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N Engl J Med. 1993 Sep 16;329(12):834-9.

Reversibility of unawareness of hypoglycemia in patients with insulinomas.

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Second Department of Internal Medicine, Propaedeutic, Athens University, Greece.



A lack of appropriate autonomic warning symptoms before the development of neuroglycopenia occurs frequently in patients with diabetes mellitus. The pathogenesis of this phenomenon is unclear, but it is associated with intensive insulin therapy, prolonged duration of diabetes, frequent episodes of hypoglycemia, and impaired glucose counterregulation. Recently, it has been proposed that repeated episodes of hypoglycemia may themselves induce the phenomenon.


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 hypoglycemic-clamp studies in 6 patients with insulinomas before and approximately six months after curative surgery and in 14 normal subjects matched for age, weight, and sex.


Before surgery, the patients with insulinomas had lower scores than the normal subjects for autonomic symptoms (mean [+/- SD], 3.5 +/- 0.8 vs. 9.6 +/- 4.5) and neuroglycopenic symptoms (2.8 +/- 1.5 vs. 8.9 +/- 5.3). The patients also had impaired counterregulatory hormonal responses (their plasma epinephrine, norepinephrine, glucagon, growth hormone, and cortisol responses before surgery were 187 +/- 227 pg per milliliter [1.03 +/- 1.25 nmol per liter], 223 +/- 85 pg per milliliter [1.32 +/- 0.50 nmol per liter], 86 +/- 21 ng per liter, 7.4 +/- 5.2 micrograms per liter, and 12.1 +/- 1.5 micrograms per deciliter [334 +/- 41 nmol per liter], respectively, as compared with 842 +/- 439 pg per milliliter [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 micrograms per liter, and 26.3 +/- 1.2 micrograms per deciliter [726 +/- 33 nmol per liter] in the normal subjects) and less deterioration in cognitive function than the normal subjects during hypoglycemia (sum of z scores for seven tests of cognitive function, 1.7 +/- 1.9 vs. 8.9 +/- 3.5) (P < 0.02 for all comparisons). Surgical cure reversed all these abnormalities (P not significant for all comparisons with the normal subjects).


Hypoglycemia itself can induce unawareness of the autonomic and neuroglycopenic symptoms of hypoglycemia and decrease the counterregulatory hormonal responses to hypoglycemia.

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