Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Characterizing the Incretin Effect of Amino Acids and Defining GLP-1 Role on Skeletal Muscle (Incretin)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02370745
Recruitment Status : Completed
First Posted : February 25, 2015
Last Update Posted : May 2, 2018
Sponsor:
Information provided by (Responsible Party):
University of Nottingham

Brief Summary:

This study has two protocols the aims of which are:

  1. To identify age-related effects of AA on incretin secretion and whether and to what extent AA exhibit a true incretin effect (gut- mediated increases in plasma insulin) in younger individuals. (Protocol 1)
  2. To define the extra-pancreatic ''novel'', insulin independent effects of glucagon like peptide-1 (GLP-1) on postprandial muscle protein and glucose metabolism and microvascular blood flow. (Protocol 2)

Condition or disease Intervention/treatment Phase
Sarcopenia Drug: GLP-1 Drug: Insulin Actrapid Dietary Supplement: Oral amino acids Drug: GIP Drug: Intravenous amino acids Not Applicable

Detailed Description:

Protocol 1:

This will explore the first aim. 8 Healthy younger volunteers will be recruited to under go 3 arms cross over studies. Interventions will include oral and intravenous amino acids, in addition to intravenous GLP-1 and glucose dependent insulinotropic polypeptide (GIP).

8 older subjects also will be recruited for comparison of the response of GI hormones to amino acids oral feed between young and older men.

Therefore the total number will be recruited to perform this protocol is 16.

Post intervention in all visits, measurements will be taken for:

Insulin, Amino acids, GLP-1, GIP, Ghrelin and peptide YY (PYY).

The measurable end points for this protocol are:

  1. Gut hormones levels in response to the 2 methods of AA delivery (I.V and oral)
  2. Differences in gut hormones levels between young and older subjects when AA's are delivered orally

Protocol 2:

This will explore the second aim. 16 healthy older subjects will be recruited and subdivided randomly into two groups to receive either post absorptive or postprandial insulin concentrations with or without GLP-1 at physiological ranges in a cross over fashion . During acute study parameters of muscle glucose and amino acids metabolism will be tested together with muscle microvascular recruitment and macro vascular flow in the tested leg.

The measurable end points for this protocol are:

  1. Muscle Glucose uptake, assessed by measuring 2-deoxyglucose (2-DOG) phosphate in muscle biopsies
  2. Myofibrillar protein synthesis, assessed via muscle biopsy fractional synthesis rate (FSR)
  3. Whole Leg Muscle Protein Synthesis, assessed via Arterial-Venous difference (AV method)
  4. Whole Leg Muscle Protein Breakdown, assessed via AV method
  5. Whole Leg Net Protein Balance, assessed via AV method
  6. Muscle microvascular recruitment, assessed via microvascular contrast bubbles filling and refilling post destruction by ultrasound waves.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Characterizing the Incretin Effect of Amino Acids (AA) and Defining the Effect of GLP-1 on Muscle Microvascular Blood Flow and Muscle Protein and Glucose Metabolism in Older Age.
Actual Study Start Date : November 2014
Actual Primary Completion Date : March 2018
Actual Study Completion Date : March 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Post absorptive insulin without GLP-1

Subjects with receive post absorptive insulin concentrations while measures of muscle metabolism and microvascular blood flow are taken through the acute study hours.

The intervention in this group is Insulin Actrapid to achieve post absorptive insulin levels and glucose infusion to achieve postprandial glucose levels of 7.0-7.5 mmol/L . This will form base line measurement for the next arm which will receive GLP-1 in addition.

Drug: Insulin Actrapid
Skeletal muscle metabolic and microvascular parameters will be tested under specified insulin concentrations with or without GLP-1
Other Name: Actrapid

Experimental: Postabsorptive insulin with GLP-1

Subjects will receive post absorptive insulin concentrations with GLP-1 while measures of muscle metabolism and microvascular blood flow are taken through the acute study hours. This arm will cross over with the previous arm.

The intervention in this group is in the form of GLP-1, Insulin Actrapid to achieve post absorptive insulin levels and glucose infusion to achieve postprandial glucose levels of 7.0-7.5 mmol/L .

Drug: GLP-1
GLP-1 effects on skeletal muscle glucose and amino acid metabolism and microvascular blood flow will be scrutinised under the specified insulin concentrations. It will also be used to test the effect of intravenous feed on insulin secretion.
Other Name: Incretin

Drug: Insulin Actrapid
Skeletal muscle metabolic and microvascular parameters will be tested under specified insulin concentrations with or without GLP-1
Other Name: Actrapid

Experimental: Postprandial insulin without GLP-1

Subjects will receive postprandial insulin concentrations without GLP-1 while measures of muscle metabolism and microvascular blood flow are taken through the acute study hours.

The intervention in this group is Insulin Actrapid to achieve postprandial insulin levels and glucose infusion to achieve postprandial glucose levels of 7.0-7.5 mmol/L . This will form base line measurement for the next arm which will receive GLP-1 in addition

Drug: Insulin Actrapid
Skeletal muscle metabolic and microvascular parameters will be tested under specified insulin concentrations with or without GLP-1
Other Name: Actrapid

Experimental: Postprandial insulin with GLP-1

Subjects with receive postprandial insulin concentrations with GLP-1 while measures of muscle metabolism and microvascular blood flow are taken through the acute study hours. This arm will cross over with the previous arm.

The intervention in this group is in the form of GLP-1, Insulin Actrapid to achieve postprandial insulin levels and glucose infusion to achieve postprandial glucose levels of 7.0-7.5 mmol/L .

Drug: GLP-1
GLP-1 effects on skeletal muscle glucose and amino acid metabolism and microvascular blood flow will be scrutinised under the specified insulin concentrations. It will also be used to test the effect of intravenous feed on insulin secretion.
Other Name: Incretin

Drug: Insulin Actrapid
Skeletal muscle metabolic and microvascular parameters will be tested under specified insulin concentrations with or without GLP-1
Other Name: Actrapid

Experimental: Oral amino acids-Young

Gut hormones will be measured post oral drink containing 15 g of amino acids in young persons. This will cross over with the following 2 arms.

The intervention here is: 15g of mixed essential amino acid drink.

Dietary Supplement: Oral amino acids
Oral amino acids containing 15 g of amino acids
Other Name: mixed EAA

Experimental: Intravenous (IV) amino acids- Young

Gut hormones will be measured after intravenous amino acid infusion delivering iso equivalent amount of amino acids in young persons.

The intervention in this group: Intravenous amino acids delivering iso-equivalent amount of 15g mixed essential amino acids

Drug: Intravenous amino acids
This will aim to deliver iso equivalent amount to the amino acids administered orally
Other Name: IV AA

Experimental: IV amino acids, GLP-1, GIP -Young

Gut hormones will be measured after intravenous amino acid infusion delivering iso equivalent amount of amino acids, GLP-1, GIP in young persons.

The intervention in this group: Intravenous amino acids iso-equivalent to oral 15 g mixed essential amino acids, GLP-1 infusion and GIP infusion

Drug: GLP-1
GLP-1 effects on skeletal muscle glucose and amino acid metabolism and microvascular blood flow will be scrutinised under the specified insulin concentrations. It will also be used to test the effect of intravenous feed on insulin secretion.
Other Name: Incretin

Drug: GIP
This will be co infused with GLP-1 and intravenous amino acids
Other Name: Incretin

Drug: Intravenous amino acids
This will aim to deliver iso equivalent amount to the amino acids administered orally
Other Name: IV AA

Experimental: Oral amino acids- Older

Gut hormones will be measured post oral drink containing 15 g of mixed essential amino acids in older persons.

The intervention in this arm: 15 gram of oral mixed essential amino acid drink

Dietary Supplement: Oral amino acids
Oral amino acids containing 15 g of amino acids
Other Name: mixed EAA




Primary Outcome Measures :
  1. Muscle protein and glucose metabolism [ Time Frame: 12 months ]
    Assessed from muscle biopsies taken for measurement of protein synthesis and breakdown and glucose uptake.


Secondary Outcome Measures :
  1. Leg Microvascular blood flow [ Time Frame: 12 months ]
    Assessed via contrast enhanced ultrasound.

  2. Leg Macrovascular blood flow [ Time Frame: 12 months ]
    Assessed via ultrasound doppler scans

  3. Insulin secretion in response to oral and intravenous amino acids to assess their ability to exert incretin effect. [ Time Frame: 12 months ]
    Assessed via serial blood draws measuring insulin level at baseline and and post intervention.

  4. Gut hormones secretion in response to amino acids in young and older people [ Time Frame: 12 months ]
    Assessed via serial blood draws measuring gut hormones at baseline and post intervention.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

- For protocol 1: i. Aged between 18-40 or 65-75 years ii. A body mass index (BMI) >18 and <28 kg/m2

- For Protocol 2: i. Age 65-75 years ii. A body mass index (BMI) >18 and <28 kg/m2

Exclusion Criteria:

  • For protocol 1:

    i. A BMI < 18 or > 28 kg·m2 ii. Active cardiovascular disease: uncontrolled hypertension (BP > 160/100), angina, heart failure (class III/IV), arrhythmia, right to left cardiac shunt or recent cardiac event iii. Cerebrovascular disease: previous stroke, aneurysm (large vessel or intracranial) iv. Respiratory disease including pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma or an forced expiratory volume in 1 minute (FEV1) less than 1.5 litre.

    v. Metabolic disease: hyper and hypo-parathyroidism, untreated hyper and hypothyroidism, Cushing's disease, types 1 or 2 diabetes vi. Active inflammatory bowel or renal disease vii. Malignancy viii. Recent steroid treatment (within 6 month), or hormone replacement therapy ix. Clotting dysfunction x. Musculoskeletal or neurological disorders xi. Family history of early (<55y) death from cardiovascular disease

  • For protocol 2:

Same as protocol 1 in addition to:

i. Overt muscle wasting i.e. muscle mass is more than 1 standard deviation below normal muscle or fat-free mass for age.

ii. Taking beta-adrenergic blocking agents or non-steroidal anti-inflammatory drugs iii. Known sensitivity to SONOVUE or any other drug used in the study. iv. Subject deemed unsuitable for femoral cannulation at screening visit.


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): NCT02370745


Locations
Layout table for location information
United Kingdom
Division of Medical Sciences and Graduate Entry Medicine - School of Medicine - University of Nottingham
Derby, United Kingdom, DE22 3DT
Sponsors and Collaborators
University of Nottingham
Investigators
Layout table for investigator information
Principal Investigator: Philip Atherton, PhD University of Nottingham
Principal Investigator: Iskandar Idris, DM, FRCP University of Nottingham
Publications:
Layout table for additonal information
Responsible Party: University of Nottingham
ClinicalTrials.gov Identifier: NCT02370745    
Other Study ID Numbers: G12122013 MSGEM
First Posted: February 25, 2015    Key Record Dates
Last Update Posted: May 2, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by University of Nottingham:
Incretin
GLP-1
Skeletal muscle metabolism
Microvascular recruitment
Amino Acids
Microvascular blood flow
Additional relevant MeSH terms:
Layout table for MeSH terms
Sarcopenia
Muscular Atrophy
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Atrophy
Pathological Conditions, Anatomical
Insulin
Insulin, Globin Zinc
Incretins
Hypoglycemic Agents
Physiological Effects of Drugs
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists