Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the link between insulin resistance and alterations in skeletal muscle mitochondrial redox homeostasis

Official Title
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Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle

Conditions
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Insulin Resistance

Intervention / Treatment
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* Drug: Intralipid, 20% Intravenous Emulsion
* Dietary Supplement: MitoQ
* Drug: Salbutamol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) ≥25 and <40 kg/m2 Fasting plasma glucose ≥ 5.6 mmol/L or HbA1c ≥ 5.7% HOMA2-IR > 1.4 VO2max <45 ml/kg/min Exclusion Criteria: Treatment with >2 antidiabetic medications Insulin usage Chronic disease deemed by the study responsible medical doctor to interfere with any part of the study Chronic use of prescription medicine deemed by the study responsible medical doctor to interfere with any part of the study Smoking

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 60 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lipid infusion + MitoQ<br>Subjects undergo a hyperinsulinemic isoglycemic clamp preceded by MitoQ administration and intravenous lipid infusion | Drug: Intralipid, 20% Intravenous Emulsion<br>* Lipid infusion<br>Dietary Supplement: MitoQ<br>* Oral administration of MitoQ capsules<br>* Other names: MitoQ10;|
| Placebo Comparator: Lipid infusion + placebo<br>Subjects undergo a hyperinsulinemic isoglycemic clamp preceded by placebo administration and intravenous lipid infusion | Drug: Intralipid, 20% Intravenous Emulsion<br>* Lipid infusion<br>|
| No Intervention: Control<br>Subjects undergo a hyperinsulinemic isoglycemic clamp | |
| Other: Lipid infusion + beta2-agonist<br>Subjects undergo a hyperinsulinemic isoglycemic clamp with intravenous infusion of lipid and salbutamol | Drug: Intralipid, 20% Intravenous Emulsion<br>* Lipid infusion<br>Drug: Salbutamol<br>* Beta2-agonist infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole body Insulin sensitivity | Whole body insulin sensitivity is determined by hyperinsulinemic isoglycemic clamp method | 5 hours after lipid infusion | 
| Skeletal muscle insulin sensitivity | Insulin-dependent skeletal muscle glucose uptake is determined by hyperinsulinemic isoglycemic clamp method integrated with measurements of femoral artery blood flow and arteriovenous difference of glucose | 5 hours after lipid infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mitochondrial respiration | Mitochondrial O2 flux is determined in skeletal muscle biopsies by high-resolution fluorespirometry | Baseline | 
| Mitochondrial reactive oxygen species | Mitochondrial H2O2 emission rate is determined in skeletal muscle biopsies by high-resolution fluorespirometry | Baseline | 
| Mitochondrial oxidative stress | Peroxiredoxin3 dimer/monomer ratio is determined in skeletal muscle biopsies | Before (baseline) as well as 3 and 5 hours after lipid infusion | 
| Muscle redox status | GSH/GSSG ratio is determined in skeletal muscle biopsies | Before (baseline) as well as 3 and 5 hours after lipid infusion | 
| Insulin signalling | Phosphorylation status of proteins modulating insulin action is determined in skeletal muscle biopsies | Before (baseline) as well as 3 and 5 hours after lipid infusion |