1. This study was designed to determine whether the duration and pattern of prior insulin exposure modulate the symptomatic and counterregulatory responses to hypoglycaemia.

2. Ten healthy non-obese subjects (five males/five females age 25 + 1 years, mean + SEM) were made hypoglycaemic in three ways: (i) a hyperinsulinaemic (60 m-units min−1 m−2; plasma insulin concentration 95 m-units/l) clamp, with 1 h of euglycaemia, blood glucose level 4.5 mmol/l, followed by 30 min of hypoglycaemia, at a stable glucose nadir of 2.0 mmol/l (i.e. euglycaemic then hypoglycaemic clamp: E+HC); (ii) an identical hypoglycaemic clamp without preceding hyperinsulinaemic euglycaemia (i.e. a hypoglycaemic clamp: HC); (iii) insulin infusion only, discontinued at a blood glucose level of 3.0 mmol/l (II). Blood glucose level reached the same nadir as on E+HC and HC, and did not fall further. At the glucose nadir, and 15 and 30 min after, the plasma insulin concentration was 23, 7 and 4 m-units/l, respectively, on the II visit.

3. At the glucose nadir, plasma glucagon level, plasma adrenaline level, sweating rate, heart rate, blood pressure, and overall and individual symptom scores (using visual analogue scales) were the same on E+HC, HC and II.

4. There were no significant differences in neurohormonal response between E+HC and HC, but more subjects felt hypoglycaemic on E+HC on arrival at the glucose nadir (P <0.05). There was significantly more blurring of vision (1.3+0.5 versus 0.2+0.1 cm) and tingling (1.2+0.4 versus 0.2+0.1 cm) 30 min after arriving at the glucose nadir on E+HC than HC (P <0.05, analysis of variance).

5. Significant differences were only found between E+HC or HC and the II visit 15 min after arriving at the glucose nadir, when the blood glucose level had risen significantly to 2.9 mmol/l, and 30 min after arrived at the glucose nadir, by which time the blood glucose level had recovered to 3.8 mmol/l.

6. A 1 h run-in period of euglycaemic hyperinsulinaemia does not affect the hormonal or physiological response to an identical degree of hypoglycaemia, but appears to cause increased symptoms of neuroglycopenia during subsequent stable hypoglycaemia.

7. A difference in plasma insulin level within the physiological range does not affect the magnitude of symptomatic, hormonal or physiological responses to the same degree of hypoglycaemia.

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