Insulin analogues

Yeung, C.W.T., Moule, M.L., and Yip, C.C. (1980) Photoaffinity labeling of insulin receptor with an insulin analogue selectively modified at the amino terminal of the B chain. Biochemistry 19, 2196-2203. 

Humalog (Insulin lispro) Recombinant short-acting human insulin analogue produced in E. coli Engineered inversion of native B28-B29 proline-lysine sequence Eli Lilly 1996 (USA and EU)... 

NovoRapid (Insulin Aspart) Recombinant shortacting human insulin analogue produced in S. cerevisiae Engineered B28 proline replaced by aspartic acid Novo Nordisk 1999 (EU)... 

Glulisine) acting insulin analogue produced in E. coli is replaced by a lysine and B29 lysine is replaced by glutamic acid. pharmaceuticals (USA)... 

Recombinant DNA technology facilitates not only production of human insulin in microbial systems, but also facilitates generation of insulins of modified amino acid sequences. The major aims of generating such engineered insulin analogues include ... 

A number of studies have also focused upon the generation of longer-acting insulin analogues. The currently used Zn-insulin suspensions, or protamine-Zn-insulin suspensions, generally display a plasma half-life of 20-25 h. Selected amino acid substitutions have generated insulins which, even in soluble form, exhibit plasma half-lives of up to 35 h. 

Bristow, A. 1993. Recombinant DNA derived insulin analogues as potentially useful therapeutic agents. Trends in Biotechnology 11, 301-305. 

Vajo, Z., Fawcett, J., and Duckworth, W.C. 2001. Recombinant DNA technology in the treatment of diabetes insulin analogues. Endocrine Reviews 22(5), 706-717. 

NovoRapid (Insulin Aspart, short-acting rh-insulin analogue)... 

Insulin Aspart is a second fast-acting engineered human insulin analogue now approved for general medical use. It differs from native human insulin in that the proline residue has been replaced by aspartic acid. This single amino acid substitution also decreases the propensity of individual molecules to self-associate, ensuring that they begin to enter the bloodstream from the site of injection immediately upon administration. 

Insulin Lispro was the first recombinant fast-acting insulin analogue to gain marketing approval (Table 8.3). It displays an amino acid sequence identical to native human insulin, with one alteration — an inversion of the natural proline lysine sequence found at positions 28 and 29 of the insulin jS-chain. This simple alteration significantly decreased the propensity of individual insulin molecules to self-associate when stored at therapeutic dose concentrations. The dimerization constant for Insulin Lispro is 300 times lower than that exhibited by unmodified human insulin. Structurally, this appears to occur as the change in sequence disrupts the formation of inter-chain hydrophobic interactions critical to self-association. 

Rapid-acting insulin analogues (lispro, insulin aspart [Humalog, Novo log]) have been engineered to contain amino acid modifications that promote rapid entry into the circulation from subcutaneous tissue. They begin to exert their effects as early as 5 to 10 minutes after administration. Lispro insulin, the first insulin analogue to be approved in Europe and the United States, is produced by switching the positions of lysine-proline amino acid residues 28 and 29 of the carboxy terminus of the p-chain. Lispro insulin displays very similar actions to insulin and has a similar affinity for the insulin receptor, but it cannot form stable hexamers or dimers in subcutaneous tissue, which promotes its rapid uptake and absorption. 

B. Indications and use Humalog is an insulin analogue that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. It has a more rapid onset and shorter duration of action than human regular insulin. 

---