Vol 5, No 4 (2004): Practical Diabetology
Other materials agreed with the Editors
Published online: 2004-07-21
One week's treatment with the long-acting glucagon-like peptide 1 derivate liraglutide (NN2211) markedly improves 24-h glycemia and α- and β-cell function and reduces endogenous glucose release in patients with type 2 diabetes
Diabetologia Praktyczna 2004;5(4):225-236.
Abstract
Glucagon-like peptide 1 (GLP-1) is potentially a very
attractive agent for treating type 2 diabetes. We
explored the effect of short-term (1 week) treatment
with a GLP-1 derivative, liraglutide (NN2211), on 24-h
dynamics in glycemia and circulating free fatty acids,
islet cell hormone profiles, and gastric emptying
during meals using acetaminophen. Furthermore,
fasting endogenous glucose release and gluconeogenesis
(3-3Hglucose infusion and 2H2O ingestion, respectively)
were determined, and aspects of pancreatic
islet cell function were elucidated on the subsequent
day using homeostasis model assessment
and first- and second-phase insulin response during
a hyperglycemic clamp (plasma glucose ~16 mmol/l),
and, finally, on top of hyperglycemia, an arginine
stimulation test was performed. For accomplishing
this, 13 patients with type 2 diabetes were examined
in a double-blind, placebo-controlled crossover
design. Liraglutide (6 μg/kg) was administered subcutaneously
once daily. Liraglutide significantly reduced
the 24-h area under the curve for glucose
(P = 0.01) and glucagon (P = 0.04), whereas the area
under the curve for circulating free fatty acids was
unaltered. Twenty-four-hour insulin secretion rates
as assessed by deconvolution of serum C-peptide
concentrations were unchanged, indicating a relative
increase. Gastric emptying was not influenced at
the dose of liraglutide used. Fasting endogenous
glucose release was decreased (P = 0.04) as a result
of a reduced glycogenolysis (P = 0.01), whereas gluconeogenesis
was unaltered. First-phase insulin response
and the insulin response to an arginine stimulation
test with the presence of hyperglycemia
were markedly increased (P < 0.001), whereas the
proinsulin/insulin ratio fell (P = 0.001). The disposition
index (peak insulin concentration after intravenous
bolus of glucose multiplied by insulin sensitivity
as assessed by homeostasis model assessment)
almost doubled during liraglutide treatment (P < 0.01).
Both during hyperglycemia per se and after arginine
exposure, the glucagon responses were reduced
during liraglutide administration (P < 0.01 and
P = 0.01). Thus, 1 week’s treatment with a single
daily dose of the GLP-1 derivative liraglutide, operating
through several different mechanisms including
an ameliorated pancreatic islet cell function in individuals
with type 2 diabetes, improves glycemic control
throughout 24 h of daily living, i.e., prandial and
nocturnal periods. This study further emphasizes
GLP-1 and its derivatives as a promising novel concept
for treatment of type 2 diabetes.
Keywords: liraglutideglucagon-like peptide 1glycemic controltype 2 diabetes