The truncated metabolite GLP-2 (3–33) interacts with the GLP-2 receptor as a partial agonist

Thulesen, Jesper; Knudsen, Lotte Bjerre; Hartmann, Bolette; Hastrup, Sven; Kissow, Hannelouise; Jeppesen, Palle Bekker; Ørskov, Cathrine; Holst, Jens J.; Poulsen, Steen Seier

doi:10.1016/s0167-0115(01)00316-0

Cited by 71 publications

(78 citation statements)

References 27 publications

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“…Our findings suggest that the N-and Ctermini of GLP-2 are needed for maintaining the intrinsic and binding activities, respectively, of human summarizes their binding and intrinsic agonistic activities. GLP-2(3-33) had 1/300 the EC 50 value of GLP-2 but retained about 60% of its intrinsic activity, as reported by Thulesen et al (24). GLP-2(6-33) exhibited similar activity to GLP-2(3-33).…”

Section: Resultssupporting

confidence: 68%

“…GLP-2(3-33), which is generated by DPPIV in vivo (8,12), exhibits partial agonist and antagonist properties (24). This peptide has been used as a GLP-2R antagonist in both in vitro and in vivo experiments (1,2,14,22).…”

Section: Resultsmentioning

confidence: 99%

“…GLP-2(3-33) has been used as an antagonist of GLP-2R and is generated naturally by DPPIV in vivo (8,12). However, this peptide is also a partial agonist with relatively high activity (24). To search for more potent antagonists to help investigate the binding mode of action of agonists and ago-allosteric modulators of GLP-2R, we examined several truncated GLP-2 peptides.…”

Section: Generation Of Cell Lines Stably Expressing Cre-plapmentioning

confidence: 99%

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A novel truncated glucagon-like peptide 2 (GLP-2) as a tool for analyzing GLP-2 receptor agonists

et al. 2013

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Glucagon-like peptide 2 (GLP-2) is an intestinotropic peptide that binds to GLP-2 receptor (GLP-2R), a class-B G protein-coupled receptor. The GLP-2R antagonist GLP-2(3-33) has relatively high partial agonistic activity, and there are as yet no ideal known potent GLP-2R antagonists. We therefore prepared several truncated forms of human GLP-2 and characterized them by binding and reporter assays to find antagonists more potent than GLP-2(3-33). We found that GLP-2(11-33) was the most potent orthosteric GLP-2R antagonist, with binding activity almost equal to those of GLP-2 and GLP-2(3-33) and weaker intrinsic agonistic activity than GLP-2(3-33). GLP-2(11-33) retained weak agonistic activity toward human, cynomolgus monkey, dog, and Syrian hamster GLP-2Rs. However, it had no agonistic activity toward rat GLP-2R. GLP-2(11-33) potentiated the agonistic activity of an ago-allosteric modulator of GLP-2R, compound 1 (N-[1-(2,5-dichlorothiophen-3-yl)-2-(phenylsulfanyl)ethylidene]hydroxylamine), synergistically toward human GLP-2R. In the case of rat GLP-2R, GLP-2(11-33) decreased the agonistic activity of compound 1, although GLP-2 and GLP-2(3-33) increased this activity additively. These findings suggest that the binding sites of the ago-allosteric modulator and GLP-2 overlap, at least in rat GLP-2R. GLP-2(11-33) is a novel, useful tool for analyzing the mode of action of agonists and ago-allosteric modulators of GLP-2R.

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Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Generation Of Cell Lines Stably Expressing Cre-plapmentioning

confidence: 99%

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A novel truncated glucagon-like peptide 2 (GLP-2) as a tool for analyzing GLP-2 receptor agonists

et al. 2013

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“…GLP2 is cleaved to inactive GLP2 (3-33) by DPP-IV; consequently, the halflife of intravenous GLP2 is very short, about 7 min in healthy humans . Indeed, GLP2 (3-33) may act as a weak agonist at pharmacological concentrations (Shin et al 2005); however, it is able to act as a competitive antagonist of the GLP2 receptor (GLP2R) in rodents (Thulesen et al 2002, Shin et al 2005. Then DPP-IV-resistant GLP2 analogues, such as [Gly 2 ]-GLP2 (teduglutide), exhibit greater bioactivity relative to native molecule, due to their longer circulating half-lives (Tavares et al 2000, Baldassano & Amato 2014.…”

Section: Overview On Glp2mentioning

confidence: 99%

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

Amato¹,

Baldassano²,

Mulè³

2016

Journal of Endocrinology

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Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide produced by intestinal enteroendocrine L-cells and by a discrete population of neurons in the brainstem, which projects mainly to the hypothalamus. The main biological actions of GLP2 are related to the regulation of energy absorption and maintenance of mucosal morphology, function and integrity of the intestine; however, recent experimental data suggest that GLP2 exerts beneficial effects on glucose metabolism, especially in conditions related to increased uptake of energy, such as obesity, at least in the animal model. Indeed, mice lacking GLP2 receptor selectively in hypothalamic neurons that express proopiomelanocortin show impaired postprandial glucose tolerance and hepatic insulin resistance (by increased gluconeogenesis). Moreover, GLP2 acts as a beneficial factor for glucose metabolism in mice with high-fat diet-induced obesity. Thus, the aim of this review is to update and summarize current knowledge about the role of GLP2 in the control of glucose homeostasis and to discuss how this molecule could exert protective effects against the onset of related obesity type 2 diabetes.

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“…Parallel studies using the sister incretin hormone, GLP-1, have also shown that the truncated GLP-1(9-36) amide degradation product can act as a GLP-1 receptor antagonist (Knudsen & Pridal 1996, Green et al 2004b). Interestingly, GLP-2(3-33), which also arises from proglucagon processing in the intestine, may act as a competitive GLP-2 receptor antagonist (Thulesen et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Parker

Lavery

Irwin

et al. 2006

Journal of Endocrinology

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Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and AbstractGlucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important enteroendocrine hormones that are rapidly degraded by an ubiquitous enzyme dipeptidyl peptidase IV to yield truncated metabolites GIP(3-42) and GLP-1(9-36)amide. In this study, we investigated the effects of sub-chronic exposure to these major circulating forms of GIP and GLP-1 on blood glucose control and endocrine pancreatic function in obese diabetic (ob/ob) mice. A once daily injection of either peptide for 14 days had no effect on body weight, food intake or pancreatic insulin content or islet morphology. GLP-1(9-36)amide also had no effect on plasma glucose homeostasis or insulin secretion. Mice receiving GIP(3-42) exhibited small but significant improvements in non-fasting plasma glucose, glucose tolerance and glycaemic response to feeding. Accordingly, plasma insulin responses were unchanged suggesting that the observed enhancement of insulin sensitivity was responsible for the improvement in glycaemic control. These data indicate that sub-chronic exposure to GIP and GLP-1 metabolites does not result in physiological impairment of insulin secretion or blood glucose control. GIP(3-42) might exert an overall beneficial effect by improving insulin sensitivity through extrapancreatic action.

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The truncated metabolite GLP-2 (3–33) interacts with the GLP-2 receptor as a partial agonist

Cited by 71 publications

References 27 publications

A novel truncated glucagon-like peptide 2 (GLP-2) as a tool for analyzing GLP-2 receptor agonists

A novel truncated glucagon-like peptide 2 (GLP-2) as a tool for analyzing GLP-2 receptor agonists

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

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