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.
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Research Article|
November 28 2011
Receptor-isoform-selective insulin analogues give tissue-preferential effects
Sara G. Vienberg;
Sara G. Vienberg
1
*Department of Insulin Biology, Novo Nordisk A/S, Måløv, Denmark
1To whom correspondence should be addressed (email savi@novonordisk.com).
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Stephan D. Bouman;
Stephan D. Bouman
†Department of Insulin Pharmacology, Novo Nordisk A/S, Måløv, Denmark
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Heidi Sørensen;
Heidi Sørensen
†Department of Insulin Pharmacology, Novo Nordisk A/S, Måløv, Denmark
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Carsten E. Stidsen;
Carsten E. Stidsen
*Department of Insulin Biology, Novo Nordisk A/S, Måløv, Denmark
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Thomas Kjeldsen;
Thomas Kjeldsen
‡Department of Diabetes Protein Engineering, Novo Nordisk A/S, Måløv, Denmark
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Tine Glendorf;
Tine Glendorf
‡Department of Diabetes Protein Engineering, Novo Nordisk A/S, Måløv, Denmark
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Anders R. Sørensen;
Anders R. Sørensen
*Department of Insulin Biology, Novo Nordisk A/S, Måløv, Denmark
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Grith S. Olsen;
Grith S. Olsen
*Department of Insulin Biology, Novo Nordisk A/S, Måløv, Denmark
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Birgitte Andersen;
Birgitte Andersen
*Department of Insulin Biology, Novo Nordisk A/S, Måløv, Denmark
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Erica Nishimura
Erica Nishimura
*Department of Insulin Biology, Novo Nordisk A/S, Måløv, Denmark
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Publisher: Portland Press Ltd
Received:
May 17 2011
Revision Received:
August 18 2011
Accepted:
August 18 2011
Accepted Manuscript online:
August 18 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 440 (3): 301–308.
Article history
Received:
May 17 2011
Revision Received:
August 18 2011
Accepted:
August 18 2011
Accepted Manuscript online:
August 18 2011
Citation
Sara G. Vienberg, Stephan D. Bouman, Heidi Sørensen, Carsten E. Stidsen, Thomas Kjeldsen, Tine Glendorf, Anders R. Sørensen, Grith S. Olsen, Birgitte Andersen, Erica Nishimura; Receptor-isoform-selective insulin analogues give tissue-preferential effects. Biochem J 15 December 2011; 440 (3): 301–308. doi: https://doi.org/10.1042/BJ20110880
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