Synthetic insulin
Amore recent development of insulin glargine is a three times concentrated formulation, U300, or 300 units/ml, which, because it forms larger micro-precipitates in the subcutaneous space than U100 (100 units/ml) insulin glargine, has a longer duration of action. The most recently marketed soluble basal insulin is insulin degludec. It has a less variable PK/PD profile than insulin glargine or insulin detemir, with very little peak in action (17). Insulin degludec has a more complicated structure than previous basal insulin analogues but is closer in design to insulin detemir than insulin glargine. The amino acid threonine has been removed from position B30, and, in its place, a 16-carbon fatty diacid with a glutamic acid group has been attached to the lysine at B29 (11). Insulin degludec is dissolved in a solution of the same chemicals as insulin detemir (18), though the ratios of concentration between themvaries frombatch to batch. Before injection, the insulin degludec hexamers are in the presence of phenol, causing one end of the hexamer to open. Due to the interaction between fatty diacid side chains of one hexamer and the Zn 2+ ion of another, the hexamers bond together to form stable dihexamers. Upon injection, however, the phenol diffuses away from the site, causing both ends of the dihexamers to open. This allows long, multihexamer chains to form in the subcutaneous tissue at the injection site (11). Over time, the Zn 2+ ions at each end start to diffuse away, causing the chains to dissociate, first into dimers, and then into monomers. These insulin degludec monomers are then absorbed into the blood. As the multihexamer chains can only be broken down from each end, the result is a highly protracted, flat PK/PD profile. There is further protection from proteolysis (enzymatic breakdown) and clearance by the kidneys because of reversible binding to albumin in blood. The half-life of insulin degludec (concentration of 100 units/ml) was shown to be 25.4 hours with a variation in glucose lowering effect four times lower than that of insulin glargine in a 42-hour glucose clamp study of subjects with type 1 diabetes. Due to the extremely flat profile of its effect, adjustments in blood insulin concentration occur very slowly (11). Thus, in the past hundred years, pharmaceutical insulins have developed from being chemically uncharacterized extracts of canine, bovine and porcine pancreas into highly specific, genetically- engineered molecules produced efficiently on vast scales. The outcome of these discoveries has been the development of reliable treatments for diabetes, a disease that was, for millennia, thought to be incurable. This has saved the lives of tens of millions of people. Undoubtedly, in the future, more advances will come. Prototypes of implantable insulin pumps with built-in blood glucose sensors are being tested (19). Other groups are attempting treatment through restoring or protecting beta-cells, primarily through stem-cell and pancreatic tissue engineering (19). Other approaches include methods to reduce human error in dosing, to improve the design of insulin delivery devices, and to create newmodes of insulin delivery, such as by inhalation (19). Reducing the variability of action is a crucial aspect of any development, as this enables better anticipation of insulin needs. A highly-desired treatment is self-regulating, glucose-sensitive insulin analogues; however, this field of research is still in its infancy. Finally, bearing in mind that the majority of people with diabetes live in developing countries, it is imperative that the cost of new treatments is controlled, to make them accessible to all in need (19).
References
1. Lakhtakia R. (2013) ‘ The History of Diabetes Mellitus ’, Sultan Qaboos University Medical Journal, 13(3): 368-370.
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