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Secretion, Degradation, and Elimination of Glucagon-Like

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Secretion, Degradation, and Elimination of Glucagon-Like Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects Juris J. Meier,1 Michael A. Nauck,1,2 Daniel Kranz,1 Jens J. Holst,3 Carolyn F. Deacon,3 Dirk Gaeckler,4 Wolfgang E. Schmidt,1 and Baptist Gallwitz1 CRI patients vs. healthy control subjects, respectively. ؎ ؎ Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important factors in the patho- Plasma half-lives of intact GIP were 6.9 1.4 and 5.0 ؎ ؎ ؍ genesis of type 2 diabetes and have a promising thera- 1.2 min (P 0.31) and 38.1 6.0 and 22.4 3.0 min for ؍ peutic potential. Alterations of their secretion, in vivo the GIP metabolite (P 0.032) for CRI patients vs. degradation, and elimination in patients with chronic healthy control subjects, respectively. Insulin concen- renal insufficiency (CRI) have not yet been character- trations tended to be lower in the patients during all ized. Ten patients with CRI (aged 47 ؎ 15 years, BMI experiments, whereas C-peptide levels tended to be kg/m2, and serum creatinine 2.18 ؎ 0.86 elevated. These data underline the importance of the 2.2 ؎ 24.5 mg/dl) and 10 matched healthy control subjects (aged kidneys for the final elimination of GIP and GLP-1. The years, BMI 24.9 ؎ 3.4 kg/m2, and serum creati- initial dipeptidyl peptidase IV–mediated degradation of 12 ؎ 44 nine 0.89 ؎ 0.10 mg/dl) were included. On separate both hormones is almost unaffected by impairments in occasions, an oral glucose tolerance test (75 g), an renal function. Delayed elimination of GLP-1 and GIP in intravenous infusion of GLP-1 (0.5 pmol ⅐ kg؊1 ⅐ min؊1 renal insufficiency may influence the pharmacokinetics over 30 min), and an intravenous infusion of GIP (1.0 and pharmacodynamics of dipeptidyl peptidase IV–resis- pmol ⅐ kg؊1 ⅐ min؊1 over 30 min) were performed. Venous tant incretin derivatives to be used for the treatment of blood samples were drawn for the determination of patients with type 2 diabetes. Diabetes 53:654–662, glucose (glucose oxidase), insulin, C-peptide, GLP-1 2004 (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 per- formed using repeated-measures and one-way ANOVA. nsulin secretion after the ingestion of a mixed meal After the oral glucose load, plasma concentrations of is stimulated not only by the rise in glucose concen- intact GLP-1 and intact GIP reached similar levels in trations but also by the secretion of incretin hor- respectively). The ,0.87 ؍ and P 0.31 ؍ both groups (P concentrations of GIP (3-42) and GLP-1 (9-36 amide) Imones, namely glucagon-like peptide 1 (GLP-1) and were significantly higher in the patients than in the gastric inhibitory polypeptide (GIP; also referred to as respec- glucose-dependent insulinotropic polypeptide), from the ,0.027 ؍ and P 0.0021 ؍ control subjects (P tively). During and after the exogenous infusion, GLP-1 gut (1,2). Both hormones are currently considered for the (9-36 amide) and GIP (3-42) reached higher plasma treatment of type 2 diabetes because of their glucose- concentrations in the CRI patients than in the control lowering activity (3,4). However, the therapeutic use of the .respectively), peptides is still limited by their short in vivo half-lives ,0.0033 ؍ subjects (P < 0.001 and P whereas the plasma levels of intact GLP-1 and GIP were Both hormones are cleaved within minutes at the NH - 2 ,0.27 ؍ and P 0.29 ؍ not different between the groups (P ,(terminus by the enzyme dipeptidyl peptidase IV (DPP IV ؎ ؎ respectively). Plasma half-lives were 3.4 0.6 and 2.3 yielding the fragments GLP-1 (9-36 amide) and GIP (3-42) and 5.3 ؎ 0.8 and (0.13 ؍ min for intact GLP-1 (P 0.4 for (5,6). The cleavage products have lost their insulinotropic (0.029 ؍ min for the GLP-1 metabolite (P 0.4 ؎ 3.3 activity and may even act as partial antagonists at their respective receptors (7–9). Different approaches are currently being evaluated to From the 1Department of Medicine I, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany; the 2Diabeteszentrum Bad Lauterberg, Bad make use of the therapeutic potential of the incretin Lauterberg, Germany; the 3Department of Medical Physiology, The Panum hormones: DPP IV–resistant analogues of GIP and GLP-1 Institute, University of Copenhagen, Copenhagen, Denmark; and the 4Outpa- have been synthesized to extend the in vivo half-life of the tient Center for Diabetology and Nephrology, Bochum, Germany. Address correspondence and reprint requests to Dr. Juris J. Meier, Division peptides (10,11), and inhibitors of the degrading enzyme of Endocrinology and Diabetes, Keck School of Medicine, University of DPP IV have been generated to block the rapid degrada- Southern California, 1333 San Pablo St., Los Angeles, CA 90033. E-mail: [email protected]. tion of endogenous GIP and GLP-1 (11a). Received for publication 22 September 2003 and accepted in revised form Earlier studies already indicated that both incretin hor- 21 November 2003. mones are eliminated by the kidneys (12,13). This was CRI, chronic renal insufficiency; DPP IV, dipeptidyl peptidase IV; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1. supported by elevated plasma concentrations of GIP and © 2004 by the American Diabetes Association. GLP-1 found in patients with uremia (13a,13b). However, 654 DIABETES, VOL. 53, MARCH 2004 J.J. MEIER AND ASSOCIATES TABLE 1 Characteristics of the subjects/patients Healthy control Parameter subjects Patients with CRI Significance (P value)* Anthropometric data Sex (female/male) 4/6 5/5 0.65 Age (years) 44 Ϯ 12 47 Ϯ 15 0.59 BMI (kg/m2) 24.9 Ϯ 3.4 24.5 Ϯ 2.2 0.80 Waist-to-hip ratio (cm/cm) 0.81 Ϯ 0.09 0.92 Ϯ 0.05 0.31 Hematological, metabolic, and lipid parameters Hemoglobin (g/dl) 14.3 Ϯ 0.44 11.9 Ϯ 0.3 0.00033 Fasting glucose (mmol/l) 5.66 Ϯ 0.56 5.28 Ϯ 0.72 0.24 120-min glucose (mmol/l)† 6.94 Ϯ 1.0 6.17 Ϯ 1.33 0.17 Ϯ Ϯ HbA1c (%) 5.9 0.5 5.6 0.7 0.38 Ϯ Ϯ HOMAB-cell function (% normal)‡ 88 55 78 59 0.70 Ϯ Ϯ HOMAinsulin resistance (fold normal)‡ 2.48 2.08 1.49 1.19 0.21 Total cholesterol (mmol/l) 5.67 Ϯ 1.37 5.05 Ϯ 0.73 0.21 HDL cholesterol (mmol/l) 1.11 Ϯ 0.44 1.27 Ϯ 0.65 0.54 LDL cholesterol (mmol/l) 4.144 Ϯ 1.22 3.21 Ϯ 0.47 0.039 Triglycerides (mmol/l) 1.85 Ϯ 1.2 1.49 Ϯ 0.87 0.46 Hypertension (yes/no) 0/10 9/1 Ͻ0.0001 Blood pressure Systolic (mmHg) 121 Ϯ 12 127 Ϯ 11 0.25 Diastolic (mmHg) 82 Ϯ 784Ϯ 4 0.43 Parameters of kidney function Serum creatinine (mg/dl) 0.89 Ϯ 0.10 2.18 Ϯ 0.86 0.00016 Serum urea (mg/dl) 25.9 Ϯ 3.86 84.7 Ϯ 27.7 Ͻ0.0001 Creatinine clearance (ml/min)§ 107 Ϯ 27 46 Ϯ 24 Ͻ0.0001 Cystatin C (mg/l) 0.71 Ϯ 0.13 1.9 Ϯ 0.46 Ͻ0.0001 Albuminuria (mg/day) 20.7 Ϯ 46 350.2 Ϯ 602 0.12 Proteinuria (mg/day) 150 Ϯ 151 827 Ϯ 128 0.14 Data are means Ϯ SD. *ANOVA or ␹2 test. †120 min after oral glucose ingestion. ‡Calculated according to (24). §Calculated according to (25). because those studies were based on immunoassays that ments of standard hematologic and clinical chemistry parameters. Urine was were unable to discriminate the intact hormone levels collected over 24 h for the determination of albumin and protein by standard methods. Patients with anemia (hemoglobin Ͻ10 g/dl) and elevation in liver from their respective degradation products, it was not enzymes (alanine aminotransferase, aspartate aminotransferase, AP, ␥-glu- possible to take DPP IV–mediated degradation of the tamine transferase) to higher activities than double the respective normal hormones into consideration. The availability of specific value were excluded. The participant characteristics are presented in Table 1. The diagnoses leading to renal insufficiency included immunoglobulin A antibodies raised against the NH2-termini of intact GIP (1-42) and GLP-1 (7-36 amide) now allows determination nephropathy (Berger’s disease) in three cases, amyloidosis in one case, cystic kidney disease in two cases, secondary nephroangiosclerosis in two cases, of their degradation and elimination in more detail (6,20). and hereditary renal dysplasia in two cases. Five CRI patients and four control Type 2 diabetes is often complicated by the develop- subjects who had participated in the screening were excluded because they ment of renal insufficiency (17). This may have an influ- had impaired glucose tolerance. Nine patients with renal insufficiency re- ence on the pharmacokinetic and pharmacodynamic ceived one or more antihypertensive drugs: angiotensin-converting enzyme inhibitors in seven, angiotensin II receptor antagonists in four, ␤-blocking properties of incretin derivatives to be used as antidiabetic agents in three, diuretics in five, calcium antagonists in three, and ␣-blocking drugs. Therefore, we studied the secretion as well as the agents in two cases. In contrast, none of the control subjects received degradation and elimination of GIP and GLP-1 in patients antihypertensive medication.
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