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Hypoglycemia due to Paraneoplastic Secretion of Insulin-Like Growth Factor-I in a Patient with Metastasizing Large-Cell Carcinoma of the Lung

Department of Medicine (M.A.N., A.M.F., W.S.), Ruhr-University, Knappschafts-Krankenhaus, D-44892 Bochum, Germany, and Diabeteszentrum Bad Lauterberg (M.A.N.), D-37431 Bad Lauterberg im Harz, Germany; Division of Neuroendocrinology (M.R., G.B., J.Z.), Institute of Anatomy, University of Zurich, and Department of Internal Medicine (C.Z., J.Z.), University Hospital, Zurich, Switzerland; Institute of Pathology (A.P.), University Hospital, CH-8057 Zürich, Switzerland; Medical Research Laboratories (J.F., A.F.), Institute of Experimental Clinical Research, Aarhus University Hospital, DK-8000 Aarhus, Denmark; Department of Internal Medicine (P.G.L.), Städtische Kliniken D-21339 Lüneburg, Germany; Department of Pediatrics (W.F.B.), University of Giessen, Giessen, and Eli Lilly & Co., D-61350 Bad Homburg, Germany; and Department of Pathology (G.K.), Christian-Albrecht-University, D-24105 Kiel, Germany

Address all correspondence and requests for reprints to: Michael A. Nauck, M.D., Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg, Germany. E-mail: M.Nauck{at}diabeteszentrum.de.

Context: Nonpancreatic tumors may cause recurrent hypoglycemia known as nonislet cell tumor hypoglycemia. It is due to overproduction and secretion by the tumor of incompletely processed IGF-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 computed tomography 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 IGF-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 after 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, and 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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