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Regulation of Endogenous Glucose Production by Brain Insulin Action in Insulin Resistance (NI EGP highBMI)

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ClinicalTrials.gov Identifier: NCT03383822
Recruitment Status : Completed
First Posted : December 26, 2017
Last Update Posted : December 26, 2017
Sponsor:
Information provided by (Responsible Party):
University Health Network, Toronto

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. It has previously been shown that a nasal spray can deliver insulin directly to the brain without affecting circulating insulin concentration in humans. Intranasal spray of insulin suppressed hepatic glucose production in lean subjects. It is unknown whether this effects is blunted in subjects with insulin resistance.

Condition or disease Intervention/treatment Phase
Insulin Resistance Drug: Intranasal insulin Drug: Intranasal placebo Phase 1 Phase 2

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 #063636 802721, Item 10271) immediately prior to use. This device dispenses 0.1ml (10 IU) per puff. 4 x 0.1 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  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Egulation of Endogenous Glucose Production by Brain Insulin Action in Insulin Resistance
Actual Study Start Date : September 8, 2015
Actual Primary Completion Date : July 31, 2017
Actual Study Completion Date : December 1, 2017

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Intranasal insulin
40 IU of intranasal insulin
Drug: Intranasal insulin
Humalog lispro 40 IU intranasally
Other Name: Insulin
Placebo Comparator: Intranasal placebo
Placebo comparator to intranasal insulin
Drug: Intranasal placebo
Diluent intranasally
Other Name: Placebo



Primary Outcome Measures :
  1. Endogenous glucose production [ Time Frame: 8 hours ]
    Effects of intranasal insulin and placebo on endogenous glucose production will be assessed



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Men and women, aged 18 to 60 years
  2. Body mass index >30 kg/m2
  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.

Exclusion Criteria:

  1. 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 myocardial infarction or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on electrocardiogram, 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: aspartate transaminase > 2x upper limit of normal; alanine aminotransferase > 2x upper limit of normal; thyroid-stimulating hormone > 6 micro unit/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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03383822


Locations
Canada, Ontario
Tornto General Hospital, UHN
Toronto, Ontario, Canada, M5G 1L7
Sponsors and Collaborators
University Health Network, Toronto

Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT03383822     History of Changes
Other Study ID Numbers: NI EGP highBMI 12-5032A
First Posted: December 26, 2017    Key Record Dates
Last Update Posted: December 26, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin, Globin Zinc
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs