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

May 1, 2018 updated by: University of Nottingham

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.

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)

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Derby, United Kingdom, DE22 3DT
        • Division of Medical Sciences and Graduate Entry Medicine - School of Medicine - University of Nottingham

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / 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 Names:
  • 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: Insulin Actrapid
Skeletal muscle metabolic and microvascular parameters will be tested under specified insulin concentrations with or without GLP-1
Other Names:
  • Actrapid
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 Names:
  • Incretin
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 Names:
  • 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: Insulin Actrapid
Skeletal muscle metabolic and microvascular parameters will be tested under specified insulin concentrations with or without GLP-1
Other Names:
  • Actrapid
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 Names:
  • Incretin
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 Names:
  • 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 Names:
  • 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 Names:
  • Incretin
Drug: Intravenous amino acids
This will aim to deliver iso equivalent amount to the amino acids administered orally
Other Names:
  • IV AA
Drug: GIP
This will be co infused with GLP-1 and intravenous amino acids
Other Names:
  • Incretin
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 Names:
  • mixed EAA

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Muscle protein and glucose metabolism
Time Frame: 12 months
Assessed from muscle biopsies taken for measurement of protein synthesis and breakdown and glucose uptake.
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Leg Microvascular blood flow
Time Frame: 12 months
Assessed via contrast enhanced ultrasound.
12 months
Leg Macrovascular blood flow
Time Frame: 12 months
Assessed via ultrasound doppler scans
12 months
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.
12 months
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.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Nottingham

Investigators

  • Principal Investigator: Philip Atherton, PhD, University of Nottingham
  • Principal Investigator: Iskandar Idris, DM, FRCP, University of Nottingham

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2014

Primary Completion (Actual)

March 1, 2018

Study Completion (Actual)

March 1, 2018

Study Registration Dates

First Submitted

November 10, 2014

First Submitted That Met QC Criteria

February 18, 2015

First Posted (Estimate)

February 25, 2015

Study Record Updates

Last Update Posted (Actual)

May 2, 2018

Last Update Submitted That Met QC Criteria

May 1, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • G12122013 MSGEM

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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