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Objectives: To compare awareness of hypoglycaemia and physiological responses to hypoglycaemia with human and porcine insulin in diabetic patients who reported loss of hypoglycaemia awareness after transferring to human insulin., Design: Double blind randomised crossover study of clinical experience and physiological responses during slow fall hypoglycaemic clamping with porcine and human insulin., Setting: Clinical investigation unit of teaching hospital recruiting from diabetes clinics of five teaching hospitals and one district general hospital., Subjects: 17 patients with insulin dependent diabetes mellitus of more than five years' duration who had reported altered hypoglycaemia awareness within three months of transferring to human insulin., Main Outcome Measures: Glycaemic control and frequency of hypoglycaemic episodes during two months' treatment with each insulin. Glucose thresholds for physiological and symptomatic responses during clamping., Results: Glycaemic control did not change with either insulin. 136 hypoglycaemic episodes (eight severe) were reported with human insulin and 149 (nine severe) with porcine insulin (95% confidence interval -4 to 2.5, p = 0.63). 20 episodes of biochemical hypoglycaemia occurred with human insulin versus 18 with porcine insulin (-0.8 to 1, p = 0.78). During controlled hypoglycaemia the mean adrenaline response was 138 nmol/l/240 min for both insulins; neurohormonal responses were triggered at 3.0 (SE 0.2) versus 3.1 (0.2) mmol/l of glucose for adrenaline and 2.5 (0.1) versus 2.5 (0.1) mmol/l for subjective awareness., Conclusions: These data suggest that human insulin per se does not affect the presentation of hypoglycaemia or the neurohumoral, symptomatic, and cognitive function responses to hypoglycaemia in insulin dependent diabetic patients with a history of hypoglycaemia unawareness.

Objective: To investigate the apparent increased risk of severe hypoglycaemia associated with use of human insulin by comparing the pattern of symptoms of hypoglycaemia with human insulin and porcine insulin., Design: Randomised controlled double blind crossover trial of treatment with human insulin and porcine insulin, with two treatment periods of six weeks., Setting: Diabetes outpatient department of a university teaching hospital in Berne, Switzerland., Patients: 44 patients (25 men, 19 women) aged 14 to 60 years, with insulin dependent diabetes mellitus. All patients met the following criteria: receiving treatment with fast acting soluble insulin and long acting protamine insulin; performing multiple daily fingerstick blood glucose self measurements; and had stable glycaemic control with about one mild hypoglycaemic episode a week during the preceding two months., Intervention: Patients were randomised to receive either human or porcine insulin for six weeks and were then changed over to the other type of insulin for a further six weeks., Main Outcome Measure: Questionnaire recording "autonomic" and "neuroglycopenic" symptoms that occurred during hypoglycaemic episodes confirmed by a blood glucose concentration less than or equal to 2.8 mmol/l., Results: Insulin doses and blood glucose, glycated haemoglobin A1c, and fructosamine concentrations were similar during the two treatment periods. 493 questionnaires on hypoglycaemia (234 during treatment with human insulin and 259 during treatment with porcine insulin) were analysed. With human insulin patients were more likely to report lack of concentration (52% v 35%, p = 0.0003) and restlessness (53% v 45%, p = 0.004) and less likely to report hunger (33% v 42%, p = 0.016) than during treatment with porcine insulin. The difference in the pattern of symptoms during the two treatments was similar to that between the 12 patients with a history of recurrent hypoglycaemic coma and the 32 patients without such a history., Conclusions: The pattern of symptoms associated with human insulin could impair patients' ability to take appropriate steps to avoid severe hypoglycaemia. Caution should be exercised when transferring patients from animal insulin to human insulin, and a large scale randomised trial of the two types of insulin may be justified.

Objective: To examine the traditional view that unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation in insulin dependent diabetes mellitus are manifestations of autonomic neuropathy., Design: Perspective assessment of unawareness of hypoglycaemia and detailed assessment of autonomic neuropathy in patients with insulin dependent diabetes according to the adequacy of their hypoglycaemic counterregulation., Setting: One routine diabetic unit in a university teaching hospital., Patients: 23 Patients aged 21-52 with insulin dependent diabetes mellitus (seven with symptoms suggesting autonomic neuropathy, nine with a serious clinical problem with hypoglycaemia, and seven without symptoms of autonomic neuropathy and without problems with hypoglycaemia) and 10 controls with a similar age distribution, without a personal or family history of diabetes., Main Outcome Measures: Presence of autonomic neuropathy as assessed with a test of the longest sympathetic fibres (acetylcholine sweatspot test), a pupil test, and a battery of seven cardiovascular autonomic function tests; adequacy of hypoglycaemic glucose counterregulation during a 40 mU/kg/h insulin infusion test; history of unawareness of hypoglycaemia; and response of plasma pancreatic polypeptide during hypoglycaemia, which depends on an intact and responding autonomic innervation of the pancreas., Results: There was little evidence of autonomic neuropathy in either the 12 diabetic patients with a history of unawareness of hypoglycaemia or the seven patients with inadequate hypoglycaemic counterregulation. By contrast, in all seven patients with clear evidence of autonomic neuropathy there was no history of unawareness of hypoglycaemia and in six out of seven there was adequate hypoglycaemic counterregulation. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation were significantly associated (p less than 0.01). The response of plasma pancreatic polypeptide in the diabetic patients with adequate counterregulation but without autonomic neuropathy was not significantly different from that of the controls (change in plasma pancreatic polypeptide 226.8 v 414 pmol/l). The patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response (3.7 pmol/l), but this response was also blunted in the patients with inadequate hypoglycaemic counterregulation (72.4 pmol/l) compared with that of the controls (p less than 0.05)., Conclusions: Unawareness of hypoglycaemia and inadequate glucose counterregulation during hypoglycaemia are related to each other but are not due to autonomic neuropathy. The blunted plasma pancreatic polypeptide responses of the patients with inadequate hypoglycaemic counterregulation may reflect diminished autonomic activity consequent upon reduced responsiveness of a central glucoregulatory centre, rather than classical autonomic neuropathy.