Renal Catabolism of Truncated Glucagon-Like Peptide 1

Ruiz-Grande, Carmen; Alarcón, Cristina; Alcántara, Ana; Castilla, Carlos; Novoa, José Miguel López; Villanueva-Peñacarrillo, María Luisa; Valverde, Isabel

doi:10.1055/s-2007-1002190

Cited by 64 publications

(38 citation statements)

References 9 publications

(11 reference statements)

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“…Earlier studies already indicated that both incretin hormones are eliminated by the kidneys (12,13). This was supported by elevated plasma concentrations of GIP and GLP-1 found in patients with uremia (13a,13b).…”

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confidence: 80%

Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects

et al. 2004

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over 30 min), and an intravenous infusion of GIP (1.0 pmol ⅐ kg ؊1 ⅐ 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. Diabetes 53:654 -662, 2004

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confidence: 80%

Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects

et al. 2004

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“…Thus, it was concluded that the kidneys are not the primary site of DPPIV-mediated metabolism of GLP-1, but are important in the final elimination of its metabolites [11]. Only one study has sought to investigate the mechanisms behind the renal metabolism of GLP-1 and suggested that both glomerular filtration and tubular metabolism take place [12]. In rats, the half-life of GLP-1 was increased following bilateral ureteral ligation or nephrectomy, indicating that renal extraction of GLP-1 is not always dependent on the occurrence of glomerular filtration.…”

Section: Discussionmentioning

confidence: 99%

“…The same study also showed that renal clearance by the isolated kidney exceeded the simultaneously measured GFR, in agreement with the present study. Paradoxically however, renal clearance was almost eliminated in the non-filtering kidney [12], further underlining that additional studies are required to clarify precisely which mechanisms are involved.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the substantial enzymatic degradation, several studies have pointed to the kidney as an important mediator in the final elimination of GLP-1 and its metabolites. Autoradiographic studies demonstrated a tendency for GLP-1 to accumulate in the kidneys shortly after intravenous administration [10], while studies in nephrectomised rats and in patients with renal failure revealed reduced clearance of GLP-1 [11,12]. These findings have prompted much research into identifying metabolically stable analogues/derivatives of GLP-1 suitable for therapeutic use.…”

Section: Introductionmentioning

confidence: 99%

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Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

2006

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Aims/hypothesis: The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as a new agent for the treatment of type 2 diabetes mellitus. Exendin-4 is less prone to enzymatic degradation, but it is still unclear what other factors contribute to the increased metabolic stability. Materials and methods:The overall metabolism of GLP-1 and exendin-4 was directly compared in anaesthetised pigs (n=9). Results: Metabolism of GLP-1 (C-terminal RIA; t 1/2 2.0±0.2 min, metabolic clearance rate [MCR] 23.2±2.8 ml min −1 kg −1 ; N-terminal RIA; t 1/2 1.5±0.2 min, MCR 88.1±10.6 ml min −1 kg −1 ) was significantly faster than the metabolism of exendin-4 (t 1/2 22.0±2

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“…Elimination of bioactive GLP-1 from the circulation may occur via at least three different mechanisms: renal clearance, [30][31][32] hepatic clearance, 31 and degradation in the circulation by mainly dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5). 33,34 The differences in GLP-1 and insulin concentrations and dynamics between AAs and C, warrants further exploration.…”

Section: Discussionmentioning

confidence: 99%

Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects

et al. 2003

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Obese African-American (AA) subjects have higher resting and stimulated insulin concentrations than obese Caucasians (C), which could not be explained by the severity of obesity or the degree of insulin sensitivity. We investigated whether differences in glucagon-like peptide-1 (GLP-1), the most potent incretin that regulates insulin secretion, might explain racial differences in insulin response. Accordingly, we measured fasting and stimulated glucose, insulin, and GLP-1 levels during a 3-h oral glucose tolerance test (OGTT) in 26 obese C (age 3872 y, body mass index 4471 kg/m 2 ) and 16 obese AA (age 3672 y, BMI 4672 kg/ m 2 ) subjects. Corrected insulin response (CIR 30 ), a measure of b-cell activity, whole body insulin sensitivity index (WBISI), and area under the curve (AUC) for insulin, GLP-1, and C-peptide/insulin ratio were computed from the OGTT. Glucose levels, fasting and during the OGTT, were similar between racial groups; 32% of the C and 31% of the AA subjects had impaired glucose tolerance. Keywords: GLP-1; insulin; racial; b-cell activity Obesity is characterized by hyperinsulinemia and increased insulin resistance. 1 Several in vitro and in vivo studies have shown that hyperinsulinemia may play an important role in the pathogenesis of obesity through regulation of appetite, fat cell metabolism, and energy expenditure. 2-4 Recent different cross-sectional and longitudinal studies have reported that both lean and obese African Americans (AA) exhibit higher fasting and stimulated insulin levels when compared with their white counterparts. 5,6 Several studies have reported increased b-cell activity as the primary mechanism for this hyperinsulinemic state in black patients; 6 while others, have suggested that the hyperinsulinemia is the result of decreased hepatic insulin clearance 7 and reduced insulin sensitivity. 8 Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide gastric inhibitory polypeptide (GIP) are the two most important incretins. 9 In humans, GLP-1 results from post-translational processing of proglucagon in the intestinal L-cells and accounts for 80% of the intestinal incretin effect. 10 GLP-1's action is mediated by its binding to cell surface receptors (GLP-1R) that are highly expressed on the cell membranes of pancreatic b-cells. 10,11 In addition to stimulating insulin secretion, GLP-1 has been shown to have other profound biological effects on b-cells. 12 GLP-1 regulates b-cell function by maintaining a portion of the b-cell population in a glucose-competent state by making resistant islets glucose sensitive. [13][14][15][16] Recent evidence suggests that GLP-1 may also promote regeneration of islet cells and expansion of the b-cell mass. 12,17 Racial differences in GLP-1 concentrations in obese subjects have not been previously reported. Based on GLP-

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Renal Catabolism of Truncated Glucagon-Like Peptide 1

Cited by 64 publications

References 9 publications

Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects

Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects

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