Pork insulin differs from human by only one amino acid residue, a difference largely invisible to the human immune system, which means that pork insulin is only weakly antigenic and causes few allergic reactions. Porcine insulin was traditionally favoured by the Danish insulin manufacturers, since their farming industry was orientated towards pork rather than beef. Highly purified pork insulin is virtually indistinguishable from biosynthetic human insulin in its clinical effects, although the latter is slightly more soluble and thus absorbed more rapidly. Some patients have reported loss of hypoglycaemic warning symptoms on switching from pork to human insulin and should therefore be treated with their preferred insulin, although objective evidence for this phenomenon is lacking.
The Danish insulin manufacturers Nordisk and Novo began manufacturing pork insulin in the 1920s and produced this almost exclusively thereafter. The decision was based simply upon availability, and it was not appreciated that pork insulin was closer than beef to human insulin until some 50 years later.
Danish insulin was always noted for its purity, and was marketed in the 1930s without the addition of disinfectants, considered essential by manufacturers elsewhere. When glucagon was finally eliminated from other insulins in the 1950s, it was already shown to be absent from Novo insulin. See History of glucagon.
The introduction of monocomponent (highly purified, single peak) pork insulin in the 1970s stimulated considerable interest in the role of insulin antibodies in modifying the pharmacokinetics of injected insulin and, coincidentally, represented the first involvement of immunologists in the study of diabetes. See the Discovery of type 1 diabetes.
Highly purified insulin represented a unique selling point for Danish insulin, both because of its increased purity and its closer molecular identity with human insulin. The manufacturers assumed that reduced immunogenicity would reduce the possibility of insulin resistance caused by antibody binding to circulating insulin, and would also result in a cleaner pharmacokinetic profile. A copious literature appeared on these subjects, and generally supported these assumptions, although the effect size was smaller than anticipated.
The great benefit of improved purity was the virtual elimination of lipoatrophy and lipohypertrophy at injection sites, which were frequent and distressing problems at the time.
Was human insulin better?
Clean pork insulin meets E coli, source of biosynthetic insulinBiosynthetic human insulin is an example of a major scientific advance with limited practical significance. Despite the enormous fanfare, the clinical benefits were modest. A Cochrane review concluded that:
"Human insulin has become the insulin of choice for newly diagnosed patients with diabetes mellitus. Insulin companies are eventually not going to maintain different species formulations for a declining proportion of the population with diabetes using animal insulin. Concerns exist about increased hypoglycaemia following transfer to human insulin and availability of animal insulin especially in developing countries. In our systematic review we could not identify substantial differences in the safety and efficacy between insulin species. Many important patient-oriented outcomes like health-related quality of life and effects on diabetic complications and mortality were never investigated. Human insulin was introduced into the market without scientific proof of advantage over existing purified animal insulins, especially porcine insulin".
Two tons of pancreas made 8 ounces of insulinOne advantage of biosynthetic insulin was that it assured future insulin supplies in the face of a finite supply of animal pancreas. The disadvantages were increased price and concentration of global insulin production in the hands of just three producers (see also our page on Generic and biosimilar insulins ).
Does insulin formulation affect hypoglycaemia recognition?
A number of patients reported loss of hypoglycaemic warning symptoms after starting human insulin, and early clinical studies appeared to support this. Things came to a head when a British pathologist reported several deaths in young people with diabetes who died in their sleep, the so-called "dead-in-bed" syndrome. He suggested that they had become hypoglycaemic without warning whilst asleep, and had died from the consequences. The association with human insulin was not confirmed subsequently.
Subsequent blinded cross-over studies in patients who had reported hypoglycaemia unawareness found no difference in their experience of hypoglycaemia on either insulin, casting doubt on the physiological basis of these reports.
Nonetheless, many patients lost faith in human insulin in consequence and clinicians in general supported their demand for continued access to animal-sourced insulins. In response, Novo-Nordisk continued to make pork insulin until December 2007.
Is pork insulin still available?
Pork insulin is still marketed in the UK as Hypurin pork insulin, made by Wockhardt UK, which can also be prescribed in Canada; all manufacture of porcine insulin ended in the USA in 2006.
^ Egger M. et al. Influence of human insulin on symptoms and awareness of hypoglycaemia: a randomised double blind crossover trial. BMJ 1991; 303: 622-626.
^ Maran A et al. Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawaress after transferral to human insulin. BMJ 1993;306:167-71 http://www.ncbi.nlm.nih.gov/pubmed/8443479