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Degradation of Endogenous and Exogenous Gastric Inhibitory Polypeptide in Healthy and in Type 2 Diabetic Subjects as Revealed Using a New Assay for the Intact Peptide¹

Department of Medical Physiology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark; and Medizinische Klinik 1, St. Josef Hospital, Klinikum der Ruhr Universitäts Bochum (M.A.N.), and Medizinische Universitätsklinik, Knappschafts Krankenhaus (J.M., K.H.), D-44791 Bochum, Germany

Address all correspondence and requests for reprints to: Dr. C. F. Deacon, Department of Medical Physiology, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: deacon{at}mfi.ku.dk

Gastric inhibitory polypeptide (GIP) is susceptible to degradation, but only recently has dipeptidyl peptidase IV been identified as the enzyme responsible. Most RIAs recognize both intact GIP-(1–42) and the noninsulinotropic N-terminally truncated metabolite, GIP-(3–42), hampering measurement of plasma concentrations. The molecular nature of GIP was examined using high pressure liquid chromatography and a newly developed RIA specific for the intact N-terminus of human GIP. In healthy subjects after a mixed meal, intact GIP (N-terminal RIA) accounted for 37.0 ± 2.5% of the total immunoreactivity determined by C-terminal assay. High pressure liquid chromatographic analysis of fasting samples by C-terminal assay revealed one major peak (73.8 ± 2.9%) coeluting with GIP-(3–42). One hour postprandially, two major peaks were detected, corresponding to GIP-(3–42) and GIP-(1–42) (58.1 ± 2.7% and 35.7 ± 4.2%, respectively). GIP-(3–42) was not detected by N-terminal assay; the major peak coeluted with intact GIP (86.4 ± 5.8% and 81.3 ± 0.9%, 0 and 1 h, respectively). After iv infusion, intact GIP constituted 37.1 ± 4.1% and 41.3 ± 3.4% of the total immunoreactivity in healthy and type 2 diabetic subjects, respectively. The plasma t_1/2 was shorter (P < 0.0001) when determined by N-terminal compared with C-terminal assay (7.3 ± 1.0 vs. 16.8 ± 1.6 and 5.2 ± 0.6 vs. 12.9 ± 0.9 min, healthy and diabetic subjects, respectively), and both t_1/2 were shorter in the diabetic group (P < 0.05). We conclude that dipeptidyl peptidase IV is important in GIP metabolism in humans in vivo, and that an N-terminally directed assay is required for determination of plasma concentrations of biologically active GIP.

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