The insulin hypoglycemia test: Hypoglycemic criteria and reproducibility

The insulin hypoglycemia test (IHT) is widely regarded as the 'gold standar d' for dynamic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis . This study aimed to investigate the temporal relationship between a rapid decrease in plasma glucose and the corresponding rise in plasma adenocorti cotropic hormone (ACTH), and to assess the reproducibility of hormone respo nses to hypoglycemia in normal humans. Ten normal subjects underwent IHTs, using an insulin dose of 0.15 U/kg. Of these, eight had a second IHT (IHT2) and three went on to a third test (IHT3). Plasma ACTH and cortisol were me asured at 15-min intervals and, additionally, in four IHT2s and the three I HT3s, ACTH was measured at 2.5- or 5-min intervals. Mean glucose nadirs and mean ACTH and cortisol responses were not significantly different between IHT1, IHT2 and IHT3. Combined data from all 21 tests showed the magnitude o f the cortisol responses, but not the ACTH responses, correlated significan tly with the depth and duration of hypoglycemia. All subjects achieved gluc ose concentrations of of less than or equal to 1.6 mmol/l before any detect able rise in ACTH occurred. In the seven tests performed with frequent samp ling, an ACTH rise never preceeded the glucose nadir, but occurred at the n adir, or up to 15 min after. On repeat testing, peak ACTH levels varied mar kedly within individuals, whereas peak cortisol levels were more reproducib le (mean coefficient of variation 7%). In conclusion, hypoglycemia of less than or equal to 1.6 mmol/l was sufficient to cause stimulation of the HPA axis in all 21 IHTs conducted in normal subjects. Nonetheless; our data can not reveal whether higher glucose nadirs would stimulate increased HPA axis activity in all subjects. Overall, the cortisol response to hypoglycemia i s more reproducible than the ACTH response but, in an individual subject, t he difference in peak cortisol between two IHTs may exceed 100 nmol/l.