Case Study: Diagnosis of Insulinoma Using Continuous Glucose Monitoring System in a Patient With Diabetes

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:TBL1 

At that time, she had a normal hemoglobin A_1c, 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 1and 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); andμ-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.

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.

1. What is the differential diagnosis of high insulin?

2. What are the indications for CGMS use?

3. 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.