Insulin Therapy - Principles

Principles

Insulin is required for all animal life (excluding certain insects). Its mechanism of action is almost identical in nematode worms (e.g.C. elegans), fish, and mammals, and it is a protein that has been highly conserved across evolutionary time. Insulin must be administered to patients who experience such a deprivation. Clinically, this condition is called diabetes mellitus type 1.

The initial sources of insulin for clinical use in humans were cow, horse, pig or fish pancreases. Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Differences in suitability of beef-, pork-, or fish-derived insulin for individual patients have historically been due to lower preparation purity resulting in allergic reactions to the presence of non-insulin substances. Though purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to high-pressure liquid chromatography (HPLC) methods, but minor allergic reactions still occur occasionally, although the same types of allergic reactions have also been known to occur in response to synthetic "human" insulin varieties. Insulin production from animal pancreases was widespread for decades, but very few patients today rely on insulin from animal sources, largely because few pharmaceutical companies sell it anymore.

Biosynthetic "human" insulin is now manufactured for widespread clinical use using genetic engineering techniques using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities, although there is no clinical evidence to substantiate this claim. Eli Lilly marketed the first such insulin, Humulin, in 1982. Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell (E. coli in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce a synthetic version of human insulin. However, the clinical preparations prepared from such insulins differ from endogenous human insulin in several important respects; an example is the absence of C-peptide which has in recent years been shown to have systemic effects itself. Genentech developed the technique Lilly used to produce Humulin, although the company never commercially marketed the product themselves.

Novo Nordisk has also developed a genetically engineered insulin independently using a yeast process. According to a survey that the International Diabetes Federation conducted in 2002 on the access to and availability of insulin in its member countries, approximately 70% of the insulin that is currently sold in the world is recombinant, biosynthetic 'human' insulin. A majority of insulin used clinically today is produced this way, although the clinical evidence has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction. Adverse reactions have been reported, these include loss of warning signs that sufferers may slip into a coma through hypoglycemia, convulsions, memory lapse and loss of concentration. However, the International Diabetes Federation's position statement is very clear in stating that "there is NO overwhelming evidence to prefer one species of insulin over another" and " animal insulins remain a perfectly acceptable alternative."

Since January 2006, all insulins distributed in the U.S. and some other countries are synthetic "human" insulins or their analogues. A special FDA importation process is required to obtain bovine or porcine derived insulin for use in the U.S., although there may be some remaining stocks of porcine insulin made by Lilly in 2005 or earlier, and porcine insulin is also sold and marketed under the brand name Vetsulin(SM) in the U.S. for veterinary usage in the treatment of companion animals with diabetes. Wockhardt/

There are several problems with insulin as a clinical treatment for diabetes:

• Mode of administration.
• Selecting the 'right' dose and timing. Usually one unit of insulin is ~15grams of CHO.
• Selecting an appropriate insulin preparation (typically on 'speed of onset and duration of action' grounds).
• Adjusting dosage and timing to fit food intake timing, amounts, and types.
• Adjusting dosage and timing to fit exercise undertaken.
• Adjusting dosage, type, and timing to fit other conditions, for instance the increased stress of illness.
• Variability in absorption into the bloodstream via subcutaneous delivery
• The dosage is non-physiological in that a subcutaneous bolus dose of insulin alone is administered instead of combination of insulin and C-peptide being released gradually and directly into the portal vein.
• It is simply a nuisance for patients to inject whenever they eat carbohydrate or have a high blood glucose reading.
• It is dangerous in case of mistake (most especially 'too much' insulin).