Each subject will be allocated to 2 periods of 3 months of once daily dosing with either
liraglutide (1.2 mg) or placebo treatment (in random sequence) as add on to usual intensive
insulin treatment. Wash-out period between treatments will be 1 month.
The trial can be divided into the following periods:
- Treatment period 1
- Washout period
- Treatment period 2
- Follow up Visit
Mixed Meal Tolerance Test (MMTT) enriched with paracetamol:
At the beginning and end of each period a MMTT (Fortimel complete) enriched with paracetamol
will be performed to assess the remaining beta-cell function via obtained maximal plasma
C-peptide levels as well as the gastric emptying.
Experimental / Hypoglycaemic clamp :
At the end of each period (Visit 8, 15) a hypoglycaemic clamp will be performed. After the
subject completed the MMTT on day 1, the subject will stay in the clinical unit to prepare
for the hypoglycaemic clamp with an variable insulin infusion intravenously in order to
obtain a steady state of a plasma glucose (PG) level of 5.5 mmol/L overnight until
approximately 08:00. At 05:00 hours 10%-[6,6-2H2] glucose solution will be given i.v. as a
primed (9.6mg/kg/min) for one minute and a constant (0.08 mg/kg/min) infusion until the last
blood sampling of the plateau 4.0 mmol/L will be performed.
At 08:00 hours in the morning at day 2, insulin infusion will be increased to 1.5 mU/kg/min
for each subject and the PG will be kept at a plateau of 5.5 mmol/L by a controlled variable
intravenous infusion of glucose (10% glucose enriched with 4mg [6,6-2H2] glucose /ml) for one
hour. Afterwards, PG is allowed to fall to a plateau of 3.5 mmol/L, then to a nadir of 2.5
mmol/L, then to a blood glucose of 4.0 mmol/L and finally back to a level of 5.5 mmol/L for
safety reasons. Blood sampling for measurement of [6,6-2H2] glucose, glucagon, insulin,
counterregulatory hormones, lactate, free fatty acids, glycerol, vital signs, hypoglycaemic
symptoms questionnaire and hypoglycaemic awareness will be performed at each PG plateau.