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Regulation of Endogenous Glucose Production by Brain Insulin Action (Nasal insulin)

Primary Purpose

Insulin Resistance, Diabetes

Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Intranasal insulin
Intranasal placebo
Sponsored by
University Health Network, Toronto
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Insulin Resistance, Diabetes focused on measuring Insulin resistance, Brain insulin action, Type 2 Diabetes

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  1. Men and women, aged 18 to 60 years
  2. Body mass index 20-27.
  3. Hemoglobin in the normal range.
  4. Normal glucose tolerance in response to a 75g, 2-hr oral glucose tolerance test
  5. Women of reproductive age should be on contraception (oral contraceptive pill or intra-uterine device/coil) for at least 2 months prior to and after the study.

Volunteers who have taken part in the study with the previously approved protocol will be eligible to participate in the amended study, if they provide their informed consent

Exclusion Criteria:

Study participant with a history of hepatitis/hepatic disease that has been active within the previous two years.

2. Any current or previous history of biliary disease (including gall stones, biliary atresia and cholecystitis) or pancreatitis.

3. Any current or previous history of endocrine disease, dyslipidemia or malignancy 4. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (Cr > 1.5 mg/dL) genitourinary, hematological systems, or has severe uncontrolled treated or untreated hyper/ hypotension (sitting diastolic BP > 100 or systolic > 180 or systolic BP<100) or proliferative retinopathy 5. Use of immunosuppressive agents at any time during the study 6. Allergy to any study medication 7. Pregnancy or breastfeeding 8. Heavy smoker 9. Prior nasoduodenal tube insertion under fluoroscopic guidance. 10. Fasting blood glucose > 6.0 mmol/l or known diabetes. 11. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or decompensated heart failure.

12. Any nasal pathology likely to affect absorption of insulin or insertion of nasoduodenal tube.

13. Any laboratory values: AST > 2x ULN; ALT > 2x ULN TSH > 6 mU/l 14. Current addiction to alcohol or substances of abuse as determined by the investigator.

15. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation 16. Taking any regular prescription or non-prescription medications at the time of the study. Occasional use of medications such as acetoaminophen or Tylenol 1 or any use of natural health products may be permitted at the discretion of the investigator.

17. Will not donate blood three months prior to and three months post study procedures

Sites / Locations

  • Tornto General Hospital, UHN

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Intranasal insulin

Intranasal placebo

Arm Description

40 IU of intranasal insulin

Placebo comparator to intranasal insulin

Outcomes

Primary Outcome Measures

Endogenous glucose production
Effects of intranasal insulin and placebo on endogenous glucose production will be assessed

Secondary Outcome Measures

Full Information

First Posted
May 2, 2014
Last Updated
November 30, 2015
Sponsor
University Health Network, Toronto
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1. Study Identification

Unique Protocol Identification Number
NCT02131948
Brief Title
Regulation of Endogenous Glucose Production by Brain Insulin Action
Acronym
Nasal insulin
Official Title
Regulation of Endogenous Glucose Production by Brain Insulin Action
Study Type
Interventional

2. Study Status

Record Verification Date
November 2015
Overall Recruitment Status
Completed
Study Start Date
November 2013 (undefined)
Primary Completion Date
July 2014 (Actual)
Study Completion Date
July 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Health Network, Toronto

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
It is well known that the hormone insulin lowers blood glucose in part by acting directly on the liver and reducing hepatic glucose production. Animal studies have shown that the hormone insulin can act on the brain to indirectly lower glucose production by the liver. We aim to test whether this is true in humans by giving insulin intranasally. It has previously been shown that a nasal spray can deliver insulin directly to the brain without affecting circulating insulin concentration.
Detailed Description
Each study participant will be admitted to hospital the evening prior to the study. Following admission each study participant will be provided with a standardized dinner. At 7am (t=0) the next day we will begin a primed, constant intravenous infusion d2 glucose (a stable isotope of glucose, the enrichment of which can be measured by gas chromatography mass spectrometry, allowing us to calculate endogenous glucose production rates) and continue this for 8 hours. At the same time (7am) a pancreatic clamp will be started as described above for 8 hours. Blood samples will be analysed with a glucometer for instant blood glucose readings At 9 am (+120 minutes) intranasal placebo or insulin will be administered. The insulin (Humalog Lispro 100 IU/ml, Eli Lily, Canada) and placebo (diluent) will be transferred to a metered nasal device (Pharmasystems, Ontario UPC: 063636 802721, Item 10271) immediately prior to use. This device dispenses 0.1ml (10 IU) per puff. 4X0.1 ml puffs/vials (2 per nostril) will be administered at rate of 2 (one in each nostril) every 60 seconds. Blood will be drawn at t=0, 30, 60, 120 and every 10 minutes thereafter for 6 hours. In order to match peripheral lispro concentrations between study visits, a small dose of Humalog (lispro) insulin will be administered intravenously at 9am, during the placebo arm of the study. Based on the pharmacokinetics of Humalog lispro (personal communication from Eli Lilly), we propose to administer 0.005 IU/kg over 30 minutes. 20% dextrose will be administered to maintain euglycemia as necessary. Insulin, glucagon, and glucose isotopic enrichment will be measured. The enrichment data and glucose infusion will be used to calculate steady state glucose production.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Insulin Resistance, Diabetes
Keywords
Insulin resistance, Brain insulin action, Type 2 Diabetes

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
Participant
Allocation
Randomized
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intranasal insulin
Arm Type
Experimental
Arm Description
40 IU of intranasal insulin
Arm Title
Intranasal placebo
Arm Type
Placebo Comparator
Arm Description
Placebo comparator to intranasal insulin
Intervention Type
Drug
Intervention Name(s)
Intranasal insulin
Other Intervention Name(s)
Humalog lispro 40 IU intranasally
Intervention Description
Intranasal spray
Intervention Type
Drug
Intervention Name(s)
Intranasal placebo
Other Intervention Name(s)
Diluent intranasally
Intervention Description
Intranasal spray
Primary Outcome Measure Information:
Title
Endogenous glucose production
Description
Effects of intranasal insulin and placebo on endogenous glucose production will be assessed
Time Frame
8 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Men and women, aged 18 to 60 years Body mass index 20-27. Hemoglobin in the normal range. Normal glucose tolerance in response to a 75g, 2-hr oral glucose tolerance test Women of reproductive age should be on contraception (oral contraceptive pill or intra-uterine device/coil) for at least 2 months prior to and after the study. Volunteers who have taken part in the study with the previously approved protocol will be eligible to participate in the amended study, if they provide their informed consent Exclusion Criteria: Study participant with a history of hepatitis/hepatic disease that has been active within the previous two years. 2. Any current or previous history of biliary disease (including gall stones, biliary atresia and cholecystitis) or pancreatitis. 3. Any current or previous history of endocrine disease, dyslipidemia or malignancy 4. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (Cr > 1.5 mg/dL) genitourinary, hematological systems, or has severe uncontrolled treated or untreated hyper/ hypotension (sitting diastolic BP > 100 or systolic > 180 or systolic BP<100) or proliferative retinopathy 5. Use of immunosuppressive agents at any time during the study 6. Allergy to any study medication 7. Pregnancy or breastfeeding 8. Heavy smoker 9. Prior nasoduodenal tube insertion under fluoroscopic guidance. 10. Fasting blood glucose > 6.0 mmol/l or known diabetes. 11. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or decompensated heart failure. 12. Any nasal pathology likely to affect absorption of insulin or insertion of nasoduodenal tube. 13. Any laboratory values: AST > 2x ULN; ALT > 2x ULN TSH > 6 mU/l 14. Current addiction to alcohol or substances of abuse as determined by the investigator. 15. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation 16. Taking any regular prescription or non-prescription medications at the time of the study. Occasional use of medications such as acetoaminophen or Tylenol 1 or any use of natural health products may be permitted at the discretion of the investigator. 17. Will not donate blood three months prior to and three months post study procedures
Facility Information:
Facility Name
Tornto General Hospital, UHN
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1L7
Country
Canada

12. IPD Sharing Statement

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