The drugs industry rushed the new 'human insulin' onto the market and forced out animal insulin, leaving many diabetics far more ill and now with no alternative form of insulin.
In nearly all areas of medicine, the advances come so thick and fast that it can be hard to keep up with them. But, in one small corner of the medical world, things are still very much as they were in the 1930s. For the last 70 years, people with type I, or insulin dependent, diabetes (IDDM) have depended on daily injections of insulin to live.
Before the advent of insulin, many died painfully and prematurely. So, over the years, just keeping individuals with this crippling disease alive has been hailed a triumph, and rightly so.
But insulin is not a cure for diabetes, and its use has many downsides, including severe hypoglycaemia, which can result in coma. Even with insulin, many sufferers find that the complications of diabetes, which include nerve damage plus heart, eye and kidney disease, are overwhelming (Diabetes, 1999; 48: 2107-21).
Instead of looking for alternatives to insulin, drug companies have focused their minds and money on different ways of using insulin for example, as intermittent injections, in continuous insulin pumps or as an inhaled drug or on different types of insulin rapid acting, long acting and combinations of the two. The most devastating changes in insulin are the result of the development of alternative forms of insulin. For most of the 20th century, IDDM patients have used animal insulin, usually naturally derived from pigs or cows. Many did well on this, leading highly regimented, but otherwise normal, lives. Fifteen years ago, drug manufacturers began synthesising a new type of insulin, based on human proteins.
Scientists hailed the new insulin as a breakthrough. Despite being synthesised in the lab, they insisted that the new synthetic 'human' insulin was nearly identical to the natural animal variety. In fact, it is different from the animal variety in only one out of 51 amino acid residues. But the breakthrough was more of an aesthetic triumph than a medical one. Almost as soon as it was on the market, people who made the switch found that their health deteriorated.
The most worrying aspect of human insulin is that it appears to alter the diabetic's awareness of an oncoming hypoglycaemic episode, or 'hypo' (an extreme drop in blood sugar levels that can lead to unconsciousness and the need for medical intervention). By the early 1990s, patients were reporting personality changes, including increased feelings of aggression. In the UK, lawsuits were filed against the manufacturers of human insulin (MIMS, 1 August 1991: 12-3). The legal challenge failed, but patients continued to complain.
Between 1986 and 1989, the British Diabetic Association (BDA) whose mandate is to inform, advise and protect the interests of patients received some 3000 letters from people complaining about the adverse effects of human insulin. This prompted them to commission an independent report to analyse the content of those letters. The report was completed and due to be published in the British Medical Journal in 1993, but was suddenly withdrawn for being "too alarmist".
Six years after completion of the report, the document was leaked to the Guardian newspaper, which revealed its disturbing contents (9 March 1999).
The report gave often harrowing accounts of how people's lives had deteriorated after being switched to the synthetic insulin. Eighty per cent of the complainants examined said they could no longer control their symptoms and had lost the warning signs of an impending coma. From the data in the letters, the researchers concluded, among other things, that:
Half the patients had no warning of passing out during a hypo with the new drug
A quarter said such episodes were more frequent
One in five said they were more severe
Thirteen per cent said they became unconscious at night and five per cent suffered convulsions
Ten per cent had memory loss
Nine per cent said they lost their ability to concentrate.
Some people lost their jobs; other were refused renewal of their driving licences because they were involved in driving accidents during a hypo.
Even more worrying is that, in many cases, when a diabetic patient complained to their doctor about the human insulin, they were ignored. Although around one fifth of the patients in the survey switched back to animal insulin, many doctors refused to facilitate the switch or erroneously told their patients that animal insulin was no longer available. Not surprisingly, in some cases, the relationship between doctor and patient broke down because the patient felt that their fears were not being taken seriously.
Other experts also noted problems with synthetic insulin. In October 1997, Jenny Hirst, co-chair of the UK Insulin Dependent Diabetes Trust (IDDT) and a Trustee of the BDA at the time their report was being compiled, spoke at a conference organised by the Consumers for Ethics in Research (CERES). She revealed that the changeover to synthetic insulin often took place without the patient even knowing or without discussion ". . . a letter in the post or the pharmacist just gave them different insulin with no warnings. Our doctors assumed that 'human' insulin would be cheaper and better assumptions with no evidence except drug company sales patter."
Ms Hirst felt so strongly about the issue of deception that she resigned from the BDA, and formed the IDDT to compile and disseminate better information to diabetics.
The medical profession has taken little notice of such problems and, today, it is nearly impossible to obtain animal insulin anywhere. In 1998, Eli Lilly and Company stopped making its mixed beef and pork insulin. Because there is so little official follow up of people who have switched, we may never know the extent to which patients are suffering because of the change.
The scandal of synthetic human insulin is that it has been introduced on the basis of very little research. The first published study involved 17 diabetic men and was published in 1980 (Lancet, 1980; ii: 398-401). By 1982, human insulin was licenced and on the market. This was a remarkably short time considering this was the first genetically produced drug ever to be used on humans.
There has never been any evidence to show that synthetic human insulin has advantages over animal insulin. Those studies which do exist have been funded mainly by drug manufacturers and tend to be biased towards the drug. Bearing in mind the number of people who are dependent on insulin to live, the dearth of large scale long term studies is an issue of great concern, and one that continues to dog 'human' insulin. Most studies into its efficacy have used no more than 50 patients (Lancet, 1992; 339: 1432-5) and as few as 17 (BMJ, 1993; 306: 167-71). Such small studies are unlikely to have the power to detect significant problems.
While anecdotal evidence continued to mount regarding the problems with human insulin, the medical profession and government agencies staunchly defended its use (BMJ, 1992; 305; 355-7). And, while many IDDM sufferers would very much like to find a way to reduce their intake of insulin, signs are that the medical profession is widening the net of just exactly who gets insulin. Trials such as the DPT-1 trial are on going in the US, giving those at high risk of developing IDDM prophylactic doses of human insulin even before they show signs of the disease. Participants for these trials are partly selected on the basis of genetic risk. Yet, only 5-10 per cent of cases of IDDM are the result of genetic risk. We have no way of knowing what side effects this genetically engineered drug may have on a healthy body.
The saga of animal versus 'human' insulin overshadows the fact that new frontiers in the treatment of IDDM have been incredibly slow to manifest.
Some prominent researchers have begun pursuing and promoting surgical solutions, such as pancreas transplants and, more recently, islet (beta cell) transplantation. Neither option has proven itself to be a reasonable option for the majority of suffers (J Mol Med, 1999; 77: 148-52; Transpl Proc, 1998; 30: 1940-3. Transplantation of the pancreas is expensive and has a low success rate. Often, this invasive operation is reserved for those whose conditions have deteriorated to the extent that they have nothing much to lose by opting for surgery. However, with a failure rate of 20-25 per cent (Transplant Proc, 1992; 24: 762-6), those not in this category might consider it too much of a gamble.
Islet transplantation is a less invasive operation, but its success rate is even lower. Of the 267 islet transplants that have taken place in the last 10 years, only 12.4 per cent have resulted in insulin independence for periods of more than one week, and only 8.2 per cent have resulted in insulin independence for periods of more than one year (Brendel M et al, International Islet Transplant Registry Report, University of Giessen, 1999: 1-20). As it appears that more than one donor pancreas is required per recipient (after processing to isolate the islets, which are then transplanted in a suspension via the portal vein), there are simply not enough donors, either animal or human, to supply the close to one million islets needed per patient (N Engl J Med, 2000; 343: 230-8).
In both types of transplants, finding ways to avoid rejection is difficult. Even if the grafts are successful, the diabetic patient may switch from a lifetime of insulin to a lifetime of immunosuppressive drugs, which bring a higher risk of cancer and infection.
Type I diabetes is caused by an autoimmune reaction directed against the insulin producing beta cells in the pancreas. From birth and, some would argue, before birth these cells begin to die off in a future diabetic until the individual, usually before the age of 30, is left with no means of producing the insulin needed to transport glucose to the cells of the body. In such persons, the body literally starves to death, devoid of the energy from glucose to carry out normal functions.
The big question is, given the right conditions, are islets capable of regeneration? Many scientists believe they are at least, theoretically. There is, for instance, a dramatic natural increase in the number of islets in women during pregnancy (J Mol Med, 1999; 77: 62-6). This regeneration appears to be moderated by hormones such as prolactin, which target the beta cells and cause them to proliferate. Also, through various means, scientists have managed to regenerate islets using animal models (Diabetes, 1988; 37: 334-41; Pancreas, 2000; 21: 63-8). But the human research is simply not there. What is also missing is concrete information on what causes this autoimmune response, and how it can be corrected so that the process of beta cell destruction is not repeated.
The majority of research into IDDM is very conventional, focused on drugs, surgery and genetic medicine. However, in 1980, in an effort to widen the scope of diabetes research, the World Health Organization requested that researchers reexamine traditional medicines. Prior to 1922, diabetes was managed exclusively with botanical medicine and it was hoped that, by looking at traditional methods of managing diabetes, a way to lower patients' reliance on insulin might be found.
The most positive research has come from studies into a plant native to India, Gymnema sylvestre. The leaves of this plant have been used to treat diabetes for over 2000 years and has been relatively widely studied since the 1930s.
In one study, a water soluble extract of Gymnema leaf was given to 27 type I diabetics at a dose of 400 mg/day for 10-12 months. During the study, their insulin requirements were decreased by about half, and their average blood glucose was reduced from 232 to 152 mg/ dL. Cholesterol, triglycerides and amylase (an enzyme that breaks down sugar) were also significantly lowered. In contrast, in study patients taking insulin therapy alone, these and other biochemical markers remained high (J Ethnopharmacol, 1990; 30: 281-94).
In two animal studies, Gymnema extract doubled the number of islet and beta cells in the pancreas of diabetic rats, lending support to the theory that it increases insulin secretion by regenerating beta cells (J Ethnopharmacol, 1986; 18: 143-6). But, as encouraging as these results are, remember that animal research often doesn't apply to humans.
Some animal studies found Gymnema to be effective in lowering blood glucose only in mild to moderate diabetes where there is still some beta cell activity. However, in one study, treatment with Gymnema in rats with severe diabetes significantly prolonged life (Isr J Med Sci, 1985; 21: 540-2).
So impressive have the initial studies with Gymnema been that a US company, PharmaTerra, has put their full backing behind a remedy made from the plant ProBeta. ProBeta comes in 250-mg tablet, and has been on the market since 1998. It differs from other Gymnema products in that it is not standardised for gymnemic acid.
'Gymnemic acid' is not a single acid, but a blanket name for a series of chemicals found in the leaves of the plant. While the plant contains chemicals that are known to retard glucose absorption across the small intestine, it also contains other chemicals that may inhibit the absorption of other nutrients as well and may also limit the regeneration of the pancreas. ProBeta, claims its manufacturer, has been formulated to overcome any potential adverse effects of gymnemic acid.
Other promising botanical research has focused on Momordica charantia (bitter melon, bitter gourd) commonly found in China, India and Africa, where it has a history of medicinal use. It contains many active ingredients (Uppsala J Med Sci, 1977; 82: 39-41) and is structurally and pharmacologically comparable to bovine insulin (J Nat Med, 1993; 4: 16-21)
When one of Momordica's active ingredients, p-insulin, was given to nine diabetic patients, researchers found an onset of action similar to bovine insulin (30-60 min) and a peak hypoglycaemic effect after four hours in type I diabetics, compared with two to three hours with regular insulin (Uppsala J Med Sci, 1977; 82: 39-41).
The hypoglycaemic effects of this plant appear to be, in part, due to extrapancreatic activity, including increased glucose utilisation by the liver, decreased glucose synthesis by depression of key gluconeogenic enzymes and enhanced glucose oxidation.
Several animal studies have confirmed the blood sugar lowering effects of Momordica extracts (Pharmacol Res, 1996; 33: 1-4; Biochem J, 1993; 292: 267- 70) while others have not (Plants Med, 1990; 56: 426-9). One recent study found that, like Gymnema, bitter melon was able to regenerate beta cells in diabetic rats (Diabetes Res Clin Pract, 1998; 40: 145-51). Again, remember this may not apply to humans.
Nobody is suggesting that type I diabetics throw away their insulin and start taking herbs. However, botanical research provides a useful way of taking our thinking about diabetes into a new direction. At the moment, all of the trials of new therapies for diabetes both conventional and botanical are small, and far too many use animals when human data are what is needed.