Regulation of Endogenous Glucose Production by Brain Insulin Action in Insulin Resistance

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.

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.

Eligibility 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