Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due t...
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| Veröffentlicht in: | Science advances 2020-08, Vol.6 (35), p.eaaz9890 |
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| creator | Gilroy, C A Capozzi, M E Varanko, A K Tong, J D'Alessio, D A Campbell, J E Chilkoti, A |
| description | There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease. |
| doi_str_mv | 10.1126/sciadv.aaz9890 |
| format | Article |
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Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.aaz9890</identifier><identifier>PMID: 32923621</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Delayed-Action Preparations - pharmacology ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Type 2 - drug therapy ; Engineering ; Fibroblast Growth Factors - agonists ; Glucagon-Like Peptide 1 - metabolism ; Glucagon-Like Peptide-1 Receptor - agonists ; Health and Medicine ; Humans ; Hyperglycemia - drug therapy ; Hyperglycemia - prevention & control ; Mice ; Obesity - drug therapy ; Obesity - metabolism ; Peptides - pharmacology ; SciAdv r-articles</subject><ispartof>Science advances, 2020-08, Vol.6 (35), p.eaaz9890</ispartof><rights>Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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Distributed under a Creative Commons Attribution License 4.0 (CC BY). 2020 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-a6506d214f9af15797a75e21499eecd4fe786608afe12800f3003bfac865aa63</citedby><cites>FETCH-LOGICAL-c390t-a6506d214f9af15797a75e21499eecd4fe786608afe12800f3003bfac865aa63</cites><orcidid>0000-0003-4358-6331 ; 0000-0002-5614-3671 ; 0000-0002-7587-0663 ; 0000-0001-8225-6314 ; 0000-0002-1569-2228</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449677/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449677/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32923621$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gilroy, C A</creatorcontrib><creatorcontrib>Capozzi, M E</creatorcontrib><creatorcontrib>Varanko, A K</creatorcontrib><creatorcontrib>Tong, J</creatorcontrib><creatorcontrib>D'Alessio, D A</creatorcontrib><creatorcontrib>Campbell, J E</creatorcontrib><creatorcontrib>Chilkoti, A</creatorcontrib><title>Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.</description><subject>Animals</subject><subject>Delayed-Action Preparations - pharmacology</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Engineering</subject><subject>Fibroblast Growth Factors - agonists</subject><subject>Glucagon-Like Peptide 1 - metabolism</subject><subject>Glucagon-Like Peptide-1 Receptor - agonists</subject><subject>Health and Medicine</subject><subject>Humans</subject><subject>Hyperglycemia - drug therapy</subject><subject>Hyperglycemia - prevention & control</subject><subject>Mice</subject><subject>Obesity - drug therapy</subject><subject>Obesity - metabolism</subject><subject>Peptides - pharmacology</subject><subject>SciAdv r-articles</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc9r2zAUx8VYaUPba49Dx12cSrItW5fBCEs6CGzQ3sWL_JSq2JYnyQHvr5_bZKE9vV_f930PPoTccbbkXMj7aBw0hyXAX1Ur9oksRF6VmSiL-vO7_IrcxvjCGOOFlCVXl-QqF0rkUvAFmR7HmMD12NCALUJE6i0Futn-zjiFvqHrzVpw2ozQUtj73sVEbfDdPKOuf0GTYNcibXDwiQ7Bp7kTaecMHmV-h9Gl6c3qeRow7NvJYOfghlxYaCPenuI1eVr_eFo9ZNtfm5-r79vM5IqlDGTJZCN4YRVYXlaqgqrEuVYK0TSFxaqWktVgkYuaMZszlu8smFqWADK_Jt-OtsO467Ax2KcArR6C6yBM2oPTHye9e9Z7f9BVUShZVbPB15NB8H9GjEl3LhpsW-jRj1GLohClkkzVs3R5lJrgYwxoz2c406_E9JGYPhGbF768f-4s_88n_weJlpVU</recordid><startdate>20200801</startdate><enddate>20200801</enddate><creator>Gilroy, C A</creator><creator>Capozzi, M E</creator><creator>Varanko, A K</creator><creator>Tong, J</creator><creator>D'Alessio, D A</creator><creator>Campbell, J E</creator><creator>Chilkoti, A</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4358-6331</orcidid><orcidid>https://orcid.org/0000-0002-5614-3671</orcidid><orcidid>https://orcid.org/0000-0002-7587-0663</orcidid><orcidid>https://orcid.org/0000-0001-8225-6314</orcidid><orcidid>https://orcid.org/0000-0002-1569-2228</orcidid></search><sort><creationdate>20200801</creationdate><title>Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia</title><author>Gilroy, C A ; 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Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. 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| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Animals Delayed-Action Preparations - pharmacology Diabetes Mellitus, Experimental - drug therapy Diabetes Mellitus, Type 2 - drug therapy Engineering Fibroblast Growth Factors - agonists Glucagon-Like Peptide 1 - metabolism Glucagon-Like Peptide-1 Receptor - agonists Health and Medicine Humans Hyperglycemia - drug therapy Hyperglycemia - prevention & control Mice Obesity - drug therapy Obesity - metabolism Peptides - pharmacology SciAdv r-articles |
| title | Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia |
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