Liva S L Krogh, Mads M Helsted, Anders Englund, Natasha C Bergmann, Kirsa Skov-Jeppesen, Casper K Nielsen, Carsten P Hansen, Mette M Rosenkilde, Bolette Hartmann, Jens J Holst, Filip K Knop, Asger B Lund, Lærke S Gasbjerg
{"title":"GIP和GLP-1受体拮抗剂在全胰切除个体中的急性效应：一项随机、双盲、安慰剂对照的交叉研究","authors":"Liva S L Krogh, Mads M Helsted, Anders Englund, Natasha C Bergmann, Kirsa Skov-Jeppesen, Casper K Nielsen, Carsten P Hansen, Mette M Rosenkilde, Bolette Hartmann, Jens J Holst, Filip K Knop, Asger B Lund, Lærke S Gasbjerg","doi":"10.1111/dom.70186","DOIUrl":null,"url":null,"abstract":"<p><strong>Aims: </strong>The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals.</p><p><strong>Methods: </strong>Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH<sub>2</sub> (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH<sub>2</sub> (450 pmol/kg/min), GIP(3-30)NH<sub>2</sub> + exendin(9-39)NH<sub>2</sub>, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment.</p><p><strong>Results: </strong>Infusions of GIP(3-30)NH<sub>2</sub> and GIP(3-30)NH<sub>2</sub> + exendin(9-39)NH<sub>2</sub> attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) (ps <0.05)). During exendin(9-39)NH<sub>2</sub> and exendin(9-39)NH<sub>2</sub> + GIP(3-30)NH<sub>2</sub> co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH<sub>2</sub> or exendin(9-39)NH<sub>2</sub> did not affect other measurements.</p><p><strong>Conclusion: </strong>Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.7000,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study.\",\"authors\":\"Liva S L Krogh, Mads M Helsted, Anders Englund, Natasha C Bergmann, Kirsa Skov-Jeppesen, Casper K Nielsen, Carsten P Hansen, Mette M Rosenkilde, Bolette Hartmann, Jens J Holst, Filip K Knop, Asger B Lund, Lærke S Gasbjerg\",\"doi\":\"10.1111/dom.70186\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aims: </strong>The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals.</p><p><strong>Methods: </strong>Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH<sub>2</sub> (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH<sub>2</sub> (450 pmol/kg/min), GIP(3-30)NH<sub>2</sub> + exendin(9-39)NH<sub>2</sub>, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment.</p><p><strong>Results: </strong>Infusions of GIP(3-30)NH<sub>2</sub> and GIP(3-30)NH<sub>2</sub> + exendin(9-39)NH<sub>2</sub> attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) (ps <0.05)). During exendin(9-39)NH<sub>2</sub> and exendin(9-39)NH<sub>2</sub> + GIP(3-30)NH<sub>2</sub> co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH<sub>2</sub> or exendin(9-39)NH<sub>2</sub> did not affect other measurements.</p><p><strong>Conclusion: </strong>Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.</p>\",\"PeriodicalId\":158,\"journal\":{\"name\":\"Diabetes, Obesity & Metabolism\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2025-10-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Diabetes, Obesity & Metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/dom.70186\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetes, Obesity & Metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/dom.70186","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study.
Aims: The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals.
Methods: Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH2 (450 pmol/kg/min), GIP(3-30)NH2 + exendin(9-39)NH2, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment.
Results: Infusions of GIP(3-30)NH2 and GIP(3-30)NH2 + exendin(9-39)NH2 attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) (ps <0.05)). During exendin(9-39)NH2 and exendin(9-39)NH2 + GIP(3-30)NH2 co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH2 or exendin(9-39)NH2 did not affect other measurements.
Conclusion: Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.
期刊介绍：
Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.
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