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Increased Insulin-Like Growth Factor II Production and Consequent Suppression of Growth Hormone Secretion: A Dual Mechanism for Tumor-Induced Hypoglycemia

Laboratory of Molecular Endocrinology and the Howard Hughes Medical Institute (D.R., A.C.P.) Boston, Massachusetts 02114
The Diabetes Unit of the Medical Services (J.E.G., L.A.), Massachusetts General Hospital; the Department of Medicine, Harvard Medical School Boston, Massachusetts 02114
The Nichols Institute (M.R.P.) San Juan Capistrano, California 92675

Address all correspondence and requests for reprints to: Lloyd Axelrod, M.D., Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.

We investigated the pathophysiology of fasting hypoglycemia associated with large tumors of mesenchymal origin. We studied two patients with symptomatic fasting hypoglycemia (plasma glucose, 1.92 and 2.03 mmol/L) and a large mesenchymal neoplasm. Before therapy, the plasma insulin-like growth factor II (IGF-II) level measured by RIA was elevated (1879 and 1084 µg/L; normal range, 358–854 (µg/L), the serum GH response to hypoglycemia was impaired, and the plasma IGF-I level was low in both patients. After treatment of the tumor, all of these abnormalities resolved in both patients. Northern blot analysis of tumor RNA revealed extremely high levels of IGF-II mRNA (>100-fold higher than those in normal adult liver). Tumor fragments released IGF-II into tissue culture medium (2.1 and 7.2 µg IGF-II/g tissue·24 h). These findings indicate that secretion of IGF-II into the circulation by the tumor was the likely source of the elevated plasma IGF-II levels.

We suggest that the primary event in tumor-induced hypoglycemia is overproduction of IGF-II by the tumor, which gives rise to hypoglycemia by a dual mechanism: increased glucose utilization mediated by the insulin-like actions of IGF-II and inhibition of GH secretion.

^* Supported by a Research and Development Award from the American Diabetes Association.

Received October 17, 1988.

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