title: Receptor-isoform-selective insulin analogues give tissue-preferential effects.
abstract: The relative expression patterns of the two IR (insulin receptor) isoforms, +/- exon 11 (IR-B/IR-A respectively), are tissue-dependent. Therefore we have developed insulin analogues with different binding affinities for the two isoforms to test whether tissue-preferential biological effects can be attained. In rats and mice, IR-B is the most prominent isoform in the liver (> 95%) and fat (> 90%), whereas in muscles IR-A is the dominant isoform (> 95%). As a consequence, the insulin analogue INS-A, which has a higher relative affinity for human IR-A, had a higher relative potency [compared with HI (human insulin)] for glycogen synthesis in rat muscle strips (26%) than for glycogen accumulation in rat hepatocytes (5%) and for lipogenesis in rat adipocytes (4%). In contrast, the INS-B analogue, which has an increased affinity for human IR-B, had higher relative potencies (compared with HI) for inducing glycogen accumulation (75%) and lipogenesis (130%) than for affecting muscle (45%). For the same blood-glucose-lowering effect upon acute intravenous dosing of mice, INS-B gave a significantly higher degree of IR phosphorylation in liver than HI. These in vitro and in vivo results indicate that insulin analogues with IR-isoform-preferential binding affinity are able to elicit tissue-selective biological responses, depending on IR-A/IR-B expression.
authors.affiliation: Department of Insulin Biology, Novo Nordisk A/S, Måløv, Denmark. savi@novonordisk.com
authors.forename: Sara G
authors.initials: SG
authors.lastname: Vienberg
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Bouman
authors.forename: Heidi
authors.initials: H
authors.lastname: Sørensen
authors.forename: Carsten E
authors.initials: CE
authors.lastname: Stidsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Kjeldsen
authors.forename: Tine
authors.initials: T
authors.lastname: Glendorf
authors.forename: Anders R
authors.initials: AR
authors.lastname: Sørensen
authors.forename: Grith S
authors.initials: GS
authors.lastname: Olsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Andersen
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000031:analogs & derivatives* / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D010766:Phosphorylation; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D034421:Sus scrofa
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D020033:Protein Isoforms; C569304:insulin, A8H,B25N,B27E,desB30-; C569303:insulin, B(1-29)-valyl-glycyl-leucyl-seryl-seryl-glycyl-glutaminyl-A(1-21)-A18Q-; D006003:Glycogen; D011972:Receptor, Insulin