Insulinomas – A detailed study

Although rare, insulinomas are the most common functioning islet cell tumor of the pancreas. This tumor secretes excessive amounts of insulin. Recognition of the key neuroglycopenic symptoms should trigger the initial investigation. Biochemical proof of endogenous hyperinsulinemic hypoglycemia establishes the diagnosis and helps to rule out other conditions of hypoglycemia. Several options are available for imaging and localizing these tumors including ultrasonography, computed tomography, and intra-arterial calcium stimulation with venous sampling. The tumors are usually small, single, benign, well-circumscribed, and evenly distributed throughout the pancreas. This tumor may be a part of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Surgical treatment is the only curative method. Patients are almost invariably cured lifelong with complete excision of a benign insulinoma.


Insulinoma is a rare clinical entity, however it is the most common pancreatic endocrine neoplasm, secreting excessive insulin with an estimated annual incidence of four cases per million. Most of the insulinomas are benign (90%). Approximately 10% of insulinomas are malignant and metastases are present. 10% of them are multiple, particularly in patients with multiple endocrine neoplasia type 1 (MEN 1). Consideration should be given to screen patient’s family members for this disorder. The male-to-female ratio for insulinomas is 2:3. The age range for peak incidence of insulinoma is between 30 and 60 ,except in insulinoma patients with MEN 1, in whom the median age is the mid 20s In one series, patients with benign disease were younger (mean age of 38 y) than those with metastases (mean age of 52 y). Though, clinically an uncommon disorder, prompt recognition and accurate diagnosis are critical in this often surgically curable disease.


Clinical manifestations

– Insulinomas are characterized clinically by the Whipple triad:

– Episodic hypoglycemia

Central nervous system (CNS) dysfunction related to hypoglycemia (confusion, anxiety, stupor, convulsions, blurred vision, coma), and neurologic abnormalities such as confusion, behavior change, loss of consciousness, blurred vision, and seizures

– Dramatic reversal of CNS abnormalities by glucose administration.

Many subjects report an association between symptoms and meals or activity and stress; others report the symptoms during night time. In malignant tumors the postprandial episodes are frequent.

Biochemical examination

The biochemical diagnosis is established in 95% of patients during prolonged fasting (up to 72 h). This 72-hour supervised fasting study remains the standard diagnostic test of insulinoma in which 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) -Elevated plasma C pepetide levels along with very high insulin levels is diagnostic of insulinoma.

– Proinsulin levels greater than 25% (or up to 90%) that of immunoreactive insulin

– Screening for sulfonylurea negative.(However, current sulphonylurea assays fail to detect the new generation sulphonylureas eg glicazide, glimepiride)

The calculation of ratios of insulin (µU/mL) to plasma glucose (mg/dL) is diagnostic.

– Healthy patients maintain a rate of less than 0.25. Obese patients may have a slightly higher rate.

– In patients with insulinoma, the ratio rises during fasting.

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

Only once the diagnosis has been confirmed biochemically, preoperative localization should be done .The small size of the insulinomas limits its visibility by CT scan or transabdominal ultrasonography. The sensitivities of tumor localization with arteriography, CT, preoperative ultrasonography, MRI, MRI with gadolinium contrast, transhepatic venous sampling, intra-operative palpation of the pancreas and intra-operative ultrasonography were 47%, 24%, 50%, 30%, 40%, 55%, 76% and 91% respectively. Intra-operative ultrasound is more sensitive than pre-operative and other intra-operative techniques for localizing insulinoma. Thus surgery should not be delayed in the patient with negative imaging studies as the best means of tumor localization is with intra-operative ultrasound.

Differential diagnosis

Many other causes can be attributed to the hypoglycemic state. They are as follows.

Inadvertent ingestion of sulfonylurea or insulin: In the former condition, serum insulin and C-peptide levels are elevated and sulfonylurea can be detected in the urine while elevated plasma insulin with a normal to low C-peptide level is seen in hypoglycemic patients, suggestive of factitious use of insulin.

Autoimmune hypoglycemia: A rare disorder characterized by persistent high serum insulin level with normal C peptide levels.

Nesidioblastosis: It is a predominantly neonatal disorder characterised by the hyperplasia of the islet cells causing hyperinsulinemic hypoglycemia. Nowadays, the term has been resurrected to acquired hyperinsulinism with beta cell hyperplasia found in adults, especially after gastrointestinal surgery. Most clinical and biochemical features are identical to those of an insulinoma, except the proinsulin-like component of circulating immunoreactive insulin, which is usually within the normal range .

Noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS): A condition of pancreatic islet hyperplasia which manifests itself with postprandial neuroglycopenia, a negative normal fasting test, negative pancreatic imaging results and positive intra-arterial calcium stimulation of serum insulin.

Other causes of hypoglycemia include liver disease, endocrine deficiencies, extra pancreatic insulin-producing tumors (an insulin-secreting small-cell carcinoma of the cervix recently has been described), Familial persistent hyperinsulinemia and pentamidine-induced hypoglycemia.

Misdiagnosis of insulinoma

Although insulinoma causes hyperinsulimia and hypoglycemia, severe asthenia, profuse diaphoresis and tremors, they also present with neurologic symptoms such as confusion, personality changes, bizarre behavior, amnesia, diplopia, dizziness, irritability, seizures, drowsiness, loss of consciousness, and coma which leads to delayed diagnosis or misdiagnosis as psychiatric conditions or neurological disorders.



Currently the therapy of choice is resection with or without previous octreotide treatment. Care should be taken to achieve total tumor capsule removal to prevent tumor recurrence. If enucleation is not possible, a larger pancreatic resection including pancreaticoduodenectomy may be necessary.

When metastatic insulinoma is found on a patient’s initial presentation (the organ of metastasis being liver and sometimes bone), then total pancreatectomy   is avoided. However, even then surgical excision is often feasible before any medical, chemotherapeutic, or other interventional therapy is considered.

If insulinoma is associated with MEN 1, the management strategy is modified Definite cure by surgery is rare. Subtotal pancreatectomy with enucleation of tumors from the pancreatic head and uncinate processes often is recommended over simple enucleation because of frequent multiple tumors in MEN

Medical Care

Medical therapy is indicated in patients with malignant insulinomas or those who cannot undergo surgery. In malignant insulinomas, dietary therapy with frequent oral feedings or enteral feedings may control mild symptoms of hypoglycemia. A trial of glucagon may be attempted to control hypoglycemia.

-Diazoxide is the main stay of medical therapy and aims at reducing insulin secretion. Adverse effects include sodium retention, a tendency to congestive cardiac failure, and hirsutism.

-Hydrochlorothiazide is often prescribed to counteract the edema and hyperkalemia secondary to diazoxide and to potentate its hyperglycemic effect.

-Of patients with insulinoma, 50% may benefit from the somatostatin analogue octreotide to prevent hypoglycemia. The effect of the therapy depends on the presence of somatostatin receptor subtype 2 on insulinoma tumor cells.

Combination treatment with streptozocin and doxorubicin favored first-line therapy in advanced disease. An open-label prospective trial showed that the addition of interferon alpha to octreotide might prolong survival in a subgroup of patients with metastatic diseases unresponsive to octreotide.


Prognosis in surgically treated insulinomas varies depending on whether the disease is benign, malignant or associated with MEN I. The 10-year survival rate is estimated at 91% and 29% for benign and malignant insulinoma, respectively Relapse is common in MEN I syndrome and malignant insulinoma. After the excision of the tumor, subjects can develop diabetes.

Medico legal Pitfalls

-Monitor blood glucose levels carefully during surgery, especially when the insulinoma is being palpated and manipulated.

-Exclude factitious hypoglycemia before surgery, particularly in patients from the medical profession.

-Screen for MEN 1. When results are positive, the hypercalcemia must be corrected before abdominal surgery is performed.

Recent developments

The most recent developments in this area are the recognition of noninsulinoma pancreatogenous hypoglycemia syndrome as a cause of organic hypoglycemia, and the development of laparoscopic techniques to excise these tumors. . Somatostatin receptor scintigraphy (SRS) has emerged as an easy and noninvasive technique to detect small neuroendocrine tumors and metastases not visualized with conventional imaging methods. Nevertheless, its role in the localization of insulinomas is controversial because SRS has been reported to have a lower detection rate for insulinomas than for other pancreatic endocrine tumors.

Intra-arterial calcium stimulation with pancreatic venous sampling has recently emerged as a very sensitive and specific localization procedure.

In vitro studies have demonstrated that receptors for glucagon-like peptide 1 (GLP-1) are highly over expressed in almost all insulinomas. Therefore, GLP-1-like radioligands retaining high binding affinity to GLP-1 receptors have been developed and indicates that GLP-1–receptor scanning may offer a new diagnostic approach that permits the successful localization of small insulinomas. Since virtually all insulinomas express GLP-1 receptors, it is speculated that the rate of success of such diagnostic scintigraphy will be high.


To summarize, insulinoma is a rare clinical entity. The hallmark of this disorder is fasting hypoglycemia with inappropriately high endogenous insulin concentrations while excluding the presence of insulin secretagogues. Standard preoperative localization procedures including CT, US, and MRI may be negative due to the small size of these lesions; endoscopic US and intra-arterial calcium stimulation test with venous sampling has shown promise to localize tumors not readily seen by other  methods. The diagnosis of neuroglycopoenia should be considered in all the subjects who present common problems such as spells, psychological complaints, and altered memory or seizure disorders. Hyperinsulinemic hypoglycemia is an incapacitating and potentially debilitating condition that is surgically curable. Metastatic insulinoma is a rare disease with an indolent course. Patients with malignant insulinoma should be followed closely, and those not responding to standard therapy should be enrolled in chemotherapy trials.

Key points
-Insulinomas present with hypoglycemia, hyperinsulinemia, elevated C-peptide levels, and a negative urinary sulfonylurea screen.
-Liver is the most common site of metastasis.
-Surgery is the only curative treatment; and palliation can be achieved with octreotide, diazoxide, chemotherapeutic agents.

Author Name:
Dr Aswani garg
About This Author

Post A Reply

Enjoy this blog? Please spread the word :)