Insulin and IGF-I Analogs: Novel Approaches to Improved Insulin Pharmacokinetics
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 mapping 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.
KeywordsInsulin Receptor Human Insulin Insulin Analog Human Mammary Epithelial Cell Regular Insulin
Unable to display preview. Download preview PDF.
- 2.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).PubMedCrossRefGoogle Scholar
- 5.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).PubMedCrossRefGoogle Scholar
- 6.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).Google Scholar
- 12.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).Google Scholar
- 15.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).PubMedCrossRefGoogle Scholar
- 16.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).Google Scholar
- 17.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).Google Scholar
- 19.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).Google Scholar
- 20.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).PubMedCrossRefGoogle Scholar
- 26.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).PubMedGoogle Scholar
- 27.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).Google Scholar