The Role of IntraNasal Insulin in Regulating HepaTic Lipid COntent in HUMANS (INTO_humans)

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

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.

Study Overview

• Status: Unknown
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Insulin Dilution Buffer (Novo Nordisk); Other: 1H magnetic resonance spectroscopy; Drug: Intranasal insulin administration

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna, Department of Internal Medicine III

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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].

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Insulin dilution buffer; 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); 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; Other Names: vehicle; Other: 1H magnetic resonance spectroscopy; 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.
Active Comparator: 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.	Other: 1H magnetic resonance spectroscopy; 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.; Drug: Intranasal insulin administration; 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; Other Names: insulin Actrapid

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Michael Krebs, MD, Prof., Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): July 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: June 12, 2014
• First Submitted That Met QC Criteria: June 12, 2014
• First Posted (Estimate): June 16, 2014

Study Record Updates

• Last Update Posted (Estimate): September 27, 2016
• Last Update Submitted That Met QC Criteria: September 26, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: INTO_humans; 2013-004463-32 (EudraCT Number)