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

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.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance, Diabetes
• Intervention / Treatment: Drug: Intranasal insulin; Drug: Intranasal placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1L7
      • Tornto General Hospital, UHN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intranasal insulin; 40 IU of intranasal insulin	Drug: Intranasal insulin; Intranasal spray; Other Names: Humalog lispro 40 IU intranasally
Placebo Comparator: Intranasal placebo; Placebo comparator to intranasal insulin	Drug: Intranasal placebo; Intranasal spray; Other Names: Diluent intranasally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous glucose production	Effects of intranasal insulin and placebo on endogenous glucose production will be assessed	8 hours

Collaborators and Investigators

• Sponsor: University Health Network, Toronto

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: May 2, 2014
• First Submitted That Met QC Criteria: May 2, 2014
• First Posted (Estimate): May 6, 2014

Study Record Updates

• Last Update Posted (Estimate): December 2, 2015
• Last Update Submitted That Met QC Criteria: November 30, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Insulin resistance; Type 2 Diabetes; Brain insulin action
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin Lispro
• Other Study ID Numbers: REB 12-5032A