Diabetes has been categorized into two forms, Type I and Type II. In the latter, the body does not respond optimally to the insulin that the body produces; Type II diabetes typically progresses slowly, and can be controlled through a specialized diet and exercise plan. Sometimes insulin production decreases, but it is generally not as harsh as the reduction experienced by people with Type I diabetes, whose condition usually begins in childhood or early adulthood, and involves a severe decrease or total loss of the insulin-producing cells in the pancreas. Insulin-supplying treatment is usually necessary for people who have Type I diabetes, and many of them depend on this to stay alive.
In the early 1980s the FDA approved biosynthetic human insulin (BHI) for sale in the United States. BHI was the first approved and marketed pharmaceutical produced using genetic engineering; in 1981, Diabetes Care called BHI “one of the first spectacular successes of DNA recombinant technology.”1 In 1982, Eli Lilly & Co. began producing Humulin, human insulin produced using recombinant DNA technology on E. coli bacteria. Shortly thereafter Novo Nordisk began manufacturing Novolin, another variety of “human insulin” made using genetically engineered yeast.
Now, over twenty years later, BHI is used by the vast majority of insulin-dependent people, and its predecessors, which were isolated from pig or yeast pancreas, have all but vanished from the market. Despite its commercial success, a significant minority of people who require insulin experience problems when using BHI, and need old-fashioned animal insulins to survive. Unfortunately, by 1997, beef insulin had been withdrawn from the market in the United States. Eli Lilly still manufactures a limited amount of pork insulin; however, this is not always easy to obtain. Based on these difficulties, the market dominance of BHI, at the exclusion of alternative forms of insulin, should be re-examined, keeping in mind three major promises made by its developers in 1982: to create genuine human insulin preferred by all people with diabetes; to provide a more effective treatment of diabetes with fewer side effects than animal insulins; and to ensure a constant and unthreatened supply of insulin for years to come through the use of genetically engineered bacteria and yeast as a source.
Preference for BHI
Because animal insulin is a foreign protein, it elicits an immune response in the body. People produce anti-insulin antibodies to fight it; dosages are then increased; and the cycle is repeated and magnified. The formation and build-up of anti-insulin antibodies is considered an insulin allergy, which over time may lead to insulin desensitization.2 BHI was expected to elicit the production of less or no anti-insulin antibodies. However, as will be discussed later, this has not been conclusively demonstrated.
Fearful of desensitization to insulin and encouraged by physicians and other caregivers, many people with diabetes — with or without insulin allergies — switched from animal insulin to BHI. The American Diabetes Association now recommends BHI for newly diagnosed people who require insulin therapy.
Although the majority of people with diabetes use BHI, it is not equivalent to genuine human insulin, which can only be obtained by extracting and crystallizing the protein from a human pancreas. (This is not a viable option, as pancreases obtained from organ donors and cadavers are needed for transplants and diabetes research, and could not, in any case, provide a sufficient supply of insulin.) Though BHI is purified, the process is imperfect, and impurities remain. Some of these are unknown proteins, which could potentially be allergenic and hazardous in the long term.3
THE DANGERS OF BHI
Reliable statistics on people who experience problems when taking BHI are difficult to come by. The question has not been studied in depth, and research about adverse effects of BHI is not well-funded. While the American Diabetes Association (ADA) has provided $33.8 million in research funding for the fiscal year 2003, Eli Lilly and Novo Nordisk occupy prominent positions among the ADA’s top corporate sponsors.4,5 Because information about side effects is not effectively transmitted to physicians and caregivers, many complaints are ignored or dismissed. During one twelve-month monitoring period, the FDA received 92 complaints from families claiming their loved ones had died and 600 reports of hospitalization due to BHI.6 In the same year, 4000 people reported adverse side effects, including extreme fatigue, mood swings, memory loss, weight gain, aching joints, and both recurrent and non-warning hypoglycemia.7
The latter, also known as hypoglycemic unawareness, is the most common and the most alarming problem with BHI. A normally functioning person senses when his or her blood sugar level gets too low, and stabilizes it by automatically decreasing the release of insulin into the bloodstream while simultaneously increasing the release of the hormones glucagon and epinephrine. Insufficient regulation of any of these hormones can occur in people with diabetes. Early warning signs of hypoglycemia include nervousness, fatigue, cold sweats, drastic mood swings, or sharp hunger. When people with diabetes experience these symptoms they consume juice, glucose tablets, candy or other sweets to normalize their blood sugar. But when non-warning hypoglycemia occurs, these early-warnings do not appear; the result can be seizure, coma, or even death.8 Hypoglycemic unawareness has been linked to BHI and the treatment procedures which accompany it.
There are two reasons why people with diabetes may respond to synthetic human insulin differently than they do to animal insulin. First, the effects of BHI are more rapid, intense, and of shorter duration than those of animal insulin. This can result in a need for more frequent administration and blood-glucose monitoring. Most medical insurance covers the cost of blood-glucose monitoring; however, for the many people with diabetes who do not have medical insurance, the expense of blood-glucose monitoring is a signficant problem. But even those people with Type I diabetes, and those who respond erratically to insulin but are capable of maintaining their insulin regimen, remain at risk because of BHI’s unpredictability. Unfortunately, beef “ultralente” insulin, the steadiest, least-peaking type of insulin, has disappeared from the market.
Second, there are differences in the molecular character of animal and human insulins. Animal insulin is more readily attracted to fatty tissues than human insulin, and it therefore tends to accumulate in the brain, which contains a large amount of fatty tissue.9 Research has shown that the brain may not respond correctly during attacks of hypoglycemia when biosynthetic human insulin is administered. A study, reported in the New England Journal of Medicine, which measured the uptake of glucose within the brains of insulin-dependent people during periods of hypoglycemia, showed that while blood glucose dropped, the level of glucose in the brain stayed within the normal range. Because there was no change in the brain, no signals were sent to the body, and the result was a non-warning attack of hypoglycemia.10
What (Good) Science Has to Say
In response to the removal of animal insulin from markets in the U.S. and abroad, the Rockefeller Foundation sponsored a gathering of international scientists in Bellagio, Italy in 1996 to compile a report regarding the differences between the use of animal and human insulin. The Bellagio Report indicated that “research has already demonstrated that human insulin has no clinical advantage for patients and that it has a faster absorption and consequently a shorter duration of action, so accounting for the greater fluctuations in blood-glucose levels.”
The report suggested that animal insulin should be the first treatment choice when prevention of hypoglycemia is critical, as it is in children, the elderly, people with previous hypoglycemia problems, and people unable to closely monitor their blood-glucose.11
Echoing the recommendations of the Bellagio Report came another from the Cochrane Library, which provides analyses of large bodies of scientific studies to healthcare professionals and educators. In 2003, a Cochrane Review Group monitoring animal and synthetic human insulin found that BHI shows no clear advantage over animal insulin. Furthermore, the Cochrane Review indicated that no definitive research has been conducted to verify that BHI causes the production of fewer anti-insulin antibodies than does animal insulin.12 Since the build-up of insulin allergies over time was the reason many people were encouraged to switch to human insulin, this is particularly noteworthy.
The Cochrane Review suggests a variety of future research projects needed to clarify the situation. Many of these studies are focused on quality of life and hypoglycemic unawareness. Several studies have shown that frequent episodes of hypoglycemia can lead to non-warning attacks — a finding which presents a problem for future research, since hypoglycemia must be induced during experiments which examine hypoglycemic unawareness. Until such studies can be carried out without risking the health of test subjects, they will remain at a virtual standstill.13
The Cochrane Review also warns that “the story of the introduction of human insulin might be repeated by contemporary launching campaigns to introduce pharmaceutical and technological innovations that are not backed up by sufficient proof of their advantages and safety.”14
Supply and Demand
While animal insulin is much harder to obtain today than it once was, the difficulty is not — as drug companies prophesied two decades ago — a shortage of animal pancreases. People who require beef insulin to survive import Insulin Hypurin® (Bovine) from CP Pharmaceuticals Ltd., a small company in the United Kingdom. In order to import insulin, however, they must obtain a USDA permit, which must be sent to CP pharmaceuticals along with an order form, a statement from a U.S. doctor testifying to the medical need for beef insulin, and a letter signed by the patient, swearing that the insulin is for personal use. The FDA allows people no more than a six-month supply at a time, and insists on clearing each and every insulin shipment as it enters the country.
The cost of importation fluctuates somewhat, but a vial of beef insulin costs approximately thirty dollars, with shipping costs of about sixty dollars. Imported insulin is not covered by health insurance, so expenses are paid directly by the patient.15 Insulin dosage varies from person to person; depending on the severity of their condition, people may need anywhere from one to five vials of insulin a month. At best, the cost of imported insulin is not exorbitant, though not negligible; at worst, it makes proper treatment impossible. Because of import costs and the inability of CP Pharmaceuticals to advertise its services within the U.S., few people are able to import beef insulin. According to CP Pharmaceuticals, fewer than fifty diabetics in the United States currently import beef insulin — a small fraction of those who require it, and an even smaller fraction of those who, all other things being equal, would prefer to use it.16
Some people continue to use Iletin II, a pork insulin produced by Eli Lilly. Many, however, do not realize this option is still available. In an informal survey of twenty pharmacies in the Boston and Cambridge area, only one carried Iletin II; eight said pork insulin no longer exists. The United States Food and Drug Administration (FDA) claims they are “willing to work with any sponsor interested in marketing animal insulins in the United States,” but their actions demonstrate otherwise.17 Insulin Hypurin was approved by the UK Medicines Control Agency — now known as the Medicines and Healthcare Products Regulatory Agency (MHRA) — and has been used in the UK for more than two decades. CP Pharmaceuticals’ facilities meet the specifications of both the MHRA and the FDA. Nevertheless, the FDA refused to approve Insulin Hypurin, instead preferring to maintain the unwieldy import system which currently makes it so difficult for people who need bovine insulin to procure it.18
The Future of BHI
Though it has certainly satisfied its marketers, BHI has not fulfilled all the hopes of its creators. While many people use BHI without incident, it is still not the match of “real” human insulin; neither has research ever shown BHI to be more effective than its animal counterparts, and for a significant number of people it appears to have severe negative side effects. Finally, while E. coli and yeast can provide a steady supply of insulin for years to come, the supply of animal insulin was not actually in serious jeopardy until pharmaceutical companies began discontinuing its manufacture in the early 1990s.
Left behind have been those who suffer from hypoglycemic unawareness, for whom the risk of long-term insulin allergies may seem less threatening than daily fears of non-warning hypoglycemic attacks. Perhaps no insulin therapy will ever be wholly free of risk — but when the dangers, even if only for a relatively small number of people, are as grave as seizure, coma and death, it is imperative that people have the right to decide which treatment is best, and this decision must not be constrained by the narrow interests of pharmaceutical companies.
As long as Eli Lilly holds a near-monopoly on the North American insulin industry, with Novo Nordisk as its only competition, it is unlikely that the situation will be resolved. Perhaps the complaints of people with diabetes and their physicians will eventually pressure the FDA and pharmaceutical companies to make animal insulin easier to obtain; until then, BHI will remain a largely commercial rather than medical success.
Megan Romano is a biology major from Allegheny College and will graduate in January of 2004. She was the Council for Responsible Genetics’ Summer 2003 intern in Genetics and Health.
DISCLAIMER Changes in insulin therapy can be dangerous and should always be supervised by a trained medical professional. If you are experiencing problems with your insulin, speak to your doctor before attempting to alter your insulin therapy in any way.
1 Pierre de Meyts, Philippe Halban, and K. Dieter Hepp. “In Vitro Studies on Biosynthetic Human Insulin: An Overview.” Diabetes Care 4 (1981): 144.
2 RD de Shazo and JA Galloway. “Insulin Allergy.” Annals of Allergy, Asthma, & Immunology. 76 (1996): 217.
3 David Groves. “Humulin Production.” Diabetics International Foundation. http://members.tripod.com/diabetics_world/Human-insulin-production.htm. (10 July 2003).
4 American Diabetes Association. “The American Diabetes Association Research Foundation.” http://www.diabetes.org/professional/research/researchfoundation.jsp. (10 October 2003)
5 American Diabetes Association. “Making A Difference: Recognizing Our 2003 Corporate Sponsors.” http://www.diabetes.org/aboutus/sponsors/recognize.jsp. (10 October 2003)
6 Glenn Selig. “Fox 13 Investigates: The Insulin Crisis.” Fox 13, WTVT, Tampa Bay, Florida. (February 2001).
7 Prithi Yelaja. “Insulin Inquiry Urged: Safety of synthetic product called into question.” Toronto Star February 7, 2002.
8 Philip E. Cryer. “Are Gender Differences in the Responses to Hypoglycemia Relevant to Iatrogenic Hypoglycemia in Type 1 Diabetes?” Journal of Clinical Endocrinology & Metabolism Volume 85 Number. 6 (2000): 2145.
9 Arthur Teuscher et al. Bellagio Report. (New York: The Rockefeller Foundation, 1996), 4.
10 PJ Boyle, et al. “Brain Glucose uptake and unawareness of Hypoglycemia in Patients with Insulin-Dependent Diabetes Mellitus”. New England Journal of Medicine 333 no. 26 (1995): 1726.
11 Teuscher et al., 1-2.
12 Richter B, Neises G. “‘Human’ insulin versus animal insulin in people with diabetes mellitus.” Cochrane Review. The Cochrane Library, Issue 3, 2003. Oxford: Update Software.
13 Teuscher et al., 5.
14 Ricthter B and Neises G.
15 Pam Maples. US Administrator, Insulin Dependent Diabetes Trust. “Insulin Information.” 5 October 2003. Personal email. (5 October 2003).
16 Rory Butler. Export Manager. 28 July 2003. Personal email. (28 July 2003).
17 Fox 13 WTVT Tampa Bay, FL “Full Text of FDA’s Response to Questions from FOX13 Investigative reporter Glenn Selig.” The Insulin Crisis, 2000. http://www.wtvt.com/investreptr/fda-letter.html. (10 July 2003).
18 Rory Butler. Personal email. (13 August 2003).
source: http://www.gene-watch.org/genewatch/articles/16-6romano.html 15mar04
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