Synthetic insulin
The first insulins to be commercially produced were extracted from bovine and porcine pancreas. Despite minor peptide sequence differences, they have very similar properties to human insulin. With advances in genetics in the 1970’s, human sequence insulin became the firstmedicine to be synthes ized by recombinant engineering. For many decades, insulins were available in solution, or, for longer duration of action, in suspension. The most successful long-acting preparation combined insulin with protamine, a protein extracted from fish milt, in a 5:1 molar ratio, and Zn 2+ ions, to form Neutral Protamine Hagedorn (NPH) insulin (11). NPH insulin suspension forms a depot of amorphous crystals at the injection site. This depot slowly dissolves, protracting the action of the insulin. Whilst this method provides a low-cost product, still widely used today, it has numerous problems associated with reliability of its pharmacokinetic and pharmacodynamic profiles. It requires thorough mixing before injection to ensure accurate dosing (12). Another significant source of variation in the action of NPH is the subcutaneous environment into which it is injected. Furthermore, the shape and size of the amorphous crystals of insulin may vary significantly from one injection to the next (11). The next insulins to be developed were zinc ‘ Lente ’ suspensions. These used varying concentrations of Zn 2+ ions to generate crystalline insulin without requiring the addition of protamine. Although they were in production for several decades, they have fallen out of favour because of their large intra- individual variability in pharmacokinetics and pharmacodynamics. At the beginning of the new millennium, the first soluble basal insulin analogue, insulin glargine, was introduced. The structure of insulin glargine differs from that of human sequence insulin by substitution of the asparagine at position A21 by glycine (replacing a tail consisting of an amine and ester group on the asparagine with a hydrogen on the glycine), and by the addition of two arginine amino acid residues to the end of the B chain, in the new positions B31 and B32 (11). The addition of these two positively charged guanidiniumgroups changes the isoelectric point to pH 6.7, rendering the insulin soluble in weak acids but relatively insoluble at neutral pH (13).
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