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

NCT02370745 | Completed DMC

• 1 other identifier: G12122013 MSGEM
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This study has two protocols the aims of which are:

1. 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. 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)

Conditions

Sarcopenia

Keywords

Incretin; GLP-1; Skeletal muscle metabolism; Microvascular recruitment; Amino Acids; Microvascular blood flow

Outcome Measures

Primary Outcomes (1)

• Muscle protein and glucose metabolism

  Assessed from muscle biopsies taken for measurement of protein synthesis and breakdown and glucose uptake.

  12 months

Secondary Outcomes (4)

• Leg Microvascular blood flow

  12 months

• Leg Macrovascular blood flow

  12 months

• Insulin secretion in response to oral and intravenous amino acids to assess their ability to exert incretin effect.

  12 months

• Gut hormones secretion in response to amino acids in young and older people

  12 months

Study Arms (8)

Post absorptive insulin without GLP-1

EXPERIMENTAL

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

Postabsorptive insulin with GLP-1

EXPERIMENTAL

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; Drug: Insulin Actrapid

Postprandial insulin without GLP-1

EXPERIMENTAL

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

Postprandial insulin with GLP-1

EXPERIMENTAL

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; Drug: Insulin Actrapid

Oral amino acids-Young

EXPERIMENTAL

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

Intravenous (IV) amino acids- Young

EXPERIMENTAL

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

IV amino acids, GLP-1, GIP -Young

EXPERIMENTAL

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; Drug: GIP; Drug: Intravenous amino acids

Oral amino acids- Older

EXPERIMENTAL

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

Interventions

GLP-1 DRUG

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.

Also known as: Incretin

IV amino acids, GLP-1, GIP -Young; Postabsorptive insulin with GLP-1; Postprandial insulin with GLP-1

Insulin Actrapid DRUG

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

Also known as: Actrapid

Post absorptive insulin without GLP-1; Postabsorptive insulin with GLP-1; Postprandial insulin with GLP-1; Postprandial insulin without GLP-1

Oral amino acids DIETARY_SUPPLEMENT

Oral amino acids containing 15 g of amino acids

Also known as: mixed EAA

Oral amino acids- Older; Oral amino acids-Young

GIP DRUG

This will be co infused with GLP-1 and intravenous amino acids

Also known as: Incretin

IV amino acids, GLP-1, GIP -Young

Intravenous amino acids DRUG

This will aim to deliver iso equivalent amount to the amino acids administered orally

Also known as: IV AA

IV amino acids, GLP-1, GIP -Young; Intravenous (IV) amino acids- Young

Eligibility Criteria

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

You may qualify if:

• \- 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Nottingham: lead

Study Sites (1)

Division of Medical Sciences and Graduate Entry Medicine - School of Medicine - University of Nottingham

Derby, DE22 3DT, United Kingdom

Location

Related Publications (6)

• Nilsson M, Holst JJ, Bjorck 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. doi: 10.1093/ajcn/85.4.996.

  PMID: 17413098 BACKGROUND

• 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. doi: 10.1079/BJN2002760.

  PMID: 12575908 BACKGROUND

• 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.

  PMID: 19740975 BACKGROUND

• Sjoberg 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.

  PMID: 24302010 BACKGROUND

• 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.

  PMID: 22357961 BACKGROUND

• Abdulla H, Phillips B, Wilkinson D, Gates A, Limb M, Jandova T, Bass J, Lewis J, Williams J, Smith K, Idris I, Atherton P. Effects of GLP-1 Infusion Upon Whole-body Glucose Uptake and Skeletal Muscle Perfusion During Fed-state in Older Men. J Clin Endocrinol Metab. 2023 Mar 10;108(4):971-978. doi: 10.1210/clinem/dgac613.

  PMID: 36260533 DERIVED

MeSH Terms

Conditions

Sarcopenia

Interventions

Glucagon-Like Peptide 1; Incretins; insulin, neutral; Insulin; Amino Acids

Condition Hierarchy (Ancestors)

Muscular Atrophy; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Philip Atherton, PhD

  University of Nottingham

  PRINCIPAL INVESTIGATOR

• Iskandar Idris, DM, FRCP

  University of Nottingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 10, 2014
• First Posted: February 25, 2015
• Study Start: November 1, 2014
• Primary Completion: March 1, 2018
• Study Completion: March 1, 2018
• Last Updated: May 2, 2018

Record last verified: 2018-03

Locations

GB (1)