Renal catabolism of truncated glucagon-like peptide 1.

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.

Lipolytic action of glucagon-like peptides in isolated rat adipocytes.

The lipolytic effect of GLP-1(1-36)-amide, GLP-1(7-36) amide and GLP-2 [proglucagon(126-159)] has been studied in isolated rat adipocytes. Glycerol release and cyclic AMP content were measured after incubation of adipocytes with GLPs and results have been compared with those obtained in the presence of glucagon. GLP-1(7-36)-amide and GLP-1(1-36)-amide at 10(-8), 10(-7) and 10(-6) M concentrations activated glycerol release, the truncated peptide having a more potent effect. On the other hand, GLP-2 had no effect on glycerol release. Also, it has been found that 10(-6) M GLP-1(7-36)-amide increases cyclic AMP content in adipocytes and does not compete with glucagon binding. These results demonstrate that GLP-1(7-36)-amide has a lipolytic effect on isolated rat adipocytes through different receptors than glucagon.

Renal catabolism of human glucagon-like peptides 1 and 2.

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.