Human insulins and analogs Human insulin. Over 100 million patients currently require insulin, with a worldwide market of about U.S. $6 billion. Human insulin (Humulin®, Eli Lilly) was the first therapeutic recombinant polypeptide to be approved by the FDA in October 1982. Recombinant human insulin is synthesized in E. coli bacteria and is chemically and physically equivalent to pancreatic human insulin and biologically equivalent to human and pork insulin.60,61 The advantage of human insulin lies in its lower antigenicity relative to animal-derived insulins.62 Human insulin has now largely replaced the animal-derived insulins.

Before 1986, human insulin was prepared by the production of genetically engineered A and B chains in separate fermentations. These two chains were then isolated, purified, and joined chemically. Recombinant insulin is currently produced by production of proinsulin, followed by the enzymatic cleavage of the C-peptide to produce human insulin. Humulin produced by these two manufacturing processes has been shown to have no pharmaco-kinetic or clinical difference.63

Recombinant human insulin can be used by diabetic patients in much the same way as insulin derived from animal sources. Clinical advantages that may be attributed to the recombinant product are slight and may include less immunogenicity and quicker absorption, but these depend on patient factors as well. Several formulations of Humulin are available today: regular (R), isophane or NPH (N), lente (L), ultralente (U), Humulin 50/50, and Humulin 70/30. Using one of these formulations, rapid, intermediate, or long action can be achieved. In 1996, human recombinant insulin made utilizing Saccharomyces cerevisiae (baker's yeast) as the product organism was approved (Novolin, Novo Nordisk). Human insulin analogues. Insulin analogues with reduced tendency for self-association that have a rapid onset of action and can thus better mimic meal-stimulated pharmacokinetics of insulin observed in non-diabetics are highly desired.64 Modifications in the insulin sequence led to the approval of two rapid-acting recombinant insulins, insulin lispro (Huma-log, Eli Lilly) and insulin aspart (NovoLog, Novo Nordisk), as well as a long-acting analog, insulin glargine (Lantus, Aventis). Insulin lispro and insulin aspart are now official in the 2005 European Pharmacopoeia.65 The two rapid-acting analogues can be given at mealtime or even after a meal and thus provide an important advantage.

Lispro insulin is chemically a Lys (B28), Pro (B29) analogue that is created when the amino acids at positions 28 and 29 on the insulin B chain are reversed. The gene for insulin lispro is then inserted in E. coli bacteria. Production is carried out under conditions designed to minimize the degree of microbial contamination. As per the European Pharmacopoeia, tests for host-cell-derived proteins and single-chain precursors should be carried out prior to release. The proline group at position B28 in regular insulin is important for p-sheet conformation and formation of dimer units. Reversal of the proline-lysine sequence in insulin lispro eliminates important sites for hydrophobic interactions, thereby decreasing the tendency for dimerization. Zinc is added to commercial insulin preparations for stability, and they exist as hexameric units in their containers as marketed. However, unlike regular insulin, lispro insulin dissociates more rapidly to monomers because of a decreased tendency for dimerization.66 It thus has more rapid absorption, faster onset, and shorter duration of action compared to regular insulin, allowing more flexibility in dosing and mealtime scheduling.66-69 The inversion of the proline and lysine apparently does not increase the immunoge-nicity of lispro insulin.68 The pharmacokinetics of insulin lispro is discussed in more detail in Chapter 6.

Insulin aspart was made by a single substitution of the amino acid proline by aspartic acid in position B28 and is produced utilizing baker's yeast. Insulin aspart is also approved for use by subcutaneous infusion via an external insulin pump.

Insulin glargine is made in E. coli and differs from human insulin in that the asparagine at position A21 is replaced by glycine, and two arginines are added to the C-terminus of the B chain. Because of the addition of two amino acids, its molecular weight increases to 6.1 kDa. Insulin glargine is a long-acting analogue and can provide nearly constant basal levels by a once-daily subcutaneous injection at bedtime.20

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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