{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:24:27Z","timestamp":1791260667802,"version":"4.1.0"},"reference-count":61,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fractyl Laboratories Inc"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3\u201330)NH2) and GIPA-2 (N\u03b1Ac-K10[\u03b3E\u03b3E-C16]-Arg18-hGIP(5\u201342)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute <jats:italic>in vivo<\/jats:italic> administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.<\/jats:p>","DOI":"10.1371\/journal.pone.0249239","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T17:30:50Z","timestamp":1617211850000},"page":"e0249239","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7252-8651","authenticated-orcid":true,"given":"Jason A.","family":"West","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Tsakmaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7405-0436","authenticated-orcid":true,"given":"Soumitra S.","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Parkes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikke V.","family":"Gr\u00f8nlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Maggs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harith","family":"Rajagopalan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin A.","family":"Bewick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,31]]},"reference":[{"issue":"Suppl 1","key":"pone.0249239.ref001","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/jdi.12478","article-title":"Mechanisms underlying glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secretion","volume":"7","author":"F. Reimann","year":"2016","journal-title":"J Diabetes Investig"},{"issue":"Suppl 1","key":"pone.0249239.ref002","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/dom.13129","article-title":"Incretin hormones: Their role in health and disease","volume":"20","author":"M.A. Nauck","year":"2018","journal-title":"Diabetes Obes Metab"},{"key":"pone.0249239.ref003","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.metabol.2019.04.014","article-title":"The incretin system in healthy humans: The role of GIP and GLP-1","volume":"96","author":"J.J. Holst","year":"2019","journal-title":"Metabolism"},{"issue":"5","key":"pone.0249239.ref004","doi-asserted-by":"crossref","first-page":"906","DOI":"10.2337\/db18-1123","article-title":"Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals","volume":"68","author":"L.S. Gasbjerg","year":"2019","journal-title":"Diabetes"},{"issue":"1","key":"pone.0249239.ref005","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1172\/JCI116186","article-title":"Preserved incretin activity of glucagon-like peptide 1 [7\u201336 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus","volume":"91","author":"M.A. Nauck","year":"1993","journal-title":"J Clin Invest"},{"issue":"5","key":"pone.0249239.ref006","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00125-013-2841-0","article-title":"Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies","volume":"56","author":"S. Calanna","year":"2013","journal-title":"Diabetologia"},{"issue":"8","key":"pone.0249239.ref007","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/BF00401145","article-title":"Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7\u201336 amide) in type 2 (non-insulin-dependent) diabetic patients","volume":"36","author":"M.A. Nauck","year":"1993","journal-title":"Diabetologia"},{"issue":"1","key":"pone.0249239.ref008","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/obr.12465","article-title":"Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity","volume":"18","author":"R. Burcelin","year":"2017","journal-title":"Obes Rev"},{"issue":"7","key":"pone.0249239.ref009","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.2337\/db09-1414","article-title":"The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action","volume":"59","author":"K.J. Hare","year":"2010","journal-title":"Diabetes"},{"issue":"12","key":"pone.0249239.ref010","doi-asserted-by":"crossref","first-page":"4217","DOI":"10.1172\/JCI97233","article-title":"Discovery, characterization, and clinical development of the glucagon-like peptides","volume":"127","author":"D.J. Drucker","year":"2017","journal-title":"J Clin Invest"},{"key":"pone.0249239.ref011","article-title":"Leveraging the Gut to Treat Metabolic Disease","author":"R.E. Gimeno","year":"2020","journal-title":"Cell Metab"},{"issue":"3","key":"pone.0249239.ref012","doi-asserted-by":"crossref","first-page":"514","DOI":"10.2337\/dc08-1762","article-title":"Impact of different bariatric surgical procedures on insulin action and beta-cell function in type 2 diabetes","volume":"32","author":"E. Ferrannini","year":"2009","journal-title":"Diabetes Care"},{"issue":"17","key":"pone.0249239.ref013","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1056\/NEJMoa1200111","article-title":"Bariatric surgery versus conventional medical therapy for type 2 diabetes","volume":"366","author":"G. Mingrone","year":"2012","journal-title":"N Engl J Med"},{"issue":"5","key":"pone.0249239.ref014","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1097\/01.sla.0000224726.61448.1b","article-title":"The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes","volume":"244","author":"F. Rubino","year":"2006","journal-title":"Ann Surg"},{"issue":"5","key":"pone.0249239.ref015","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.jamcollsurg.2009.12.025","article-title":"Amelioration of insulin requirement in patients undergoing duodenal bypass for reasons other than obesity implicates foregut factors in the pathophysiology of type II diabetes","volume":"210","author":"E.E. Zervos","year":"2010","journal-title":"J Am Coll Surg"},{"issue":"3","key":"pone.0249239.ref016","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cmet.2015.01.001","article-title":"The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes","volume":"21","author":"R.J. Seeley","year":"2015","journal-title":"Cell Metab"},{"issue":"9","key":"pone.0249239.ref017","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.2337\/db11-0203","article-title":"Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans","volume":"60","author":"M. Salehi","year":"2011","journal-title":"Diabetes"},{"issue":"6","key":"pone.0249239.ref018","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1016\/j.celrep.2019.01.047","article-title":"Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery","volume":"26","author":"P. Larraufie","year":"2019","journal-title":"Cell Rep"},{"issue":"2","key":"pone.0249239.ref019","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1097\/01.sla.0000133117.12646.48","article-title":"The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism","volume":"240","author":"F. Rubino","year":"2004","journal-title":"Ann Surg"},{"key":"pone.0249239.ref020","doi-asserted-by":"crossref","first-page":"625196","DOI":"10.1155\/2015\/625196","article-title":"Effect of Modified Roux-en-Y Gastric Bypass Surgery on GLP-1, GIP in Patients with Type 2 Diabetes Mellitus","volume":"2015","author":"S.W. Xiong","year":"2015","journal-title":"Gastroenterol Res Pract"},{"issue":"1","key":"pone.0249239.ref021","doi-asserted-by":"crossref","first-page":"E122","DOI":"10.1152\/ajpendo.00073.2012","article-title":"Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance","volume":"303","author":"N.B. Jorgensen","year":"2012","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"7","key":"pone.0249239.ref022","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1210\/jc.2007-2851","article-title":"Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes","volume":"93","author":"B. Laferrere","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"pone.0249239.ref023","doi-asserted-by":"crossref","DOI":"10.1210\/endrev\/bnz002","article-title":"Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies for the Treatment of Obesity, Do Agonists = Antagonists?","volume":"41","author":"E.A. Killion","year":"2020","journal-title":"Endocr Rev"},{"issue":"9","key":"pone.0249239.ref024","doi-asserted-by":"crossref","first-page":"4004","DOI":"10.1210\/endo.139.9.6288","article-title":"Functional GIP receptors are present on adipocytes","volume":"139","author":"R.G. Yip","year":"1998","journal-title":"Endocrinology"},{"issue":"3","key":"pone.0249239.ref025","doi-asserted-by":"crossref","first-page":"210","DOI":"10.2174\/187152411798047771","article-title":"Gastric inhibitory polypeptide and its receptor are expressed in the central nervous system and support neuronal survival","volume":"11","author":"S. Paratore","year":"2011","journal-title":"Cent Nerv Syst Agents Med Chem"},{"issue":"12","key":"pone.0249239.ref026","doi-asserted-by":"crossref","first-page":"8557","DOI":"10.1074\/jbc.M609088200","article-title":"Activation of lipoprotein lipase by glucose-dependent insulinotropic polypeptide in adipocytes. A role for a protein kinase B, LKB1, and AMP-activated protein kinase cascade","volume":"282","author":"S.J. Kim","year":"2007","journal-title":"J Biol Chem"},{"issue":"9","key":"pone.0249239.ref027","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.2337\/db10-0098","article-title":"Glucose-dependent insulinotropic polypeptide may enhance fatty acid re-esterification in subcutaneous abdominal adipose tissue in lean humans","volume":"59","author":"M. Asmar","year":"2010","journal-title":"Diabetes"},{"issue":"2","key":"pone.0249239.ref028","doi-asserted-by":"crossref","first-page":"292","DOI":"10.2337\/db10-0902","article-title":"Glucose-dependent insulinotropic polypeptide reduces fat-specific expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 and inhibits release of free fatty acids","volume":"61","author":"O. Gogebakan","year":"2012","journal-title":"Diabetes"},{"issue":"1","key":"pone.0249239.ref029","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41588-017-0011-x","article-title":"Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity","volume":"50","author":"V. Turcot","year":"2018","journal-title":"Nat Genet"},{"issue":"11","key":"pone.0249239.ref030","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/ng.686","article-title":"Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index","volume":"42","author":"E.K. Speliotes","year":"2010","journal-title":"Nat Genet"},{"issue":"2","key":"pone.0249239.ref031","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1530\/acta.0.1120224","article-title":"Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob\/ob) mice fed high fat and high carbohydrate cafeteria diets","volume":"112","author":"C.J. Bailey","year":"1986","journal-title":"Acta Endocrinol (Copenh)"},{"issue":"7","key":"pone.0249239.ref032","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/nm727","article-title":"Inhibition of gastric inhibitory polypeptide signaling prevents obesity","volume":"8","author":"K. Miyawaki","year":"2002","journal-title":"Nat Med"},{"issue":"7","key":"pone.0249239.ref033","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.2337\/db13-1563","article-title":"Chronic reduction of GIP secretion alleviates obesity and insulin resistance under high-fat diet conditions","volume":"63","author":"D. Nasteska","year":"2014","journal-title":"Diabetes"},{"issue":"26","key":"pone.0249239.ref034","doi-asserted-by":"crossref","first-page":"18365","DOI":"10.1074\/jbc.M710466200","article-title":"Targeted ablation of glucose-dependent insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet","volume":"283","author":"M.C. Althage","year":"2008","journal-title":"J Biol Chem"},{"key":"pone.0249239.ref035","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.peptides.2017.11.021","article-title":"Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti-diabetic agents","volume":"100","author":"L.S. Gasbjerg","year":"2018","journal-title":"Peptides"},{"issue":"9","key":"pone.0249239.ref036","doi-asserted-by":"crossref","first-page":"e3163","DOI":"10.1371\/journal.pone.0003163","article-title":"Vaccination against GIP for the treatment of obesity","volume":"3","author":"A. Fulurija","year":"2008","journal-title":"PLoS One"},{"issue":"1","key":"pone.0249239.ref037","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1515\/BC.2009.002","article-title":"Active immunisation against gastric inhibitory polypeptide (GIP) improves blood glucose control in an animal model of obesity-diabetes","volume":"390","author":"N. Irwin","year":"2009","journal-title":"Biol Chem"},{"issue":"12","key":"pone.0249239.ref038","doi-asserted-by":"crossref","first-page":"E1008","DOI":"10.1152\/ajpendo.00345.2015","article-title":"Gastric inhibitory polypeptide immunoneutralization attenuates development of obesity in mice","volume":"309","author":"M.O. Boylan","year":"2015","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"27","key":"pone.0249239.ref039","doi-asserted-by":"crossref","first-page":"19760","DOI":"10.1074\/jbc.M112.426288","article-title":"Structural and pharmacological characterization of novel potent and selective monoclonal antibody antagonists of glucose-dependent insulinotropic polypeptide receptor","volume":"288","author":"P. Ravn","year":"2013","journal-title":"J Biol Chem"},{"issue":"472","key":"pone.0249239.ref040","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aat3392","article-title":"Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models","volume":"10","author":"E.A. Killion","year":"2018","journal-title":"Sci Transl Med"},{"key":"pone.0249239.ref041","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.mce.2014.10.025","article-title":"Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice","volume":"401","author":"V. Pathak","year":"2015","journal-title":"Mol Cell Endocrinol"},{"issue":"5","key":"pone.0249239.ref042","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1111\/bph.13384","article-title":"N-terminally and C-terminally truncated forms of glucose-dependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor","volume":"173","author":"L.S. Hansen","year":"2016","journal-title":"Br J Pharmacol"},{"key":"pone.0249239.ref043","doi-asserted-by":"crossref","first-page":"1179551419875453","DOI":"10.1177\/1179551419875453","article-title":"Characterisation of Glucose-Dependent Insulinotropic Polypeptide Receptor Antagonists in Rodent Pancreatic Beta Cells and Mice","volume":"12","author":"R.A. Perry","year":"2019","journal-title":"Clin Med Insights Endocrinol Diabetes"},{"issue":"3","key":"pone.0249239.ref044","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.bbrc.2010.12.077","article-title":"Characterization and biological actions of N-terminal truncated forms of glucose-dependent insulinotropic polypeptide","volume":"404","author":"B.D. Kerr","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"issue":"9","key":"pone.0249239.ref045","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1172\/JCI126107","article-title":"Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition","volume":"129","author":"K. Kaneko","year":"2019","journal-title":"J Clin Invest"},{"key":"pone.0249239.ref046","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.molmet.2019.11.018","article-title":"Pharmacological antagonism of the incretin system protects against diet-induced obesity","volume":"32","author":"B. Svendsen","year":"2020","journal-title":"Mol Metab"},{"key":"pone.0249239.ref047","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.bcp.2017.02.012","article-title":"GIP(3\u201330)NH2 is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release","volume":"131","author":"A.H. Sparre-Ulrich","year":"2017","journal-title":"Biochem Pharmacol"},{"issue":"2","key":"pone.0249239.ref048","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s00125-017-4447-4","article-title":"GIP(3\u201330)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study","volume":"61","author":"L.S. Gasbjerg","year":"2018","journal-title":"Diabetologia"},{"key":"pone.0249239.ref049","doi-asserted-by":"crossref","first-page":"492","DOI":"10.3389\/fendo.2019.00492","article-title":"Increased Body Weight and Fat Mass After Subchronic GIP Receptor Antagonist, but Not GLP-2 Receptor Antagonist, Administration in Rats","volume":"10","author":"S. Baldassano","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"pone.0249239.ref050","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.molmet.2018.12.001","article-title":"Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism","volume":"20","author":"P.A. Mroz","year":"2019","journal-title":"Mol Metab"},{"issue":"1","key":"pone.0249239.ref051","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/nm.3997","article-title":"TCF1 links GIPR signaling to the control of beta cell function and survival","volume":"22","author":"J.E. Campbell","year":"2016","journal-title":"Nat Med"},{"issue":"5","key":"pone.0249239.ref052","doi-asserted-by":"crossref","first-page":"E931","DOI":"10.1152\/ajpendo.00270.2002","article-title":"Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis","volume":"284","author":"N. Pamir","year":"2003","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"pone.0249239.ref053","doi-asserted-by":"crossref","first-page":"170202","DOI":"10.1016\/j.peptides.2019.170202","article-title":"GIP analogues and the treatment of obesity-diabetes","volume":"125","author":"C.J. Bailey","year":"2020","journal-title":"Peptides"},{"key":"pone.0249239.ref054","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.peptides.2017.12.021","article-title":"Gut hormone polyagonists for the treatment of type 2 diabetes","volume":"100","author":"S.J. Brandt","year":"2018","journal-title":"Peptides"},{"issue":"10160","key":"pone.0249239.ref055","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1016\/S0140-6736(18)32260-8","article-title":"Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial","volume":"392","author":"J.P. Frias","year":"2018","journal-title":"Lancet"},{"key":"pone.0249239.ref056","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.molmet.2018.09.009","article-title":"LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept","volume":"18","author":"T. Coskun","year":"2018","journal-title":"Mol Metab"},{"issue":"7","key":"pone.0249239.ref057","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man","volume":"28","author":"D.R. Matthews","year":"1985","journal-title":"Diabetologia"},{"key":"pone.0249239.ref058","article-title":"GIP as a therapeutic target in diabetes and obesity: insight from incretin co-agonists","author":"J.J. Holst","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"pone.0249239.ref059","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/bph.13323","article-title":"Species-specific action of (Pro3)GIP\u2014a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors","volume":"173","author":"A.H. Sparre-Ulrich","year":"2016","journal-title":"Br J Pharmacol"},{"issue":"1","key":"pone.0249239.ref060","doi-asserted-by":"crossref","first-page":"4981","DOI":"10.1038\/s41467-020-18751-8","article-title":"Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism","volume":"11","author":"E.A. Killion","year":"2020","journal-title":"Nat Commun"},{"key":"pone.0249239.ref061","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.bcp.2018.01.040","article-title":"Human GIP(3\u201330)NH2 inhibits G protein-dependent as well as G protein-independent signaling and is selective for the GIP receptor with high-affinity binding to primate but not rodent GIP receptors","volume":"150","author":"M.B.N. Gabe","year":"2018","journal-title":"Biochem Pharmacol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0249239","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T17:31:36Z","timestamp":1617211896000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0249239"}},"subtitle":[],"editor":[{"given":"Nigel","family":"Irwin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,31]]},"references-count":61,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0249239","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,31]]}}}