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Diabetes 53:654-662, 2004
© 2004 by the American Diabetes Association, Inc.
Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects
1 Department of Medicine I, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
2 Diabeteszentrum Bad Lauterberg, Bad Lauterberg, Germany
3 Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
4 Outpatient Center for Diabetology and Nephrology, Bochum, Germany
Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important factors in the pathogenesis of type 2 diabetes and have a promising therapeutic potential. Alterations of their secretion, in vivo degradation, and elimination in patients with chronic renal insufficiency (CRI) have not yet been characterized. Ten patients with CRI (aged 47 ± 15 years, BMI 24.5 ± 2.2 kg/m2, and serum creatinine 2.18 ± 0.86 mg/dl) and 10 matched healthy control subjects (aged 44 ± 12 years, BMI 24.9 ± 3.4 kg/m2, and serum creatinine 0.89 ± 0.10 mg/dl) were included. On separate occasions, an oral glucose tolerance test (75 g), an intravenous infusion of GLP-1 (0.5 pmol · kg-1 · min-1 over 30 min), and an intravenous infusion of GIP (1.0 pmol · kg-1 · min-1 over 30 min) were performed. Venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1 (total and intact), and GIP (total and intact; specific immunoassays). Plasma levels of GIP (3–42) and GLP-1 (9–36 amide) were calculated. Statistics were performed using repeated-measures and one-way ANOVA. After the oral glucose load, plasma concentrations of intact GLP-1 and intact GIP reached similar levels in both groups (P = 0.31 and P = 0.87, respectively). The concentrations of GIP (3–42) and GLP-1 (9–36 amide) were significantly higher in the patients than in the control subjects (P = 0.0021 and P = 0.027, respectively). During and after the exogenous infusion, GLP-1 (9–36 amide) and GIP (3–42) reached higher plasma concentrations in the CRI patients than in the control subjects (P < 0.001 and P = 0.0033, respectively), whereas the plasma levels of intact GLP-1 and GIP were not different between the groups (P = 0.29 and P = 0.27, respectively). Plasma half-lives were 3.4 ± 0.6 and 2.3 ± 0.4 min for intact GLP-1 (P = 0.13) and 5.3 ± 0.8 and 3.3 ± 0.4 min for the GLP-1 metabolite (P = 0.029) for CRI patients vs. healthy control subjects, respectively. Plasma half-lives of intact GIP were 6.9 ± 1.4 and 5.0 ± 1.2 min (P = 0.31) and 38.1 ± 6.0 and 22.4 ± 3.0 min for the GIP metabolite (P = 0.032) for CRI patients vs. healthy control subjects, respectively. Insulin concentrations tended to be lower in the patients during all experiments, whereas C-peptide levels tended to be elevated. These data underline the importance of the kidneys for the final elimination of GIP and GLP-1. The initial dipeptidyl peptidase IV-mediated degradation of both hormones is almost unaffected by impairments in renal function. Delayed elimination of GLP-1 and GIP in renal insufficiency may influence the pharmacokinetics and pharmacodynamics of dipeptidyl peptidase IV-resistant incretin derivatives to be used for the treatment of patients with type 2 diabetes.
Address correspondence and reprint requests to Dr. Juris J. Meier, Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, 1333 San Pablo St., Los Angeles, CA 90033. E-mail: jmeier{at}usc.edu
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