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

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.

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

“…It is well accepted that, in type 2 diabetes, insulin clearance is usually impaired and associated with insulin resistance and loss of beta cell mass. However, it is not known whether this reduction is an early cause and precedes the other symptoms [2,30,35] or whether this is a compensatory mechanism to ameliorate the effects of lower insulin secretion and increased insulin resistance [21,36,37].…”

“…Insulin clearance was evaluated as previously described [21]. The constant rate for insulin disappearance (insulin decay) was calculated by first converting insulin measurements into natural logarithm (Ln); the slope was calculated using linear regression (time × Ln [insulin]) and multiplied by 100 to obtain the insulin decay constant rate per minute (%/min).…”

Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet

“…GLP-1 retards insulin clearance from the circulation in mice (2), which suggests that OXM may also slow insulin clearance to elevate glucose-induced plasma insulin levels. This inference is strongly supported by our finding that OXM administration more than doubled plasma insulin concentrations in the face of insulin infusion rates similar to those in placebo-treated animals during the hyperinsulinemic clamp.…”

Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

“…Insulin clearance was evaluated as described previously (Ahrén et al 2005). The constant rate for insulin disappearance (insulin decay) was calculated by first converting the insulin measurements into natural logarithm (Ln); the slope was calculated using linear regression (time!Ln(insulin)) and multiplied by 100 to obtain the insulin decay constant rate per minute (%/min).…”