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Insulinoma Workup

  • Author: Zonera Ashraf Ali, MBBS; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
Updated: Feb 21, 2016

Laboratory Studies

Failure of endogenous insulin secretion to be suppressed by hypoglycemia is the hallmark of an insulinoma. Thus, the finding of inappropriately elevated levels of insulin in the face of hypoglycemia is the key to diagnosis. Considering the reference range, the fasting plasma levels of insulin, C-peptide, and, to a lesser degree, proinsulin need not be elevated in insulinoma patients in absolute terms.

Prolonged (ie, 72 h) supervised fast in hospitalized patients provides the most reliable results. The calculation of ratios of insulin (µU/mL) to plasma glucose (mg/dL) is diagnostic: Healthy patients maintain a ratio of less than 0.25 (obese patients may have a slightly higher rate), whereas in patients with insulinoma, the ratio rises during fasting.

In a study from the Netherlands, a positive Whipple triad on a prolonged fasting test, in combination with an insulin/C-peptide ratio <1, had a sensitivity of 88.9% and a specificity of 100% for the diagnosis of insulinoma.[18]

The biochemical diagnosis is established in 95% of patients during prolonged fasting (up to 72 h) when the following parameters are found:

  • Serum insulin levels of 10 µU/mL or more (normal <6 µU/mL)
  • Glucose levels of less than 40 mg/dL
  • C-peptide levels exceeding 2.5 ng/mL (normal <2 ng/mL)
  • Proinsulin levels ≥22 pmol/L, [19] or greater than 25% (or up to 90%) that of immunoreactive insulin
  • Screening for sulfonylurea negative

Stimulation tests no longer are recommended. The intravenous application of tolbutamide, glucagon, or calcium can be hazardous, as they may induce prolonged and refractory hypoglycemia.

The presence of MEN 1 must be evaluated by excluding the following:

  • Hyperprolactinemia due to a pituitary adenoma
  • Hyperparathyroidism due to parathyroid hyperplasia
  • Hypergastrinemia due to a gastrinoma

Imaging Studies

Start imaging studies only after the diagnosis has been confirmed biochemically, because 80% of insulinomas are less than 2 cm in size and may not be visible by CT scan or transabdominal ultrasonography.

Successful preoperative tumor localization is achieved in about 60% of patients.[20] Some experienced surgeons perform only transabdominal ultrasound preoperatively. Other surgeons argue that the preoperative localization of insulinomas is not necessary at all because surgical exploration and intraoperative ultrasonography identify more than 90% of tumors.[21] Thus, the extent to which one attempts to define the anatomy of the beta cell lesion before surgery is a matter of judgment.

Helical or multislice CT scan has 82-94% sensitivity. In one study, dual-phase helical CT proved more sensitive than single-phase for detection of insulinoma; in addition, image acquisition in the arterial phase proved more helpful than acquisition during the portal-venous phase.[22]

MRI with gadolinium can be helpful in detecting a tumor in 85% of cases. One case report suggests that diffusion-weighted MRI can be useful for detecting and localizing small insulinomas, especially for those with no hypervascular pattern.[23]

The accuracy of selective arteriography is 82%, although affected by a false-positive rate of 5%. Many experts see it as the best overall preoperative localization procedure.

Arteriography with catheterization of small arterial branches of the celiac system combined with calcium injections (which stimulate insulin release from neoplastic tissue but not from normal islets), and simultaneous measurements of hepatic vein insulin during each selective calcium injection localizes tumors in 47% of patients.

A study by Wiesli et al found that proinsulin, C-peptide, and insulin are all released by insulinoma cells in response to arterial calcium stimulation; however, chromogranin A (CgA) and neuron-specific enolase (NSE) are not released. The study also concluded that pancreatic polypeptide may be released by healthy islet cells after calcium stimulation.[24]

The sensitivity of somatostatin receptor scintigraphy is 60%, although many insulinomas lack somatostatin receptor subtype 2 for successful identification.

Endoscopic ultrasonography detects 77% of insulinomas in the pancreas.[1, 2, 3] The yield can be higher if it is done in combination with CT scan. A majority of sporadic insulinomas will be detected and localized by a combination of these two investigative means. Note the following:

  • Real-time transabdominal high-resolution ultrasonography has 50% sensitivity.
  • Intraoperative transabdominal high-resolution ultrasonography with the transducer wrapped in a sterile rubber glove and passed over the exposed pancreatic surface detects more than 90% of insulinomas.
  • Performing a preoperative study to localize the tumor followed by intraoperative ultrasonography and a physical examination is not unreasonable.

Insulinomas have been shown to have a very high density of glucagon-like peptide-1 receptors (GLP-1R), and radiolabeling with an111 In-labeled GLP-1R agonist (111 In-DOTA-exendin-4) has successfully been used to localize small insulinomas both preoperatively and, with the use of a gamma probe, intraoperatively.[25] Luo et al reported that positron-emission tomography/CT scanning with 68Ga-NOTA-exendin-4 correctly detected insulinomas in 42 of 43 patients.[26]

Somatostatin receptor target imaging can diagnosis malignant insulinomas missed by GLP-1 target imaging because these malignancies often lack GLP-1 receptors.[27]


Other Tests

Other tests used in the localization of insulinoma are as follows:

  • Preoperative portal venous sampling is obsolete as a routine investigation because of a high complication rate (10%), but it may be used when all other imaging procedures fail and surgical exploration findings are negative.
  • Localization with anti-insulin labeled with iodine-131 was achieved in 50% of patients, with a 37.5% false-positive rate; therefore, it is not recommended.
  • Endoscopic ultrasound-guided fine-needle aspiration biopsy of insulinoma has been described; the technique combines endoscopic ultrasonography with local tumor biopsy and may be indicated when the tissue diagnosis must be established preoperatively.
  • Laparoscopic ultrasonography with eventual tumor biopsy may be used in rare cases when other localization techniques failed.

Histologic Findings

Insulinomas are solitary tumors in 90% of patients. In MEN 1 syndrome, multiple microinsulinomas and macroinsulinomas are found, although hypoglycemia may be caused by a single tumor. The tumors are distributed evenly throughout the pancreas. Tumor size does not relate to the severity of clinical symptoms. Ectopic insulinomas may be found in the ligament of Treitz.

No histologic criteria are available to distinguish benign from malignant insulinomas. Malignant tumors are usually larger (average size 6.2 cm), and a third of them have metastasized to the liver. Insulinoma tumor cells contain less insulin and secretory granules than normal B cells but higher levels of proinsulin. Atypical granules, or even agranular cells, are frequent. The clinical response to diazoxide and somatostatin correlates with the frequency and type of granules.



A recent tumor-node-metastasis (TNM) staging system has not been validated yet for insulinoma tumors. The staging used is similar for exocrine and endocrine tumors of pancreas.

Contributor Information and Disclosures

Zonera Ashraf Ali, MBBS Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center

Zonera Ashraf Ali, MBBS is a member of the following medical societies: American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Jules E Harris, MD, FACP, FRCPC Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD, FACP, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, Central Society for Clinical and Translational Research, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Additional Contributors

Pradyumna D Phatak, MBBS, MD Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute

Pradyumna D Phatak, MBBS, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching.


Klaus Radebold, MD, PhD Former Research Associate, Department of Surgery, Yale University School of Medicine

Disclosure: Nothing to disclose.

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CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).
Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).
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