The renal catabolism of [125I]glucagon-like peptide 1 (GLP-1) and [125I]glucagon-like peptide 2 (GLP-2) has been studied both in vivo, by the disappearance of these peptides from the plasma of bilaterally nephrectomized (BNX), ureteral-ligated (BUL) or normal rats, and in vitro, analyzing their catabolism by the isolated, perfused rat kidney. Results from in vivo studies demonstrated that half-disappearance time for both peptides was lower in controls than in BUL rats, and this value in BUL rats was not significantly different from that in BNX rats. In addition, metabolic clearance rate of GLP-1 was higher in control rats than in the other two groups of animals. Urinary clearance rate of both peptides was negligible. In isolated kidney experiments, values for organ clearance of both [125I]GLP-1 and [125I]GLP-2 were similar to those of inulin clearance, which represents the glomerular filtration rate. Urinary clearance of trichloroacetic acid precipitable radioactivity represented less than 1% of total clearance. In conclusion, these results demonstrate a significant role for the kidney in the plasma removal of [125I]GLP-1 and [125I]GLP-2 by a mechanism that involves glomerular filtration and tubular catabolism.

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We have searched for the contribution of the kidney to the catabolism of glucagon-like peptide-1 (7-36)amide or tGLP-1 by analyzing the disappearance of the [125I]tGLP-1 both in vivo, from the plasma of bilaterally nephrectomized (BNX), ureteral-ligated (BUL) and normal rats and in vitro from the perfusate of an isolated rat kidney system. Also, we have measured the degradation of the peptide by the isolated renal tubules. Results from in vivo studies demonstrated that the disappearance half-time (t1/2) of [125I]tGLP-1 was significantly lower in the control than in BUL or BNX rats with the metabolic clearance rate (MCR) being higher in the control than in BUL and BNX group; no difference was found for both parameters between BUL and BNX rats. The urinary excretion of the peptide was negligible. The data from the isolated kidney experiments showed a disappearance of the peptide, which was not due to its spontaneous degradation nor to enzymes released from the kidney to the perfusate. Degradation of the peptide also occurred in the presence of isolated tubules. It was dependent upon the concentration of tubules. This could possibly be due to the action of the brush border-associated peptidases. In conclusion, our results demonstrate that, in the rat, the kidney removes the exogenous tGLP-1 from the peripheral circulation, by a mechanism that involves glomerular filtration and tubular catabolism.

We have studied the binding of ml-GLP-l(7-36)amide to normal rat islet cells and rat insulinoma-derived RINm5F cells, and found it is time-and temperature-dependent, and directly proportional to cell concentration. In both cell types, the Scatchard plot demonstrates the presence of high-and low-affinity binding sites. The 50% inhibition of the maximal binding to 0.4 nM 1251-GLP-l(7-36)amide was obtained when cells were incubated in the presence of about 3.0 nM of unlabelled peptide. Glucagon, oxyntomodulin and GLP-l(7-36)amide at high concentrations (10 aM) do not compete with the 1251-GLP-l(7-36)amide binding. In pancreatic tumoral cells there seems to be a direct correlation between the maximal binding, the number of high-affinity binding sites and the amount of intracellular insulin.