The Role of IntraNasal Insulin in Regulating HepaTic Lipid COntent in HUMANS

Study Overview
=================
Brief Summary
-----------------
Non-alcoholic fatty liver disease (NAFLD) is a common human liver pathology, closely associated with the obesity pandemic and insulin resistance. In the insulin resistant state the liver remains sensitive to pro-lipogenic signals of insulin, which further promote lipid accumulation. Secretion of very-low-density-lipoproteins (VLDL), the main carriers of triglycerides (TG) in the plasma, is the principal pathway for the liver to mobilize and dispose of lipids. Thus, hepatic TG export must not be too low in order to prevent steatosis. Our preliminary data from animal experiments suggest that enhanced brain insulin signaling promotes hepatic VLDL secretion, and reduces lipid accumulation in the liver. It remains to be tested whether other insulin sensitive tissues, such as the myocardium or the skeletal muscle, are also affected. In humans, neuropeptides, including insulin, can be delivered to the brain via an intranasal (IN) route of administration, without causing relevant systemic side effects. Therefore, we hypothesize that by enhancing brain insulin signaling using chronic IN insulin administration hepatic TG export increases and prohibits lipid accumulation in the liver and other insulin sensitive tissues, such as the myocardium and the skeletal muscle.

Official Title
-----------------
The Role of IntraNasal Insulin in Regulating HepaTic Lipid COntent in HUMANS a Randomized, Controlled, Double Blinded Trial

Conditions
-----------------
Healthy Subjects

Intervention / Treatment
-----------------
* Drug: Intranasal insulin administration
* Drug: Insulin Dilution Buffer (Novo Nordisk)
* Other: 1H magnetic resonance spectroscopy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: BMI 22 - 27 kg/m2 Age between 18 - 65 years Male sex Exclusion Criteria: smoking regular medication metabolic or liver illnesses tendency towards claustrophobia Chronic sinusitis, diagnosed nasal polyposis, diagnosed severe septum deviation metal devices or other magnetic material in or on the subjects body which will be hazardous for NMR investigation [heart pacemaker, brain (aneurysm) clip, nerve stimulators, electrodes, ear implants, post coronary by-pass graft (epicardial pace wires), penile implants, colored contact lenses, patch to deliver medications through the skin, coiled spring intrauterine device, vascular filter for blood clots, orthodontic braces, shunt-spinal or ventricular, any metal implants (rods, joints, plates, pins, screws, nails, or clips), embolization coil, or any metal fragments or shrapnel in the body].

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

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Insulin dilution buffer<br>During a subsequent 4-week treatment phase subjects will be randomly assigned to receive intranasal insulin (40 IE) Actrapid (100IE/mL); two 0.1 ml puffs per nostril) or placebo (insulin dilution buffer Novo Nordisk; two 0.1 ml puffs per nostril) four times a day (in total 160 IE Actrapid per day) before each main meal and before going to bed. 40 IE IN insulin enhances insulin concentration in the CSF without any changes in systemic insulin and glucose concentration, and no risk for hypoglycemia. Ectopic lipid content and heart function will be assessed weekly by non-invasive 1H magnetic resonance spectroscopy. | Drug: Insulin Dilution Buffer (Novo Nordisk)<br>* intranasal insulin (40 IE) Actrapid (100IE/mL); two 0.1 ml puffs per nostril) or placebo (insulin dilution buffer Novo Nordisk; two 0.1 ml puffs per nostril) four times a day (in total 160 IE Actrapid per day) before each main meal and before going to bed. 40 IE IN insulin enhances insulin concentration in the CSF without any changes in systemic insulin and glucose concentration, and no risk for hypoglycemia<br>* Other names: vehicle;Other: 1H magnetic resonance spectroscopy<br>* 1H MR spectroscopy and imaging will be performed on the on on the 3.0-T Tim Trio System (Siemens Erlangen Germany). MR Spectroscopy and imaging measurements will last no more than 90 minutes all together.<br>|
| Active Comparator: Intranasal Insulin administration<br>During a subsequent 4-week treatment phase subjects will be randomly assigned to receive intranasal insulin (40 IE) Actrapid (100IE/mL); two 0.1 ml puffs per nostril) or placebo (insulin dilution buffer Novo Nordisk; two 0.1 ml puffs per nostril) four times a day (in total 160 IE Actrapid per day) before each main meal and before going to bed. 40 IE IN insulin enhances insulin concentration in the CSF without any changes in systemic insulin and glucose concentration, and no risk for hypoglycemia. Ectopic lipid content and heart function will be assessed weekly by non-invasive 1H magnetic resonance spectroscopy. | Drug: Intranasal insulin administration<br>* intranasal insulin (40 IE) Actrapid (100IE/mL); two 0.1 ml puffs per nostril) or placebo (insulin dilution buffer Novo Nordisk; two 0.1 ml puffs per nostril) four times a day (in total 160 IE Actrapid per day) before each main meal and before going to bed. 40 IE IN insulin enhances insulin concentration in the CSF without any changes in systemic insulin and glucose concentration, and no risk for hypoglycemia<br>* Other names: insulin Actrapid;Other: 1H magnetic resonance spectroscopy<br>* 1H MR spectroscopy and imaging will be performed on the on on the 3.0-T Tim Trio System (Siemens Erlangen Germany). MR Spectroscopy and imaging measurements will last no more than 90 minutes all together.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in total lipid content in the liver | 1H magnetic resonance spectroscopy | one week before & at baseline & 1,2,3 and 4 weeks after intranasal insulin administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of hepatic Lipid composition | 1H magnetic resonance spectroscopy | one week before & baseline & 1,2,3 and 4 weeks after intranasal insulin administration | 
| Changes of myocardial lipid content | 1H magnetic resonance spectroscopy | baseline, 2 and 4 weeks after intranasal insulin administration | 
| Changes of myocardial lipid composition | 1H magnetic resonance spectroscopy | baseline, 2 and 4 weeks after intranasal insulin administration | 
| Changes of skeletal muscle lipid content | 1H magnetic resonance spectroscopy | baseline, 2 and 4 weeks after intranasal insulin administration | 
| Changes of lipid composition in skeletal muscle | 1H magnetic resonance spectroscopy | baseline, 2 and 4 weeks after intranasal insulin administration | 
| changes in heart function | magnetic resonance imaging | baseline, 2 and 4 weeks after intranasal insulin administration |