Free Fatty Acid Induced Insulin Resistance

Study Overview
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Brief Summary
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This study aims to explore time-dependent effects of lipid infusion an intramyocellular lipid metabolites and the induction of impaired insulin signaling.

Detailed Description
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Increased availability of free fatty acids impairs glucose disposal in young healthy humans. Patients with type 2 diabetes have reduced whole body glucose disposal, increased ectopic lipid deposition in skeletal muscle and the liver and impaired mitochondrial function. Recent studies suggest that lipid metabolites such as diacylglycerol (DAG), ceramides and long-chain acyl-coA represent the active mediators inducing insulin resistance. Possible targets are DAG-sensitive Proteinkinase C (PKC θ, PKC ε) which inhibit the insulin signaling cascade and ceramides which interfere with the insulin signaling cascade at Proteinkinase B/AKT. Prior studies raised controvesial evidence, thus, it is yet unclear, whether DAG or ceramides are the primary agents inducig lipid-induced insulin resistance. Therefore, the current study aims to explore the time course of the appearance of intramyocellular lipid compunds during lipid infusion in parallel assessing markers of impaired insulin action.

Official Title
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Assessment of the Time Course of Lipid Induced Insulin Resistance

Conditions
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Insulin Resistance

Intervention / Treatment
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* Dietary Supplement: Lipovenös lipid infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: non-diabetic (OGTT), no family history of diabetes, BMI<30 kg/m2, age: 20-55 years, no medication For the athletes group additionally: VO2max > 60ml/kg/min for males and VO2max > 45ml/kg/min for females Active in endurance-exercise activities, 3 times a week for at least 2 years Stable level of training for at least 3 months Exclusion Criteria: acute illness within the last 2 weeks, autoimmune diseases, renal insufficiency (creatinine> 1.5 mg/dl), cardiovascular diseases, anemia (Hb< 12g/l), donation of blood within the last 4 weeks before the study, thyroid diseases, pregnancy, smoking, night-shift working (disturbed circadian rhythm), defective coagulation or wound healing, cancer, allergy against soja products

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| lipid infusion in untrained humans<br>healthy lean humans before and after lipid infusion | Dietary Supplement: Lipovenös lipid infusion<br>* Lipid enriched infusions will be applied for 2-6 hours.<br>* Other names: soy oil;|
| lipid infusion in athletes<br>endurance trained atheletes | Dietary Supplement: Lipovenös lipid infusion<br>* Lipid enriched infusions will be applied for 2-6 hours.<br>* Other names: soy oil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| intramyocellular lipid metabolites | Muscle biopsies are taken before, after 2.5 and 4 hours of lipid infusion | after 4 hours lipid infusion | 
| muscle glucose flux | glycogen synthesis rate, glucose-6-phosphate | during lipid infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| insulin resistance of glucose uptake and mitochondrial function | Mitochondrial function will bes assessed from muscle biopsy samples taken after 4 hours, insulin sensitivity will be assessed from hyperinsulinemic-euglycemic clamps following 4 hours lipid infusion | after 4 hours lipid infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FFA, insulin resistance, mitochondria