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

NCT02164032 | Unknown Phase 2 DMC

• 2 other identifiers: INTO_humans2013-004463-32
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Subjects

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Changes of hepatic Lipid composition

  one week before & baseline & 1,2,3 and 4 weeks after intranasal insulin administration

• Changes of myocardial lipid content

  baseline, 2 and 4 weeks after intranasal insulin administration

• Changes of myocardial lipid composition

  baseline, 2 and 4 weeks after intranasal insulin administration

• Changes of skeletal muscle lipid content

  baseline, 2 and 4 weeks after intranasal insulin administration

• Changes of lipid composition in skeletal muscle

  baseline, 2 and 4 weeks after intranasal insulin administration

Other Outcomes (2)

• Changes of parameters of glucose and lipid metabolism

  one week before & baseline & 1,2,3 and 4 weeks after initiation of intranasal insulin administration

• Lipid composition in plasma

  one week before & at baseline & 1,2,3 and 4 weeks after intranasal insulin administration

Study Arms (2)

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.

Drug: Insulin Dilution Buffer (Novo Nordisk); Other: 1H magnetic resonance spectroscopy

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.

Drug: Intranasal insulin administration; Other: 1H magnetic resonance spectroscopy

Interventions

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

Also known as: insulin Actrapid

Intranasal Insulin administration

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

Also known as: vehicle

Insulin dilution buffer

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.

Insulin dilution buffer; Intranasal Insulin administration

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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 \[heart pacemaker, brain (aneurysm) clip, nerve stimulators, electrodes, ear implants, post coronary by-pass graft (epicardial pace wires), penile implants, colored contact lenses, patch to deliver medications through the skin, coiled spring intrauterine device, vascular filter for blood clots, orthodontic braces, shunt-spinal or ventricular, any metal implants (rods, joints, plates, pins, screws, nails, or clips), embolization coil, or any metal fragments or shrapnel in the body\].

Sponsors & Collaborators

• Medical University of Vienna: lead

Study Sites (1)

Medical University Of Vienna, Department of Internal Medicine III

Vienna, Vienna, 1090, Austria

Location

MeSH Terms

Interventions

insulin, neutral; Proton Magnetic Resonance Spectroscopy

Intervention Hierarchy (Ancestors)

Magnetic Resonance Spectroscopy; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Michael Krebs, MD, Prof.

  Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. MD

Study Record Dates

• First Submitted: June 12, 2014
• First Posted: June 16, 2014
• Study Start: September 1, 2014
• Primary Completion: July 1, 2016
• Study Completion: December 1, 2016
• Last Updated: September 27, 2016

Record last verified: 2016-09

Locations

AU (1)