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

University of Nottingham

Status: Completed

Conditions: Sarcopenia

Treatments: Dietary Supplement: Oral amino acids; Drug: Insulin Actrapid; Drug: Intravenous amino acids; Drug: GIP; Drug: GLP-1

Study type: Interventional

Funder types: Other

Identifiers

NCT02370745

G12122013 MSGEM

Details and patient eligibility

About

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)

Full 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.

Enrollment: 40 patients

Sex: Male

Ages: 18 to 75 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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40 participants in 8 patient groups

Post absorptive insulin without GLP-1

Experimental group

Description:

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.

Treatment:

Drug: Insulin Actrapid

Postabsorptive insulin with GLP-1

Experimental group

Description:

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 .

Treatment:

Drug: GLP-1

Drug: Insulin Actrapid

Postprandial insulin without GLP-1

Experimental group

Description:

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

Treatment:

Drug: Insulin Actrapid

Postprandial insulin with GLP-1

Experimental group

Description:

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 .

Treatment:

Drug: GLP-1

Drug: Insulin Actrapid

Oral amino acids-Young

Experimental group

Description:

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.

Treatment:

Dietary Supplement: Oral amino acids

Intravenous (IV) amino acids- Young

Experimental group

Description:

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

Treatment:

Drug: Intravenous amino acids

IV amino acids, GLP-1, GIP -Young

Experimental group

Description:

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

Treatment:

Drug: GLP-1

Drug: GIP

Drug: Intravenous amino acids

Oral amino acids- Older

Experimental group

Description:

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

Treatment:

Dietary Supplement: Oral amino acids