There has been much debate in recent years surrounding the use of animal vs. human insulin. Since the introduction of human insulin over 10 years ago, the reputation of animal insulin has taken a beating. Critics have derided it as an antiquated, impure and a less desirable alternative, and in many countries it has been taken off the market completely. This trend, however, may be unwarranted and depriving some people of an insulin which suits them best. New research is answering many questions about this controversy.

As a patient advocate, I am in favor of keeping choice of insulins available for those who need it. But if current trends continue, all animal insulins will be pulled from the market in this country in the next few years. This has already happened in many other countries throughout the world-Italy, Norway, Sweden, Denmark, Australia, New Zealand, Austria, etc.

With most pharmaceutical preparations, if a person doesn't do well on one drug, they can benefit from being switched to another. For example: with antibiotics, birth control pills, anti-hypertensives, or even skin creams, if a person doesn't respond well on one, they are switched to another. With insulin, we have had a different situation. Patients have been told they must use human insulin because they have been assured that it is "better."

However, human insulin may have a tremendous shortcoming. Recent research shows that in some type I patients human insulin may increase chances of hypoglycemia unawareness-an abrupt, severe onset of hypoglycemia without the typical warning symptoms.

Human Insulin and Hypoglycemia Unawareness

Many patients have reported reduced awareness of hypoglycemia when transferred to human insulin. Hypoglycemia unawareness affects an estimated 25 percent of all diabetics and 50 percent of those who have had type I diabetes for more than 30 years, according to a July 1994 Diabetes Care article. Four percent of all deaths in patients with diabetes is directly attributable to hypoglycemia.

Though many studies have failed to show any difference in the frequency, severity or perception of hypoglycemia when human or animal insulin is used, I personally have talked to people around the world that have suffered a loss or warning symptoms when switched to human insulin. There is a significant minority of people with diabetes who do better when using animal insulin. I believe this minority should not be ignored.

Three studies looked at together help explain why many patients have reported reduced awareness of hypoglycemia when transferred to human insulin.

The most recent of them represents a significant milestone in explaining insulin action in the brain. In 1995 Patrick Boyle published a major work on the previously unknown interaction between glucose uptake in the brain and hypoglycemia.

Boyle's research showed that in patients with less well-controlled diabetes (HbA1c_7.9%), the glucose levels in the brain dropped during hypoglycemia as it should. This drop triggered the counter-regulatory hormones that cause the early warning symptoms of the impending hypoglycemia.1

But in patients with good or tight control (HbA1c_7.8%) and those who had experienced a recent hypoglycemic episode, the brain glucose did not drop during hypoglycemia-a dangerous situation. In effect, the brain was retaining just enough glucose so as not to sense the onset of hypoglycemia. This study was performed with human insulin.

What's significant here is that the blood glucose level in the brain did not go down in some patients during hypoglycemia. The brain was able to "hang on" to its sugar, even as the glucose levels fell in the rest of the body. Eventually the glucose level in the brain does drop, leading to hypoglycemia with fewer symptoms.

Two other studies based on the molecular differences between animal and human insulin help to further clarify insulin in the brain and hypoglycemia. Because animal insulin is more lipophilic ("fat-loving"), it can cross the blood brain barrier more readily than human insulin, which is more hydrophilic ("water-loving")2,3. As a result, animal insulin accumulates in the brain, thus lowering brain glucose levels during hypoglycemia. This logically allows for more hypoglycemia symptoms to be felt.

The Boyle research was the first to clearly illustrate the biological reason for hypoglycemic unawareness. When his study is considered in conjunction with several previously ignored studies, we can better understand how the two insulins function in the body. These additional studies show differences in neurophysiological4,5 and sensory function between human and animal insulin.6,7

In one of these studies, conducted by Kern et al., researchers observed that auditory and visual responses as well as auditory brain stem responses were significantly weaker during the first 20 minutes of hypoglycemia induced by human insulin than with animal insulin.8,9,10,11 In short, it was concluded that "human and animal insulin induced hypoglycemia differ in their actions."

A link between the rise in the incidence of hypoglycemia syndrome and the use of human insulin was put forth as far back as 1987. Controlled studies comparing human and animal insulin have now confirmed this relationship.12,13,14

The FDA found enough evidence of this link to require a warning. Since human insulin was first put on the market, the official FDA/USA labeling has read: "A few patients who experienced hypoglycemic reactions after transfer from animal source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin." In 1991 the warning was highlighted by the use of bold print.15

Advantages to Making the Switch

Beyond linking human insulin use to hypoglycemia unawareness, research has also shown that a transfer back to animal insulin brings relief in most instances from severe hypoglycemic events due to loss of warning symptoms.16

"Since some patients prefer treatment with (animal insulin) and since in many clinical circumstances there are no proven clinical advantages of human insulin, (animal) insulin should remain available," said a study by Teuscher in a May 1989 issue of Lancet.17

Studies have stressed the importance of training people to recognize hypoglycemic symptoms when they make the switch from animal to human insulin.

A letter by Willi Berger, MD in the March/April 1987 Diabetes Care suggested that when taking human insulin preparations, "the patient must learn to pay more attention to discrete signs of impending hypoglycemia." Berger goes on to say that, "(animal) insulin should be reinstated when decrease of the early warning symptoms bears the potential hazard of loss of self-control."

In a 1990 German issue of Klin Wochenschr18 the authors conclude that "there is diminished awareness of hypoglycemia induced by human as compared with (animal) insulin... When training patients this should be kept in mind so that also those treated with human insulin are able to recognize impending hypoglycemia."

This is good advice, but hard to follow.

Numerous studies indicate that the only real benefit of human insulin is in some cases when a patient experiences an allergy or resistance to animal insulin.

This is a small gain compared with the possible increase in incidence of hypoglycemic unawareness, and certainly no reason to pull animal insulin from the market entirely.

Matt Kiln, MD, and Jenny Hirst contributed to this column.

References

1. Boyle, P.J.; Kempers, S.F.; O'Conner, A.M. Nagy, R.J. Brain glucose uptake and unawareness of hypoglycemia in patients with insulin-dependent diabetes mellitus. New England Journal of Medicine 1995; 333 p. 1726-31.
2. Markussen J.; Damgaard, U.; Johansen, N.L.; Sorgensen, Soressen E.; Thim, L. Charakterisiening des sus Schweinein insulin praparierten Human-insulin. Aktuel Endokrinal 1: 104-114, 1981.
3. Chawdbury, S.A.; Dodson, E.J.; Dodson, G.G.; Reynolds, C.D.; Tolley, S.P.; Blundelt T.L.; Cleasby, A.; Pitty, J.E.; Tickle, I. J.; Wood, S.P. The crystal of three non pancreatic human insulin. Diabetologia 25: 460-464, 1983.
4. Kern, W.; Kerner, W.; Pietrowski, R.; Fehm, H.L. Effects of insulin and hypoglycemia on the auditory and brain stem response in humans. J. Neurophysical. 72: 678-683, 1994.
5. Kern, W.; Lieb, K.; Kemen, W.; Born, J.; Fehm, H.L. Differential effects of human and pork insulin-induced hypoglycemia on neuronal functions in humans. Diabetes 39(a): 1091-1098, 1990.
6. Kern, W.; Schlosser, C.; Kerner, W.; Pietrowsky, R.; Born J.; Fehm, H.L. Evidence for effects of insulin on sensory processing in humans. Diabetes 43 (b): 351-356, 1994.
7. Kern, W.; Bonn, J.; Kerner, W;. Fehm, H.L. Different effects of human and porcine insulin-induced abnormalities of brain stem sensory function. Clin. Physical Biochem 8: 122-127, 1990.
8. Kern, W.; Kerner, W. Pietrowski, R. Fehm, H.L. Effects of insulin and hypoglycemia on the auditory and brain stem response in humans. J. Neurophysical. 72: 678-683, 1994.
9. Kern, W.; Lieb, K.; Kemen, W.; Born, J.; Fehm, H.L. Differential effects of human and pork insulin-induced hypoglycemia on neuronal functions in humans. Diabetes 39(a): 1091-1098, 1990.
10. Kern, W.; Schlosser, C.; Kerner, W.; Pietrowsky, R.; Born J.; Fehm, H.L. Evdence for effects of insulin on sensory processing in humans. Diabetes 43 (b): 351-356, 1994.
11. Kern, W.; Bonn, J.; Kerner, W.; Fehm, H.L. Different effects of human and porcine insulin-induced abnormalities of brain stem sensory function. Clin. Physical Biochem 8: 122-127, 1990.
12. Egger, M.; Smith, G.D.; Teuscher, A. Risk of severe hypoglycemia in insulin-treated diabetic patients transferred to human insulin: a case control study. Br Med J 1991; 303: 617-621.
13. Egger, M.; Smith, G.D.; Teuscher, A. Influence of human insulin on symptoms and awareness of hypoglycemia: a randomized double-blind crossover trial. Br Med J 1991; 303: 622-626.
14. Egger, M.; Smith, G.D.; Teuscher, A. For Debate: Human insulin and unawareness of hypoglycemia: need for a large randomized trial. Br Med J 1992; 305: 351-355.
15. Physicians Desk Reference PDR 36th edition 1982. Medical Economics Montvale, N.J.
16. Teuscher, A.; Egger, M. Human insulin hypoglycemia unawareness. (Letter) :Lancet 1989; May: 1072.
17. Teuscher, A.; Egger, M. Human insulin hypoglycemia unawareness. (Letter) :Lancet 1989; May: 1072.
18. Jakober, B.; Lingenfelser, T.; Gluck, H.; Maassen, T.; Overkamp, D.; Renn., W.; Eggstein, M. Symptoms of Hypoglycemia-A comparison between porcine and human insulin. Klin Wochenachr (1990) 68: 447-453.

The following studies were also consulted in the writing of this article.

• Teuscher, A.; Berger, W. Hypoglycemia unawareness in diabetics transferred from beef/porcine to human insulin. Lancet 1987, ii: 382-385.
• Wolff, S.P. (Commentary) Trying times for human insulin. Nature 1992; 356 p. 375-376.
• Tattersall, R.B.; Gill, G.V. Unexplained deaths of type 1 diabetic patients. Diabetic Medicine 1991; 8:49-58.
• Thordarson, H.; Sovak, O. Dead in bed syndrome in young diabetic patients in Norway. Diabetic Medicine 1995; 12: 782-787.
• Sartor, G.; Dalquist, G. Short-term mortality in childhood onset insulin-dependent diabetes mellitus: high frequency of unexpected deaths in bed. Diabetic Medicine 1995; 12: 607-611.
• Eggstein, M.; Jackober, B. Different awareness of hypoglycemia induced by human or purified pork insulin in type I diabetic patients. Diab. Res. and Clin. Pract. 13; 29-36, 1991.
• Schluter, K.J.; Petersen, K.G.; Sontheimer, J.; Enzmann, F.; Kerp, L. Different counter regulatory response to human insulin and purified pork insulin. Diabetes Care 5 (supple. 2) 78-81, 1982.
• Poptis, S.; Karasiskos, C.; Enzmann, F.; Hatidakis, D.; Zoupa, C.; Souratzoghou, A.; Damontapoulos, E.; Mouloulous, S. Biologic activites of biosynthetic human insulin in healthy volunteers and insulin-dependent diabetic patients monitored by the artificial endocrine process. Diabetes Care 4: 155-62, 1981.
• Heine, R.J.; Von der Heydsen, E.A.P. Responses to human and porcine insulin in healthy subjects. Lancet 21.10.89. 946-48.
• Meneilly, G.S.; Milberg, W.P.; Tuokko, H. Differential effects of human and animal insulin on the responses to hypoglycemia in elderly patients with NIDDM. Diabetes 44. 272-277, 1995.
• Teuscher, A.; Berger, W.G. Hypoglycemia unawareness in diabetics transferred to the use of human insulin. Lancet ii. 382-385. 1987.
• Owens, D.R.; Vora, J.P.; Trower, B.; Keller, U.; Luzio, S.; Turker, A. Hormonal counter-regulatory responses to human (semi-synthetic and recombinant DNA) and porcine-induced hypoglycemia. Diabetes Res 1988:8 1-8.
• Petersen, K.G.; Schluter, K.J.; Kerp L. Less pronounced changes in serum potassium and epinephrine during hypoglycemia induced by human insulin (recombinant DNA) Diabetes Care 1982:5 90-2.
• Schluter, K.J.; Petersen, K.G.; Enzmann, F.; Kerp, L. Different potencies of biosynthetic human insulin and purified porcine insulin. Hormone Met. Res. 93.
• Rosak, C.; Althoff, P.H.; Enzmann, F.; Schoffling, K. Comparative studies on intermediary metabolism and hormonal counter-regulation following human insulin and purified pork insulin. Diabetes Care (supple) 1982: 5 82-9.
• Clausen; Sjobom, N.; Lins, P.E.; Adamson, U.; Theodorsson, E. (1990). A comparative study on the hormonal responses to insulin-induced hypoglycemia using semi-synthetic human insulin and pork insulin in patients with type I diabetes mellitus. Diabetic Medicine 7: 775-9.
• Fischer, B.; Gray, C.; Beastall, G.; Frier, B. Responses to acute insulin-induced hypoglycemia in diabetic patients . A comparison of short acting human and procine insulins. Diab. Res (1988) 8 1-8.
• Heller, P.; Cryer, P. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after one episode of hypoglycemia in non-diabetic humans. Diabetes 1991 vol. 40. 223-226.
• Bolli, G. et al. Reversibility of unawareness of hypoglycemia in patients with insulinomas. New Eng. J. Med. 1993 vol. 329: 834-839.
• Hirst, J.; Hill, J. Ethics and validity of hypoglcemia unawareness studies. (Letter) Lancet. 1996. 347, 1343-44.
• Heinman, L.; Richter, B. Clinical pharmacology of human insulin. Diabetes Care 16 1993. Supple 3 90-100.
• Galloway, J.A.; Root, M.A.; Bergstrom, R.; Spradlin, C.T.; Howey, D.C.; Fineberg, S.E.; Jackson, R.L. Clinical pharmacologic studies with human insulin (recombinant DNA). Diabetes Care 1982; 5 (supple 2): 13-22.
• Laupacis, A.; Wells, G.; Richardson, S.; Tugwell, P. Users guides to the medical literature. JAMA 272, 234-237 1994.
• Posner, T.R. Draft report to BDA Low Task Force on letters about the change over to human insulin. (Abstracts only published). London. British Diabetic Association 1992. 3,000 letters. 384 analyzed.
• Colagiuri, S.; Miller, J.J.; Petocz, P. Double-blind cross-over comparison of human and porcine insulins in patients reporting lack of hypoglycemia awareness. Lancet 339: 1430-35. 1992.
• Patrick, A.C.; Bodner, C.W.; Tieszen, K.L.; White, M.C.; Williams, G. Human insulin and awareness of acute hypoglycemic symptoms in insulin-dependent diabetes. Lancet 338: 528-532, 1991.
• Mokan, M.; Mitrakou, A.; Venemon, T.; Ryan, C.; Korytkowski, M.; Cryer, P.; Gerich, J. Hypoglcemia unawareness in IDDM. Diabetes Care 17: (12) 1397-1403, 1994.
• Muhlhauser, I.; Heinemann, L.; Fritsche, E.; Von Lennep, K.; Berger, M. Hypoglycemic symptoms and frequency of severe hypoglycemia in patients treated with human and animal insulin preparations. Diabetes Care (14) 8 745-49, 1991.
• Maran, A.; Lomas, J.; Aechibald, H.; MacDonald, I.A.; Gale, E.A.; Amiel, S.A. Double-blind clinical and laboratory study of hypoglycemia unawareness after transferring to human insulin. BMJ 306: 167-171, 1993.
• MacLeod, K.; Gold, A.; Frier, B. A Comparitive Study of Responses to Acute Hypoglycemia Induced by Human and Porcine Insulins in Patients with Type I Diabetes. Diab. Med. vol. 3, no. 4 346-357, 1996.
• Kiln, M.R. (letter). Treatment of patients with human insulin. Diabetologia. Feb. 1996, 248.
• Case reports of problems experienced with human insulin. Insulin Dependent Diabetes Trust. Draft report, Feb. 1996.
• Bradley, C.; Neadow, K.A.; Sourdon, A.J. General well-being and satisfaction with treatment scales for use with type I diabetics. Report to WHO Regional Office for Europe, June, 1992.
• Patrick, A.W.; Williams, G. The Liverpool Symposium on human insulin and hypoglcemia. Diabetic Medicine 1992; 9: 579-580.