The Effect of Intranasal Insulin on Hepatic and Intestinal Triglyceride-rich Lipoprotein Production

Each subject will be studied twice 4-6 weeks apart in random order in this single blinded study. In study A they will receive a single dose of insulin 40 IU through nasal spray. In study B they will receive placebo. On the day of the study subjects will drink regular liquid nutrient formula to maintain a constant fed state. A pancreatic clamp (octreotide with replacement glucose, insulin and growth hormone) will be started at 7am. From 9am a regular infusion of a stable isotope tracer will be started together with nasal spray of either insulin/placebo. Regular blood samples will be drawn to assess lipoprotein kinetics.

Inclusion criteria

• Men and women, aged 18 to 60 years
• Body mass index 20 to 40 kg/m2
• 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.

Exclusion criteria

• Study participant with a history of hepatitis/hepatic disease that has been active within the previous two years.
• Any current or previous history of biliary disease (including gall stones, biliary atresia and cholecystitis) or pancreatitis.
• Any current or previous history of endocrine disease, dyslipidemia or malignancy
• Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (creatinine > 1.5 mg/dL) genitourinary, hematological systems, or has severe uncontrolled treated or untreated hyper/ hypotension (sitting diastolic pressure > 100 or systolic > 180 or systolic pressure <100) or proliferative retinopathy
• Use of immunosuppressive agents at any time during the study
• Allergy to any study medication
• Pregnancy or breastfeeding
• Heavy smoker
• Fasting blood glucose > 6.0 mmol/l or known diabetes.
• 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.
• Any nasal pathology.
• Any laboratory values: aspartate aminotransferase > 2x upper limit of normal ; alanine aminotransferase > 2x upper limit of normal; thyroid-stimulating hormone > 6 milliunit per litre