Charakterisierung der Eliminationskinetik des glukagonähnlichen Peptids-1 als Substrat der Dipeptidyl-Peptidase-IV mit und ohne Enzymhemmung am Modell der Ratte

Orally and intravenously administered glucose yields comparable
levels of glucose in plasma but different responses of
insulin-release. Specialised mucosa cells react to glucose contents
in chyme with release of glucagon-like peptide-1 (GLP-1) into the
portal bloodstream, a peptide hormone, that makes beta-cells more
sensitive to the subsequent glucose stimulus and thereby enhances
the insulin-release exclusively under increased blood glucose
levels without causing the insulin-release directly. The capacity
of this entero-insular axis is limited primarily by the endogenous
enzyme dipeptidyl peptidase IV (DPP-IV). Prevailingly the most
progressive approach to therapy of non-insulin-dependent diabetes
mellitus (NIDDM) in human medicine is targeted on the inhibition of
DPP-IV, in order to raise GLP-1 concentration in plasma and to
increase consequently the insulin-release in dependence on elevated
blood glucose levels. In the limelight of discussion are the
advantages of certain avoidance of insulin-caused hypoglycaemia on
the one hand and the possibility of oral administration of the
antienzyme on the other hand. In contrast to the condition in dogs,
where the disease manifests almost exclusively in the form of
secondary (insulin-dependent) diabetes mellitus, the type 2 (NIDDM)
predominates in humans as well as in cats, whence it comes that the
employment of oral antidiabetics in the latter species is quite
promising, as the experience with the sulfonyl urea derivative
glipizide has shown. As however the residual capacity of beta-cells
of feline diabetics with regard to the release of endogenous
insulin is subject to considerable variation, the risk of inducing
hypoglycaemia is given by use of both insulin and sulfonyl urea
derivatives, whereas this threat is circumvented by use of
DPP-IV-inhibitors. In the present thesis the effect of DPP-IV
inhibition on the elimination kinetics of GLP-1 is described by
means of systematically combined infusion of the enzyme’s substrate
(GLP-1) and its antienzyme in the rat model. The maximum effective
dose of DPP-IV inhibitor is determined and the portion of hepatic
clearance and whole blood clearance of total elimination of GLP-1
without concurrent DPP-IV inhibition is quantified approximately by
means of isolated perfused rat livers and in-vitro-experiments.
Finally the dependence of results on the respective experimental
design is demonstrated. The total clearance of GLP-1 as substrate
of DPP-IV without concurrent inhibition amounts to at least 57 ± 17
(mL/min)/kg and under influence of the DPP-IV-inhibitor to at least
22 ± 2 (mL/min)/kg. The value of clearance is highly dependent on
the respective substrate concentration in plasma, so that the
values range from 139 ± 57 (mL/min)/kg to 73 ± 15 (mL/min)/kg
within the bounds of physiological GLP-1 concentrations in plasma.
The maximum increase of GLP-1 levels in plasma (factor 3.4) on
average of all GLP-1 infusion rates was attained by a DPP-IV
inhibitor concentration in plasma of 0.4 µmol/L. The liver as
central detoxication-organ figures out at 57 % (34/60) of total
clearance, the soluble DPP-IV fraction in plasma however accounts
for only about 1 % (0.7/60) of total clearance. The relatively low
hepatic extraction ratio of 30 ± 11 % reversely allows seven out of
ten GLP-1 molecules to enter the systemic circulation in spite of
the first-pass-effect and thereby to reach possibly the receptors
on the beta-cells (70 % bioavailability). The half-life of GLP-1
(7-36 amide) in the isolated perfused rat liver amounts to 5.0 ±
1.3 minutes, hereby differing statistically not significantly (p =
0.114) from the half-life of GLP-1 (7-37) with 6.1 ± 1.6 minutes.