The Lancet, August 15, 1987

THERAPEUTICS

HYPOGLYCEMIA UNAWARENESS IN
DIABETICS TRANSFERRED FROM BEEF/
PORCINE INSULIN TO HUMAN INSULIN

A. TEUSCHER, W.G. BERGER

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

Summary:

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.

INTRODUCTION

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-REPORTS

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.

FOLLOW-UP STUDY

Subjects

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.