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).
What are the clinical signs and symptoms of insulinomas?
How is the diagnosis of insulinoma made?
What imaging studies are best for localizing insulinomas?
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.
Contrasted abdominal CT scan illustrating enhancing mass at the head of the pancreas.
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.
- American Diabetes Association
K.D., a 20-year-old white female college student was brought by her parents for evaluation of hypoglycemia. She had experienced multiple episodes of palpitations, blurred vision, and left facial paresthesias for a year, progressively worsening and occurring more frequently in the 2 months just before her appointment.
Usually the episodes occurred between 3:00 and 7:30 p.m. The symptoms occurred without regard to meals and were relieved with food or juice. Her most severe witnessed episode, which occurred while she was at college, happened a few days before the consultation, while K.D. was working, 2 hours postprandially. Observers reported that she appeared confused, agitated, and diaphoretic. Her glucose via fingerstick by paramedics was 35 mg/dl. She received intravenous dextrose, and subsequently her glucose rose to 217 mg/dl with resolution of her symptoms. She had several episodes with neuroglycopenic symptoms and glucose levels of 35-45 mg/dl.
There was no history indicating diabetic medications in her home. She also complained of a 25-lb weight gain during the past year.
A year before her visit, K.D. was diagnosed with diabetes by oral glucose tolerance test (OGTT). The results were:
At that time, she had a normal hemoglobin A1c, and she was instructed in diet and exercise. No antidiabetic medications had been prescribed.
K.D. had a psychiatric evaluation, was diagnosed with depression, and was started on sertraline. In the month before the consultation, she also had a neurological work-up with negative computed tomography scans of the head and normal electroencephalogram.
Her family history was significant only for diabetes of a maternal aunt. She denied allergies or use of cigarettes, alcohol, or illicit drugs. She was taking sertraline, 50 mg daily for the past year; ethinyl estradiol/norgestimate, one daily for the past 2 years; and oxcarbazepine, 175 mg twice daily for the past week.
Physical examination did not reveal any orthostasis and was essentially normal. On the day of her office visit, concomitant with a random glucose of 62 mg/dl, K.D.'s insulin level was 37 μ/ml (normal: 2-15 μ/ml), and her C-peptide level was 7.7 ng/ml (normal: 1.1-4.6 ng/ml).
Her cortisol level was 18 μ/dl (normal: 3-17 μg/dl). Thyroid-stimulating hormone, liver function tests, creatinine, and electrolytes were normal. There were no measurable blood levels of sulfonylurea. She was given a glucometer and was advised to check her fasting blood glucose and also blood glucose levels whenever her symptoms suggested hypoglycemia.
K.D. returned to clinic 2 weeks later complaining of persistent hypoglycemic episodes. At that time, a continuous glucose monitoring system (CGMS) was applied (Figures 1 and 2). The patient had multiple and frequent episodes of blood glucose levels < 55 mg/dl independent of the time of the day. It is worth noticing that she had blood glucose < 40 mg/dl for more than 2 hours continuously during sleep.
The patient was hospitalized for a 72-hour fast test. Within 20 minutes of the start of the fast, her blood glucose fell to 16 mg/dl. At the same time, her insulin was 18 μ/ml; proinsulin was 534.5 pmol/l (normal: 2.1-26.8 pmol/l); C-peptide level was 7.6 ng/ml (normal: 1.1-4.6 ng/ml); and μ-hydroxybutyrate was 0.2 mmol/l (normal: 0.0-0.3 mmol/l). Drug screens for sulfonyluea and repaglinide were negative.
A magnetic resonance imaging scan with contrast of her abdomen showed a 1.2-cm lesion in the tail of the pancreas. The patient underwent successful enucleation of the tumor, which revealed insulinoma. The postoperative course was uncomplicated.
Materials and methods. The CGMS (MiniMed, Sylmar, Calif.) was placed on the patient, and glucose levels were monitored for 87 hours. The patient was instructed and trained on the use of CGMS before its placement. The patient's capillary blood glucose levels were checked and recorded at least four times a day and whenever she experience neuroglycopenic symptoms. She was also asked to record in a diary her meals and physical activity.
The continuous line represents the sensor glucose values. The blue asterisk respresents the meter blood glucose readings that were entered into the monitor. If there are no interruptions in glucose monitoring, then the number of paired sensor glucose values/meter blood glucose readings should match the number of meter blood glucose readings. In this graph, the flat line represents sensor blood glucose readings < 40 mg/dl. The CGMS cannot sense < 40 mg/dl.
CGMS is designed to continuously and automatically monitor glucose values in subcutaneous tissue fluid within a range of 40-400 mg/dl. The CGMS records sensor signals every 5 minutes, providing 288 glucose readings per day. When the glucose readings are < 40 mg/dl, the graph appears as a flat line.
C-peptide was determined by a chemiluminescent immunoassay (Associated Regional and University Pathologists, Salt Lake City, Utah). Insulin levels were quantitated by paramagnetic-particle chemiluminescent immunoassay (Beckman Coulter Access analyzer and insulin reagent pack; Chaska, Minn.) The two-site enzyme immunoassay measured the proinsulin level. The sulfonylurea panel was performed by the high performance liquid chromatography method. Finally, for the repaglinide level, the liquid chromatography-tandem mass spectrometry method was used.
This graph presents all of the CGMS data superimposed over a 24-hour period, with each day presented as a separate plot line.
What is the differential diagnosis of high insulin?
What are the indications for CGMS use?
At what point should the CGMS be used for the differential diagnosis of hypoglycemia?
Insulinoma, a rare islet tumor of the pancreas, is characterized by symptomatic hypoglycemia, inappropriately increased plasma insulin, proinsulin, and C-peptide levels during an episode of spontaneous hypoglycemia.1
The coexistence of insulinoma and diabetes is rare and has been reported in diabetic patients whose hypoglycemic symptoms were explained by the presence of insulinoma.2-9
The CGMS is a sensor system for measuring the glucose concentrations continuously in subcutaneous tissue. It has been mostly useful for detecting unrecognized hypoglycemia in patients with type 1 or type 2 diabetes.10,11
We have described here a young female patient with a diabetic OGTT and persistent symptomatic hypoglycemia for whom continuous glucose monitoring played a major role in diagnosing insulinoma. This case appears to be the first report of a patient with insulinoma and concomitant diabetes in which continuous glucose monitoring was used as an important diagnostic tool.
At the age of 20, K.D. presented with hypoglycemia associated with neuroglycopenic symptoms. Because she had had a diabetic OGTT a year before, it was initially suspected that she might have reactive hypoglycemia. What made this patient's presentation more intriguing was that her symptoms of spontaneous hypoglycemia were progressively intensifying in severity and frequency. The persistence of hypoglycemia during the day, but not reported by the patient during the night, led to the consideration of using the CGMS as a diagnostic tool to document the hypoglycemic episodes.
The insulinoma was considered as a possible diagnosis only after review of the striking CGMS results. The episodes of hypoglycemia during the night were frequent, and recovery was spontaneous. The CGMS showed low blood glucose of < 40 mg/dl throughout a 24-hour period, most strikingly nocturnally (Figures 1 and 2), despite the fact that the patient denied any hypoglycemic symptoms during the night. This was the major contribution of CGMS in suggesting the diagnosis of insulinoma.
The absence of neuroglycopenic symptoms during the night with blood glucose levels < 40 mg/dl can probably be explained by the fact that young healthy women may have plasma glucose values in the range of 40 mg/dl without any symptoms.12 Another interesting point of this case was that during the CGMS use, there was nocturnal hypoglycemia during only 1 of the 3 full days of monitoring (Figure 1). This is not commonly seen with the classical presentation of insulinomas, in which hypoglycemia is frequently seen during the longest caloric restriction, which usually occurs during the night.
The CGMS has been shown to provide a good correlation between blood and interstitial glucose levels.13,14 It has also been used in the detection of unrecognized hypoglycemia in patients with type 1 or type 2 diabetes.10,11 Here, it was used to detect possible unusual causes of hypoglycemia, such as insulinoma.
In this case, the CGMS was in place over a period of 87 hours, even though 72 hours is the norm. This difference is simply related to the patient's delay in returning the CGMS. A striking issue of this case is that the CGMS correlated perfectly with the fingerstick glucose of the patient, despite the longer use period. This is an indication that the technique of the CGMS has significantly improved, and its reliability has been increased.
The CGMS has limitations because it measures interstitial fluid glucose rather than serum levels. However, Monsod et al.15 have shown that the CGMS can accurately predict plasma glucose concentrations during hypoglycemia and hyperinsulinemia. This accuracy diminishes, though, toward the 40 mg/dl glucose level, and inaccurate readings can be obtained.16
It is likely that K.D. had two independent conditions (i.e., insulinoma and type 2 diabetes). Earlier reports in the literature have described the coexistence of diabetes and insulinoma.2-9 The diagnosis of these two coexistent diseases is very challenging. This patient is the youngest one ever reported in the literature with these two diagnoses; the age range in previous reports was 45-78 years.2-9 The time that lapsed from the onset of her symptoms until the final diagnosis was approximately 12 months, which is short when compared to the previously reported cases, where the time range was 13-24 months.
As mentioned above, this is the first reported use of a CGMS as a major adjunctive method for detecting hypoglycemia. In this case, the CGMS was well tolerated and very accurate. The CGMS should therefore be considered for the work-up of such patients because it is reliable, safe, and easily performed on an outpatient basis.
Insulinoma is a rare tumor of the pancreas that should be considered in the differential diagnosis of a young patient with hypoglycemia.
The coexistence of insulinoma and type 2 diabetes is challenging and often goes unrecognized.
The CGMS is an adjunctive method for detecting hypoglycemia.
The CGMS is a safe tool that is easily used on an outpatient basis.
Paraskevi Sapountzi, MD, is a fellow of the Division of Endocrinology and Metabolism at Loyola University Medical Center and Hives VA Hospital in Maywood, Ill. Gerald Charnogursky, MD, is an assistant professor; Mary Ann Emanuele, MD, is a professor; Donna Murphy, APN, CDE, is a nurse specialist; and Fadi Nabhan, MD, is an assistant professor at Loyola University Medical Center in Maywood, Ill. Nicholas V. Emanuele, MD, is a professor in the the Division of Endocrinology and Metabolism at Loyola University Medical Center and Hines VA Hospital in Maywood, Ill.
- American Diabetes Association