HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rakatzi, I. Articles by Eckel, J. Search for Related Content PubMed PubMed Citation Articles by Rakatzi, I. Articles by Eckel, J. Social Bookmarking                What's this?

A Novel Insulin Analog With Unique Properties

Lys^B3,Glu^B29 Insulin Induces Prominent Activation of Insulin Receptor Substrate 2, but Marginal Phosphorylation of Insulin Receptor Substrate 1

¹ Department of Clinical Biochemistry and Pathobiochemistry, German Diabetes Research Institute, Düsseldorf, Germany
² Aventis Pharma GmbH, Frankfurt, Germany

The potentially enhanced mitogenic activity of insulin analogs represents a safety risk that requires detailed analysis of new analogs considered for therapeutic applications. We assessed the signaling properties and mitogenic potency of two novel rapid-acting insulin analogs, Lys^B3,Glu^B29 insulin (HMR 1964) and Lys^B3,Ile^B28 insulin (HMR 1153) using myoblasts and cardiomyocytes. In myoblasts, both binding and internalization were two- to threefold higher for Asp^B10 insulin and HMR 1153 when compared with HMR 1964 and regular insulin. This finding correlated with a prominent Shc/IGF-I receptor interaction, tyrosine phosphorylation of Shc, activation of extracellular signal-regulated protein kinase (ERK)-1 and -2, and stimulation of DNA synthesis by HMR 1153 and Asp^B10 insulin. In contrast, HMR 1964 produced a marginal activation of the Shc/ERK kinase cascade and was equipotent to insulin in stimulating DNA synthesis in myoblasts. Further, the in vivo growth-promoting activity of this analog was found to be identical to that of regular human insulin. In myoblasts, HMR 1964 produced a minor activation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation, but a prominent activation of IRS-2, with a significantly stronger effect than insulin in human myoblasts. Predominant activation of IRS-2 was also observed in adult cardiomyocytes where HMR 1964 increased 3-O-methylglucose transport and the activation of Akt and glycogen synthase kinase-3 to the same extent as human insulin. We concluded that 1) the mitogenic properties of insulin analogs may result from a series of initial receptor interactions, including internalization and phosphorylation; 2) the mitogenic and metabolic potential of HMR 1964 is identical to that of insulin; and 3) predominant activation of IRS-2 may open new avenues for optimized insulin therapies.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Denley, J. M. Carroll, G. V. Brierley, L. Cosgrove, J. Wallace, B. Forbes, and C. T. Roberts Jr. Differential Activation of Insulin Receptor Substrates 1 and 2 by Insulin-Like Growth Factor-Activated Insulin Receptors Mol. Cell. Biol., May 15, 2007; 27(10): 3569 - 3577. [Abstract] [Full Text] [PDF]

				J. J. F. P. Luiken, I. Momken, D. D. J. Habets, M. El Hasnaoui, W. A. Coumans, D. P. Y Koonen, J. F. C. Glatz, and A. Bonen Arsenite Modulates Cardiac Substrate Preference by Translocation of GLUT4, But Not CD36, Independent of Mitogen-Activated Protein Kinase Signaling Endocrinology, November 1, 2006; 147(11): 5205 - 5216. [Abstract] [Full Text] [PDF]

				F. M Regan and D. B Dunger Use of new insulins in children Arch. Dis. Child. Ed. Pract., August 1, 2006; 91(2): ep47 - ep53. [Full Text] [PDF]

				T. P. Ciaraldi, S. A. Phillips, L. Carter, V. Aroda, S. Mudaliar, and R. R. Henry Effects of the Rapid-Acting Insulin Analog Glulisine on Cultured Human Skeletal Muscle Cells: Comparisons with Insulin and Insulin-Like Growth Factor I J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5551 - 5558. [Abstract] [Full Text] [PDF]

				A. M. Hennige, R. Lehmann, C. Weigert, K. Moeschel, M. Schauble, E. Metzinger, R. Lammers, and H.-U. Haring Insulin Glulisine: Insulin Receptor Signaling Characteristics In Vivo Diabetes, February 1, 2005; 54(2): 361 - 366. [Abstract] [Full Text] [PDF]