Today in India physicians and diabetic patients have to choose among at least 40 different commercial brands of Insulin. Although many have 'switched' over to human or highly purified porcine, a large number of patients still use bovine and porcine insulins, largely due to the cost difference. Treatment with conventional insulin preparations results inappreciable insulin antibody formation in nearly all subjects.' These antibodies have a significant clinical I relevance, but does it mean that every patient receiving bovine or porcine insulin need to 'switch' over to human insulin or highly purified porcine insulin? It also raises the doubts about the safety of using human insulin particularly as regards to the decreased awareness of 'hypo' reactions which have created enough controversy in the USA and UK. The wholesale changeover from animal to human insulin took place between 1983 and 1989 in the UK.2 In spite of the clear differences between human and animal insulins, many patients were made to change over with little explanation or even 6yaccident when the pharmacist or the GP simply substituted human insulin with the comment "your old insulin has been discontinued. This is the new one".

Not only were the patients not warned about the pharmacokinetic differences between human and animal insulins, but they and their doctors were led by advertising to believe that there was some definite advantage to an insulin which was described as identical to the 6odys own insulin or outstandingly pure and less immunogenic than the one that comes from the pancreas of pigs and cattle and hence the logical choice.

A survey of BDA (British Diabetic Association) members who were asked to write if they were dissatisfied about the changeover to human insulin revealed that there are a lot many problems with these new insulins than thought or explained by the doctors. Many patients were told that bovine insulin prolusion was going to be stopped and the patients were given a clear message that changing back to animal insulin was not an option.

Doctors in UK feel that the medical fraternity failed to communicate adequately with the patients on this issue and this is what Dr. Andel and Dr. Ro6ertTaftersoll called "outhoritarinism in diabetology', the idea that "people are like objects to be moved around like pawns on a chessboard in accordance with a grand scheme". This is possible in the UK where the cost of insulin is home by the NHS, but in our country the patient has to pay from his own packet. What should physicians in India advise their patients, to continue using animal insulin and use human insulin sparingly only when indicated or to 'switchover' to human insulin in toto ? Will it really solve the major issues such as insulin resistance and long term complications?

Do our physicians have to gulp down everything that is dished out to them by the pharma industry or should we remember, if freedom of information, justice and medicine are to prosper in a world where the consumer is increasingly the king, 16n professionals will have to learn a degree of self regulation that may clash with the more entrepreneurial instincts.

Patient related factors such as age, sex, and immunogenic background of the patients are important when comparing the immunogenicity of bovine, porcine and human insulin. There is a low or non-insulin antibody response in association with HLA DR3. The link between low immune response to 'insulin and HLA DR3 is well established. The association of high anti-insulin antibodies with HLA DR4 is now being documented. Those individuals who have autoantibodies for insulin have tendency to develop more antibodies after being treated with insulin. It is interesting developed antibodies at much lesser frequency than diabetic patients (2 of 27 non-diabetic patients in a retrospective Danish study).

Allergic reactions including urticaria and anaphylaxis, occurred with early insulin preparations, but as these were very impure, the antigen may not have been insulin. Immediate-type systemic hypersensitivity reactions to insulin are rare now and they will virtually disappear once patients switch over to highly purified insulins. In insulin allergic patients insulin specific 19E values are often 10-20 fold higher than in patients without allergy. A major problem is the cross-reactivity that occurs between anti-insulin antibodies and the various animal and human insulin preparations in patients presenting with allergy to animal insulin. In non-allergic cases positive skin test to human insulin do not necessarily have any clinical significance, because as many as, 40% - 50% patients receiving conventional insulin therapy showed wheal-and-flare responses on intra-dermal testing.)

Another manifestation of insulin allergy, which is also now relatively rare, is a delayed local reaction to injected insulin which is seen as tender subcutaneous lump that develops at the injection site 30 minutes after injection and lasts for 12 -24 hours. This is a local Arthus- type reaction, mediated by IgG rather than by 19E and is attri6uta6le to the compliment activation by insulin - IgG immune complexes. The exact frequency of allergic reactions to animal insulin preparations is unknown. However, after reviewing the entire literature on this subject one can safely conclude that the frequency has been reduced from 30% to < 5% in the post half century.

In view of the wide spectrum of immune-mediated complications of insulin therapy, muck attention has been directed to the reduced immunogencity of highly purified forms of animal insulins and more recently available recombinant and semi-synthetic form of Human insulin. Delayed- type insulin allergy and especially immediate- type were extremely rare in type 1 and type 2 diabetic patients "Who were treated exclusively with Human insulin in many centres.

As human insulin preparations are not totally non- immunogenic, local and acute systemic responses to exogenous human insulin have occasionally been reported. There are occasions where a patient with a known history of anaphylaxis to animal insulin may also develop similar reaction to human insulin. Recently Ganz et all described a type 2 diabetic patient who manifested both severe insulin resistance and persistent systemic allergy despite treatment with recombinant human insulin. However, in this case symptoms of insulin allergy had already emerged several months after initiating therapy with mixed bovine-porcine insulin. After switching to recombinant human insulin, generalised urticaria with pruritus, significant eosinophilia, and diffuse lymphoadenopathy reminiscent of serum sickness like response occurred. This case illustrates that a wide array of clinically significant responses to human insulins occur when it is used in insulin allergic patients.

Patients who are intermittently exposed to insulin because of irregular administration appear to be at a higher risk for more persistent and severe allergic reactions.

The phenomena of lipoatrophy, in which there is a loss of fat at insulin injection site was previously quite common, being reported in 10% -55% of patients treated with conventional 6ovine/porcine insulin. Patients with lipoatrophy usually have high circulating insulin antibody titres. An immune basis for this condition has been suggested by the immunehistochemical demonstration of both insulin and I9G subcutaneous tissue biopsied from lipoatrophic areas. Lipoctrophy is now very rare with highly purified porcine insulins.

This is caused by high titres of high avoid IgG antibodies to animal insulins. Affected patients may need several hundreds of units of insulin a day. Antibody - mediated resistant to insulin may be defined as an insulin requirement of more than 1.5 units/Kg/da)(in patients with type I diabetes who either show no apparent endocrine abnormalities or no other explanation. In this respect, it should be mentioned that many type I diabetic patients with very poor glycemic control have a high insulin requirement that can mimic this insulin resistance.

The choice of an appropriate insulin regimen to achieve near normal blood glucose control is important for the health of both mother and baby in a diabetic pregnancy. The fight control required, coupled with rise in insulin requirements in the third trimester, make diabetic pregnancy a stringent test of any subcutaneous insulin regimen. There have been many studies comparing porcine and human insulin on the various parameters including outcome of pregnancy. The one which is presented here is a model example. Fifty insulin dependant pregnant diabetic women were treated from presentation at an antenatal clinic at the Royal Maternity Hospital, Glasgow, The data presented in the paper by J.M.Lieper et al clearly shows that there is no difference in the group treated with highly purified porcine insulin and human insulin as regards to blood glucose, control birth weight or neonatal complications as shown in Tables 4 and 5.

A comparative shorter time action of human isophane insulin was suggested by the increased requirement for isophane insulin in the evening injection(to maintain fasting normoglycaemia) and the necessity in two cases to delay the evening isophane injection until bedtime. These findings are consistent with the known charetistics of biosnythetic isophane insulin (Eli Lilly), both in formal pharmacokinetic studies and in clinical trials in non-pregnant diabetic subjects. This information was not available at the time the study was carried out. Increasing the dose of evening isophane insulin in order to control fasting blood glucose levels carries the risk of inducing nocturnal hypoglycaemia. These problems might be avoided by the use of longer acting human insulin preparations.

1. Guntam Scherntianer Diabetes Core, 1993; 16
2. Home P. Human Insulin gone wrong? Diabetic Med. 1991;8:799
3. Tattersall R.B. & Mac Donald I . A. Human Insulin. BMJ 1989;299:1339
4. Andel M. & Tattersall R. B. Diabetic Med. 1989;6:471
5. Torsten Deckert Diabetes 1985, 34, (Suppl. 2)
6. I. Sklenar, T. M. Neri, W. Berger & P. Erb BMJ 1982,285 (Nov.)
7. J. M. Leiper, K. R. Patterson, C. B. Lunon, A. C. MocCuish Diabetic Med. 1986,3,49-51.
8. B. E. Sonnenberg & M. Berger Editorial Human Insulin : Much Ado About One Amino acid, Diobetologio;1983; 25:457-459.
9. Timon W. Von Hoeften Diabetes Care 1989;12 (9)
10. R. Goswomi, A. jollel, N. Panikot & Kochu Pillai, Diabetes Research & Clinical Prac 2000;49:7-15.
11. C. Pedersen, A. Hoegholm, Diabetic Med. 1987,4; 304 - 306.