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

Sarcopenia Clinical Trial

— Incretin  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02370745
• Other study ID #: G12122013 MSGEM
• Status: Completed
• Phase: N/A
• Start date: November 2014
• Est. completion date: March 2018

Study information

• Verified date: March 2018
• Source: University of Nottingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: March 2018
• Est. primary completion date: March 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Sarcopenia

Intervention

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.
• Insulin Actrapid
Skeletal muscle metabolic and microvascular parameters will be tested under specified insulin concentrations with or without GLP-1

Dietary Supplement:
• Oral amino acids
Oral amino acids containing 15 g of amino acids

Drug:
• GIP
This will be co infused with GLP-1 and intravenous amino acids
• Intravenous amino acids
This will aim to deliver iso equivalent amount to the amino acids administered orally

Locations

Country	Name	City	State
United Kingdom	Division of Medical Sciences and Graduate Entry Medicine - School of Medicine - University of Nottingham	Derby

Sponsors (1)

Lead Sponsor	Collaborator
University of Nottingham

Country where clinical trial is conducted

United Kingdom, 

References & Publications (5)

Chai W, Dong Z, Wang N, Wang W, Tao L, Cao W, Liu Z. Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes. 2012 Apr;61(4):888-96. doi: 10.2337/db11-1073. Epub 2012 Feb 22. — View Citation

Hall WL, Millward DJ, Long SJ, Morgan LM. Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite. Br J Nutr. 2003 Feb;89(2):239-48. — View Citation

Nilsson M, Holst JJ, Björck IM. Metabolic effects of amino acid mixtures and whey protein in healthy subjects: studies using glucose-equivalent drinks. Am J Clin Nutr. 2007 Apr;85(4):996-1004. — View Citation

Sjøberg KA, Holst JJ, Rattigan S, Richter EA, Kiens B. GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle. Am J Physiol Endocrinol Metab. 2014 Feb 15;306(4):E355-62. doi: 10.1152/ajpendo.00283.2013. Epub 2013 Dec 3. — View Citation

Wilkes EA, Selby AL, Atherton PJ, Patel R, Rankin D, Smith K, Rennie MJ. Blunting of insulin inhibition of proteolysis in legs of older subjects may contribute to age-related sarcopenia. Am J Clin Nutr. 2009 Nov;90(5):1343-50. doi: 10.3945/ajcn.2009.27543. Epub 2009 Sep 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Muscle protein and glucose metabolism	Assessed from muscle biopsies taken for measurement of protein synthesis and breakdown and glucose uptake.	12 months
Secondary	Leg Microvascular blood flow	Assessed via contrast enhanced ultrasound.	12 months
Secondary	Leg Macrovascular blood flow	Assessed via ultrasound doppler scans	12 months
Secondary	Insulin secretion in response to oral and intravenous amino acids to assess their ability to exert incretin effect.	Assessed via serial blood draws measuring insulin level at baseline and and post intervention.	12 months
Secondary	Gut hormones secretion in response to amino acids in young and older people	Assessed via serial blood draws measuring gut hormones at baseline and post intervention.	12 months