Sarcopenia
Conditions
Keywords
Incretin, GLP-1, Skeletal muscle metabolism, Microvascular recruitment, Amino Acids, Microvascular blood flow
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)
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.
Interventions
DRUGGLP-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.
DRUGInsulin Actrapid
Skeletal muscle metabolic and microvascular parameters will be tested under specified insulin concentrations with or without GLP-1
DIETARY_SUPPLEMENTOral amino acids
Oral amino acids containing 15 g of amino acids
DRUGGIP
This will be co infused with GLP-1 and intravenous amino acids
This will aim to deliver iso equivalent amount to the amino acids administered orally
Sponsors
University of Nottingham
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
18 Years to 75 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Muscle protein and glucose metabolism | 12 months | Assessed from muscle biopsies taken for measurement of protein synthesis and breakdown and glucose uptake. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Leg Microvascular blood flow | 12 months | Assessed via contrast enhanced ultrasound. |
| Leg Macrovascular blood flow | 12 months | Assessed via ultrasound doppler scans |
| Insulin secretion in response to oral and intravenous amino acids to assess their ability to exert incretin effect. | 12 months | Assessed via serial blood draws measuring insulin level at baseline and and post intervention. |
| Gut hormones secretion in response to amino acids in young and older people | 12 months | Assessed via serial blood draws measuring gut hormones at baseline and post intervention. |
Countries
United Kingdom
Outcome results
None listed