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Submitted on November 22, 2006
Accepted on February 1, 2007
Department of Medicine, Ruhr-University, Knappschafts-Krankenhaus (M.A.N.,A.M.F., W.S.) Bochum, Germany and Diabeteszentrum Bad Lauterberg (M.A.N.), Bad Lauterberg im Harz, Germany; Division of Neuroendocrinology, Institute of Anatomy (M.R., G.B., J.Z.), University of Zurich and Department of Internal Medicine, University Hospital (C.Z., J.Z), Zurich, Switzerland; Institute of Pathology, University Hospital (A.P.), Zürich, Switzerland; Medical Research Laboratories, Institute of Experimental Clinical Research (J.F., A.F.), Aarhus University Hospital, Aarhus, Denmark; Department of Internal Medicine (P.L.), Städtische Kliniken Lüneburg, Germany; Department of Pediatrics, University of Giessen, Giessen and Eli Lilly & Co. (W.F.B), Bad Homburg, Germany; Department of Pathology, Christian-Albrecht-University (G.K.), Kiel, Germany
* To whom correspondence should be addressed. E-mail: M.Nauck{at}diabeteszentrum.de.
Context: Non-pancreatic tumors may cause recurrent hypoglycemia known as non-islet cell tumor hypoglycemia (NICTH). It is due to overproduction and secretion by the tumor of incompletely processed insulin-like growth factor-II, termed big IGF-II. We recently identified a patient with recurrent hypoglycemia and low insulin, but without elevated big IGF-II. Multiple small lung nodules were detected by CT scan. An undifferentiated large-cell carcinoma was diagnosed from an axillary lymph node metastasis.
Objective: The objective was to investigate whether the patient's hypoglycemia was due to excessive IGF-I production by the tumor.
Methods: Serum IGF- I and -II, insulin and GH were measured by RIA, the distribution of IGFs between IGF binding protein complexes in serum was analyzed after neutral gel filtration. Tissue IGF-I was identified by immunohistochemistry and in situ hybridization, and by RT-PCR following RNA extraction.
Results: Total and free serum IGF-I, but not total, free and big IGF-II, was increased, and the IGF-I content of the two IGF binding protein complexes was elevated. Immunohistochemistry demonstrated IGF-I peptide, in situ hybridization IGF-I mRNA in the lymph node metastasis. Combined GH/glucocorticoid treatment prevented hypoglycemia, but did not lower IGF-I. After chemotherapy with carboplatinum/etoposide the lung nodules largely regressed, serum IGF-I and the IGF-I content of the two binding protein complexes became normal. Hypoglycemia did not recur despite discontinuation of GH/glucocorticoid treatment.
Conclusion: Our findings are compatible with a new form of tumor hypoglycemia caused by circulating tumor-derived IGF-I.
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