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Daniel J Drucker - One of the best experts on this subject based on the ideXlab platform.

  • discovery characterization and clinical development of the glucagon like Peptides
    Journal of Clinical Investigation, 2017
    Co-Authors: Daniel J Drucker, Joel F Habener, Jens J. Holst
    Abstract:

    The discovery, characterization, and clinical development of Glucagon-Like-peptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance.

  • Glucagon-Like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway
    Elsevier, 2017
    Co-Authors: Bernardo Yusta, Dianne Matthews, Grace B. Flock, John R. Ussher, Brigitte Lavoie, Gary M. Mawe, Daniel J Drucker
    Abstract:

    Objective: Glucagon-Like Peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown. Methods: We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, Glp2r−/− and Tgr5−/− mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized ex vivo. Results: Acute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose-dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous Glp2r in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in Tgr5−/− mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in Glp2r−/− but not in Tgr5−/− mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM ex vivo, in a tetrodotoxin-sensitive manner. Conclusions: Our data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease. Keywords: Bile acids, Gallbladder, Enteroendocrine, Glucagon-Like peptide, TGR5, GLP-1, GLP-

  • GASTROENTEROLOGY 2000;119:744–755 Enteroendocrine Localization of GLP-2 Receptor Expression in Humans and Rodents
    2013
    Co-Authors: Bernardo Yusta, Sylvia L. Asa, Lilly Huang, Donald Munroe, Gabrielle Wolff, Robert Fantaske, Sadhana Sharma, Lidia Demchyshyn, Daniel J Drucker
    Abstract:

    product of the proglucagon gene, is expressed in enteroendocrine cells of the small and large intestine and is trophic to the gastrointestinal mucosa. GLP-2 also inhibits gastric acid secretion and emptying and upregulates intestinal hexose transport. GLP-2 acts via binding to a single G protein–coupled GLP-2 receptor (GLP-2R), but the cellular targets for the diverse actions of GLP-2 remain unknown. Methods: GLP-2R expression in rodent and human tissues was examined using a combination of Northern blotting, reverse-transcription polymerase chain reaction (RT-PCR), and immunocytochemistry. Results: A single major GLP-2R messenger RNA transcript was detected by Northern blot analysis in rodent stomach, duodenum, jejunum, ileum, and colon, but not in rodent esophagus. GLP-2R expression was also detected by RT-PCR in RNA from the hypothalamus, brain stem, and lung. Immunocytochemical localization of human GLP-2R expression using specific antisera detected GLP-2R immunopositivity in subsets of endocrine cell populations in the epithelium of the stomach and both the small and large bowel. Conclusions: These findings suggest that enteroendocrine-derived GLP-2 acts directly on endocrine cells to induce one or more downstream mediators of GLP-2 action in the gastrointestinal tract. The proglucagon gene encodes multiple Peptides related in amino acid sequence that are liberated in a tissue-specific manner in the brain, pancreas, and the enteroendocrine cells of the gastrointestinal tract. Glucagon, a 29–amino acid peptide, is secreted from islet A cells and plays a key role in glucose homeostasis. In contrast, several Peptides with distinct biological activities are secreted from enteroendocrine cells of the small and large bowel, including glicentin, oxyntomodulin, and 2 Glucagon-Like Peptides (GLPs) designated GLP-

  • minireview glucagon like Peptides regulate cell proliferation and apoptosis in the pancreas gut and central nervous system
    Endocrinology, 2004
    Co-Authors: P L Brubaker, Daniel J Drucker
    Abstract:

    Gut Peptides exert diverse effects regulating satiety, gastrointestinal motility and acid secretion, epithelial integrity, and both nutrient absorption and disposal. These actions are initiated by activation of specific G protein-coupled receptors and may be mediated by direct or indirect effects on target cells. More recent evidence demonstrates that gut Peptides, exemplified by Glucagon-Like Peptides-1 and 2 (GLP-1 and GLP-2), directly regulate signaling pathways coupled to cell proliferation and apoptosis. GLP-1 receptor activation enhances beta-cell proliferation and promotes islet neogenesis via activation of pdx-1 expression. The proliferative effects of GLP-1 appear to involve multiple intracellular pathways, including stimulation of Akt, activation of protein kinase Czeta, and transactivation of the epidermal growth factor receptor through the c-src kinase. GLP-1 receptor activation also promotes cell survival in beta-cells and neurons via increased levels of cAMP leading to cAMP response element binding protein activation, enhanced insulin receptor substrate-2 activity and, ultimately, activation of Akt. These actions of GLP-1 are reflected by expansion of beta-cell mass and enhanced resistance to beta-cell injury in experimental models of diabetes in vivo. GLP-2 also promotes intestinal cell proliferation and confers resistance to cellular injury in a variety of cell types. Administration of GLP-2 to animals with experimental intestinal injury promotes regeneration of the gastrointestinal epithelial mucosa and confers resistance to apoptosis in an indirect manner via yet-to-be identified GLP-2 receptor-dependent regulators of mucosal growth and cell survival. These proliferative and antiapoptotic actions of GLP-1 and GLP-2 may contribute to protective and regenerative actions of these Peptides in human subjects with diabetes and intestinal disorders, respectively.

  • glucagon like Peptides regulators of cell proliferation differentiation and apoptosis
    Molecular Endocrinology, 2003
    Co-Authors: Daniel J Drucker
    Abstract:

    Peptide hormones are secreted from endocrine cells and neurons and exert their actions through activation of G protein-coupled receptors to regulate a diverse number of physiological systems including control of energy homeostasis, gastrointestinal motility, neuroendocrine circuits, and hormone secretion. The Glucagon-Like Peptides, GLP-1 and GLP-2 are prototype peptide hormones released from gut endocrine cells in response to nutrient ingestion that regulate not only energy absorption and disposal, but also cell proliferation and survival. GLP-1 expands islet mass by stimulating pancreatic beta-cell proliferation and induction of islet neogenesis. GLP-1 also promotes cell differentiation, from exocrine cells or immature islet progenitors, toward a more differentiated beta-cell phenotype. GLP-2 stimulates cell proliferation in the gastrointestinal mucosa, leading to expansion of the normal mucosal epithelium, or attenuation of intestinal injury in experimental models of intestinal disease. Both GLP-1 and GLP-2 exert antiapoptotic actions in vivo, resulting in preservation of beta-cell mass and gut epithelium, respectively. Furthermore, GLP-1 and GLP-2 promote direct resistance to apoptosis in cells expressing GLP-1 or GLP-2 receptors. Moreover, an increasing number of structurally related peptide hormones and neuroPeptides exert cytoprotective effects through G protein-coupled receptor activation in diverse cell types. Hence, peptide hormones, as exemplified by GLP-1 and GLP-2, may prove to be useful adjunctive tools for enhancement of cell differentiation, tissue regeneration, and cytoprotection for the treatment of human disease.

Jens J. Holst - One of the best experts on this subject based on the ideXlab platform.

  • postprandial dyslipidemia hyperinsulinemia and impaired gut Peptides bile acids in adolescents with obesity
    The Journal of Clinical Endocrinology and Metabolism, 2020
    Co-Authors: Victoria Higgins, Bolette Hartmann, Jens J. Holst, Shervin Asgari, Jill Hamilton, Anna Wolska, Alan T Remaley, Khosrow Adeli
    Abstract:

    Background With increased rates of obesity and insulin resistance in youth, development of postprandial dyslipidemia, an important cardiovascular disease risk factor, is a concern. Glucagon-Like Peptides (ie, GLP-1 and GLP-2) and bile acids have been shown to regulate dietary fat absorption and postprandial lipids in animal models and humans. We hypothesize that the physiological response of GLPs and bile acids to dietary fat ingestion is impaired in adolescents with obesity and this associates with marked postprandial dyslipidemia and insulin resistance. Methods In this cross-sectional study, normal weight adolescents and adolescents with obesity underwent a 6-hour oral fat tolerance test. The postprandial lipoprotein phenotype profile was determined using various assays, including nuclear magnetic resonance spectroscopy, to characterize lipoprotein particle number, size, lipid content, and apolipoproteins. GLP-1 and GLP-2 were quantified by electrochemiluminescent immunoassays. Total bile acids were measured by an automated enzymatic cycling colorimetric method and the bile acid profile by mass spectrometry. Results Adolescents with obesity exhibited fasting and postprandial dyslipidemia, particularly augmented postprandial excursion of large triglyceride-rich lipoproteins. Postprandial GLPs were reduced and inversely correlated with postprandial dyslipidemia and insulin resistance. Postprandial bile acids were also diminished, particularly lithocholic acid, a potent stimulator of GLP-1 secretion. Conclusion Blunted postprandial GLP and bile acid response to dietary fat ingestion strongly associates with marked postprandial dyslipidemia. Further investigation is needed to assess their potential utility as early biomarkers for postprandial dyslipidemia in adolescents with obesity.

  • discovery characterization and clinical development of the glucagon like Peptides
    Journal of Clinical Investigation, 2017
    Co-Authors: Daniel J Drucker, Joel F Habener, Jens J. Holst
    Abstract:

    The discovery, characterization, and clinical development of Glucagon-Like-peptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance.

  • acute effects of continuous infusions of glucagon like peptide glp 1 glp 2 and the combination glp 1 glp 2 on intestinal absorption in short bowel syndrome sbs patients a placebo controlled study
    Regulatory Peptides, 2013
    Co-Authors: K B Madsen, Bolette Hartmann, Jens J. Holst, C Askovhansen, Rahim M Naimi, Christopher F Brandt, P B Mortensen, P Jeppesen
    Abstract:

    Abstract Background and aims The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of Glucagon-Like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients. Methods SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1 + 2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast. Results Nine SBS patients (5 women/4 men, aged 52 ± 11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1 + 2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1 + 2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2. Conclusion GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1 + 2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the Glucagon-Like Peptides or analogs, alone or in combination, in the treatment of SBS patients.

  • acute effects of continuous infusions of glucagon like peptide glp 1 glp 2 and the combination glp 1 glp 2 on intestinal absorption in short bowel syndrome sbs patients a placebo controlled study
    Regulatory Peptides, 2013
    Co-Authors: K B Madsen, Bolette Hartmann, Jens J. Holst, C Askovhansen, Rahim M Naimi, Christopher F Brandt, P B Mortensen, P Jeppesen
    Abstract:

    Abstract Background and aims The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of Glucagon-Like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients. Methods SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1 + 2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast. Results Nine SBS patients (5 women/4 men, aged 52 ± 11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1 + 2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1 + 2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2. Conclusion GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1 + 2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the Glucagon-Like Peptides or analogs, alone or in combination, in the treatment of SBS patients.

  • enteral bile acid treatment improves parenteral nutrition related liver disease and intestinal mucosal atrophy in neonatal pigs
    American Journal of Physiology-gastrointestinal and Liver Physiology, 2012
    Co-Authors: Ajay K Jain, Jens J. Holst, Douglas G Burrin, Barbara Stoll, David D Moore
    Abstract:

    Total parenteral nutrition (TPN) is essential for patients with impaired gut function but leads to parenteral nutrition-associated liver disease (PNALD). TPN disrupts the normal enterohepatic circulation of bile acids, and we hypothesized that it would decrease intestinal expression of the newly described metabolic hormone fibroblast growth factor-19 (FGF19) and also Glucagon-Like Peptides-1 and -2 (GLP-1 and GLP-2). We tested the effects of restoring bile acids by treating a neonatal piglet PNALD model with chenodeoxycholic acid (CDCA). Neonatal pigs received enteral feeding (EN), TPN, or TPN + CDCA for 14 days, and responses were assessed by serum markers, histology, and levels of key regulatory Peptides. Cholestasis and steatosis were demonstrated in the TPN group relative to EN controls by elevated levels of serum total and direct bilirubin and also bile acids and liver triglyceride (TG) content. CDCA treatment improved direct bilirubin levels by almost fourfold compared with the TPN group and also normalized serum bile acids and liver TG. FGF19, GLP-1, and GLP-2 were decreased in plasma of the TPN group compared with the EN group but were all induced by CDCA treatment. Intestinal mucosal growth marked by weight and villus/crypt ratio was significantly reduced in the TPN group compared with the EN group, and CDCA treatment increased both parameters. These results suggest that decreased circulating FGF19 during TPN may contribute to PNALD. Moreover, we show that enteral CDCA not only resolves PNALD but acts as a potent intestinal trophic agent and secretagogue for GLP-2.

Bolette Hartmann - One of the best experts on this subject based on the ideXlab platform.

  • postprandial dyslipidemia hyperinsulinemia and impaired gut Peptides bile acids in adolescents with obesity
    The Journal of Clinical Endocrinology and Metabolism, 2020
    Co-Authors: Victoria Higgins, Bolette Hartmann, Jens J. Holst, Shervin Asgari, Jill Hamilton, Anna Wolska, Alan T Remaley, Khosrow Adeli
    Abstract:

    Background With increased rates of obesity and insulin resistance in youth, development of postprandial dyslipidemia, an important cardiovascular disease risk factor, is a concern. Glucagon-Like Peptides (ie, GLP-1 and GLP-2) and bile acids have been shown to regulate dietary fat absorption and postprandial lipids in animal models and humans. We hypothesize that the physiological response of GLPs and bile acids to dietary fat ingestion is impaired in adolescents with obesity and this associates with marked postprandial dyslipidemia and insulin resistance. Methods In this cross-sectional study, normal weight adolescents and adolescents with obesity underwent a 6-hour oral fat tolerance test. The postprandial lipoprotein phenotype profile was determined using various assays, including nuclear magnetic resonance spectroscopy, to characterize lipoprotein particle number, size, lipid content, and apolipoproteins. GLP-1 and GLP-2 were quantified by electrochemiluminescent immunoassays. Total bile acids were measured by an automated enzymatic cycling colorimetric method and the bile acid profile by mass spectrometry. Results Adolescents with obesity exhibited fasting and postprandial dyslipidemia, particularly augmented postprandial excursion of large triglyceride-rich lipoproteins. Postprandial GLPs were reduced and inversely correlated with postprandial dyslipidemia and insulin resistance. Postprandial bile acids were also diminished, particularly lithocholic acid, a potent stimulator of GLP-1 secretion. Conclusion Blunted postprandial GLP and bile acid response to dietary fat ingestion strongly associates with marked postprandial dyslipidemia. Further investigation is needed to assess their potential utility as early biomarkers for postprandial dyslipidemia in adolescents with obesity.

  • acute effects of continuous infusions of glucagon like peptide glp 1 glp 2 and the combination glp 1 glp 2 on intestinal absorption in short bowel syndrome sbs patients a placebo controlled study
    Regulatory Peptides, 2013
    Co-Authors: K B Madsen, Bolette Hartmann, Jens J. Holst, C Askovhansen, Rahim M Naimi, Christopher F Brandt, P B Mortensen, P Jeppesen
    Abstract:

    Abstract Background and aims The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of Glucagon-Like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients. Methods SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1 + 2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast. Results Nine SBS patients (5 women/4 men, aged 52 ± 11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1 + 2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1 + 2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2. Conclusion GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1 + 2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the Glucagon-Like Peptides or analogs, alone or in combination, in the treatment of SBS patients.

  • acute effects of continuous infusions of glucagon like peptide glp 1 glp 2 and the combination glp 1 glp 2 on intestinal absorption in short bowel syndrome sbs patients a placebo controlled study
    Regulatory Peptides, 2013
    Co-Authors: K B Madsen, Bolette Hartmann, Jens J. Holst, C Askovhansen, Rahim M Naimi, Christopher F Brandt, P B Mortensen, P Jeppesen
    Abstract:

    Abstract Background and aims The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of Glucagon-Like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients. Methods SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1 + 2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast. Results Nine SBS patients (5 women/4 men, aged 52 ± 11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1 + 2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1 + 2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2. Conclusion GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1 + 2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the Glucagon-Like Peptides or analogs, alone or in combination, in the treatment of SBS patients.

  • functional ontogeny of the proglucagon derived peptide axis in the premature human neonate
    Pediatrics, 2008
    Co-Authors: Harish Amin, Bolette Hartmann, Jens J. Holst, Laurie E Wallace, James G Wright, David L Sigalet
    Abstract:

    BACKGROUND. The regulation of intestinal growth and development in human neonates is incompletely understood, which hinders the provision of nutrients enterally. The “hindgut” hormones Glucagon-Like Peptides 1 and 2 have been shown to play an important role in the regulation of nutrient assimilation, intestinal growth, and function. OBJECTIVE. Our goal was to investigate the production of Glucagon-Like Peptides 1 and 2 in premature human infants and examine the effects of prematurity and feeding on hormone release. PATIENTS AND METHODS. With informed consent, premature infants who were admitted to a tertiary neonatal intensive care nursery (gestational age: 28 –32 weeks) were monitored with weekly determinations of postprandial Glucagon-Like peptide 1 and 2 levels. Comparison studies with groups of normal infants and adults were performed. Hormone levels were obtained by using specific radioimmunoassay for Glucagon-Like peptide 1 (1–36) and Glucagon-Like peptide 2 (1–33), modified for small sample volumes; accurate monitoring of enteral intake was performed at all of the sampling time points. RESULTS. Forty-five infants with a mean gestational age of 29.6 1.9 weeks were studied; fasting levels of both Glucagon-Like Peptides 1 and 2 were elevated. There was no correlation between gestational age and Glucagon-Like peptide 2 output. However, both Glucagon-Like peptide 1 and 2 levels were correlated with the caloric value of feeds. CONCLUSIONS. The premature human neonate has significantly higher fasting levels of Glucagon-Like Peptides 1 and 2 compared with adults; feeding increases these levels further. These findings suggest that the proglucagon-derived Peptides may have a role in normal intestinal development and nutrient handling.

  • role of gastrointestinal hormones in postprandial reduction of bone resorption
    Journal of Bone and Mineral Research, 2003
    Co-Authors: Dennis B. Henriksen, Eva E G Henriksen, Thure Krarup, Nina Hannover Bjarnason, Tina Vilsboll, Bolette Hartmann, Inger Byrjalsen, Peter Alexandersen, Jens J. Holst, Claus Christiansen
    Abstract:

    Collagen type I fragments, reflecting bone resorption, and release of gut hormones were investigated after a meal. Investigations led to a dose escalation study with glucagon like peptide-2 (GLP-2) in postmenopausal women. We found a dose-dependent effect of GLP-2 on the reduction of bone resorption. Introduction: The C-terminal telopeptide region of type I collagen as measured in serum (s-CTX) can be used to assess bone resorption. This marker of bone resorption has a significant circadian variation that is influenced by food intake. However, the mediator of this variation has not been identified. Materials and Methods: We studied the release of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-Like peptide-2 (GLP-2; a representative of the intestinal proglucagon-derived Peptides) after ingestion of glucose, fat, protein, and fructose, as well as their effects after parenteral administration in relation to bone turnover processes in healthy volunteers. Furthermore, we studied the effect on bone turnover of a single subcutaneous injection of GLP-2 in four different dosages (100, 200, 400, or 800 g GLP-2) or placebo in 60 postmenopausal women (mean age, 61 5 years). Results: All macronutrients significantly (p 0.05) reduced bone resorption as assessed by s-CTX (39 -52% from baseline), and only the Glucagon-Like Peptides were secreted in parallel. Parenteral administration of GIP and GLP-1 did not result in a reduction of the s-CTX level, whereas GLP-2 caused a statistically significant and dose-dependent reduction in the s-CTX level from baseline compared with placebo (p 0.05). Urine DPD/creatinine, a marker of bone resorption, was significantly reduced by 25% from baseline in the 800-g GLP-2 group (p 0.01). An area under the curve (AUC 0-8 h) analysis for s-CTX after GLP-2 injection confirmed the dose-dependent decrease (ANOVA, p 0.05). The s-osteocalcin level was unaffected by the GLP-2 treatment. Conclusion: These studies exclude both GIP and GLP-1 as key mediators for the immediate reduction in bone resorption seen after a meal. The dose-dependent reduction of bone resorption markers found after subcutaneous injection of GLP-2 warrants further investigation into the mechanism and importance of GLP-2 for the bone turnover processes. J Bone Miner Res 2003;18:2180 -2189

P Jeppesen - One of the best experts on this subject based on the ideXlab platform.

  • the endogenous preproglucagon system is not essential for gut growth homeostasis in mice
    Molecular metabolism, 2017
    Co-Authors: Pernille Wismann, Niels Vrang, Pernille Barkholt, Thomas Secher, Henrik B Hansen, P Jeppesen, Laurie L Baggio, Jacqueline A Koehler, Darleen A. Sandoval
    Abstract:

    Objective The prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are Glucagon-Like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of Glucagon-Like Peptides and bariatric surgery in mice.

  • acute effects of continuous infusions of glucagon like peptide glp 1 glp 2 and the combination glp 1 glp 2 on intestinal absorption in short bowel syndrome sbs patients a placebo controlled study
    Regulatory Peptides, 2013
    Co-Authors: K B Madsen, Bolette Hartmann, Jens J. Holst, C Askovhansen, Rahim M Naimi, Christopher F Brandt, P B Mortensen, P Jeppesen
    Abstract:

    Abstract Background and aims The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of Glucagon-Like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients. Methods SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1 + 2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast. Results Nine SBS patients (5 women/4 men, aged 52 ± 11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1 + 2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1 + 2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2. Conclusion GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1 + 2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the Glucagon-Like Peptides or analogs, alone or in combination, in the treatment of SBS patients.

  • acute effects of continuous infusions of glucagon like peptide glp 1 glp 2 and the combination glp 1 glp 2 on intestinal absorption in short bowel syndrome sbs patients a placebo controlled study
    Regulatory Peptides, 2013
    Co-Authors: K B Madsen, Bolette Hartmann, Jens J. Holst, C Askovhansen, Rahim M Naimi, Christopher F Brandt, P B Mortensen, P Jeppesen
    Abstract:

    Abstract Background and aims The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of Glucagon-Like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients. Methods SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1 + 2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast. Results Nine SBS patients (5 women/4 men, aged 52 ± 11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1 + 2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1 + 2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2. Conclusion GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1 + 2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the Glucagon-Like Peptides or analogs, alone or in combination, in the treatment of SBS patients.

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  • discovery characterization and clinical development of the glucagon like Peptides
    Journal of Clinical Investigation, 2017
    Co-Authors: Daniel J Drucker, Joel F Habener, Jens J. Holst
    Abstract:

    The discovery, characterization, and clinical development of Glucagon-Like-peptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance.

  • the glucagon like Peptides
    Endocrine Reviews, 1999
    Co-Authors: Timothy J Kieffer, Joel F Habener
    Abstract:

    I. Introduction II. History of the Incretin Concept: Discovery of Gastric Inhibitory Polypeptide III. Discovery of GLP-1 IV. Structures of GLPs and Family of Glucagon-Related Peptides V. Tissue Distribution of the Expression of GLPs A. Pancreatic α-cells B. Intestinal L cells C. Central nervous system VI. Proglucagon Biosynthesis A. Organization/structure of the proglucagon gene B. Regulation of glucagon gene expression C. Posttranslational processing of proglucagon VII. Regulation of GLP Secretion A. Overview B. Intracellular signals C. Carbohydrates D. Fats E. Proteins F. Endocrine G. Neural H. GLP-2 VIII. Metabolism of GLPs A. GLP-1 B. GLP-2 IX. Physiological Actions of GLPs A. Overview B. Pancreatic islets C. Counterregulatory actions of GLP-1 and leptin on β-cells D. Stomach E. Lung F. Brain G. Liver, skeletal muscle, and fat H. Pituitary, hypothalamus, and thyroid I. Cardiovascular system J. GLP-2 X. GLP Receptors A. Structure B. Signaling C. Distribution D. Regulation E. GLP-2 XI. Pathophysiology o...

  • pou domain transcription factor brain 4 confers pancreatic alpha cell specific expression of the proglucagon gene through interaction with a novel proximal promoter g1 element
    Molecular and Cellular Biology, 1997
    Co-Authors: Mehboob A Hussain, Christopher Miller, Joel F Habener
    Abstract:

    The proglucagon gene is expressed in a highly restricted tissue-specific manner in the a cells of the pancreatic islet, the hypothalamus, and the small and large intestines. Proglucagon is processed to glucagon and Glucagon-Like Peptides GLP-1 and -2. Glucagon is expressed in a cells and regulates glucose homeostasis. GLP-1 is implicated in the control of insulin secretion, food intake, and satiety signaling, and GLP-2 is implicated in regulating small-bowel growth. Cell-specific expression of the proglucagon gene is mediated by proteins that interact with the proximal G1 promoter element which contains several AT-rich domains with binding sites for homeodomain transcription factors. In an attempt to identify major homeodomain proteins involved in pancreatic a-cell-specific proglucagon expression, we found that the POU domain transcription factor brain 4 is abundantly expressed in proglucagon-producing islet cell lines and rat pancreatic islets. In the latter, brain 4 and glucagon immunoreactivity colocalize in the outer mantle of islets. Electrophoretic mobility shift assays with specific antisera identify brain 4 as a major constituent of nuclear proteins of glucagonproducing cells that bind to the G1 element of the proglucagon gene proximal promoter. Transcriptional transactivation experiments reveal that brain 4 is a major regulator of proglucagon gene expression by its interaction with the G1 element. The finding that a neuronal transcription factor is involved in glucagon gene transcription may explain the presence of proglucagon in certain areas of the brain as well as in pancreatic a cells. Further, this finding supports the idea that the neuronal properties of endodermis-derived endocrine pancreatic cells may find their basis in regulation of gene expression by neuronal transcription factors. The endocrine pancreas consists of isolated nests of hormone-producing cells, known as the islets of Langerhans, which are anatomically embedded in the exocrine pancreas. The hormones produced by the islets regulate nutrient homeostasis during feeding and fasting and include insulin (b cells), glucagon (a cells), and somatostatin (d cells), all of which are synthesized in the form of prohormones. Proglucagon and prosomatostatin further undergo tissue-specific posttranslational processing to produce the bioactive hormones. The rat proglucagon gene is expressed in the a cells of the pancreatic islets, selected neurons of the hypothalamus and brain stem, and enteroendocrine cells of the small and large intestines (2, 6, 8). Transcription of the proglucagon gene results in the production of a single proglucagon mRNA that is identical in these tissues. Posttranslational processing of proglucagon is highly tissue specific, resulting in the formation of unique profiles of proglucagon-derived Peptides in the pancreas, intestine, and brain (26, 31). Glucagon appears to be the most important biologically active proglucagon-derived peptide produced in pancreatic islets. Glucagon is secreted from the a cells of the endocrine pancreas during fasting and stimulates glycogenolysis and gluconeogenesis to maintain blood glucose levels in the absence of the intake of nutrients. In contrast to the pattern of posttranslational processing of proglucagon in the pancreas, the processing of proglucagon in enteroendocrine cells of the small and large intestines results in the alternative formation of the Peptides oxyntomodulin, Glucagon-Like peptide (GLP)-1, and glicentin, as well as GLP-2 and two intervening Peptides, IP-1 and IP-2 (26). Of these Peptides derived from the intestine, GLP-1 is a potent insulinotropic hormone that stimulates insulin secretion and production (14). In the brain, glucagon gene expression is found in select ganglia of the brain stem and in the hypothalamus (6). Furthermore, GLP-1 is reported to be involved in the regulation of food intake and satiety signaling (47). GLP-2 appears to stimulate proliferation of the intestinal epithelium (7).