Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity

Study Overview
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Brief Summary
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Early research found that high levels of fat within muscle meant poorer control of blood sugar. However, more recent research has shown that athletes have similar levels of fat within muscle, but in contrast, they have very good control of blood sugar. The investigators are not sure why this is and want to find out if the fat within muscle can be changed to improve blood sugar control, as good blood sugar control reduces the risk of heart disease, diabetes and stroke.

Detailed Description
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Higher levels of triglycerides (TG) and diacylglycerols (DAG) are found in skeletal muscle of patients with obesity/diabetes as well as in trained athletes. Despite similar metabolic storage, patients and athletes have opposite insulin sensitivity phenotypes and an explanation for this is lacking. The investigators' objective is to understand how these fat compartments can be beneficially modulated to improve insulin resistance and cardio-metabolic risk. The investigators will investigate if either structural differences (saturated versus unsaturated balance of TG and DAG side-chains) or different handling abilities (fast versus slow lipid pool turnover) will be induced by exercise capacity interventions in athletes and in diabetic patients. In a longitudinal study pre- and post-exercise, the investigators will use novel, non-invasive 1H-Magnetic Resonance Spectroscopy to benchmark the saturated/unsaturated compartments against skeletal muscle biopsies for the first time and stable isotope analysis for fat compartments' rate of turnover.

Official Title
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Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity - the MISTY Study

Conditions
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Diabetes

Intervention / Treatment
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* Other: Training or detraining


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetic patients, aged between 20-65, diagnosed as per WHO criteria, diet controlled or diet and any of the following oral hypoglycemics: metformin, sulphonylureas, glitazones, gliptins, acarbose, but not requiring insulin for controlling of blood glucose. Trained, athletic healthy controls, aged 18 and over. Participant who is willing and able to give informed consent for participation in the study. Able to perform exercise testing. Exclusion Criteria: Any history of known coronary artery disease. Other endocrine conditions Impaired renal function defined as eGFR<60mls/min/1.73m2 Known resting/24 hour BP >160/100mmHg Participants on ACE inhibitors Participants on PPAR agonists Participants on omega 3 fatty acids The existence of any medical or surgical condition that in the judgement of the investigators may interfere with the exercise regime, FA metabolism or may compromise the safety of the subject Presence of other significant concomitant heart diseases such as ischaemic, valvular, pericardial heart disease or cardiomyopathy, skeletal muscle disorders Healthy volunteers that are on any chronic medication that in the judgment of the investigators is likely to affect the outcome of the study Significant asthma Significant pulmonary disease Participants unable to cycle on the ergometer Unable to perform exercise testing (e.g. prosthetic limbs)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Volunteers<br>Healthy volunteers will undergo the following: CPEX with/without stable isotope infusion Muscle biopsies Magnetic Resonance Spectroscopy Followed by a period of detraining. They will then undergo the following: CPEX with/without stable isotope infusion Muscle biopsies Magnetic Resonance Spectroscopy | Other: Training or detraining<br>* A period of detraining or a supervised exercise program.<br>* Other names: Detraining or training;|
| Experimental: Diabetic Patients<br>Diabetic patients will undergo the following: CPEX with/without stable isotope infusion Muscle biopsies Magnetic Resonance Spectroscopy They will then undergo a supervised training period. They will then undergo the following: CPEX with/without stable isotope infusion Muscle biopsies Magnetic Resonance Spectroscopy | Other: Training or detraining<br>* A period of detraining or a supervised exercise program.<br>* Other names: Detraining or training;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-invasive 1H Magnetic Resonance Spectroscopy of vastus lateralis | Assessment of energetics of vastus lateralis by MRS | One Hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saturated and unsaturated lipid pool turnover examined by stable isotopes | Lipid pool turnover as examined by stable isotope infusion | One hour |