Reduced insulin clearance contributes to the increased insulin levels after administration of glucagon-like peptide 1 in mice

Diabetologia. 2005 Oct;48(10):2140-6. doi: 10.1007/s00125-005-1915-z. Epub 2005 Aug 23.

Abstract

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) is known to be a potent stimulator of insulin secretion. However, whether GLP-1 also affects insulin clearance is not known. To explore this, we developed a technique to determine prehepatic insulin secretion in mice, based on deconvolution of plasma C-peptide concentrations. The estimated beta cell secretion was then related to plasma insulin levels to allow determination of clearance rate of endogenously produced insulin.

Materials and methods: Kinetic parameters of C-peptide were estimated after i.v. injection of human C-peptide (0.8 or 3 nmol/kg) or glucose (1 g/kg), either alone or together with GLP-1 (10 nmol/kg), in anaesthetised NMRI mice.

Results: C-peptide was distributed in two compartments (distribution volume 11.4+/-0.4 ml, 42+/-2% of which was in the accessible compartment). Fractional C-peptide clearance was 8.2+/-0.6% of the total distribution volume per minute. GLP-1 markedly enhanced prehepatic insulin secretion; more than 80% of prehepatic secretion occurred during the first minute after injection. Fractional clearance of endogenously released insulin after glucose was 0.66+/-0.11 min(-1) and this was reduced to 0.36+/-0.10 min(-1) by GLP-1 (p=0.04).

Conclusions/interpretation: It is possible to perform C-peptide deconvolution for estimating prehepatic insulin secretion in mice. GLP-1 reduces the clearance of endogenously released insulin; therefore, it may affect insulin levels by increasing prehepatic insulin secretion and by reducing insulin clearance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Area Under Curve
  • C-Peptide / metabolism
  • Female
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Injections, Intravenous
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Kinetics
  • Mice

Substances

  • C-Peptide
  • Insulin
  • Glucagon-Like Peptide 1
  • Glucose