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 peptide.
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 t1/2 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 t1/2 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.
Deacon
C F
CF
Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark. deacon@mfi.ku.dk
Nauck
M A
MA
Meier
J
J
Hücking
K
K
Holst
J J
JJ
D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans
D005749:Gastric Inhibitory Polypeptide