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

J Clin Endocrinol Metab. 2007 May;92(5):1600-5. doi: 10.1210/jc.2006-2573. Epub 2007 Feb 13.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Blood Glucose / metabolism
  • Carboplatin / administration & dosage
  • Carcinoma, Large Cell / drug therapy
  • Carcinoma, Large Cell / metabolism*
  • Carcinoma, Large Cell / pathology
  • Chromatography, Gel
  • Etoposide / administration & dosage
  • Female
  • Human Growth Hormone / blood
  • Humans
  • Hypoglycemia / etiology*
  • Immunohistochemistry
  • In Situ Hybridization
  • Insulin / blood
  • Insulin-Like Growth Factor Binding Proteins / blood
  • Insulin-Like Growth Factor I / biosynthesis*
  • Insulin-Like Growth Factor II / biosynthesis
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Lymphatic Metastasis
  • Middle Aged
  • Paraneoplastic Endocrine Syndromes / metabolism*
  • RNA / biosynthesis
  • RNA / genetics
  • Reverse Transcriptase Polymerase Chain Reaction


  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Blood Glucose
  • Insulin
  • Insulin-Like Growth Factor Binding Proteins
  • Human Growth Hormone
  • RNA
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Etoposide
  • Carboplatin