Hypoglycemia due to paraneoplastic secretion of insulin-like growth factor-I in a patient with metastasizing large-cell carcinoma of the lung.
BACKGROUND
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.


CONCLUSIONS
Our findings are compatible with a new form of tumor hypoglycemia caused by circulating tumor-derived IGF-I.
Nauck
Michael A
MA
Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany. M.Nauck@diabeteszentrum.de
Reinecke
Manfred
M
Perren
Aurel
A
Frystyk
Jan
J
Berishvili
Giorgi
G
Zwimpfer
Cornelia
C
Figge
Anja M
AM
Flyvbjerg
Allan
A
Lankisch
Paul G
PG
Blum
Werner F
WF
Klöppel
Günter
G
Schmiegel
Wolff
W
Zapf
Jürgen
J
D000970:Antineoplastic Agents / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002850:Chromatography, Gel; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007328:Insulin / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009384:Paraneoplastic Endocrine Syndromes / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001786:Blood Glucose; D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; D019382:Human Growth Hormone; D012313:RNA; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D005047:Etoposide; D016190:Carboplatin