Assessment of Intranasal Glucagon on Endogenous Glucose Production
Condition: Diabetes
Study type: Interventional
Phase: Phase 1

Summary: 
      Peripheral glucagon action increases hepatic glucose production. In rodents hypothalamic
      action of glucagon paradoxically suppresses glucose production. Intranasally administered
      peptides have been shown to preferentially enter the central nervous system. We assessed the
      effects of intranasal glucagon on hepatic glucose production
    

Detailed description: 
      Fifteen healthy, lean, non-diabetic males and females will undergo two studies each (single
      blinded crossover), in random order, 4-6 weeks apart.

      Study A. Intranasal placebo administration with measurement of endogenous glucose production
      under pancreatic clamp conditions.

      Study B. Intranasal glucagon (glucagon, Eli Lilly, Canada) administration with measurement of
      endogenous glucose production under pancreatic clamp conditions Each study participant will
      be admitted to the Metabolic Test Centre of the Toronto General Hospital the day before the
      study at 12pm. They will be provided with a standardized dinner (consisting of 7 Kcal/kg; 50%
      carbohydrate, 30% fat, and 20% protein) and will then be required to fast for 12 hr overnight
      (can have water but no other food or drinks).

      At 7am (t=0) the next day, we will begin a primed, constant intravenous infusion of
      [6,6-2H2]glucose (D2 glucose; Cambridge Isotope Laboratories, MA; a stable isotope of
      glucose, the enrichment of which can be measured by GC/MS, allowing us to calculate
      endogenous glucose production rates). The infusion will continue for 8 hours.

      At the same time (7am) a pancreatic clamp will be started for 8 hours in order to suppress
      pancreatic hormone secretion with somatostatin while providing basal infusions of pancreatic
      hormones and growth hormone by intravenous infusion. This method will permit us to study the
      effect of intranasal glucagon on hepatic glucose and TRL production without the confounding
      effects it may have on pancreatic hormone secretion. A simultaneous infusion of somatostatin
      (Sandostatin, Novartis Pharma, Miss, ON 30mcg/hr), insulin (Humulin R, Eli Lilly,
      Scarborough, ON, 0.05mU/kg/min), glucagon (Eli Lilly, Miss, ON 0.325ng/kg/min) and growth
      hormone (Humatrope, Eli Lilly, Mississauga, ON 3ng/kg/min) will be started and continued
      throughout the study. All hormones were diluted in 1 liter of normal saline and infused with
      a syringe pump (B. Braun Medical Inc., Bethlehem, PA). Autologous serum (3 mL), freshly
      prepared from the subject's blood, was added to the saline as carrier prior to hormone
      dilution.

      A study nurse and/or doctor will be by the bedside throughout the clamp and will be
      monitoring the participant's blood glucose every 30 minutes after the onset of the clamp and
      every 10 minutes after administration of glucagon (if clinically indicated, sampling may be
      more frequent) to ensure participants do not develop hypo/hyperglycemia. Blood samples will
      be analysed with a glucometer for instant blood glucose readings. If intranasal glucagon
      reduces endogenous glucose production, a reduction in plasma glucose is likely. 20% dextrose
      will be administered if necessary to maintain euglycemia At 9 am (+120 minutes) intranasal
      placebo or glucagon will be administered. The glucagon (Eli Lily, Canada) and placebo
      (diluent) will be transferred to a metered nasal device (Pharmasystems, Markham, Ontario UPC:
      063636 802721, Item 10271) immediately prior to use. This device dispenses 0.1ml (0.1mg) per
      puff. A maximum of 15 X0.1 ml puffs/vials (7 in 1 nostril and 8 in the other nostril) will be
      administered at rate of 2 (one in each nostril) every 60 seconds. This dose may be titrated
      down if necessary to reduce peripheral spillover.

      Blood samples will be collected every 30 minutes after the start of the clamp and every 10
      minutes after administration of intranasal glucagon or placebo (total of 400 ml). The blood
      samples will be collected into chilled sterile tubes containing 0.1% EDTA and preservative (
      aprotinin, sodium azide) and processed as indicated below.

      In order to match peripheral glucagon concentrations between study visits, a small dose of
      glucagon will likely need to be administered intravenously at 9am, during the placebo arm of
      the study. Based on the pharmacokinetics of glucagon, we are likely to administer
      0.00625mg-0.025mg, although further dose titration may be necessary (maximum dose 0.1mg).
      Free fatty acids, triglycerides, insulin, glucagon, C-peptide, glucagon-like peptide-1
      (GLP-1) and GIP,as well as glucose isotopic enrichment will be measured.
    

Intervention name(s): Intranasal glucagon; Intranasal placebo
Intervention type(s): Drug; Drug
Intervention description(s): Glucagon will be administered via a nasal dispenser; Placebo
Intervention MeSH terms: Glucagon
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment