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

Phase 2

• Conditions: Healthy Subjects
• Interventions: Drug: Insulin Dilution Buffer (Novo Nordisk); Drug: Intranasal insulin administration; Other: 1H magnetic resonance spectroscopy

• Registration Number: NCT02164032
• Lead Sponsor: Medical University of Vienna

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-06-12
• Study First Submitted QC: 2014-06-12
• Study First Posted: 2014-06-16
• Study Start: 2014-09
• Primary Completion: 2016-07
• Status Verified: 2016-09
• Last Update Submitted: 2016-09-26
• Last Update Posted: 2016-09-27
• Study Completion: 2016-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Male
• Target Recruitment: 20

Inclusion Criteria

• BMI 22 - 27 kg/m2
• Age between 18 - 65 years
• Male sex

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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].

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Insulin dilution buffer	Insulin Dilution Buffer (Novo Nordisk)	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.
Insulin dilution buffer	1H magnetic resonance spectroscopy	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.
Intranasal Insulin administration	1H magnetic resonance spectroscopy	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.
Intranasal Insulin administration	Intranasal insulin administration	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.

Primary Outcome Measures

Name	Time	Method
Changes in total lipid content in the liver	one week before & at baseline & 1,2,3 and 4 weeks after intranasal insulin administration	1H magnetic resonance spectroscopy

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Medical University Of Vienna, Department of Internal Medicine III; 🇦🇹 Vienna, Austria