Reversibility of Unawareness of Hypoglycemia in Patients with Insulinomas
A. Mitrakou, C. Fanelli, T. Veneman, G. Perriello, S. Calderone, D. Platanisiotis, A. Rambotti, S. Raptis, P. Brunetti, P. Cryer, J. Gerich, and G. Bolli
Background A lack of appropriate autonomic warning symptomsbefore the development of neuroglycopenia occurs frequentlyin patients with diabetes mellitus. The pathogenesis of thisphenomenon is unclear, but it is associated with intensive insulintherapy, prolonged duration of diabetes, frequent episodes ofhypoglycemia, and impaired glucose counterregulation. Recently,it has been proposed that repeated episodes of hypoglycemiamay themselves induce the phenomenon.
Methods To test this hypothesis and to determine whether thephenomenon is reversible, we assessed autonomic and neuroglycopenicsymptoms, counterregulatory hormonal responses, and cognitivefunction during stepped hypoglycemic-clamp studies in 6 patientswith insulinomas before and approximately six months after curativesurgery and in 14 normal subjects matched for age, weight, andsex.
Results Before surgery, the patients with insulinomas had lowerscores than the normal subjects for autonomic symptoms (mean[±SD], 3.5 ±0.8 vs. 9.6 ±4.5) and neuroglycopenicsymptoms (2.8 ±1.5 vs. 8.9 ±5.3). The patientsalso had impaired counterregulatory hormonal responses (theirplasma epinephrine, norepinephrine, glucagon, growth hormone,and cortisol responses before surgery were 187 ±227 pgper milliliter [1.03 ±1.25 nmol per liter], 223 ±85pg per milliliter [1.32 ±0.50 nmol per liter], 86 ±21ng per liter, 7.4 ±5.2 µg per liter, and 12.1 ±1.5µg per deciliter [334 ±41 nmol per liter], respectively,as compared with 842 ±439 pg per milliliter [4.63 ±2.41nmol per liter], 519 ±150 pg per milliliter [3.07 ±0.89nmol per liter], 201 ±58 ng per liter, 25.3 ±13.7µg per liter, and 26.3 ±1.2 µg per deciliter[726 ±33 nmol per liter] in the normal subjects) andless deterioration in cognitive function than the normal subjectsduring hypoglycemia (sum of z scores for seven tests of cognitivefunction, 1.7 ±1.9 vs. 8.9 ±3.5) (P<0.02 forall comparisons). Surgical cure reversed all these abnormalities(P not significant for all comparisons with the normal subjects).
Conclusions Hypoglycemia itself can induce unawareness of theautonomic and neuroglycopenic symptoms of hypoglycemia and decreasethe counterregulatory hormonal responses to hypoglycemia.
Source Information
From the Second Department of Internal Medicine, Propaedeutic, Athens University, Athens, Greece (A.M., D.P., S.R.); the Istituto di Medicina Interna e Scienze Endocrine e Metaboliche, University of Perugia, Perugia, Italy (C.F., G.P., S.C., A.R., P.B., G.B.); the Whittier Institute for Diabetes and Endocrinology, La Jolla, Calif. (T.V., J.G.); and the Department of Medicine, Washington University School of Medicine, St. Louis (P.C.).
Address reprint requests to Dr. Gerich at the Whittier Institute for Diabetes and Endocrinology, 9894 Genesee Ave., La Jolla, CA 92037.
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