Effects of Intranasal Insulin Administration on Tissue Specific Insulin Sensitivity (NASO-PET)

January 24, 2018 updated by: Turku University Hospital

Recent research has suggested that intranasally administered insulin can reach the brain quickly without passing through circulation and evoke increased insulin sensitivity and tissue glucose consumption during insulin stimulation (low-dose hyperinsulinemic, euglycemic clamp). It is still not known what mechanism causes these changes or what tissues are involved in this.

In this study, the changes in tissue-specific insulin sensitivity and glucose uptake will be investigated by using glucose-analogue radiotracer ([18F]-fluorodeoxyglucose) with positron emission tomography (PET) imaging during insulin stimulation. Ten healthy males are studied, each receiving nasal sprays containing insulin or placebo in a randomized order on two separate days. After spray administration, glucose uptake in skeletal muscle, liver, subcutaneous and visceral adipose tissue, myocardium, intestines, brown adipose tissue and brain assessed by PET imaging and glucose uptake in these tissues is analyzed. Endogenous glucose production is calculated facilitating the measurements glucose and radiotracer uptake in tissues and tracer loss into urine.

As skeletal muscle consumes most of the glucose available, it is likely that administration of insulin sprays will result in an increased uptake in this tissue. Some increase in glucose uptake might also be seen in other tissue types after insulin spray versus placebo spray administration.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The objective of this study is to investigate the effects of intranasally administered insulin versus placebo on tissue specific glucose uptake of the key metabolic organs as well as on endogenous glucose production.

SAMPLE SIZE:

A total of ten (n=10) healthy males are planned to be included, and the study is conducted with a cross-over design with each subject being investigated twice, once using intranasal insulin and once using intranasal placebo in single-blinded randomized order.

SCREENING VISIT/ELIGIBILITY:

Main inclusion and exclusion criteria will be evaluated at a screening visit. This visit will include a frequently-sampled 75 g oral glucose tolerance test as well as anthropometric measurements and clinical examination.

PET STUDY VISITS:

On the PET study days two cannulas will be inserted, one in a radial or an antecubital vein for tracer injection and infusion of glucose and insulin, another in the opposite radial or antecubital vein for blood sampling. The arm where the samples are taken will be kept warm to obtain arterialized venous blood. The subjects will rest in supine position on the PET/CT scanner bed during the study.

HYPERINSULINEMIC EUGLYCEMIC CLAMP:

Whole-body insulin sensitivity will be assessed by hyperinsulinemic euglycemic clamp with an primed insulin infusion rate of 0.25 mU/kg/min. To maintain the glucose level at 5.0 mmol/l intravenous glucose infusion is administered individually as needed to maintain euglycemia.

NASAL SPRAY ADMINISTRATION:

After 30 minutes of intravenous insulin infusion, the subjects will receive either 160 IU human insulin or placebo intranasally. The small amount of insulin known to be absorbed into circulation after the insulin nasal spray will be mimicked on placebo day. Therefore subjects will be administered 2.5 mU/kg of additional intravenous insulin over 15 minutes together with placebo spray administration.

LABORATORY SAMPLES:

To verify comparable insulin levels in circulation during the study, serum insulin and C-peptide levels will be determined in fasting state, and repeatedly throughout the experiment.

BLINDING:

The clinician and the study nurse are aware which spray is given, but subjects are blinded and additional insulin infusion on placebo day is done in a manner that the subjects remain blinded. The sprays are given on a randomized order. The randomization code was generated by a statistician using SAS, version 9.3 for Windows. The randomization block size was four and the method was permuted block randomization. The randomization was done for 16 subjects in case of discontinuations.

HEART RATE VARIABILITY:

Heart rate variability is recorded to evaluate changes in autonomous nervous system activity after spray administration on both visits. Polar RS800CX heart rate monitor (Polar Electro Ltd., Kempele, Finland) with two electrodes is used.

FDG-PET-IMAGING:

70 minutes after the start of clamp and 40 minutes after the application of nasal sprays the positron emission tomography (PET) scanning is started with the injection of glucose-analogue tracer labeled with positron-emitting fluorine-18 ([18F]-fluorodeoxyglucose, [18F]-FDG). PET/CT, GE DiscoveryTM ST System (General Electric Medical Systems, Milwaukee, WI, USA) with final resolution of 3.75 mm in PET images is used. All data will be corrected for dead-time, decay and measured photon attenuation. Dynamic PET-scans will be reconstructed with iterative reconstruction method. Radiotracer [18F]-FDG is produced in the PET Centre radiochemistry laboratory. Plasma radioactivity is measured with an automatic gamma counter by a medical technologist in the laboratory of the Turku PET Centre (Wizard 1480 3", Wallac, Turku, Finland).

PET-IMAGE ANALYSIS:

To determine tissue-specific glucose uptake during insulin stimulation from PET data, time-activity-curves of tissue activity and activity measured from plasma during the scanning are analysed graphically to define tracer's fractional uptake (Ki). To calculate glucose uptake rate (reported as µmol/kg/min), Ki is multiplied with plasma glucose level, divided with a constant that accounts for the differences in transport and dephosphorylation rates between D-glucose and FDG (lumped constant, LC) and divided with tissue specific gravity. Based on previous studies the LC is 1,2 for skeletal muscle; 1,0 for heart and liver; 1,14 for adipose tissue; 1,1 for intestines and 0,8 for brain. After the PET/CT an urine sample will be collected to quantify endogenous glucose production (EGP). This will be determined by subtracting urine loss and glucose infusion rate from rate of glucose disappearance.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Finland
      • Turku, Finland, 20520
        • Turku PET Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 35 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  1. BMI 18,5-25 kg/m2
  2. Fasting plasma glucose less than 6.1 mmol/l
  3. Normal 2-hour oral glucose tolerance test (OGTT)

Exclusion Criteria:

  1. Any chronic disease or medication that could affect glucose metabolism
  2. History of anorexia nervosa or bulimia
  3. Smoking of tobacco, taking of snuffs, or use of narcotics
  4. Abusive use of alcohol
  5. Any other condition that in the opinion of the investigator could create a hazard to the subject safety, endanger the study procedures or interfere with the interpretation of study results

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Insulin nasal spray

Subjects administer 2 intranasal sprays into each nostril every minute for 4 minutes, a total of 16 sprays. Sprays contain fast-acting human insulin Actrapid (Novo Nordisk A/S, Bagsvaerd, Denmark). The glass spray flasks are produced by AeroPump GmBH, Germany and give 0,1 ml of fluid per spray. To account for the small amount of insulin absorbed into circulation after the insulin nasal sprays, on the placebo day subjects will be administered 2.5 mU/kg of additional intravenous insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark) over 15 minutes.

30 min before spray administration a hyperinsulinemic euglycemic clamp will be started and continued for 170 minutes. 40 min after spray administration [18F]-FDG PET-CT scan lasting 100 min is started.
Drug: Actrapid
Subjects administer 2 intranasal sprays into each nostril every minute for 4 minutes, a total of 16 sprays or 160 IU of fast-acting human insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark). The glass spray flasks are produced by AeroPump GmBH, Germany and give 0,1 ml of fluid per spray.
Other Names:
  • ATC-code A10AB01
Radiation: [18F]-FDG PET-CT
All subjects will undergo two positron emission tomography (PET) studies. On both visits they are injected with 185 MBq [18F]-fluorodeoxyglucose and scanned with a combined PET and computed tomography scanner.
Other Names:
  • Tissue specific insulin sensitivity measurement
Drug: Hyperinsulinemic euglycemic clamp
All subjects will undergo two hyperinsulinemic euglycemic clamp studies. The insulin infusion will be administered intravenously at a steady rate of 0.25 mU/kg/min for approximately 170 minutes. Glucose will be administered intravenously as a 200 mg/ml fluid to at varying rate to maintain euglycemia.
Other Names:
  • Whole-body insulin sensitivity measurement
PLACEBO_COMPARATOR: Placebo nasal spray

Subjects administer 2 intranasal sprays into each nostril every minute for 4 minutes, a total of 16 sprays. Sprays contain Insulin Diluting Medium for Novorapid and Levemir (Novo Nordisk A/S, Bagsvaerd,Denmark). The glass spray flasks are produced by AeroPump GmBH, Germany and give 0,1 ml of fluid per spray. To account for the small amount of insulin absorbed into circulation after the insulin nasal sprays, on the placebo day subjects will be administered 2.5 mU/kg of additional intravenous insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd,Denmark) over 15 min.

30 min before spray administration a hyperinsulinemic euglycemic clamp will be started and continued for 170 minutes. 40 min after spray administration [18F]-FDG PET-CT scan lasting 100 min is started.
Radiation: [18F]-FDG PET-CT
All subjects will undergo two positron emission tomography (PET) studies. On both visits they are injected with 185 MBq [18F]-fluorodeoxyglucose and scanned with a combined PET and computed tomography scanner.
Other Names:
  • Tissue specific insulin sensitivity measurement
Drug: Hyperinsulinemic euglycemic clamp
All subjects will undergo two hyperinsulinemic euglycemic clamp studies. The insulin infusion will be administered intravenously at a steady rate of 0.25 mU/kg/min for approximately 170 minutes. Glucose will be administered intravenously as a 200 mg/ml fluid to at varying rate to maintain euglycemia.
Other Names:
  • Whole-body insulin sensitivity measurement
Drug: Placebo
Subjects administer 2 intranasal sprays into each nostril every minute for 4 minutes, a total of 16 sprays. Sprays contain Insulin Diluting Medium for Novorapid and Levemir (Novo Nordisk A/S, Bagsvaerd, Denmark). The glass spray flasks are produced by AeroPump GmBH, Germany and give 0,1 ml of fluid per spray. To account for the small amount of insulin absorbed into circulation after the insulin nasal sprays, on the placebo day subjects will be administered 2.5 mU/kg of additional intravenous insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark) over 15 minutes.
Other Names:
  • Insulin Diluting Medium for Novorapid and Levemir

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Skeletal muscle glucose uptake
Time Frame: Data is collected during 100 min PET scan started 40 min after spray administration.
Change in skeletal muscle insulin stimulated glucose uptake (μmol/min/kg) after insulin versus placebo nasal spray administration.
Data is collected during 100 min PET scan started 40 min after spray administration.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Endogenous glucose production
Time Frame: Data is collected during 100 min PET scan started 40 min after spray administration.
Change in endogenous glucose production after insulin versus placebo nasal spray administration (μmol/min/kg) . Endogenous glucose production is determined by subtracting urine loss and glucose infusion rate from rate of glucose disappearance facilitating measurements of fluorodeoxyglucose concentrations in plasma after the injection and in urine right after the end of PET scanning.
Data is collected during 100 min PET scan started 40 min after spray administration.
Liver glucose uptake
Time Frame: Data is collected during 100 min PET scan started 40 min after spray administration.
Change in liver insulin stimulated glucose uptake (μmol/min/kg) after insulin versus placebo nasal spray administration.
Data is collected during 100 min PET scan started 40 min after spray administration.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Turku University Hospital

Collaborators

University Hospital Tuebingen

Investigators

  • Principal Investigator: Pirjo Nuutila, MD,PhD, Turku University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

April 1, 2016

Primary Completion (ACTUAL)

December 1, 2016

Study Completion (ACTUAL)

December 1, 2016

Study Registration Dates

First Submitted

May 11, 2016

First Submitted That Met QC Criteria

October 12, 2016

First Posted (ESTIMATE)

October 14, 2016

Study Record Updates

Last Update Posted (ACTUAL)

January 26, 2018

Last Update Submitted That Met QC Criteria

January 24, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • T210/2015
  • 2015-005392-24 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Insulin Resistance

Clinical Trials on Actrapid

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Pakistan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe