A Rare Case of Insulin-Like Growth Factor (IGF-2) Induced Hypoglycemia Associated With Metastatic Colon Cancer

The occurrence of hypoglycemia in patients without diabetes is rare, and non-islet cell tumor hypoglycemia (NICTH) accounts for a small portion of these instances. One of the infrequent causes is associated with tumor cell production of Insulin-like growth factor (IGF)-2. Here is a case of a 66-year-old man with stage IV colon cancer who presented to the emergency department with breathlessness during chemotherapy (Bevacizumab plus FOLFOX4 regimen). He had undergone partial colectomy and chemotherapy three years prior but was recently diagnosed with metastatic liver disease. A CT scan revealed a 15 cm hepatic mass occupying the entire right hepatic lobe. Despite receiving dextrose infusions, he experienced persistent hypoglycemia after meals and during fasting. Given that he had no history of diabetes and denied using any oral hypoglycemic agents, the Endocrinology service was consulted for further evaluation. Plasma blood glucose (BG) was measured at 74 mg/dL (reference range 74-106) during dextrose administration. An 8 AM cortisol test yielded a result of 8.08 mcg/dL (4.30-22.40), ruling out adrenal insufficiency. A 72-hour fast was initiated but terminated at eight hours due to symptomatic hypoglycemia with a plasma BG of 48 mg/dL. C-peptide and Insulin levels were both low, measuring <0.05 ng/mL (0.48-5.05) and <1.0 mU/L (3.0-25), respectively, while beta-hydroxybutyrate (BHB) levels were normal at 1.1 mg/dL (0.2-2.8). Administration of 1 mg glucagon during the fast increased BG to 112 mg/dL within 2 hours. IGF-1 levels were undetectable (<1.9 nmol/L), while IGF-2 levels were at 23 nmol/L (44-129 nmol/L), resulting in an IGF2:IGF1 ratio of 12 (>10), confirming IGF-2 mediated NICTH. Treatment with dexamethasone 10 mg daily was initiated, maintaining blood glucose levels above 70 mg/dL without dextrose infusion. In approximately 50% of cases of NICTH, the tumor is detected before the onset of hypoglycemia, yet up to half the patients may remain asymptomatic despite having very low BG. Despite having a known hepatic lesion, our patient exhibited minimal symptoms despite severely low BG levels. The mechanisms underlying NICTH may involve tumor secretion of insulin, replacement of hepatic tissue, increased glucose utilization by the tumor, or, most commonly, secretion of IGF-2. In cases of IGF-2-mediated hypoglycemia, insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels are typically low. IGF-2 stimulates the insulin receptors resulting in increased glucose uptake by skeletal muscles and suppression of gluconeogenesis, glycogenolysis, and ketogenesis by the liver. Insulin secretion from pancreatic β-cells is suppressed. IGF-1 levels are usually low, while IGF-2 levels may be high or normal, as many IGF-2omas produce IGF-2 precursors (pro-IGF-2). An elevated IGF-2:IGF-1 ratio (>10) confirms the diagnosis which may be helpful when IGF-2 levels are normal. The primary treatment is through surgical removal or debulking of the tumor. Neoadjuvant therapies such as radiation and chemotherapy may reduce occurrences of hypoglycemia, but only temporarily. Glucocorticoids may be used when the underlying malignancy cannot be treated.