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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-004463-32 | EudraCT Number |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Insulin dilution buffer | Placebo Comparator | 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. |
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| Intranasal Insulin administration | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intranasal insulin administration | Drug | 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 |
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Changes of parameters of glucose and lipid metabolism | fasting Glucose, HbA1c, Cholesterol, LDL, HDL, TGs, non-HDL Cholesterol, FFAs | one week before & baseline & 1,2,3 and 4 weeks after initiation of intranasal insulin administration |
| Lipid composition in plasma |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Krebs, MD, Prof. | Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Medical University Of Vienna, Department of Internal Medicine III | Vienna | State of Vienna | 1090 | Austria |
| Type | Date | Date Unknown |
|---|---|---|
| Release | Feb 22, 2017 | |
| Reset | Apr 6, 2017 |
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| Release Date | Unrelease Date | Unrelease Date Unknown | Reset Date | MCP Release Number |
|---|---|---|---|---|
| Feb 22, 2017 | Apr 6, 2017 |
| ID | Term |
|---|---|
| C000006 | insulin, neutral |
| D066244 | Proton Magnetic Resonance Spectroscopy |
| ID | Term |
|---|---|
| D009682 | Magnetic Resonance Spectroscopy |
| D013057 | Spectrum Analysis |
| D002623 | Chemistry Techniques, Analytical |
| D008919 | Investigative Techniques |
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| Insulin Dilution Buffer (Novo Nordisk) | Drug | 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 |
|
|
| 1H magnetic resonance spectroscopy | Other | 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. |
|
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 |
| one week before & at baseline & 1,2,3 and 4 weeks after intranasal insulin administration |