A New Model of Acute Febrile Disease

Study Overview
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Brief Summary
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The investigators want to establish a new model of acute febrile disease by mimicking the conditions seen in hospitalized patients in regards to inflammation, immobilisation and fasting. In this new model of disease, healthy young adults will be given lipopolysaccharide (LPS) to induce endotoxemia and inflammation/fever and then fast and bedrest for 36 hours. Glucose, fat and protein metabolism will be investigated using clamp technique and tracer methodology together with intracellular signalling pathway activation in muscle and fat biopsies. This new model of disease will later be used in another study to investigate different protein supplement´s effect on muscle waste during acute febrile disease.

Detailed Description
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The investigators want to establish a new model of acute febrile disease by mimicking the conditions seen in hospitalized patients in regards to inflammation, immobilisation and fasting. In this new model of disease, healthy young adults will be given lipopolysaccharide (LPS) to induce endotoxemia and inflammation on study day 1 and then fast and bedrest for 36 hours (Study day 2). Glucose, fat and protein metabolism will be investigated using clamp technique and tracer methodology together with intracellular signalling pathway activation in muscle and fat biopsies. This new model of disease will later be used in another study to investigate different protein supplement´s effect on muscle waste during acute febrile disease.

Official Title
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A New Model of Acute Febrile Disease - Combining Endotoxemia, Immobilisation and Fasting in Healthy Young Males.

Conditions
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Immobilization, Tonic, Fasting, Endotoxemia, Metabolism

Intervention / Treatment
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* Other: LPS, 36 hour immobilization and fast


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male sex 20 < BMI < 30 20 < Age < 40 years Written consent prior to trial Exclusion Criteria: Participation in trials using ionized radiation a year prior to this trial. Comprehensive x-ray examinations in the study period. In case of immobilization of an extremity, the extremity should be fully re- habilitated and this should be stated by a physician or physiotherapist. The test subject's word for this will be sufficient. Allergies to eggs or soy oil. Diseases: Diabetes, epilepsy, ongoing infectious disease, immunodeficiency, heart disease, dysregulated hypertension.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 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: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Healthy young adults will be randomized to either intervention Endotoxemia, 36 hour immobilization and fasting or overnight fast being the control day.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LPS, 36 hour immobilization and fast<br>Interventions: Test subjects undergo 48 hour exercise restriction and overnight fast. Study day 1: - LPS (1 ng/kg) will be administered. Test subjects will fast and bedrest for the rest of the study period. Study day 2: 3 hour Basal period: Continued fast and bedrest. Phenylalanine, tyrosine, carbamide, glucose and palmitate tracers are infused. Muscle and fat biopsies are taken from m. vastus lateralis and stomach. 3 hour hyperinsulinemic euglycemic clamp period with muscle and fat biopsies. Study day 3: - Blood sample. | Other: LPS, 36 hour immobilization and fast<br>* LPS endotoxin is administered on study day 1 and immobilization and fast continue throughout study day 1 and 2.<br>|
| No Intervention: Control<br>Test subjects undergo overnight fast. No exercise restrictions. 3 hour Basal period: Continued fast and bedrest. Phenylalanine, tyrosine, carbamide, glucose and palmitate tracers are infused. Muscle and fat biopsies are taken from m. vastus lateralis and stomach. 3 hour hyperinsulinemic euglycemic clamp period with muscle and fat biopsies. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| insulin sensitivity | Measured by hyperinsulinemic euglycemic clamp technique | After a 3 hour clamp | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protein metabolism | Quantified by phenylalanine and tyrosine tracer methodology (whole body and the forearm model) | measured at baseline and after 3 hours of clamp | 
| ketone body metabolic changes | measurement of ketone bodies | measured at baseline and after 3 hours of clamp | 
| inflammation | Quantified by C-reactive peptide (CRP), white blood cell count, cytokines | measurements over 36 hours | 
| Intracellular signalling pathway activation | Intracellular signalling pathway activation in muscle and fat | measured at baseline and after 3 hours of clamp | 
| Energy expenditure | measured by indirect calorimetry | measured at baseline and after 3 hours of clamp for 15 minutes | 
| Glucose metabolism | measured by glucose tracer, calculations of rate of appearance, disappearance and endogenous glucose production | measured at baseline and after 3 hours of clamp | 
| Hormonal changes | measures of insulin, glucagon, c-peptide and growth hormone | measured at baseline and after 3 hours of clamp | 
| CD163 | measures of CD163 and soluble CD163 (sCD163) after LPS exposure | 0, 24 and 48 hours after LPS exposure | 
| Fat metabolism | measured by palmitate tracer, calculating whole body palmitate flux. Measures of free fatty acids. | measured at baseline and after 3 hours of clamp | 
| Urea balance | measured by urea tracer and urine nitrogen excretion. | measured at baseline and after 3 hours of clamp | 
| Glucose uptake by the forearm | Arterio-venous balance x blodflow | measured at baseline and after 3 hours of clamp | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immobilization, fasting, endotoxemia, LPS, metabolism, model of disease