REVERSIBILITY OF UNAWARENESS OF HYPOGLYCEMIA IN PATIENTS WITH INSULINOMAS

Background. A lack of appropriate autonomic warning symptoms before th e development of neuroglycopenia occurs frequently in patients with di abetes mellitus. The pathogenesis of this phenomenon is unclear, but i t is associated with intensive insulin therapy, prolonged duration of diabetes, frequent episodes of hypoglycemia, and impaired glucose coun terregulation. Recently, it has been proposed that repeated episodes o f hypoglycemia may themselves induce the phenomenon. Methods. To test this hypothesis and to determine whether the phenomenon is reversible, we assessed autonomic and neuroglycopenic symptoms, counterregulatory hormonal responses, and cognitive function during stepped hypoglycemi c-clamp studies in 6 patients with insulinomas before and approximatel y six months after curative surgery and in 14 normal subjects matched for age, weight, and sex. Results. Before surgery, the patients with i nsulinomas had lower scores than the normal subjects for autonomic sym ptoms (mean [+/-SD], 3.5+/-0.8 vs. 9.6+/-4.5) and neuroglycopenic symp toms (2.8+/-1.5 vs. 8.9+/-5.3). The patients also had impaired counter regulatory hormonal responses (their plasma epinephrine, norepinephrin e, glucagon, growth hormone, and cortisol responses before surgery wer e 187+/-227 pg per milliliter [1.03+/-1.25 nmol per liter], 223+/-85 p g per milliliter [1.32+/-0.50 nmol per liter], 86+/-21 ng per liter, 7 .4+/-5.2 mug per liter, and 12.1+/-1.5 mug per deciliter [334+/-41 nmo l per liter], respectively, as compared with 842+/-439 pg per millilit er [4.63+/-2.41 nmol per liter], 519+/-150 pg per milliliter [3.07+/-0 .89 nmol per liter], 201+/-58 ng per liter, 25.3+/-13.7 mug per liter, and 26.3+/-1.2 mug per deciliter [726+/-33 nmol per liter in the norm al subjects) and less deterioration in cognitive function than the nor mal subjects during hypoglycemia (sum of z scores for seven tests of c ognitive function, 1.7+/-1.9 vs. 8.9+/-3,5) (P<0.02 for all comparison s). Surgical cure reversed all these abnormalities (P not significant for all comparisons with the normal subjects). Conclusions. Hypoglycem ia itself can induce unawareness of the autonomic and neuroglycopenic symptoms of hypoglycemia and decrease the counterregulatory hormonal r esponses to hypoglycemia.