Article
Endocrinology & Metabolism
Ruben Nogueiras, Michael A. A. Nauck, Matthias H. H. Tschoep
Summary: The discovery and development of gut hormone co-agonists have revolutionized the treatment of diabetes and obesity. These therapeutics combine multiple gastrointestinal hormones into a single molecule, resulting in synergistic metabolic benefits. The GLP-1-GIP co-agonist tirzepatide, approved in 2022, has shown superior HbA1c reduction and significant weight loss in non-diabetic individuals with obesity.
Article
Pharmacology & Pharmacy
Maria Buur Nordskov Gabe, Kirsa Skov-Jeppesen, Laerke Smidt Gasbjerg, Sine Pasch Schiellerup, Christoffer Martinussen, Sarina Gadgaard, Geke Aline Boer, Jannika Oeke, Lola Julia Torz, Simon Veedfald, Maria Saur Svane, Kirstine Nyvold Bojsen-Moller, Sten Madsbad, Jens Juul Holst, Bolette Hartmann, Mette Marie Rosenkilde
Summary: The intestinal hormones GIP and GLP-2 are important regulators of postprandial bone turnover. Co-administration of these hormones has shown greater effect on bone turnover than individual administration. Researchers have designed GIPR-GLP-2R co-agonists as potential treatment for osteoporosis.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Long Teng, Tuchen Guan, Beibei Guo, Chao Ma, Ge Lin, Ronghua Wu, Man Xu, Mei Liu, Yan Liu
Summary: This study established an in vitro model to screen for genes involved in neurite outgrowth, and found that the GIP-GIPR axis can promote axonal outgrowth; the results showed that GIP significantly improved extension of axon.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Review
Gastroenterology & Hepatology
Giovanni Targher, Alessandro Mantovani, Christopher Byrne
Summary: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that stimulate insulin secretion. Tirzepatide, a dual GLP-1 and GIP receptor agonist, is effective in promoting weight loss. Incretin signalling not only decreases the risk of developing NAFLD, but also has beneficial effects in treating NAFLD and its complications.
LANCET GASTROENTEROLOGY & HEPATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Florent X. Smit, Wijnand J. C. van der Velden, Husun S. Kizilkaya, Amalie Norskov, Michael Luckmann, Tobias N. Hansen, Alexander H. Sparre-Ulrich, Katrine Qvotrup, Thomas M. Frimurer, Mette M. Rosenkilde
Summary: The study investigates the structure and function of the GIP receptor (GIPR) and identifies key residues involved in ligand binding and receptor activation. The findings suggest that disrupting a specific salt bridge by GIPR antagonists can significantly reduce GIPR activation, providing insights for rational ligand design targeting the GIPR.
Article
Endocrinology & Metabolism
Kimberley El, Jonathan D. Douros, Francis S. Willard, Aaron Novikoff, Ashot Sargsyan, Diego Perez-Tilve, David B. Wainscott, Bin Yang, Alex Chen, Donald Wothe, Callum Coupland, Mattias H. Tschoep, Brian Finan, David A. D'Alessio, Kyle W. Sloop, Timo D. Mueller, Jonathan E. Campbell
Summary: This study shows that tirzepatide, through dual activation of GLP-1R and GIPR, is highly effective in treating type 2 diabetes and obesity. It predominantly stimulates insulin secretion through GLP-1R in mouse islets, but enhances hormone secretion through both incretin receptors in human islets.
Article
Pharmacology & Pharmacy
Geke Aline Boer, Jenna Elizabeth Hunt, Maria Buur Nordskov Gabe, Johanne Agerlin Windelov, Alexander Hovard Sparre-Ulrich, Bolette Hartmann, Jens Juul Holst, Mette Marie Rosenkilde
Summary: This study investigated the characteristics of the GIP antagonist mGIPAnt-1, and found that it has antagonistic properties both in vitro and in vivo, and effectively inhibits high-fat diet-induced weight gain in ovariectomised mice. This provides a new research direction for the treatment of obesity.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Endocrinology & Metabolism
Martin Haljeta Friedrichsen, Lars Endahl, Frederik Flindt Kreiner, Ronald Goldwater, Martin Kankam, Soren Toubro, Sune Boris Nygard
Summary: NNC9204-1177 (NN1177) is a glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonist used for weight loss treatment. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of NN1177 through three phase 1 trials. While NN1177 showed some efficacy in weight loss, it also presented several treatment-related safety signals.
MOLECULAR METABOLISM
(2023)
Article
Multidisciplinary Sciences
K. El, S. M. Gray, M. E. Capozzi, E. R. Knuth, E. Jin, B. Svendsen, A. Clifford, J. L. Brown, S. E. Encisco, B. M. Chazotte, K. W. Sloop, D. J. Nunez, M. J. Merrins, D. A. D'Alessio, J. E. Campbell
Summary: The study reveals that GIP enhances amino acid-stimulated glucagon secretion and plays a role in insulin secretion by promoting paracrine alpha to beta cell communication. Loss of GIPR activity in alpha cells prevents glucagon secretion in response to a meal stimulus, affecting insulin secretion and leading to glucose intolerance.
Article
Medicine, General & Internal
Soyeon Yoo, Dongkyu Kim, Gwanpyo Koh
Summary: The study investigated changes in glucagon levels in people with diabetes after meal ingestion, finding that poorly controlled patients may have a greater increase in postprandial glucagon levels, which is not mediated by incretin.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Endocrinology & Metabolism
Ali A. Rizvi, Manfredi Rizzo
Summary: The incretin pathway is a self-regulating feedback system that connects the gut with the brain, pancreas, and liver. It primarily affects postprandial glucose levels, but also has effects on fat metabolism and endovascular function. Dual agonists, which simultaneously activate the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have been found to have powerful benefits for glucose control and weight reduction in patients with type 2 diabetes, as well as potentially favorable cardiovascular effects.
DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Taisuke Yamauchi, Megumi Miyabe, Nobuhisa Nakamura, Mizuho Ito, Takeo Sekiya, Saki Kanada, Rina Hoshino, Tatsuaki Matsubara, Ken Miyazawa, Shigemi Goto, Keiko Naruse
Summary: This study investigated the effects of glucose-dependent insulinotropic polypeptide (GIP) on force-induced bone remodeling during orthodontic tooth movement. The results suggest that GIP promotes osteoblast formation and suppresses osteoclasts in force-induced bone remodeling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Endocrinology & Metabolism
Yusuke Seino, Yuji Yamazaki
Summary: This article introduces the different roles of GIP and GLP-1 in glucose metabolism and weight regulation. GIP is mainly secreted in the upper small intestine, while GLP-1 is mainly secreted in the lower small intestine and colon. GIP promotes fat deposition while GLP-1 suppresses food consumption and gastric emptying.
JOURNAL OF DIABETES INVESTIGATION
(2022)
Article
Endocrinology & Metabolism
Ville Karhunen, Iyas Daghlas, Verena Zuber, Marijana Vujkovic, Anette K. Olsen, Lotte Bjerre Knudsen, William G. Haynes, Joanna M. M. Howson, Dipender Gill
Summary: By leveraging human genetic data, this study found that GIP signaling plays a beneficial role in improving cardiometabolic health, with genetic associations at GIP and GIPR genes in relation to type 2 diabetes liability co-localizing with some cardiometabolic outcomes. Mendelian randomisation analyses further supported the association of genetically proxied GIP signaling with improved metabolic outcomes.
Review
Endocrinology & Metabolism
Shangyu Chai, Ruya Zhang, Richard David Carr, Carolyn F. Deacon, Yiman Zheng, Swapnil Rajpathak, Jingya Chen, Miao Yu
Summary: This meta-analysis showed that DPP4 inhibitors effectively increase both fasting and postprandial GIP concentrations in T2DM patients, with consistent results in sensitivity analyses. Subgroup analyses indicated that study characteristics did not significantly impact the influence of DPP4 inhibitors on GIP levels in T2DM patients.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Endocrinology & Metabolism
Amalia Christina Vadmand, Anne Anker Nissen, Sidsel Mathiesen, Maria Schou Ebbesen, Tina Gerbek, Martin Kaj Fridh, Kaspar Sorensen, Bolette Hartmann, Jens Juul Holst, Klaus Muller
Summary: This study demonstrates that survivors of pediatric HSCT previously treated with total body irradiation have altered production of incretin hormones, resulting in dyslipidemia and abdominal adiposity.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2023)
Article
Pharmacology & Pharmacy
Maria Buur Nordskov Gabe, Liv von Voss, Jenna Elizabeth Hunt, Sarina Gadgaard, Laerke Smidt Gasbjerg, Jens Juul Holst, Hannelouise Kissow, Bolette Hartmann, Mette Marie Rosenkilde
Summary: Biased GLP-2R agonists with modifications at the N-terminal have shown improved therapeutic effects on gut and bone growth. Variants like [F6A], [F6W], and [S7W] have less GLP-2R internalization and enhanced gut trophic actions, including increased small intestine weight, villus height, and crypt depth.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Endocrinology & Metabolism
Morten Hindso, Nora Hedbaeck, Maria S. Svane, Andreas Moller, Christoffer Martinussen, Nils B. Jorgensen, Carsten Dirksen, Laerke S. Gasbjerg, Viggo B. Kristiansen, Bolette Hartmann, Mette M. Rosenkilde, Jens J. Holst, Sten Madsbad, Kirstine N. Bojsen-Moller
Summary: The study explored the effects of GLP-1 and GIP blockade on postprandial beta-cell function after different bariatric surgeries. It was found that GLP-1 secretion was significantly increased after RYGB and SG, while GIP secretion was lowest after RYGB. GLP-1 was identified as the most important incretin hormone after RYGB, while GIP and GLP-1 were equally important after SG.
Article
Physiology
Marina. K. K. Gerstenberg, Daniel. B. B. Andersen, Lola Torz, Carlos. M. M. Castorena, Angie. L. L. Bookout, Bolette Hartmann, Jens. F. F. Rehfeld, Natalia Petersen, Jens. J. J. Holst, Rune. E. E. Kuhre
Summary: After weight loss, the secretion of appetite-inhibiting hormones such as GLP-1 and PYY is still reduced, and other appetite-inhibiting hormones are also decreased. These results suggest that the reduced secretion of gut hormones in individuals with obesity may persist after weight loss and contribute to their susceptibility to weight regain.
Article
Allergy
Lise Gether, Heidi Storgaard, Sanja Kezic, Ivone Jakasa, Bolette Hartmann, Kirsa Skov-Jeppesen, Jens J. Holst, Anders J. Pedersen, Julie Forman, Gerrit van Hall, Ole E. Sorensen, Lone Skov, Mads A. Ropke, Filip K. Knop, Jacob Pontoppidan Thyssen
Summary: This study investigated whether whole-body treatment with topical corticosteroids for atopic dermatitis could lead to insulin resistance and increased bone resorption. The results showed that short-term use of these corticosteroids did not affect glucose metabolism but had a negative impact on bone formation.
Article
Endocrinology & Metabolism
Simon B. K. Jensen, Christian R. Juhl, Charlotte Janus, Julie R. Lundgren, Christoffer Martinussen, Christoffer Wiingaard, Cecilie Knudsen, Ruth Frikke-Schmidt, Bente M. Stallknecht, Jens J. Holst, Sten Madsbad, Signe S. Torekov
Summary: This study aimed to investigate the effects of exercise, liraglutide, or their combination on glucose tolerance, glucagon response, and beta cell function after weight loss. The results showed that only the combination of exercise and liraglutide improved glucose tolerance, beta cell function, and glucagon response after weight loss.
Article
Endocrinology & Metabolism
Marta Guimaraes, Ana Marta Pereira, Sofia S. Pereira, Rui Almeida, Carolina B. Lobato, Bolette Hartmann, Jens J. Holst, Mariana P. Monteiro
Summary: Comparing the outcomes of BPD/DS and SADI-S in genetically identical individuals, it was found that BPD/DS resulted in greater weight loss and lower blood glucose levels than SADI-S.
OBESITY RESEARCH & CLINICAL PRACTICE
(2023)
Article
Endocrinology & Metabolism
Grit E. Legaard, Mark P. P. Lyngbaek, Thomas P. Almdal, Kristian Karstoft, Sebastian L. Bennetsen, Camilla S. Feineis, Nina S. Nielsen, Cody G. Durrer, Benedikte Liebetrau, Ulrikke Nystrup, Martin Ostergaard, Katja Thomsen, Beckey Trinh, Thomas P. J. Solomon, Gerrit Van Hall, Jan Christian Brond, Jens J. Holst, Bolette Hartmann, Robin Christensen, Bente K. Pedersen, Mathias Ried-Larsen
Summary: A randomized clinical trial showed that adding exercise to diet-induced weight loss can improve beta-cell function in people with newly diagnosed type 2 diabetes. The study found that exercise volume is important for improving beta-cell function, and there was a dose-dependent relationship between exercise and beta-cell function improvement.
Article
Endocrinology & Metabolism
Signe Foghsgaard, Louise Vedtofte, Emilie S. Andersen, Emilie Bahne, Camilla Andreasen, Anne L. Sorensen, Julie L. Forman, Elisabeth R. Mathiesen, Jens A. Svare, Tine D. Clausen, Peter Damm, Jens J. Holst, Filip K. Knop, Tina Vilsboll
Summary: A 52-week treatment with liraglutide improved glucose tolerance, fasting plasma glucose, glycated hemoglobin, and bodyweight in women with overweight/obesity and previous gestational diabetes mellitus. However, the effects disappeared after a 1-week drug wash-out.
DIABETES OBESITY & METABOLISM
(2023)
Article
Biochemistry & Molecular Biology
Sidsel Madsen, Steffen Yde Bak, Christian Clement Yde, Henrik Max Jensen, Tine Ahrendt Knudsen, Cecilie Baech-Laursen, Jens Juul Holst, Christoffer Laustsen, Mette Skou Hedemann
Summary: This study investigated the preventive effect of rosemary extract on obesity-related conditions and found that it can alleviate the effects of a high-fat diet through increased GLP-1 secretion and changes in microbiota composition.
Article
Multidisciplinary Sciences
Sasha A. S. Kjeldsen, Lise L. Gluud, Mikkel P. Werge, Julie S. Pedersen, Flemming Bendtsen, Kleopatra Alexiadou, Tricia Tan, Signe S. Torekov, Eva W. Iepsen, Nicole J. Jensen, Michael M. Richter, Jens P. Goetze, Jorgen Rungby, Bolette Hartmann, Jens J. Holst, Birgitte Holst, Joachim Holt, Finn Gustafsson, Sten Madsbad, Maria S. Svane, Kirstine N. Bojsen-Moller, Nicolai J. Wewer Albrechtsen
Summary: Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.
Article
Chemistry, Medicinal
Jon Vabeno, Marta Oliva-Santiago, Astrid S. Jorgensen, Stefanie Karlshoj, Mette M. Rosenkilde
Summary: Research has shown that residue positions 3.32 and 7.39 play a critical role in signal transduction of CXCR1, but have less effect on CXCR2. These positions form a salt bridge between TM helices 3 and 7, which is important for CXCR1 function.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Multidisciplinary Sciences
Andreas Lindqvist, Mia Abels, Liliya Shcherbina, Mtakai Ngara, Dmytro Kryvokhyzha, Sabrina Chriett, Matteo Riva, Abul Fajul, Mohammad Barghouth, Cheng Luan, Lena Eliasson, Olav Larsen, Mette M. Rosenkilde, Enming Zhang, Erik Renstrom, Nils Wierup
Summary: CART is expressed in pancreatic islet cells and neuronal elements, and has insulinotropic effects. We identified GPR162 as the receptor that mediates the effects of CART in pancreatic beta cells. Silencing GPR162 reduced the binding of CART to the receptor and attenuated CART-induced exocytosis and insulin secretion. Furthermore, CART was found to regulate cytoskeletal arrangement through GPR162.
Article
Biochemistry & Molecular Biology
Olav Larsen, Sara Schuermans, Anna Walser, Stavroula Louka, Ida Aaberg Lillethorup, Jon Vabeno, Katrine Qvortrup, Paul Proost, Mette M. Rosenkilde
Summary: This study investigates the signaling capacity of peptides related to inflammatory chemokines. The peptides showed weak potency but retained their signaling on CCR1, while none of the peptides generated a signal on CCR5. However, a tetrapeptide derived from CCL3 acted as a positive modulator on CCR5.
Article
Chemistry, Multidisciplinary
Viktoria Madeline Skovgaard Kjaer, Tomasz Maciej Stepniewski, Brian Medel-Lacruz, Lisa Reinmuth, Marija Ciba, Elisabeth Rexen Ulven, Massimiliano Bonomi, Jana Selent, Mette Marie Rosenkilde
Summary: The G protein-coupled receptor GPR183 uses two ligand entry channels to recognize chemically diverse ligands. The study reveals the ligand binding pathway of GPR183 and its importance in understanding the receptor's functionality and ligand recognition.