Abstract
Current insulin formulations do not mimic the normal glucose-induced release of insulin by the pancreas in a physiological manner.1 One limitation is the delayed absorption of hexameric insulin from the subcutaneous site of injection, such that soluble insulins (currently the most rapid acting formulations) are too slow and have too long a duration of action.2 Another limitation is that longer acting insulin formulations, such as human ultralente, exhibit too short a duration of action, show a pronounced peak in activity and are suspensions, resulting in variability in administration.3 The use of recombinant DNA technology and peptide chemistry have allowed the generation of insulin analogs with a wide variety of amino acid substitutions, which in turn halve been useful in map** regions of the insulin nucleus that are associated with Zn2+ binding, dimer formation and insulin receptor interaction. This report will review the physical, biological and clinical characterization of several insulin analogs that have been designed to improve absorption characteristics and pharmacodynamics. Because of the structural homology between insulin and insulin-like growth factor-I (IGF-I), we have investigated specific IGF-like modifications in the insulin sequence to determine if these will transfer to pharmacokinetic differences in insulin absorption and clearance.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
M. Berger, H. J. Cuppers, H. Hegner, V. Jörgens and P. Berchtold, Absorption kinetics and biologic effects of subcutaneously injected insulin preparations, Diabetes Care 5:77 (1982).
J. A. Galloway, C. T. Spradlin, R. L. Nelson, S. M. Wentworth, J. A. Davidson and J. L. Swarner, Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures, Diabetes Care 4:366 (1981).
P. Hildebrandt , P. Sejrsen , S. L. Nielsen, K. Birch and L. Sestoft, Diffusion and polymerization determines the insulin absorption in diabetic patients, Scand J Clin Lab Invest 45:685 (1985).
J. Brange, U. Ribel, J. F. Hansen, G. Dodson, M. T. Hensen, S. Havelund, S. G. Melburg, F. Norris, K.Norris, L. Snel, A. R. Sørensen and H. O. Voigt, Monomeric insulins obtained by protein engineering and their medical implications, Nature (Lond) 333:679 (1988).
S. Kang, F. M. Creagh, J. R. Peters, J. Brange, A. Vølund and D. R. Owens, Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type I diabetic subjects, Diabetes Care 14:571 (1991).
R. D. DiMarchi, J. P. Mayer, L. Fan, D. N. Brems, B. H. Frank, L. K. Green, J. A. Hoffmann, D. C.Howey, H. B. Long, W. N. Shaw , J. E. Shields, L. J. Slieker , K. S. E. Su, K. L. Sundell and R. E. Chance, Synthesis of a fast-acting insulin analog based upon structural homology with insulin-like growth factor-I, in: Peptides: Chemistry and Biology. Proceedings of the Twelfth American Peptide Symposium, J. A. Smith and J. E. Rivier, eds., 26–28, ESCOM, Leiden (1992).
Y. Oh, H. L. Müller, D-Y. Lee, P. J. Fielder and R. G. Rosenfeld, Characterization of the affinities of insulin-like growth factor (IGF)-binding proteins 1–4 for IGF-I, IGF-II, IGF-I/insulin hybrid, and IGF-I analogs, Endocrinology 132:1337 (1993).
M. A. Cascieri, R. Saperstein, N. Hayes, B. G. Green, G. G. Chicchi, J. Applebaum and M. L. Bayne, Serum half-life and biological activity of mutants of human insulin-like growth factor I which do not bind to serum binding proteins, Endocrinology 123:373 (1988).
D. R. Clemmons, D. L. Dehoff, W. H. Busby, M. L. Bayne and M. A. Cascieri, Competition for binding to insulin-like growth factor (IGF) binding protein-2,3,4 and 5 by the IGFs and IGF analogs, Endocrinology 131:890 (1992).
P. A. Gruppuso, B. H. Frank and R. Schwartz, Binding of proinsulin and proinsulin conversion intermediates to human placental insulin-like growth factor-I receptors, J Clin Endocrinol Metab 67:194 (1988).
M. L. Bayne, M. A. Cascieri, B. Kelder, J. Applebaum, G. G. Chicchi, J. A. Shapiro, F. Pasleau and J. J.Köpenick, Expression of a synthetic gene encoding human insulin-like growth factor I in cultured mouse fibroblasts, Proc Natl Acad Sci USA 85:2638 (1987).
W. H. Busby, D. G. Clapper and D. R. Clemmons, Purification of a 31-kDa IGF binding protein from human amniotic fluid, J Biol Chem 263:14302 (1988).
D. N. Brems, L. A. Alter, M. J. Beckage, R. E. Chance, R. D. DiMarchi, L. K. Green, H. B. Long, A. H.Pekar, J. E. Shields and B. H. Frank, Altering the association properties of insulin by amino acid replacement, Protein Engineering 5:527 (1992).
D. N. Brems, P. L. Brown, C. Bryant, R. E. Chance, L. K. Green, H. B. Long, A. A. Miller, R. Millican, J.E. Shields and B. H. Frank, Improved insulin stability through amino acid substitution, Protein Engineering 5:519 (1992).
M. A. Weiss, Q-X. Hua, C. S. Lynch, B. H. Frank and S. E. Shoelson, Heteronuclear 2D NMR studies of an engineered insulin monomer: Assignment and characterization of the receptor-binding surface by selective 2H and 13C labeling with application to protein design, Biochemistry 30:7373 (1991).
D. C. Howey, S. A. Hooper and R. R. Bowsher, [Lys(B28), Pro(B29)]-Human insulin: An equipotent analog of insulin with rapid onset and short duration of action, Diabetes 40(Supp 1): 423A (1991).
L. J. Slieker and K. L. Sundell, Modifications in the 28–29 position of the insulin B-chain alter binding to the IGF-I receptor with minimal effect on insulin receptor binding, Diabetes 40(Supp 1): 168A (1991).
J. F. Cara, R. G. Mirmira, S. H. Nakagawa and H. S. Tager, An insulin-like growth factor I/insulin hybrid exhibiting high potency for interaction with the type I insulin-like growth factor and insulin receptor of placental plasma membranes, J Biol Chem 265:17820 (1990).
H. Wolpert, L. J. Slieker, K. Sundell and G. King, Identification of an insulin analog with enhanced growth effect in aortic smooth muscle cells, Diabetes 39(Supp 1):140A (1990).
K. E. Bornfeldt, R. A. Gidlöf, A. Wasteson, M. Lake, A. Skottner and H. J. Arnqvist, Binding and biological effects of insulin, insulin analogues and insulin-like growth factors in rat aortic smooth muscle cells. Comparison of maximal growth promoting activities, Diabetologia 34:307 (1991).
K. Drejer, The bioactivity of insulin analogues from in vitro receptor binding to in vivo glucose uptake, Diabetes/Metabolism Reviews 8:259 (1992).
S. Gray, P. Cowan, U. Di Mario, R. A. Elton, B. F. Clarke and L. P. J. Duncan, Influence of insulin antibodies on pharmacokinetics and bioavailability of recombinant human insulin and highly purified beef insulins in insulin-dependent diabetics, Br Med J 290:1687 (1985).
R. S. Bar, D. R. Clemmons, M. Boes, W. H. Busby, B. A. Booth, B. L. Dake and A. Sandra. Endocrinology 127:1078 (1990).
H-P. Guler, J. Zapf and E. R. Froesch, Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults, N Engl J Med 317:137 (1987).
M. L. Bayne, J. Applebaum, G. G. Chichi, N. S. Hayes, B. G. Green and M. A. Cascieri, Structural analogs of human insulin-like growth factor I with reduced affinity for serum binding proteins and the type II insulin-like growth factor receptor, J Biol Chem 263:6233 (1988).
D. R. Clemmons, M. A. Cascieri, C. Camacho-Hubner, R. H. McCusker and M. L. Bayne, Discrete alterations of the insulin-like growth factor I molecule which alter its affinity for insulin-like growth factor-binding proteins result in changes in bioactivity, J Biol Chem 265:12210 (1990).
M. L. Bayne, J. Applebaum, D. Underwood, G. G. Chicchi, B. G. Green, N. S. Hayes and M. A. Cascieri, The C region of human insulin-like growth factor (IGF) I is required for high affinity binding to the type I IGF receptor, J Biol Chem 264:11004 (1988).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1994 Springer Science+Business Media New York
About this chapter
Cite this chapter
Slieker, L.J. et al. (1994). Insulin and IGF-I Analogs: Novel Approaches to Improved Insulin Pharmacokinetics. In: Le Roith, D., Raizada, M.K. (eds) Current Directions in Insulin-Like Growth Factor Research. Advances in Experimental Medicine and Biology, vol 343. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2988-0_3
Download citation
DOI: https://doi.org/10.1007/978-1-4615-2988-0_3
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6301-9
Online ISBN: 978-1-4615-2988-0
eBook Packages: Springer Book Archive