Immunoblockade of endogenous glucagon-like peptide-1 by monoclonal antibodies in conscious rats: Effect on the insulin response to intragastric glucose

The physiological action of endogenous active forms of glucagon-like peptid e-1 (GLP-1) on the insulin response to intragastric glucose was studied in conscious male Wistar rats by immunoblockade with two monoclonal antibodies directed against different epitopes of GLP-1(7-36)amide. Plasma concentrat ions of intraperitoneally injected monoclonal antibodies were determined be fore and during each experiment by an enzyme-linked immunosorbent assay (EL ISA) specific for GLP-1-binding antibodies. Three hours after injection of the two monoclonal antibodies, the plasma insulin response (area under the curve) following intragastric glucose 1 g/kg was reduced to a mean level (m ean +/- SEM) of 60% +/- 8% (n = 11) of control responses previously determi ned in the same rats, and the time course of the response showed almost no increase in insulin during the first 10 minutes, reaching a maximum of 45.1 +/- 4.6 mu U/mL at 30 minutes, in contrast to the rapid increase of the co ntrol response to a maximum of 64.5 +/- 5.1 mu U/mL at 15 minutes. Total C- terminally amidated GLP-1 measured by radioimmunoassay (RIA) of acid ethano l-extracted plasma increased from a mean basal lever of 10 +/- 2 pmol/L to a peak of 31 +/- 5 pmol/L at 15 minutes in the control experiments, white b asal and response levels greater than 100 pmol/L were recorded after antibo dy treatment. The increase of plasma glucose was reduced in the presence of the antibodies, peaking at a mean of 9.7 +/- 0.3 mmol/L at 30 minutes, com pared with 11.8 +/- 0.5 mmol/L at 30 minutes in the control experiments. Th e action of GLP-1 appears particularly important for the early insulin resp onse to ingested glucose, and the unexpected effect of the antibodies on th e glucose response may point to a net promoting effect of GLP-1 on intestin al glucose absorption. Copyright (C) 1999 by W.B. Saunders Company.