanisms that control muscle mass and metabolism in the obese human. Previous research from work in cells and animals has shown the cytokines reduce the synthesis of muscle proteins and simultaneously enhance their rate of breakdown, resulting in a loss of muscle mass. Furthermore, research suggests that the same cytokines may inhibit carbohydrate oxidation, a pivotal step in muscle metabolism. However, despite these potential negative consequences for skeletal muscle function, the effect of low-level and persistent inflammation as seen in obese humans, remains largely unknown. In the current study, the investigators plan to measure the rates of synthesis and breakdown of muscle proteins in conjunction with rates of carbohydrate oxidation in obese older participants, and compare them to rates determined in healthy non-obese individuals. Furthermore, participants will undergo a 12-week course of either pioglitazone, an insulin sensitiser often prescribed to type II diabetics, or a placebo. Pioglitazone has been shown previously to normalise the levels of cytokines in the blood of chronically inflamed individuals. By repeating after the 12-week intervention period the initial measurements described above, and by accurately determining the levels of the cytokines, the identification of the negative effects of obesity-induced inflammation in older adults on muscle metabolism will be determined.

Conditions

Obesity; Sarcopenia

Outcome Measures

Primary Outcomes (1)

• Change in muscle protein synthesis response to simulated feeding with data reported as % fractional synthetic rate per hour.

  Assessed at study visits pre and post 90 day drug intervention period

Secondary Outcomes (3)

• Change in leg protein breakdown response to simulated feeding with data reported as nmol/min/100g leg mass.

  Assessed at study visits pre and post 90 day drug intervention period

• Change in respiratory exchange ratio response to simulated feeding with data reported as the ratio between the volume of CO2 produced and O2 consumed in air breathed.

  Assessed at study visits pre and post 90 day drug intervention period

• Change in plasma concentration of pro-inflammatory cytokines with data reported as picograms per ml of plasma.

  Assessed pre- and post- 90 day drug intervention period

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo tablet taken once daily for 12 weeks. For study visits performed pre- and post 12-week placebo treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, \[2H5\]phenylalanine and \[1-13C\]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.

Drug: Insulin; Drug: Octreotide; Drug: Glucose; Drug: Mixed Amino Acids; Other: [2H5]phenylalanine; Other: [1-13C]leucine

Pioglitazone

EXPERIMENTAL

30mg pioglitazone encapsulated and taken once daily for 12 weeks. For study visits performed pre- and post 12-week pioglitazone treatment for the assessment of muscle protein synthesis and leg protein breakdown, the following substances are administered as part of the analytical technique: insulin, octreotide, glucose, mixed amino acids, \[2H5\]phenylalanine and \[1-13C\]leucine. The doses administered change as the analytical technique is conducted and for clarity are described in detail in the protocol.

Drug: Pioglitazone; Drug: Insulin; Drug: Octreotide; Drug: Glucose; Drug: Mixed Amino Acids; Other: [2H5]phenylalanine; Other: [1-13C]leucine

Interventions

Pioglitazone DRUG

Described elsewhere

Also known as: Actos

Pioglitazone

Insulin DRUG

Administered to simulate the feeding response in study visits. Description of amount administered provided elsewhere.

Also known as: Actrapid

Pioglitazone; Placebo

Octreotide DRUG

Administered to simulate the feeding response in study visits. Description of amount administered provided elsewhere.

Also known as: Sandostatin

Pioglitazone; Placebo

Glucose DRUG

Administered to simulate the feeding response in study visits. Description of amount administered provided elsewhere.

Also known as: Dextrose

Pioglitazone; Placebo

Mixed Amino Acids DRUG

Administered to simulate the feeding response in study visits. Description of amount administered provided elsewhere.

Also known as: Glamin

Pioglitazone; Placebo

[2H5]phenylalanine OTHER

Administered to allow the determination of leg protein breakdown rates in study visits. Description of amount administered provided elsewhere.

Pioglitazone; Placebo

[1-13C]leucine OTHER

Administered to allow the determination of muscle protein synthesis rates in study visits. Description of amount administered provided elsewhere.

Pioglitazone; Placebo

Eligibility Criteria

• Age: 55 Years - 75 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male
• years old
• Body Mass Index 20-25 or \>30 kg/m2
• Residing in Nottinghamshire area

You may not qualify if:

• Taking statin medication
• Clotting disorders of previous central venous access (CVA) / thrombosis-inducing activity (TIA)/ deep vein thrombosis (DVT)
• Metabolic disease e.g. diabetes, thyroid dysfunction
• Inflammatory conditions e.g. Rheumatoid Arthritis, Crohn's Disease
• Tobacco smoker in previous 3 years
• Lower limb circulation problems e.g. Claudication
• Epilepsy
• Renal pathology
• Respiratory problems including asthma

Sponsors & Collaborators

• University of Nottingham: lead
• Biotechnology and Biological Sciences Research Council: collaborator

Study Sites (1)

David Greenfield Physiology Laboratories

Nottingham, Nottinghamshire, NG7 2UH, United Kingdom

Location

MeSH Terms

Conditions

Obesity; Sarcopenia

Interventions

Pioglitazone; Insulin; Octreotide; Glucose

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Muscular Atrophy; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Hexoses; Monosaccharides; Sugars; Carbohydrates

Study Officials

• Paul L Greenhaff, PhD

  The University of Nottingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 10, 2014
• First Posted: December 2, 2014
• Study Start: October 1, 2009
• Primary Completion: October 1, 2011
• Study Completion: September 1, 2012
• Last Updated: December 2, 2014

Record last verified: 2014-11

Locations

GB (1)