The Lancet, August 15, 1987




Section of Diabetes, Medizinische Universitaetskilinik, Inselspital Bern, CH-3010 Bern, Switzerland; and Section of Endochrinology and Metabolism, Universitaetsspital, Basel, Switzerland


The case histories of 3 patients with insulin-dependent diabetes mellitus (IDDM) suggested that, after a switch from beef/porcine to human insulin, a given level of hypoglycemia may cause less pronounced sympathoadrenal symptoms (tremor, sweating, etc.), so that there is less warning of impending unconsciousness. This possibility was investigated by questioning of 176 IDDM patients who had switched from beef/porcine to human insulin with negligible change in dosage 1-48 months earlier. 66 (36%) said that their symptoms of hypoglycemia had changed from those of sympathoadrenal activation to those of neuroglycemia. This disadvantage of human insulin is an argument for continued availability of beef/porcine insulin.


PHYSICIANS are told in advertisements that "human insulin [is] for all"(1), and this claim is backed by quotations from clinical   reports(2)(5), stating that human insulin is "indistinguishable from porcine insulin effectiveness"(3) and that "no adverse reactions were encountered in any of the patients"(2). It has also been said that patients can be transferred from purified porcine insulin to human insulin without any precautions.(5)

In contrast, product information on human insulin for American patients tells us that "a few patients who experienced hypoglycemic reactions after being transferred to Humulin have reported that these early warning symptoms were less pronounced than they were with animal-source insulin"(6). This phenomenon which we now call hypoglycemia unawareness has been described before(7) but has not received sufficient attention. We report three patients with peculiar and serious hypoglycemia reactions on human insulin and an informal follow-up study of patterns of hypoglycemia in ambulatory diabetic patients changed from beef/porcine to human insulin.


Case 1

Insulin-dependent diabetes mellitus (IDDM) developed in a   male pharmacy student in 1983 when he was aged 20. He was  moderately well controlled on 6 units of 'Actrapid MC' and 10 units of 'Lente MC' each morning and 10 units Lente MC each evening, experiencing several episodes of hypoglycemic coma always associated with tremor and sweating. In 1986 the patient was switched to human insulin (10-15 units 'Huminsulin Normal' and 10-17 units 'Huminsulin Basa;' each morning) with good glycemic control (total hemoglobin [Hb] A1 8%, fasting blood-glucose 4.4-12 mmol/L, and blood-glucose before the evening meal 3.2-14.5 mmol/L).

On Sept. 9, 1986, the patient took one less equivalent of bread at his midday meal because he had 5% glycosuria. After running for 30 min. in the afternoon he took a bath and was found unconscious; most of the water had splashed out of the tub, presumably because of convulsions. On recovery in hospital he said he had no warning signs of hypoglycemia (blood glucose 1.7 mmol/L).

Two weeks later he recorded a fasting blood-glucose of 8.5 mmol/L at 0710 h and took 12 units normal and 18 units basal Huminsulin. He consumed his usual weighted breakfast and spent the morning studying. The patient's mother prepared his usual lunch and both parents left the house at 1130 h. At 1700 h they found the patient unconscious on the kitchen floor with the meal untouched (blood-glucose 1.0 mmol/L). He remained in deep coma in hospital despite intensive treatment. He had bilateral convulsions, positive bilateral Babinski reflexes, and symmetrical and increased deep-tendon reflexes. A brain scan showed cerebral edema but not focal lesions or hemorrhage. Electroencephalography (EEG) showed suppression-burst activity and, periodically, continuous are active sub-delta activity, but no epileptic foci. His blood-glucose was stable for 4 days between 20 and 30 mmol/L with intravenous glucose and intravenous insulin (36-52 units/24 h). Assisted ventilation was stopped 4 days at the request of the parents and the patient died.

Case 2

A male history student became diabetic in 1976 when he was aged 15. Good glycemic control was eventually attained (total HbA1 5-7.5%) with 6 units Actrapid MC and 20 units Lente MC each morning and 3-5 units Actrapid MC and 4 units Lente MC before the evening meal.

In 1986 the patient was transferred to human insulin (8 units Actrapid HM and 18 units 'Protaphane HM' [NPH] in the morning, 4 units Actrapid HM before supper, and 4 units Protophane MH at bedtime), with an insulin dose regimen similar to that for the monocomponent beef/porcine insulin. He was switched to human insulin, at the suggestion of one of us (A. T.), because of the report of a distinct decrease of hypoglycemic reactions in individual patients(4). Subsequently, the patient had at least one episode of hypoglycemia associated with cramps and convulsions at night without warning symptoms; double vision and lack of muscular coordination developed, occurring during the day. On one occasion while studying before lunch the patient lapsed into a 7-hour coma without warning signs.

In late December the patient was examined after his usual morning dose of insulin, complaining of visual disturbance and lightheadedness, without sweating, tremor, or hunger (blood-glucose 1.2 mmol/L). The symptoms resolved after 20 g glucose. He took his usual midmorning snack but lapsed into coma while studying later in the morning. He recovered in hospital but had no memory of warning symptoms (blood-glucose 0.6 mmol/L).

Despite continued careful adjustments in insulin he was found unconscious in early 1987 in a car park on his way home to lunch, having walked for 2 h in a semiconscious state (blood-glucose 1.0 mmol/L). He remained unconscious for 19 h, despite intensive care in hospital, and subsequently had retrograde amnesia for 5 weeks. EEG showed diffuse non-specific changes consistent with metabolic brain damage and no epileptic foci. A computerized tomography scan of the brain showed no focal lesions. Psychomotor function tests remain abnormal, despite a normal electroencephalogram.

Case 3

IDDM developed in a male office clerk in 1972 when he was aged 14. He was maintained on 24 units Lente MC twice daily for 11 years with only occasional episodes of hypoglycemic symptoms with sweating and tremor. When first seen in 1984 (total HbA1 15%) he was changed to 4 units normal and 28 units basal Huminsulin twice daily. After 6 months his HbA1 was 11.7%.

In early 1985 he presented with slurred speech and no other symptoms (blood-glucose 2.0 mmol/L). Despite a decrease in  insulin to 4 units normal and 24 units basal Huminsulin twice daily, on three occasions in the following 6 months blood-glucose concentrations of 2.2, 2.3, and 2.2 mmol/L were noted before the evening meal, without hypoglycemic symptoms. On one occasion he complained only of lightheadedness, when his blood-glucose was 1.0 mmol/L. In late 1985 he delayed his dinner and lapsed into a coma (blood-glucose 1.8 mmol/L at 2130 h) that needed hospital treatment.

The next month he needed hospital treatment for severe lack of coordination and disorientation (blood-glucose 2.2 mmol/L). Despite a further decrease in dose of Huminsulin (normal and basal) he had frequent episodes of low blood-glucose values with light-headedness.

Two months later the patient had a car accident, less than half an hour after lunch, as a result of hypoglycemic coma; he had had 4 units of normal and 16 units of basal Huminsulin at 0645 h and 4 units of normal and 12 units of basal Huminsulin at 1900 h the evening before. A few days later he was admitted to hospital in a deep coma (blood-glucose 1.7 mmol/L on admission) after a reduced dose of morning insulin (4 units of normal and 12 units of basal Huminsulin at 0645 h) and his usual meal and having had 4 units of normal and 8 units of basal Huminsulin at 1900 h the evening before, but he recovered with 8 g of intravenous glucose.

The next month the patient asked to be switched back to porcine insulin and after adjustments in dose schedules had no further symptoms of hypoglycemia in the next 8 months.



A total of 413 diabetic patients were examined at a diabetes clinic during 6 months in 1986-87. Table I shows treatment groups and sex distribution. Of 315 diabetic patients on insulin, 206 (65%) were on human insulin (Novo, Lilly, Nordisk) and 109 (35%) on beef/porcine or porcine "monocomponent" (MC Novo) or porcine "rare immunogenum" (RI Nordisk) insulin. 176 patients were transferred from beef/porcine or porcine insulin to human insulin between 1983 and 1987 and 30 were on human insulin from the beginning of their insulin treatment. The reasons for transfer were, in order of importance, non-availability of beef/porcine or porcine insulin, interest of the patients in advertisements for "insulin that is   identical to the natural insulin", and expectations of a reduction in insulin dose. Hypoglycemic episodes were not an indication for transfer except in cases 1 and 2, as reported above.

No. of patients with diabetes 413 (100%) 228 (55%) 185 (45%)

Treatment groups:

Diet alone 39 (10%) 22 (56%) 17 (44%)
Oral hypoglycemic drugs 59 (14%) 36 (61%) 23 (39%)
Insulin 315 (76%) 173 (55%) 142 (45%)
IDDM 252 (61%) 143 (57%) 103 (43%)
NIDDM 161 (39%) 85 (53%) 76 (47%)

IDDM=insulin-dependent diabetes, NIDDM=non-insulin-dependent diabetes.(8)


Men (n=33) Women (n=33)

Age (yr.)

39 (19-65) 41 (23-77)

Duration of diabetes (yr.)

15 (3-37) 23 (4-43)

Beef/Porcine insulin (yr.)

13 (05-35) 17 (1-39)

Human insulin (mo.)

10 (1-36) 14 (1-48)

      Means (range) shown

Study Protocol

66 insulin-dependent diabetic patients (IDDM) who had been switched to human insulin (Novo n=47, Lilly n=18, Nordisk n=1) were selected for interview after they had spontaneously reported changes in reactions to hypoglycemia or after a positive response to the question "Has there been a difference in your hypoglycemic symptoms since you changed from beef/porcine or porcine to human insulin?".

Hypoglycemic symptoms were classed in two groups: (1) sympathoadrenal (including sweating, tremor, voracious hunger, warmth, palpitations, tachychardia, and pallor); and (2) neuroglycopenic (including lightheadedness, anxiety and fear, inability to concentrate, visual disturbances, slurred speech, drowsiness, abnormal behavior, headache, lack of coordination, stomachache, and a vague feeling of hunger).An important feature of the neuroglycopenic symptoms is a nebulous but overriding fear with feelings of foreboding and loss of control.

All interviews were conducted at the diabetes clinic. The patients were not aware that the condition of hypoglycemia unawareness was being studied.

Further results of this survey are presented elsewhere.(10)

Statistical Analysis


Of the 176 patients transferred from beef/porcine to human insulin, 66 (36%) (table II) reported that early hypoglycemia symptoms  had changed from sympathoadrenal to neuroglycopenic.
  • Sweating and tremor, the main sympathoadrenal symptoms of hypoglycemia, were evaluated in particular. 55 (83%) patients had early sweating during hypoglycemic reactions on beef/porcine insulin and 11 (17%) did not mention sweating. On human insulin 21 (32%) of the same patients observed sweating as a late symptom of hypoglycemia and in 45 (68%) it was absent. Tremor was present in 51 (77%) patients on beef/porcine insulin and in 16 (24%) on human insulin.

  • The mean dose of beef/porcine insulin before transfer was 43.7 units; for human insulin the mean doses were 42.7 and 42.6 units at the first and the last visit after transfer, respectively. The mean daily difference in insulin dose was -0.96 (last visit -1.15 units); the daily doses did not differ (paired t-test p=0.068 [last visit, p=0.237] 95% confidence intervals of the difference -2.01 to -0.07 [last visit CI, -3.08 to -0.77]).

  • 7 patients with hypoglycemia unawareness on human insulin were transferred back to beef/porcine insulin, 3 at their own request, and all lost the neuroglycopenic symptoms and regained their awareness of hypoglycemia.


We believe that insufficient attention has been directed to possible differences in symptoms between beef/porcine and human insulin hypoglycemia. Our main concern is a change in the quality of insulin reactions with the same insulin dose. The high proportion (more than a third) of patients with hypoglycemia unawareness cannot be explained by a higher daily insulin dose. In a clinical trial of biosynthetic human insulin (BHI) 6 of 94 patients withdrew, in 3 cases because of hypoglycemia while taking BHI:(11) 1 patient was admitted to hospital because of severe hypoglycemia and later changed to porcine insulin, and 2 requested withdrawal from human insulin. The workers concluded that "BHI appears to be a safe alternative to porcine or bovine insulin".

Berger and Althaus(12) have, however, warned of the hazards of the change in early hypoglycemic symptoms in diabetic patients who had been switched to human insulin. They found in 39 IDDM patients transferred from porcine to human insulin that perception of hypoglycemia, as defined by onset of hunger and perspiration, was better with porcine insulin in 25 (64%) and with human in 1, and was unchanged in 13 (33.5%).

The hypothesis of decreased neurotransmitter secretion in diabetic patients with hypoglycemia unawareness on human insulin is of practical importance because it seems in our experience to be reversible(13,14). It should also be noted that the classic early warning signs of insulin hypoglycemia of sweating and tremor may arise later in human-insulin induced hypoglycemia. Patients with human-insulin induced hypoglycemia tend to have unusually little time to act between onset of symptoms and severe hypoglycemic reactions. Our observations should lead to further investigations of the differences in mechanisms of hypoglycemic reactions in patients on human and beef/porcine insulin.

Hypoglycemia unawareness with a blood glucose of 1-3 mmol/L was a characteristic finding in patients treated with human insulin. Self-monitoring of blood-glucose may be especially important to detect very low but "silent" blood-glucose values. The general wellbeing of such patients may seem to improve because of reduced frequency of hypoglycemic symptoms. This observation is important for car-drivers.

We would like to add the spontaneous observations of a supervisory nurse in a major teaching hospital with extensive experience with diabetic patients. Although not responsible for the direct administration of insulin, and therefore not aware of whether the patients received beef/porcine or human insulin, she volunteered that patients who later proved to be on human insulin showed remarkable symptoms, such as behavioral changes, singing in the night, unconsciousness, and convulsions, all without sweating.

Our observations agree with earlier brief reports (7) that treatment of IDDM patients with human insulin might be more likely to induce neuroglycopenic than sympathoadrenal hypoglycemic effects. We believe that double-blind prospective trials should be conducted in patients on beef/porcine and human insulin, together with double-blind studies of counter-regulatory-hormone release as already performed in open trials in non-diabetic(15,16) and IDDM patients(17,18), before manufacturers stop producing beef/porcine insulin.

The only universally accepted benefits of human insulin at present are the management of the few patients with insulin allergy and the possible reversibility of the very rare insulin resistance. These seem to be small gains in comparison with the possible loss of wellbeing and the life-threatening hazards associated with hypoglycemia unawareness. We are therefore concerned about the apparent marketing effort of manufacturers to influence physicians and patients to switch from animal to human insulin.

(We thank Dr. Phillip A. Corfman of the US Food and Drug Administration, Rockville Maryland USA, for editorial advice; Dr. Timothy P. Corfman of the Veterans Administration Hospital in Long Beach, California USA for assistance in preparing the script; Dr. Peter Diem of the Diabetes Section, Medizinische Universitaetsklinik, Inselspital Bern, for critical advice; and Dr. Matthias Egger of the Department of Epidemiology, London School of Hygiende and Tropical Medicine, London, for statistical assistance. Mrs. Heidi Bollhalder was responsible for much of the data collection and analysis.)


1. Advertisement (Humulin) Clin Diabetes 1986; 4: no 5.

2. Jensen BM, Kuehl C. Investigation of the safety and efficacy of Actrapid HM and Protophane HM "Human monocomponent insulin" (Novo Product information). Data on file. Novo Industri A/S, Copenhagen, 1983

3. Charles AA, Szkeres A, Staten M, WorcesterB, Waslh KM. Comparison of porcine insulin and human insulin (Novo) using the glucose-controlled insulin infusion system, glucose-insulin dose-response curves, and the outpatient effectiveness of human insulin (Novo) in insulin-dependent diabetes. Diabetes Care 1983; 6 (suppl 1):29-34

4. Karam J, Brink S, Clements R, Miller L, Raskin P. Evaluation of efficacy and safety of human insulin (Novo) in the treatment of insulin-dependent diabetes mellitus: a double-blind multicenter clinical trial. Diabetes Care 1983; 6 (suppl 1): 56-60.

5. Lyngsoe J, Vestermark S. The efficacy and safety of human insulin (Novo) in insulin-dependent diabetic patients. Diabetes Care 1983; 6 (suppl 1): 53-55.

6. Physicians Desk Reference. Medical Economics Co. Oradell NJ Product information: HUmulin 1987: 1142-44.

7. Berger W, Althaus B, Aerederungen der Hypoglykaemie-Fruehsymptome bei Weschel von tierischem Insulin auf Humaninsulin. Schweiz Aerztezeit 1986; 67: 1130-31.

8. Diabetes Mellitus. Report of a WHO-study group. WHO Tech Rep Ser 1985; 727.

9. Advertisement (Humulin) in: Diabetes Forecast 1987; 40 (no 1).

10. Jaeggi E, Teuscher A, Buetikofer K, Berger W. Reduced perception of early hypoglycemic symptoms in type 1 (insulin-dependent)  diabetics after changing from porcine to human insulin. Annual Meeting of the European Association for the Study of Diabetes, Leipzig, 1987 (abstract).

11. Clark AJL, Adeniyi-Jones RO, Knight G, et al. Biosythetic human insulin in the treatment of diabetes. A double-blind, cross-over trial in established diabetic patients. Lancet 1982; ii: 354-57.

12. Berger WG, Althaus BU. Reduced awareness of hypoglycemia after changing from porcine to human insulin in IDDM.
Diabetes Care 1987; 10: 260.

13. Nakao K, Nakai Y, Jingami H, Oki S, Fukata J, Imura H. Substantial rise of plasma B-endorphin levels after insulin-induced hypoglycemia in human subjects. J Clin Endocrinol Metab 1979; 49: 838-41.

14. Guillermin R, VArgo T, Rossier J, et al. B-endorphin and adrenocorticotropin are secreted concomittently by the anterior gland. Science 1977; 197: 1367-69.

15. Landgraf-Leurs MM, Brugelman T, Kammerer S, Lorenz R. Counter-regulatory hormone release after human and porcine insulin in healthy subjects and patients with pituitary disorders. Klin Wochenschr 1984; 62: 659-68.

16. Schlueter KJ, Peterson KG, Sontheimer J, Enzman F, Kerp L. Different counterregulatory response to human insulin (Novo) and purified pork insulin. Diabetes Care 1983; 5 (suppl 2): 78-81.

17. Home PD, Sheperd AA, Noy G, et al. Comparison of the activity and pharmakokinetics of porcine and human insulin (Novo) as assessed by the glucose clamp technique in normal and diabetic man. Diabetes Care 1983; 6 (suppl 1): 23-28.

18. Buetikofer K. Vergleich der Hypoglykaemiesymptomatik unter Schweine-Humaninsulin bei Typ 1-Diabetikern unter besonder Breruecksuchtigung der humoralen Gegenregulation. University of Basle MD thesis, 1987.

Top of Page