I.H. is an 82-year-old white woman who presented to her primary care physician with a 10-year history of episodic confusion and somnolence. The episodes occurred about twice a year, typically in the morning, just after waking. They lasted minutes and were relieved when she ate her breakfast or had juice. Over the 8–10 months before presentation, the patient noted that the episodes were increasing in frequency as well as occurring throughout the day.

When I.H. presented to her primary care doctor with the above complaints, the patient was reassured. As she was waiting for check-out, she developed confusion, a capillary blood glucose test was performed, and she was noted to have a plasma glucose level of 28 mg/dl. She was given juice and her symptoms resolved after a few moments.

The patient was subsequently admitted to the hospital for further work up.

On exam, I.H. was found to be a well-nourished woman in no apparent distress. Her vital signs were significant only for mild hypertension. Her physical and neurological exams were unremarkable. Her admission lab values were significant for a glucose level of 36 mg/dl. She was completely asymptomatic upon presentation and was thus placed on a fasting protocol. Subsequent laboratory results are listed in Table 1.

In this case (as is true in most centers), the serum insulin, serum C-peptide, and sulfonylurea levels were not readily available. Therefore, the fasting protocol was continued until she became symptomatic. The subsequent lab results were consistent with the suspected diagnosis of an insulin secreting tumor. To localize the tumor, I.H. had an abdominal CT with contrast, which revealed an enhancing mass in the pancreatic head suggestive of an insulinoma (Figure 1).

  1. What are the clinical signs and symptoms of insulinomas?

  2. How is the diagnosis of insulinoma made?

  3. What imaging studies are best for localizing insulinomas?

  4. What are the treatment options for insulinoma?

Insulinomas are almost always islet cell tumors of the pancreas and occur as single or multiple tumors. They are typically benign, although malignant tumors have been reported as well.1 Insulinomas present with the neuroglycopenic and sympathoadrenal symptoms induced by hypoglycemia.2 I.H. presented with confusion, which is typical of insulinoma. Other symptoms include visual changes, unusual behavior, palpitations, diaphoresis, and tremulousness.3 

Interestingly, I.H. had none of the sympathoadrenal symptoms. This phenomenon is known as “hypoglycemia unawareness” and is seen most often in type 1 diabetic patients who experience frequent episodes of hypoglycemia. This occurs because the set point for catecholamine secretion in response to hypoglycemia is lowered. I.H. did not have weight gain, which is noted in about 18% of insulinoma cases according to one study.4 

Misdiagnosis of insulinoma is common. In one study, as many as 20% of patients had been misdiagnosed with a psychiatric, seizure, or other neurological disorder before the true diagnosis of insulinoma was made.4 

Diagnosis of insulinoma is established by demonstrating inappropriately high serum levels of endogenous insulin in the setting of hypoglycemia.5 Decrease in plasma glucose level occurs during fasting under normal physiological conditions. However, the fall in plasma glucose is accompanied by a concurrent fall in plasma insulin levels.6 In cases where the diagnosis of insulinoma is suspected and the patient is observed with symptoms of hypoglycemia, the serum blood glucose, C-peptide, insulin, and sulfonylurea levels should be drawn immediately before intervention.

In patients who present for diagnostic work-up, a brief, observed fast should be performed in which the above lab values are measured every 4–6 hours initially and then every 1–2 hours after the patient’s serum blood glucose level falls to < 60 mg/dl. The fast should be discontinued once the patient becomes symptomatic and the serum glucose falls below 45 mg/dl. A final set of labs should be drawn. The patient should then be given juice and monitored for resolution of symptoms. (Of note in patient I.H., the finding of a serum glucose of 36 mg/dl and evidence of insulin secretion probably would have sufficed.) The fast should be continued for 72 hours if symptomatic hypoglycemia does not occur.

Insulinoma patients have a tendency to develop hypoglycemia early during a fasting period, typically in the first 10–12 hours.7 The change of insulin relative to glucose is inappropriate; thus, the insulin-to-glucose ratio increases rather than decreases as it does in normal subjects.7 A serum insulin concentration of ≥ 6 μU/ml when the serum glucose concentration is < 45 mg/dl indicates inappropriate secretion of insulin, consistent with insulinoma.8 

It is also very important to measure C-peptide concentrations, which should be inappropriately normal or high in the case of insulinoma. Proinsulin is the immediate precursor to insulin and is stored in the β-cell. Insulin is formed when the connecting peptide (C-peptide) is cleaved from the proinsulin molecule. This occurs at the time of insulin secretion, and thus both insulin and C-peptide are released into the circulation.9 

In a patient with a low or undetectable level of serum C-peptide in the setting of hyperinsulinemia, self-induced hypoglycemia secondary to the administration of insulin should be suspected and evaluated. Self-induced hypoglycemia may present in a similar way to that of insulinoma and is typically achieved by administering insulin or oral secretagogues such as sulfonylurea. Findings, however, in these cases do not typically correlate with food ingestion, because the agent is administered irregularly.9 Patients presenting with self-induced hypoglycemia typically have access to hypoglycemic agents either through their work or through relatives. Factitious hypoglycemia induced by sulfonylurea administration has a laboratory presentation similar to that of insulinoma. The insulin and C-peptide levels will both be elevated; thus, it is imperative that the sulfonylurea level is measured as well.

Imaging and localization of insulinomas may be done by spiral CT, arteriography, ultrasonography (transabdominal, endoscopic, and intraoperative), or 111-In-penteotreotide or octreotide scintigraphy.10 I.H., in addition to a CT scan, had an octreotide scan, which aided in characterizing the tumor’s secretory nature and function. It illustrated a small focus of mildly increased activity in the upper abdominal region between the upper portion of the kidney just to the right of midline, placing it in the region of the pancreas. Self-induced hypoglycemia is often seen in patients seeking the attention of family and medical professionals or some other form of secondary gain.

I.H. had an open laparotomy with intraoperative ultrasound and enucleation of a 1.1-by-1.2 cm discrete, firm nodule in the center of the pancreatic head identified by palpation and ultrasound. Pancreatojejunostomy in Roux-en-Y fashion was performed in case of operative pancreatic ductal injury. Surgical resection is the treatment of choice for insulinoma. Enucleation of the insulinoma, partial distal pancreatectomy, enucleation of the insulinoma and partial pancreatectomy, a Whipple procedure (removal of the head of the pancreas, gastrectomy, duodenectomy, and splenectomy), and total pancreatectomy have all been reported. Enucleation of the tumor is the most common surgical procedure. Pathology revealed a 1.3-cm insulin-secreting endocrine neoplasm that was likely benign.

For patients who are not good surgical candidates, who refuse surgery, or whose insulinoma was missed during surgery, as well as for patients with metastatic disease, medical therapy should be attempted. The goal of medical therapy is to prevent symptomatic hypoglycemia. Medications that have been used for this purpose include diazoxide, verapamil, phenytoin, and octreotide. Diazoxide diminishes insulin secretion and is the most effective drug for controlling hypoglycemia. Octreotide, the somatostatin analog, is also a common treatment for patients with unresectable tumors.1 

Postoperatively, I.H.’s glucose levels stabilized to the low 100s after an initial short period of hyperglycemia. Her postoperative course was complicated only by an ileus that resolved on postoperative day 11. The patient was discharged on a regular diet and has done well.

  • Insulinoma should be suspected in patients who present with symptoms of neuroglycopenic and sympathoadrenal symptoms induced by hypoglycemia.

  • If the patient is symptomatic, a capillary blood glucose level should be measured immediately. If noted to be low, then serum glucose, serum insulin, C-peptide, and sulfonylurea levels should be measured before intervention.

  • Factitious hypoglycemia should be suspected in patients who have access to insulin or antidiabetic secretagogue drugs through work or relatives.

  • Imaging and localization of insulinoma is typically obtained by CT scan. If undetected and the clinical suspicion is still high, then arteriography, ultrasonography (transabdominal, endoscopic, and intraoperative), or 111-In-penteotreotide or octreotide scintigraphy may be pursued.

  • First-line treatment of insulinoma is surgical resection. However, medical therapy may be initiated if the patient is not a good surgical candidate or the tumor is unresectable.

Figure 1.

Contrasted abdominal CT scan illustrating enhancing mass at the head of the pancreas.

Figure 1.

Contrasted abdominal CT scan illustrating enhancing mass at the head of the pancreas.

Close modal
Table 1.

Laboratory Results for Patient I.H. on Fasting Protocol

Laboratory Results for Patient I.H. on Fasting Protocol
Laboratory Results for Patient I.H. on Fasting Protocol

Saleemah Yasmeen Fahmi, MD, is a third-year resident, and Philip Raskin, MD, is a professor of medicine in the Department of Internal Medicine and a Clifton and Betsy Robinson Chair in Biomedical Research at the University of Texas Southwestern Medical Center in Dallas, Tex.

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