{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:15:16Z","timestamp":1789168516037,"version":"build-2803163510"},"reference-count":112,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,17]],"date-time":"2018-02-17T00:00:00Z","timestamp":1518825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Insulin signaling, as mediated through the insulin receptor (IR), plays a critical role in metabolism. Aberrations in this signaling cascade lead to several pathologies, the majority of which are classified under the umbrella term \u201cmetabolic syndrome\u201d. Although many of these pathologies are associated with insulin resistance, the exact mechanisms are not well understood. One area of current interest is the possibility of G-protein-coupled receptors (GPCRs) influencing or regulating IR signaling. This concept is particularly significant, because GPCRs have been shown to participate in cross-talk with the IR. More importantly, GPCR signaling has also been shown to preferentially regulate specific downstream signaling targets through GPCR agonist bias. A novel study recently demonstrated that this GPCR-biased agonism influences the activity of the IR without the presence of insulin. Although GPCR-IR cross-talk has previously been established, the notion that GPCRs can regulate the activation of the IR is particularly significant in relation to metabolic syndrome and other pathologies that develop as a result of alterations in IR signaling. As such, we aim to provide an overview of the physiological and pathophysiological roles of the IR within metabolic syndrome and its related pathologies, including cardiovascular health, gut microflora composition, gastrointestinal tract functioning, polycystic ovarian syndrome, pancreatic cancer, and neurodegenerative disorders. Furthermore, we propose that the GPCR-biased agonism may perhaps mediate some of the downstream signaling effects that further exacerbate these diseases for which the mechanisms are currently not well understood.<\/jats:p>","DOI":"10.3390\/ijms19020575","type":"journal-article","created":{"date-parts":[[2018,2,20]],"date-time":"2018-02-20T03:54:22Z","timestamp":1519098862000},"page":"575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Biased G-Protein-Coupled Receptor Agonism Bridges the Gap between the Insulin Receptor and the Metabolic Syndrome"],"prefix":"10.3390","volume":"19","author":[{"given":"Iryna","family":"Liauchonak","sequence":"first","affiliation":[{"name":"Postgraduate Medical Education, Graduate Diploma and Professional Master in Medical Sciences, School of Medicine, Queen\u2019s University, Kingston, ON K7L 3L4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fady","family":"Dawoud","sequence":"additional","affiliation":[{"name":"Postgraduate Medical Education, Graduate Diploma and Professional Master in Medical Sciences, School of Medicine, Queen\u2019s University, Kingston, ON K7L 3L4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yatin","family":"Riat","sequence":"additional","affiliation":[{"name":"Postgraduate Medical Education, Graduate Diploma and Professional Master in Medical Sciences, School of Medicine, Queen\u2019s University, Kingston, ON K7L 3L4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4984-7299","authenticated-orcid":false,"given":"Bessi","family":"Qorri","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Science, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manpreet","family":"Sambi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Science, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Jain","sequence":"additional","affiliation":[{"name":"Postgraduate Medical Education, Graduate Diploma and Professional Master in Medical Sciences, School of Medicine, Queen\u2019s University, Kingston, ON K7L 3L4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina-Veronicka","family":"Kalaydina","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Science, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Mendonza","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Science, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komal","family":"Bajwa","sequence":"additional","affiliation":[{"name":"Postgraduate Medical Education, Graduate Diploma and Professional Master in Medical Sciences, School of Medicine, Queen\u2019s University, Kingston, ON K7L 3L4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8471-5481","authenticated-orcid":false,"given":"Myron R.","family":"Szewczuk","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Science, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6272","DOI":"10.1128\/MCB.22.17.6272-6285.2002","article-title":"Insulin induces heterologous desensitization of g protein-coupled receptor and insulin-like growth factor I signaling by downregulating \u03b2-arrestin-1","volume":"22","author":"Dalle","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"943162","DOI":"10.1155\/2014\/943162","article-title":"A comprehensive review on metabolic syndrome","volume":"2014","author":"Kaur","year":"2014","journal-title":"Cardiol. Res. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrm.2017.89","article-title":"Biochemical and cellular properties of insulin receptor signalling","volume":"19","author":"Haeusler","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.tibs.2008.06.003","article-title":"The insulin receptor: A prototype for dimeric, allosteric membrane receptors?","volume":"33","year":"2008","journal-title":"Trends Biochem. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15688","DOI":"10.1074\/jbc.M010884200","article-title":"Insulin and insulin-like growth factor i receptors utilize different G protein signaling components","volume":"276","author":"Dalle","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.bmcl.2015.12.024","article-title":"Biased agonism: An emerging paradigm in GPCR drug discovery","volume":"26","author":"Rankovic","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1097\/FJC.0000000000000356","article-title":"G protein-coupled receptor biased agonism","volume":"67","author":"Hodavance","year":"2016","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.cellsig.2017.12.006","article-title":"Biased G protein-coupled receptor agonism mediates neu1 sialidase and matrix metalloproteinase-9 crosstalk to induce transactivation of insulin receptor signaling","volume":"43","author":"Haxho","year":"2018","journal-title":"Cell. Signal."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Roberts, C.K., Hevener, A.L., and Barnard, R.J. (2013). Metabolic syndrome and insulin resistance: Underlying causes and modification by exercise training. Compr. Physiol., 3.","DOI":"10.1002\/cphy.c110062"},{"key":"ref_10","first-page":"a008946","article-title":"The insulin receptor: Both a prototypical and atypical receptor tyrosine kinase","volume":"5","author":"Hubbard","year":"2013","journal-title":"Perspect. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/j.cellsig.2014.02.015","article-title":"A novel insulin receptor-signaling platform and its link to insulin resistance and type 2 diabetes","volume":"26","author":"Alghamdi","year":"2014","journal-title":"Cell. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1158\/1078-0432.CCR-09-2229","article-title":"Crosstalk between insulin\/insulin-like growth factor-1 receptors and g protein-coupled receptor signaling systems: A novel target for the antidiabetic drug metformin in pancreatic cancer","volume":"16","author":"Rozengurt","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1542\/pir.33.10.459","article-title":"Metabolic syndrome","volume":"33","author":"Lee","year":"2012","journal-title":"Pediatr. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"C82","DOI":"10.1152\/ajpcell.00287.2006","article-title":"Angiotensin ii cell signaling: Physiological and pathological effects in the cardiovascular system","volume":"292","author":"Mehta","year":"2007","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1136\/hrt.2005.072280","article-title":"Cell signalling in the cardiovascular system: An overview","volume":"91","year":"2005","journal-title":"Heart"},{"key":"ref_16","first-page":"1","article-title":"The renin-angiotensin system: Systemic and local function","volume":"77","author":"Gohlke","year":"1988","journal-title":"Zeitschrift f\u00fcr Kardiologie"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1124\/mol.55.1.142","article-title":"Angiotensin ii receptor coupling to phospholipase d is mediated by the \u03b2\u03b3 subunits of heterotrimeric G proteins in vascular smooth muscle cells","volume":"55","author":"Alexander","year":"1999","journal-title":"Mol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1161\/01.ATV.0000046231.17365.9D","article-title":"Functional interplay between angiotensin ii and nitric oxide","volume":"23","author":"Yan","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1161\/01.HYP.28.5.772","article-title":"Angiotensin II\u2013stimulated phospholipase C responses of two vascular smooth muscle\u2013derived cell lines","volume":"28","author":"Baines","year":"1996","journal-title":"Hypertension"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1097\/00005344-199907000-00005","article-title":"Effects of quinapril and losartan on insulin sensitivity in genetic hypertensive rats with different metabolic abnormalities","volume":"34","author":"Nakagawa","year":"1999","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1161\/hy1101.092970","article-title":"Selective angiotensin II receptor antagonism reduces insulin resistance in obese zucker rats","volume":"38","author":"Henriksen","year":"2001","journal-title":"Hypertension"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1172\/JCI10762","article-title":"Insulin resistance and cardiovascular disease","volume":"106","author":"Ginsberg","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1161\/01.HYP.0000028979.98877.0C","article-title":"Ace inhibitor improves insulin resistance in diabetic mouse via bradykinin and no","volume":"40","author":"Shiuchi","year":"2002","journal-title":"Hypertension"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1172\/JCI6609","article-title":"Protein\u2013protein interaction in insulin signaling and the molecular mechanisms of insulin resistance","volume":"103","author":"Ueki","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"C1355","DOI":"10.1152\/ajpcell.00125.2006","article-title":"Akt phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells","volume":"291","author":"Lee","year":"2006","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1161\/CIRCRESAHA.110.231225","article-title":"G protein\u2013dependent and G protein\u2013independent signaling pathways and their impact on cardiac function","volume":"109","author":"Tilley","year":"2011","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1161\/01.HYP.0000051891.90321.12","article-title":"Insulin-induced akt activation is inhibited by angiotensin II in the vasculature through protein kinase c-\u03b1","volume":"41","author":"Motley","year":"2003","journal-title":"Hypertension"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C494","DOI":"10.1152\/ajpcell.00439.2003","article-title":"Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced AKT activation in vascular smooth muscle cells","volume":"287","author":"Taniyama","year":"2004","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1161\/01.RES.0000126501.34994.96","article-title":"Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on ser-312 and ser-616 in human umbilical vein endothelial cells","volume":"94","author":"Andreozzi","year":"2004","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"116S","DOI":"10.1016\/S0895-7061(01)02078-7","article-title":"Insulin resistance and cardiovascular disease","volume":"14","author":"Egan","year":"2001","journal-title":"Am. J. Hypertens."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.jacc.2005.11.046","article-title":"Metabolic syndrome: Connecting and reconciling cardiovascular and diabetes worlds","volume":"47","author":"Grundy","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/s00011-011-0325-6","article-title":"PI3K-AKT signaling pathway is involved in the pathogenesis of ulcerative colitis","volume":"60","author":"Huang","year":"2011","journal-title":"Inflamm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cgh.2007.09.016","article-title":"The incidence of arterial thromboembolic diseases in inflammatory bowel disease: A population-based study","volume":"6","author":"Bernstein","year":"2008","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1093\/jnci\/89.13.948","article-title":"Leisure-time physical activity, body size, and colon cancer in women. Nurses\u2019 health study research group","volume":"89","author":"Martinez","year":"1997","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"376","DOI":"10.4103\/1319-3767.87177","article-title":"Metabolic syndrome frequency in inflammatory bowel diseases","volume":"17","author":"Yorulmaz","year":"2011","journal-title":"Saudi J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1476-5381.2012.02136.x","article-title":"Exacerbation of dss-induced colitis in mice lacking kinin b(1) receptors through compensatory up-regulation of kinin b(2) receptors: The role of tight junctions and intestinal homeostasis","volume":"168","author":"Marcon","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1136\/gut.43.3.365","article-title":"Kallikrein-kininogen system activation and bradykinin (b2) receptors in indomethacin induced enterocolitis in genetically susceptible lewis rats","volume":"43","author":"Stadnicki","year":"1998","journal-title":"Gut"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1023\/A:1026694732602","article-title":"Effect of icatibant, a bradykinin b2 receptor antagonist, on the development of experimental ulcerative colitis in mice","volume":"44","author":"Arai","year":"1999","journal-title":"Dig. Dis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.regpep.2006.12.013","article-title":"Pharmacological and biochemical characterization of bradykinin b2 receptors in the mouse colon: Influence of the tnbs-induced colitis","volume":"141","author":"Hara","year":"2007","journal-title":"Regul. Pept."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.dld.2005.01.021","article-title":"Kallikrein-kinin system in inflammatory bowel diseases: Intestinal involvement and correlation with the degree of tissue inflammation","volume":"37","author":"Devani","year":"2005","journal-title":"Dig. Liver Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1254\/jjp.90.59","article-title":"Suppression of dextran sulfate sodium-induced colitis in kininogen-deficient rats and non-peptide b2 receptor antagonist-treated rats","volume":"90","author":"Kamat","year":"2002","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1016\/S1567-5769(02)00146-7","article-title":"Activation of bradykinin b1 receptor by ace inhibitors","volume":"2","author":"Ignjatovic","year":"2002","journal-title":"Int. Immunopharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1139\/cjpp-2016-0063","article-title":"Beneficial effects of kinin b1 receptor antagonism on plasma fatty acid alterations and obesity in zucker diabetic fatty rats","volume":"94","author":"Talbot","year":"2016","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6187","DOI":"10.1038\/s41598-017-06464-w","article-title":"Pi3k p85\u03b1 subunit-deficient macrophages protect mice from acute colitis due to the enhancement of il-10 production","volume":"7","author":"Hayashi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S283","DOI":"10.1016\/S1590-8658(07)60011-5","article-title":"Impact of prebiotics on human health","volume":"38","author":"Bruzzese","year":"2006","journal-title":"Dig. Liver Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/MCG.0b013e31823711fd","article-title":"The intestinal microbiota and obesity","volume":"46","author":"Kallus","year":"2012","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1038\/4441022a","article-title":"Microbial ecology: Human gut microbes associated with obesity","volume":"444","author":"Ley","year":"2006","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev-med-012510-175505","article-title":"Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes","volume":"62","author":"Musso","year":"2011","journal-title":"Annu. Rev. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"16767","DOI":"10.1073\/pnas.0808567105","article-title":"Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, gpr41","volume":"105","author":"Samuel","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11312","DOI":"10.1074\/jbc.M211609200","article-title":"The orphan G protein-coupled receptors gpr41 and gpr43 are activated by propionate and other short chain carboxylic acids","volume":"278","author":"Brown","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1073\/pnas.2637002100","article-title":"Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor gpr41","volume":"101","author":"Xiong","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1038\/ncomms2852","article-title":"The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor gpr43","volume":"4","author":"Kimura","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.2337\/db06-1491","article-title":"Metabolic endotoxemia initiates obesity and insulin resistance","volume":"56","author":"Cani","year":"2007","journal-title":"Diabetes"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3070","DOI":"10.4049\/jimmunol.176.5.3070","article-title":"Enterocyte tlr4 mediates phagocytosis and translocation of bacteria across the intestinal barrier","volume":"176","author":"Neal","year":"2006","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1007\/s00125-006-0334-0","article-title":"Antibiotic treatment partially protects against type 1 diabetes in the bio-breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes?","volume":"49","author":"Brugman","year":"2006","journal-title":"Diabetologia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1210\/jcem.87.6.8739","article-title":"The tissue distribution of the mrna of ghrelin and subtypes of its receptor, GHSR, in humans","volume":"87","author":"Gnanapavan","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/35038090","article-title":"Ghrelin induces adiposity in rodents","volume":"407","author":"Smiley","year":"2000","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/35051587","article-title":"A role for ghrelin in the central regulation of feeding","volume":"409","author":"Nakazato","year":"2001","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"E297","DOI":"10.1152\/ajpendo.00582.2003","article-title":"Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues","volume":"287","author":"Cummings","year":"2004","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"707","DOI":"10.2337\/diabetes.50.4.707","article-title":"Circulating ghrelin levels are decreased in human obesity","volume":"50","author":"Tschop","year":"2001","journal-title":"Diabetes"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4837","DOI":"10.3390\/ijms15034837","article-title":"The growth hormone secretagogue receptor: Its intracellular signaling and regulation","volume":"15","author":"Yin","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"124","DOI":"10.2337\/diabetes.51.1.124","article-title":"Ghrelin is present in pancreatic \u03b1-cells of humans and rats and stimulates insulin secretion","volume":"51","author":"Date","year":"2002","journal-title":"Diabetes"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5667","DOI":"10.1074\/jbc.M103898200","article-title":"Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells","volume":"277","author":"Murata","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/45230","article-title":"Ghrelin is a growth-hormone-releasing acylated peptide from stomach","volume":"402","author":"Kojima","year":"1999","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3389\/fendo.2011.00093","article-title":"The insulin receptor: A new target for cancer therapy","volume":"2","author":"Malaguarnera","year":"2011","journal-title":"Front. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.15252\/embr.201540530","article-title":"Ins and outs of gpcr signaling in primary cilia","volume":"16","author":"Schou","year":"2015","journal-title":"EMBO Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.canlet.2016.03.031","article-title":"G protein-coupled receptors as promising cancer targets","volume":"376","author":"Liu","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1210\/en.2006-1711","article-title":"Insulin potentiates Ca2+ signaling and phosphatidylinositol 4,5-bisphosphate hydrolysis induced by gq protein-coupled receptor agonists through an mtor-dependent pathway","volume":"148","author":"Kisfalvi","year":"2007","journal-title":"Endocrinology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"32081","DOI":"10.1074\/jbc.M502876200","article-title":"Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity","volume":"280","author":"Nogueira","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1007\/s00432-008-0359-5","article-title":"Antineoplastic effect of rapamycin is potentiated by inhibition of IRS-1 signaling in prostate cancer cells xenografts","volume":"134","author":"Oliveira","year":"2008","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e201","DOI":"10.1038\/emm.2015.93","article-title":"The role of amino acid-induced mammalian target of rapamycin complex 1(mTORC1) signaling in insulin resistance","volume":"48","author":"Yoon","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.bbrc.2010.09.036","article-title":"Crosstalk between insulin receptor and g protein-coupled receptor signaling systems leads to Ca(2+) oscillations in pancreatic cancer panc-1 cells","volume":"401","author":"Young","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1038\/sj.onc.1204183","article-title":"Autocrine and paracrine signaling through neuropeptide receptors in human cancer","volume":"20","author":"Heasley","year":"2001","journal-title":"Oncogene"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1158\/1078-0432.CCR-03-0502","article-title":"Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer","volume":"10","author":"Bruns","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3389\/fonc.2017.00140","article-title":"Ip(3) receptor-mediated calcium signaling and its role in autophagy in cancer","volume":"7","author":"Kania","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.18632\/aging.101117","article-title":"Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes","volume":"8","author":"Reifsnyder","year":"2016","journal-title":"Aging"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6539","DOI":"10.1158\/0008-5472.CAN-09-0418","article-title":"Metformin disrupts crosstalk between G protein\u2013coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth","volume":"69","author":"Kisfalvi","year":"2009","journal-title":"Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1210\/er.2011-1034","article-title":"Insulin resistance and the polycystic ovary syndrome revisted: An update on mechanisms and implications","volume":"33","author":"Dunaif","year":"2012","journal-title":"Endocr. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40618-016-0523-8","article-title":"New markers of insulin resistance in polycystic ovary syndrome","volume":"40","author":"Polak","year":"2017","journal-title":"J. Endocrinol. Investig."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/nature05414","article-title":"An obesity-associated gut microbiome with increased capacity for energy harvest","volume":"444","author":"Turnbaugh","year":"2006","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1177\/1933719116672588","article-title":"The ovarian renin-angiotensin system (OVRAS): A major factor in ovarian function and disease","volume":"23","author":"Palumbo","year":"2016","journal-title":"Reprod. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/S0015-0282(16)56098-1","article-title":"Immunohistochemical localization of renin and angiotensin in the ovary: Comparison between normal woman and patients with histologically proven polycystic ovarian disease","volume":"60","author":"Palumbo","year":"1993","journal-title":"Fertil. Steril."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"7076","DOI":"10.1016\/S0021-9258(18)48205-1","article-title":"Rat ovarian angiotensin ii receptors: Characterization and coupling to estrogen secretion","volume":"262","author":"Pucell","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/BF00338068","article-title":"In vitro effects of angiotensin ii on steroid production by hamster follicles and on ultrastructure of the theca interna","volume":"268","author":"Kitzman","year":"1992","journal-title":"Cell Tissue Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11906-012-0323-2","article-title":"The renin angiotensin aldosterone system and insulin resistance in humans","volume":"15","author":"Underwood","year":"2013","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_87","unstructured":"Marcus, Y., Shefer, G., and Stern, N. (2012). Adipose tissue renin-angiotensin-aldosterone system (RAAS) and progression of insuline resistance. Mol. Cell. Endocrinol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1159\/000342776","article-title":"The renin-angiotensin system in the pathophysiology of type 2 diabetes","volume":"5","author":"Goossens","year":"2012","journal-title":"Obes. Facts"},{"key":"ref_89","first-page":"3925","article-title":"Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin ii","volume":"83","author":"Karlsson","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Naftolin, F., Palumbo, A., and Pepperell, J.R. (1996). Potential role of the renin-angiotensin system in polycystic ovaries. Polycystic Ovary Syndr., 71\u201388.","DOI":"10.1007\/978-1-4613-8483-0_5"},{"key":"ref_91","first-page":"774","article-title":"Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis","volume":"18","author":"Dunaif","year":"1997","journal-title":"Endocr. Rev."},{"key":"ref_92","first-page":"353","article-title":"Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction","volume":"5","author":"Stoeckel","year":"2016","journal-title":"F1000Research"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1161\/STR.0b013e3182299496","article-title":"Vascular contributions to cognitive impairment and dementia","volume":"42","author":"Gorelick","year":"2011","journal-title":"Stroke"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.jalz.2014.10.008","article-title":"Vascular contributions to cognitive impairment and dementia including alzheimer\u2019s disease","volume":"11","author":"Snyder","year":"2015","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_95","first-page":"161","article-title":"Insulin in the brain: Its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer\u2019s disease","volume":"5","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1210\/er.2007-0034","article-title":"Cognitive dysfunction and diabetes mellitus","volume":"29","author":"Kodl","year":"2008","journal-title":"Endocr. Rev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S1474-4422(04)00681-7","article-title":"Insulin and neurodegenerative disease: Shared and specific mechanisms","volume":"3","author":"Craft","year":"2004","journal-title":"Lancet Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ejphar.2004.02.045","article-title":"Insulin and the insulin receptor in experimental models of learning and memory","volume":"490","author":"Zhao","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"34893","DOI":"10.1074\/jbc.274.49.34893","article-title":"Brain insulin receptors and spatial memory correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats","volume":"274","author":"Zhao","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.neurobiolaging.2005.08.021","article-title":"Insulin resistance syndrome and Alzheimer\u2019s disease: Age-and obesity-related effects on memory, amyloid, and inflammation","volume":"26","author":"Craft","year":"2005","journal-title":"Neurobiol. Aging"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1001\/archneurol.2010.225","article-title":"Insulin resistance and alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes","volume":"68","author":"Baker","year":"2011","journal-title":"Arch. Neurol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"13434","DOI":"10.1039\/C5CC05264E","article-title":"Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in alzheimer\u2019s disease","volume":"51","author":"Rajasekhar","year":"2015","journal-title":"Chem. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/S0140-6736(13)62154-6","article-title":"Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future","volume":"383","author":"Kahn","year":"2014","journal-title":"Lancet"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.pharmthera.2012.07.006","article-title":"Insulin in the brain: There and back again","volume":"136","author":"Banks","year":"2012","journal-title":"Pharmacol. Therap."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/jcp.1041610218","article-title":"Identification and distribution of insulin receptors on cultured bovine brain microvessel endothelial cells: Possible function in insulin processing in the blood\u2013brain barrier","volume":"161","author":"Miller","year":"1994","journal-title":"J. Cell. Physiol."},{"key":"ref_106","first-page":"13","article-title":"G-protein-coupled receptors, pancreatic islets, and diabetes","volume":"3","author":"Layden","year":"2010","journal-title":"Nat. Educ."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/nrn2977","article-title":"The role of g protein-coupled receptors in the pathology of Alzheimer\u2019s disease","volume":"12","author":"Thathiah","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/nn940","article-title":"Alzheimer\u2019s disease: Treatments in discovery and development","volume":"5","author":"Citron","year":"2002","journal-title":"Nat. Neurosci."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Hurley, J.H., Zhang, S., Bye, L.S., Marshall, M.S., DePaoli-Roach, A.A., Guan, K., Fox, A.P., and Yu, L. (2003). Insulin signaling inhibits the 5-ht 2c receptor in choroid plexus via map kinase. BMC Neurosci., 4.","DOI":"10.1186\/1471-2202-4-10"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0006-8993(85)90856-X","article-title":"Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors","volume":"346","author":"Pazos","year":"1985","journal-title":"Brain Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1177\/38.9.2167329","article-title":"Evidence for separate receptors for insulin and insulin-like growth factor-i in choroid plexus of rat brain by quantitative autoradiography","volume":"38","author":"Davidson","year":"1990","journal-title":"J. Histochem. Cytochem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0197-4580(03)00039-3","article-title":"Insulin inhibits amyloid \u03b2-induced cell death in cultured human brain pericytes","volume":"25","author":"Rensink","year":"2004","journal-title":"Neurobiol. Aging"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/575\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:55:31Z","timestamp":1760194531000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/575"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,17]]},"references-count":112,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2]]}},"alternative-id":["ijms19020575"],"URL":"https:\/\/doi.org\/10.3390\/ijms19020575","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,17]]}}}