Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists
Abstract Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true the...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-022-28561-9 |
| _version_ | 1827329061854117888 |
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| author | Margaret Wu Ester Carballo-Jane Haihong Zhou Peter Zafian Ge Dai Mindy Liu Julie Lao Terri Kelly Dan Shao Judith Gorski Dmitri Pissarnitski Ahmet Kekec Ying Chen Stephen F. Previs Giovanna Scapin Yacob Gomez-Llorente Scott A. Hollingsworth Lin Yan Danqing Feng Pei Huo Geoffrey Walford Mark D. Erion David E. Kelley Songnian Lin James Mu |
| author_facet | Margaret Wu Ester Carballo-Jane Haihong Zhou Peter Zafian Ge Dai Mindy Liu Julie Lao Terri Kelly Dan Shao Judith Gorski Dmitri Pissarnitski Ahmet Kekec Ying Chen Stephen F. Previs Giovanna Scapin Yacob Gomez-Llorente Scott A. Hollingsworth Lin Yan Danqing Feng Pei Huo Geoffrey Walford Mark D. Erion David E. Kelley Songnian Lin James Mu |
| author_sort | Margaret Wu |
| collection | DOAJ |
| description | Abstract Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes. |
| first_indexed | 2024-03-07T15:28:24Z |
| format | Article |
| id | doaj.art-12bfc20a079d44f5b507280558359df6 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T15:28:24Z |
| publishDate | 2022-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-12bfc20a079d44f5b507280558359df62024-03-05T16:33:55ZengNature PortfolioNature Communications2041-17232022-02-0113111510.1038/s41467-022-28561-9Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonistsMargaret Wu0Ester Carballo-Jane1Haihong Zhou2Peter Zafian3Ge Dai4Mindy Liu5Julie Lao6Terri Kelly7Dan Shao8Judith Gorski9Dmitri Pissarnitski10Ahmet Kekec11Ying Chen12Stephen F. Previs13Giovanna Scapin14Yacob Gomez-Llorente15Scott A. Hollingsworth16Lin Yan17Danqing Feng18Pei Huo19Geoffrey Walford20Mark D. Erion21David E. Kelley22Songnian Lin23James Mu24Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Abstract Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes.https://doi.org/10.1038/s41467-022-28561-9 |
| spellingShingle | Margaret Wu Ester Carballo-Jane Haihong Zhou Peter Zafian Ge Dai Mindy Liu Julie Lao Terri Kelly Dan Shao Judith Gorski Dmitri Pissarnitski Ahmet Kekec Ying Chen Stephen F. Previs Giovanna Scapin Yacob Gomez-Llorente Scott A. Hollingsworth Lin Yan Danqing Feng Pei Huo Geoffrey Walford Mark D. Erion David E. Kelley Songnian Lin James Mu Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists Nature Communications |
| title | Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists |
| title_full | Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists |
| title_fullStr | Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists |
| title_full_unstemmed | Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists |
| title_short | Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists |
| title_sort | functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists |
| url | https://doi.org/10.1038/s41467-022-28561-9 |
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