GLP-1 Provoked Severe Hypoglycemia in an Individual With Type 2 Diabetes and a Benign Insulinoma

This is a case of a severe hypoglycemia caused by an excess of GLP-1 receptors on a benign insulinoma in an individual with type 2 diabetes. The hypoglycemia was likely induced by a GLP-1 receptor agonist. The patient is a 54-year-old Caucasian female evaluated for “reactive” hypoglycemia that had worsened over the past 10 years. She had gained 20 pounds and reported intermittent episodes of “lightheadedness and shakiness,” which she treated with carbohydrates. One morning after a breakfast of pancakes and syrup, her husband described an episode that required him to feed her “a lot of orange juice to keep her awake.”

She had no pertinent past medical history and a normal physical exam. Diabetes was diagnosed based on an oral glucose tolerance test with a fasting plasma glucose of 7.05 mmol/L, a 120-min value of 11.71 mmol/L, and a HbA_1c of 5.1% (32 mmol/mol). At diagnosis, therapy with pioglitazone/metformin (15 mg/850 mg/day) and liraglutide 0.6 mg/day was started based on the protocol at the center where she was treated (1). Following the second dose of liraglutide 0.6 mg, she experienced confusion. In the emergency department, her blood glucose level was 1.38 mmol/L. It was difficult to raise and sustain her glucose levels and she required hospitalization on intravenous dextrose for 6 days. Her glucose levels were 2.22–3.0 mmol/L with insulin levels that ranged from 240 to 5,778 pmol/L. During this hospitalization she was found to have a pancreatic mass. A partial pancreatectomy was performed and histopathological examination confirmed a benign insulinoma.

The patient’s tumor underwent standard histological evaluation, revealing strongly positive staining for immunoreactive insulin. Due to the hypoglycemia following administration of a GLP-1 receptor agonist, immunohistochemistry for GLP-1 receptors (2) as well as insulin, glucagon, pancreatic polypeptide, somatostatin, and cytokeratin-19 was performed. Normal-appearing pancreatic tissue adjacent to the insulinoma served as internal positive control. The insulinoma cells were consistently immunopositive for GLP-1 receptors and insulin. Normal-appearing islets demonstrated a normal distribution of endocrine cells with GLP-1 receptor expression only seen in β-cells. No other compartments in the pancreas, including ductal epithelium, as identified by cytokeratin-19 staining, contained GLP-1 receptor immunoreactive cells (Fig. 1).

In this case, a patient with an insulinoma and type 2 diabetes diagnosed with an oral glucose tolerance test was started on a triple-drug regimen to slow disease progression. This produced a prolonged episode of hypoglycemia that led to the diagnosis of a benign insulinoma. In vitro and in vivo studies have revealed that benign insulinomas overexpress GLP-1 receptors, although less common in malignant insulinomas (3). The presence of GLP-1 receptors on β-cells is consistent with their mechanism of action resulting in increased insulin secretion. Thus, should a patient develop severe hypoglycemia on a GLP-1 receptor agonist an insulinoma should be considered.