Insulin glargine
Manufactureis made by recombinant DNA technology with Escherichia coli.[1] Insulin glargine was originally created by Aventis Pharmaceuticals and was accepted for use in 2000 in the USA and the EU.[2] Insulin glargine is created through the manipulation of amino acid sequence of human insulin.[2] A glycine is added to the C-terminal A-chain asparagine and two arginines are added to the C-terminal B-chain threonine.[2] The final drug product forms at a pH of 4 through the expression of E. coli and the generation of the precursor proinsulin.[3] Insulin glargine is on the WHO Model Lists of Essential Medicines. StructureInsulin glargine is a hormone protein consisting of 52 amino acids in an asymmetric unit. It has two unique chains, chain A and B. The structure was determined by X-ray diffraction and was measured at a resolution of 1.66 Angstroms. Chain A is 21 amino acids long and consists of two alpha helices and one beta sheet. It is modified from normal insulin by the at the twenty first amino acid of the chain. It also has an L-cystine protein modification at amino acids C6 and C11 of the chain.[4] This modification consists of a disulfide bond formed between the side chains of two cysteine residues within the amino acid chain; this occurs via an oxidation reaction.[5] Chain B is 31 amino acids long and consists of two alpha helices and one beta sheet.[4][6] It is modified from normal insulin by the addition of to the C-terminus of the chain.[6] These modifications raise the isoelectric point (pI) from 5.4 to 6.7, improving solubility under mildly acidic conditions.[7] These two chains are held together by formed between cysteine side chains on opposing chains. One disulfide bond is formed between the cysteine residues at amino acid seven of chain A and amino acid seven of chain B. Another disulfide bond is formed between the cysteine residues at amino acid 21 of chain A and amino acid 19 of chain B.[6] These disulfide linkages, general structure of insulin glargine, and its sequence differences with normal human insulin are shown by a figure presented by Agin et. al.[6]
MechanismAfter subcutaneous injection, glargine becomes metabolized into M1 (A21-Gly-insulin) and M2 (A21-Gly-des-30B-Thr-insulin); M1 has been shown to be the pharmacologically active metabolite of glargine.[8][9] Insulin glargine’s mechanism is akin to human insulin’s mechanism.[1] Insulin glargine has been found to have a ~6.5 fold increase in IGF-I receptor binding affinity compared to , as well as increased rate of dissociation from the receptor. These combined effects have shown a higher mitogenic potency in comparison to human insulin.[10] Medical UseInsulin glargine functions as an insulin analogue, providing basal control of glycaemia for patients with Type 1 and Type 2 diabetes.[1] The pH 4 glargine solution is subcutaneously injected to form a microprecipitate in physiological pH. The effectiveness of glargine is dampened when mixed with more neutral insulins due to resulting disruption of precipitate formation.[11] Insulin glargine’s stability allows the formed microprecipitate to be slowly administered simulating non-diabetic basal insulin secretion.[7] This enables insulin glargine to be an extended release insulin treatment administered once per day. |
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ReferencesReferences
- ↑ 1.0 1.1 1.2 McKeage, K., & Goa, K. L. (2001). Insulin glargine. Drugs, 61(11), 1599-1624. doi:10.2165/00003495-200161110-00007
- ↑ 2.0 2.1 2.2 Baeshen, N. A., Baeshen, M. N., Sheikh, A., Bora, R. S., Ahmed, M. M. M., Ramadan, H. A., ... & Redwan, E. M. (2014). Cell factories for insulin production. Microbial cell factories, 13(1), 141. doi: 10.1186/s12934-014-0141-0
- ↑ Walsh, G. (2005). Therapeutic insulins and their large-scale manufacture. Applied microbiology and biotechnology, 67(2), 151-159. doi:10.1007/s00253-004-1809-x
- ↑ 4.0 4.1 Barba de la Rosa, A. P., Lara-Gonzalez, S., Montero-Moran, G. M., Escobedo-Moratilla, A., and Perez-Urizar, J.T. Physiochemical and structural analysis of a biosimilar insulin glargine formulation and its reference. In Press. doi:10.2210/pdb4iyd/pdb
- ↑ Gortner, R. A., & Hoffmann, W. F. (1925). l-Cystine. Organic Syntheses, 5, 39. doi:10.15227/orgsyn.005.0039
- ↑ 6.0 6.1 6.2 6.3 Agin, A., Jeandidier, N., Gasser, F., Grucker, F., and Sapin, R. (2007) Glargine blood biotransformation: in vitro appraisal with human insulin immunoassay, Diabetes and Metabolism 33, 205-212. doi:10.1016/j.diabet.2006.12.002
- ↑ 7.0 7.1 Bolli, G. B. & Owens, D. R. (2000). Insulin glargine. The Lancet, 356(9228), 443-445. doi:10.1016/S0140-6736(00)02546-0
- ↑ Kuerzel, G. U., Shukla, U., Scholtz, H. E.,Pretorius, S. G., Wessels, D. H., Venter, C., Potgieter, M. A., Lang, A. M., Koose, T. & Bernhardt, E. (2003). Biotransformation of insulin glargine after subcutaneous injection in healthy subjects, Current Medical Research and Opinion, 19:1, 34-40.
- ↑ Lucidi, P., Porcellati, F., Candeloro, P., Cioli, P., Marinelli Andreoli, A., Marzotti, S., Schmidt, R., Bolli, G.B. & Fanelli, C.G. (2014). Glargine metabolism over 24 h following its subcutaneous injection in patients with type 2 diabetes mellitus: A dose response study. Nutrition, Metabolism & Cardiovascular Diseases, 24, 709-716. doi:10.1016/j.numecd.2014.02.008
- ↑ Kurtzhals, P., Schäffer, L., Sørensen, A., Kristensen, C., Jonassen, I., Schmid, C., & Trüb, T. (2000). Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes, 49(6), 999-1005. doi: 10.2337/diabetes.49.6.999
- ↑ Havelund, S., Plum, A., Ribel, U., Jonassen, I., Vølund, A., Markussen, J., & Kurtzhals, P. (2004). The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharmaceutical research, 21(8), 1498-1504. doi:10.1023/B:PHAM.0000036926.54824.37