Bovine insulin

Beef insulin differs from human insulin by three amino acid residues, whereas pork insulin differs by only one. Beef insulin is slightly less soluble than pork or human, and is therefore absorbed rather more slowly. It is also more likely to promote antibody formation and allergic reactions. None of this was known to Banting and Best, who extracted insulin from cows for the simple and practical reason that bovine pancreas was readily available from slaughterhouses in large quantities, and beef insulin remained the mainstay of the treatment of diabetes for 50 years. The main competition came from pork insulin from Denmark, a by-product of a flourishing trade in bacon. Many of the differences between the species were due to differences in purity (Danish insulin was cleaner), but comparison of purified versions of each insulin showed that pork insulin had somewhat faster pharmacokinetics and was less visible to the immune system. Beef insulin is still available for use by a minority of patients who prefer animal-sourced insulin

Background

The insulin extracted by Frederick Banting and Charles Best was described as a "thick brown muck", and their first injection into Leonard Thompson was a dismal failure. They were rescued when John Macleod recruited James Bertram Collip to purify their pancreatic extract.

Collip’s Recipe for Insulin, 1923:

1 Add equal proportions of freshly minced pancreas and 95% ethyl alcohol
2 Allow to stand for a few hours, shake occasionally
3 Strain through cheese-cloth, then add two portions by volume of 95% ethyl alcohol to the filtrate
4 Wait some hours for the protein to precipitate. Then filter and distil in a vacuum at 300 centigrade
5 Remove the lipoid substances by extraction with sulfuric ether in a separating funnel. Repeat once
6 Add the watery solution that remains to the vacuum still and allow to concentrate further until it reaches a pasty consistency
7 Now add 80% ethyl alcohol and centrifuge
8 You will now see four distinct layers in the tube; the uppermost is clear and contains the active principle. Pipette this into 95% or 100% alcohol. The active principle will precipitate along with adherent substances
9 Catch on a Buchner funnel, dissolve in distilled water and distil further until the desired concentration has been reached
10 Pass through a Berkfeld filter, check for sterility and deliver to the clinic.

Early Developments

Insulin manufacture in the 1920s. beef pancreas is sorted and fed into a mincer
Insulin manufacture in the 1920s. beef pancreas is sorted and fed into a mincer
As with the later discovery of penicillin, an enormous amount of work was needed to translate a laboratory procedure into industrial-scale production, and many industrial chemists, especially those at Eli Lilly, deserve the credit for this achievement. The story of the development of insulin in the 1920s and 1930s is well related by Hans Jensen[1], whereas the story of the subsequent development of Danish insulin (predominantly pork) is told by Torsten Deckert[2].

Beef insulin in the post-war period

lipoatrophy in a child
lipoatrophy in a child
By the 1950s insulin was made by many factories around the world, easily recognisable by their smell. Despite the pioneering observations of Erik Jorpes, the need for increased purity was not well appreciated, and allergic responses to insulin such as lipoatrophy at the injection site (disfiguring hollows in the skin due to local disappearance of subcutaneous fat) were common. This is now considered an extreme rarity, but can occur with modern insulins[3].

Such lesions were considered almost unavoidable at the time, and unrelated to insulin formulation: insulin was indeed often viewed as a generic product, in much the way that a motorist might feel unconcerned about the brand of petrol he uses at a filling station.

Current status of beef insulin

The role of antibodies to injected insulin in altering the kinetics of insulin action was hotly debated in the 1970s, but was soon superseded by the introduction of less immunogenic insulins. Assuming equal purity (not always achieved), beef insulin remained somewhat less soluble and more immunogenic than pork insulin, but was probably equally effective in clinical terms. The debate between beef and pork was soon of historical interest only, following the introduction of biosynthetic insulin, although the advantages of this proved somewhat marginal in comparison with high quality animal-sourced insulins.

There were claims that transfer from animal to human insulin could promote loss of hypoglycaemic warning, possibly associated with more rapid absorption of the human molecule. This is discussed further under Porcine insulin. In all events, some people have experienced problems with the change to more modern insulins from beef or pork insulin, and both patient associations and physicians have supported them in their resolve to remain on animal insulin. Animal insulin (beef and pork) is still available under the brand name Hypurin, manufactured by Wockhardt in the UK.

The introduction of Generic and biosimilar insulins may resurrect some of these earlier concerns, and will require careful monitoring[4]

References

  1. ^ Jensen HF. Insulin. Its chemistry and physiology. New York and London, 1938

  2. ^ Deckert T. H.C.Hagedorn and Danish Insulin. Poul Kristensen, Herning, Denmark 2000

  3. ^ Babiker A, Datta V. Lipoatrophy with insulin analogues in type 1 diabetes. Arch Dis Child 2011;96:101-2

  4. ^ Gebel E. Making insulin. //www.diabetesforecast.org/2013/jul/making-insulin.html

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