Evaluation of the Glucoregulatory Effects of GLP-1 Receptor Activation in Patients with Type 2 Diabetes Mellitus

You will participate in a study in which new methods for the assessment of
future drug research for Type 2 Diabetes Mellitus medication are developed.
Insulin is a hormone produced by the human body naturally and is involved in
the regulation of the metabolism of sugar and fat in the body. Insulin causes
cells in the liver, muscle, and fat tissue to take up blood sugar (glucose)
from the blood, storing it as a long-term energy depot in the liver and muscle.
When the natural control of insulin production by the body fails, the
complication diabetes mellitus will develop. The insulin that will be
administered temporarily, is used on a large scale and is internationally
registered (NovoRapid) and approved. In this study, you will receive a glucose
solution and an Oxyntomodulin infusion. Oxyntomodulin is a hormone that is
naturally produced in your body which suppresses appetite.

In this study, you will also receive a single subcutaneous injection of
Liraglutide in the evening prior to the Oxyntomodulin and glucose infusion.
Liraglutide is a GLP-1 like peptide (stimulates insulin release) and registered
for the treatment of type 2 diabetes.

Primary:
to assess the glycemic effects of a single dose of OXM on the ambient glucose
levels during a GGI assessment
to assess the insulinotropic effects of a single dose of OXM measured as a
change in "*" during a GGI assessment

Secondary:
to assess the reproducibility of the measures of insulinotropic effects and
glycemic excursion in the setting of a GGI in patients with T2DM
to assess the treatment effects and dose response of a SD of 0.6 and 1.2 mg of
liraglutide on glycemic excursion and insulinotropic effects in the setting of
a GGI in patients with T2DM
to compare the treatment effects of a SD of OXM and those of liraglutide 0.6
and 1.2 mg on insulinotropic effects and glycemic excursions in the setting of
a GGI in patients with T2DM
to assess the operational characteristics and feasibility of evaluating
glucoregulatory effects in the setting of a GGI in a T2DM population

Design:
a double blind, randomized, placebo-controlled, four-period cross-over, single
dose study with one cohort of twelve obese T2DM subjects; subjects will be
randomized to one of eight sequences, during each of the periods, each subject
will receive both a continuous infusion and subcutaneous injection to maintain
the blind, during the first three periods each subject will receive one
treatment period each with continuously infused OXM or placebo or subcutaneous
liraglutide or placebo or double-placebo; furthermore, in period four, six
subjects will receive 1.2 mg of liraglutide and the remaining six subjects will
receive double placebo

Procedures and assessments
Screening and follow-up:
clinical laboratory, physical examination, weight, 12-lead ECG, vital signs
(including oral temperature); at eligibility screening: medical history, HbA1c,
lipid panel, HBsAg, anti HCV, anti-HIV 1/2, urine drug screen; weight and vital
signs to be repeated upon admission

Observation period:
four periods in clinic from 24 h before start of the GGI up to completion of
the weaning procedure in the afternoon of Day 1

Blood sampling:
for pharmacokinetics of oxyntomodulin: 30 min before start of the GGI and 20,
40, 80, 120 an 160 min after start of the GGI
for pharmacokinetics of liraglutide archive: 9 h and 30 minutes before start of
the GGI and 40, 80, 120 and 160 min after start of the GGI
for glucose * central laboratory: every 30 minutes during overnight insulin
infusion, at start of the GGI, and 20, 40, 60, 80, 100, 120, 140 and 160 min
after start of GGI
for glucose * YSI: every 30 minutes during overnight insulin infusion, 10
minutes before start of the GGI, and 40, 80, 120 and 160 min after start of GGI
for C-peptide: at start of the GGI, and 20, 40, 60, 80, 100, 120, 140 and 160
min after start of GGI
for insulin: at start of the GGI, and 20, 40, 60, 80, 100, 120, 140 and 160 min
after start of GGI
for GLP-1/glucagon: at the start of the GGI and 40, 80, 120 and 160 min after
start of GGI
for archive: 30 min before start of GGI and 160 min after start of GGI
for genetic and other biomedical research: 12 h before start of the GG
I
Urine sampling:
for glucose: interval from 15 min before start of GGI up to 160 min after start
of GGI

Safety assessments:
adverse events: throughout the study; vital signs: 12 h and 60 min before GGI
and prior to discharge; blood sample for glucometer: every 3 hour during
overnight insulin infusion, at start of the GGI and 40, 80, 120 and 160 min
after start of GGI and 10 times during the weaning procedure

Insulin Infusion Procedures:
IV catheter placement: ~60 min before start of the insulin infusion; overnight
insulin infusion: 11 * 1 h before GGI, blood glucose concentration should be
kept between 5 mmol/L and 7.2 mmol/L

GGI Procedure:
infusion of glucose: 0 - 160 min on Day 1, glucose (20% glucose) will be
administered as a stepwise, graded infusion of 2, 4, 6, and 10 mg/kg/min
(down-regulated to 8 mg/kg/min at last step if applicable), each infusion step
should be maintained over exactly 40 minutes

Bionalysis:
analysis of oxyntomodulin samples using a validate method by Sponsor
analysis of liraglutide samples using a validate method by Sponsor
analysis of glucose samples using a clinical chemistry method by PRA
analysis of C-peptide samples using a clinical chemistry method by PRA
analysis of insulin samples using a clinical chemistry method by PRA
analysis of GLP-1/glucagon samples using a validated method by PRA

Insulin infusion
Oxyntomodulin infusion
Liraglutide injection

Procedures: pain, light bleeding, heamatoma and possibly an infection.