EVIDENCE FOR A HYPOTHALAMIC-PITUITARY VERSUS ADRENAL-CORTICAL EFFECT OF GLYCEMIC CONTROL ON COUNTERREGULATORY HORMONE RESPONSES TO HYPOGLYCEMIA IN INSULIN-DEPENDENT DIABETES-MELLITUS

The epinephrine and cortisol responses to hypoglycemia are reduced in insulin-dependent diabetes mellitus (IDDM) patients in strict glycemic control. However, it is not known whether these abnormalities are med iated at a central (hypothalamic-pituitary) or peripheral (adrenal) le vel. To examine this question, we measured counterregulatory hormone s ecretion during a 3-h hypoglycemic hyperinsulinemic clamp (12 pmol/kg . min) that lowered glucose from 5.0 to 2.2 mmol/L in steps of 0.55 mm ol/L every 30 min in 13 well controlled IDDM subjects (hemoglobin A(1) , 7.8 +/- 0.2%), 14 poorly controlled IDDM subjects (hemoglobin A(1), 12.3 +/- 1.5%), and 20 healthy volunteers. Basal levels of ACTH, corti sol, and epinephrine were similar in all 3 groups before hypoglycemia. At the nadir glucose level (2.2 mmol/L), ACTH, cortisol, and epinephr ine levels were significantly lower in well controlled IDDM compared t o healthy controls, and the glucose levels required for significant se cretion of ACTH, cortisol, and epinephrine also were lower in well con trolled IDDM compared to those in both poorly controlled IDDM and heal thy volunteers (P < 0.05). During hypoglycemia, ACTH levels were signi ficantly correlated with cortisol levels (r = 0.43; P < 0.05). Because adrenomedullary epinephrine synthesis is partially dependent on adequ ate adrenocortical function, we also determined whether the blunted ep inephrine response might result from the reduced cortisol secretion. E leven of the control subjects underwent a second identical insulin cla mp study during which metyrapone was administered to produce adrenal c ortical blockade. Despite higher basal ACTH levels after metyrapone an d sustained elevations in ACTH during hypoglycemia, the cortisol respo nse was abolished during metyrapone treatment, indicating effective bl ockade. However, epinephrine responses did not differ during hypoglyce mia with or without metyrapone treatment. We conclude that 1) ACTH, co rtisol, and epinephrine responses during hypoglycemia are reduced in I DDM patients in strict glycemic control; 2) the lower cortisol respons e is correlated with reduced ACTH levels; and 3) in healthy subjects, the cortisol response to hypoglycemia is abolished by adrenocortical b lockade with metyrapone, whereas the epinephrine response to hypoglyce mia remains intact. These data suggest that central adaptations in hyp othalamic-pituitary responses to hypoglycemia rather than alterations in adrenal gland function per se underlie the reduced counterregulator y responses seen in IDDM subjects in strict glycemic control.