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.

[1]  J. Holst,et al.  Inhibition of dipeptidyl peptidase IV with NVP-DPP728 increases plasma GLP-1 (7–36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats , 1999, Diabetologia.

[2]  J. Holst,et al.  Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity , 1998, Diabetologia.

[3]  O. Pedersen,et al.  Glomerular hyperfiltration in microalbuminuric NIDDM patients , 1996, Diabetologia.

[4]  R. Pederson,et al.  The enteroinsular axis in dipeptidyl peptidase IV-negative rats. , 1996, Metabolism: clinical and experimental.

[5]  R. Pederson,et al.  Investigation of Glucose-dependent Insulinotropic Polypeptide(1-42) and Glucagon-like Peptide-1-(7-36) Degradation in Vitro by Dipeptidyl Peptidase IV Using Matrix-assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry , 1996, The Journal of Biological Chemistry.

[6]  J. Holst,et al.  Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. , 1996, The American journal of physiology.

[7]  J. Holst,et al.  Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day. , 1996, Scandinavian journal of gastroenterology.

[8]  S. Anderson,et al.  Current concepts of renal hemodynamics in diabetes. , 1995, Journal of diabetes and its complications.

[9]  J. Holst,et al.  Both Subcutaneously and Intravenously Administered Glucagon-Like Peptide I Are Rapidly Degraded From the NH2-Terminus in Type II Diabetic Patients and in Healthy Subjects , 1995, Diabetes.

[10]  B. Göke,et al.  Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7–36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides , 1995, Regulatory Peptides.

[11]  R. Pederson,et al.  Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. , 1995, Endocrinology.

[12]  W. Or,et al.  Glomerular filtration rate and kidney size in type 2 (non-insulin-dependent) diabetes mellitus. , 1995 .

[13]  J. Holst,et al.  Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. , 1995, The Journal of clinical endocrinology and metabolism.

[14]  K. Minaker,et al.  The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects , 1994, Regulatory Peptides.

[15]  L. B. Knudsen,et al.  Structure-activity studies of glucagon-like peptide-1. , 1994, The Journal of biological chemistry.

[16]  B. Gallwitz,et al.  Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. , 1993, European journal of biochemistry.

[17]  M. Nauck,et al.  Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. , 1993, The Journal of clinical endocrinology and metabolism.

[18]  J. Holst,et al.  Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. , 1993, The Journal of clinical investigation.

[19]  G. Weir,et al.  Glucagon-like peptide-I analogs: effects on insulin secretion and adenosine 3',5'-monophosphate formation. , 1990, Endocrinology.

[20]  M. Nauck,et al.  Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin-8. , 1989, The Journal of clinical endocrinology and metabolism.

[21]  S. Bloom,et al.  GLUCAGON-LIKE PEPTIDE-1 7-36: A PHYSIOLOGICAL INCRETIN IN MAN , 1987, The Lancet.

[22]  R. Poljak Synthetic peptides as antigen , 1986 .

[23]  J. Holst,et al.  Responses and molecular heterogeneity of IR-GIP after intraduodenal glucose and fat. , 1985, The American journal of physiology.

[24]  K. Sirinek,et al.  Chronic renal failure: effect of hemodialysis on gastrointestinal hormones. , 1984, American journal of surgery.

[25]  J. Holst,et al.  The heterogeneity of gastric inhibitory polypeptide in porcine and human gastrointestinal mucosa evaluated with five different antisera , 1984, Regulatory Peptides.

[26]  W. Meyers,et al.  The hepatic extraction of gastric inhibitory polypeptide and insulin. , 1984, Endocrinology.

[27]  J. Holst,et al.  Diminished immunoreactive gastric inhibitory polypeptide response to a meal in newly diagnosed type I (insulin-dependent) diabetics. , 1983, The Journal of clinical endocrinology and metabolism.

[28]  S. Bloom,et al.  The pharmacokinetics of porcine glucose‐dependent insulinotropic polypeptide (GIP) in man , 1982, European journal of clinical investigation.

[29]  J. Brown,et al.  Actions of GIP , 1981, Peptides.

[30]  V. Mutt,et al.  Amino acid sequence and heterogeneity of gastric inhibitory polypeptide (GIP) , 1981, FEBS letters.

[31]  R. Jorde,et al.  Removal of IR-GIP by the kidneys in man, and the effect of acute nephrectomy on plasma GIP in rats. , 1981, Scandinavian journal of gastroenterology.

[32]  E. Mazzaferri,et al.  Renal effects on serum gastric inhibitory polypeptide (GIP). , 1977, Metabolism: clinical and experimental.