Insulinoma Treatment & Management

Updated: May 31, 2020
  • Author: Zonera Ashraf Ali, MBBS; Chief Editor: Neetu Radhakrishnan, MD  more...
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Medical Care

Medical therapy is indicated in patients with malignant insulinomas and in those who will not or cannot undergo surgery. These measures are designed to prevent hypoglycemia and, in patients with malignant tumors, to reduce the tumor burden. 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 related to the thiazide diuretics and reduces insulin secretion. Adverse effects include sodium retention, a tendency to congestive cardiac failure, and hirsutism. Prescribe hydrochlorothiazide to counteract the edema and hyperkalemia secondary to diazoxide and to potentiate its hyperglycemic effect.

Of patients with insulinoma, 50% may benefit from the somatostatin analog octreotide to prevent hypoglycemia. [41] The effect of the therapy depends on the presence of somatostatin receptor subtype 2 on insulinoma tumor cells. Use of the somatostatin analogs lanreotide and pasireotide have also been reported. [2, 42]

As studies have shown, an OctreoScan is not a prerequisite before starting octreotide treatment. In patients with insulinoma and a negative scan finding, somatostatin decreased insulin levels significantly and lowered the incidence of hypoglycemic events. [43]  

Indications for chemotherapy include progressive disease with an increase of greater than 25% of the main tumor masses in a follow-up period of 12 months, or tumor symptoms not treatable with other methods. Combination regimens have achieved better results than single agents.

The current medical treatment choices are those used for any metastatic neuroendocrine gastroenteric pancreatic tumor. Options are as follows:

  • Combination therapy with streptozotocin plus doxorubicin or 5-fluorouracil: Streptozotocin alone may achieve a partial response in 50% of patients and complete response in 20%. The median survival in one study was 16 months. With streptozotocin plus 5-fluorouracil, 33% of patients show complete response, with the median survival increasing to 26 months.
  • Dacarbazine- and temozolomide-based regimens: There appears to be a correlation between expression of methylguanine DNA methyltransferase (MGMT) and temozolomide responsiveness in advanced neuroendocrine tumors. MGMT is an enzyme that is responsible for DNA repair induced by alkylating agent chemotherapy.

  • Molecularly targeted therapy: This includes vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib, sorafenib, pazopanib, or cabozantinib.

  • Mammalian target of rapamycin (mTOr) inhibitors: Everolimus, with or without octreotide

  • Peptide receptor radioligand therapy: In January 2018, the US Food & Drug Administration approved lutetium [177Lu] oxodotreotide (Lutathera) for the treatment of patients with somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors. Approval was based on results of the phase III NETTER-1 trial [44, 45]

The mTOR inhibitor everolimus is approved for treatment of locally advanced or metastatic neuroendocrine tumors of pancreatic origin. In a French study, everolimus therapy normalized blood glucose levels in 11 of 12 patients with metastatic insulinoma and refractory hypoglycemia, with the therapeutic effect maintained for a median duration of 6.5 months (range 1-35+ months). However, three patients discontinued everolimus because of cardiac and/or pulmonary adverse events, which led to two deaths. [46]  

Off-label use of other agents has been described in case reports. [47, 48] Pasireotide, a novel multireceptor somatostatin analogue, has been used for treatment of refractory hypoglycemia in malignant insulinoma. The multitargeted receptor tyrosine kinase inhibitor sunitinib has been used; sunitinib has antiangiogenic and antitumor activity, but does not appear to have a direct action on glycemic control, and indeed may worsen hypoglycemia. [48]


Ablation is a nonsurgical option that has had some long-term success. CT-guided radiofrequency ablation has been used successfully to treat insulinoma in an elderly patient whose hypoglycemia that was refractory to diazoxide, and who was not a candidate for surgery because of comorbidities and poor physical condition. [49] In addition to radiofrequency ablation, successful results have been attained with embolization and with ethanol, among other techniques. [50, 51]


Surgical Care

Because insulinoma resection achieves cure in 90% of patients, it is currently the therapy of choice. Enucleation is the preferred technique.

Preoperative management

Preoperative management is as follows:

  • Administer diazoxide on the day of surgery in patients who respond to it. Diazoxide reduces the need for glucose supplements and the risk of hypoglycemia.

  • Monitor blood glucose level throughout surgery.

  • Infuse 10% dextrose in water at a rate of at least 100 mL/h.

  • A preoperative trial with diazoxide is indicated to determine whether the patient is a responder (5-10% of patients do not respond); the trial results help determine the intraoperative strategy if the tumor is not localized.

  • In patients with multiple endocrine neoplasia type 1 (MEN 1), hypercalcemia must be corrected first by parathyroidectomy before insulinoma resection. [52]

Tumor location

If an open procedure is selected, fully expose the pancreas, including a wide Kocher maneuver to allow complete bimanual palpation.

Compared with open procedures, laparoscopy has been found to permit equivalent oncologic resection, along with decreased postoperative pain, better cosmetic results, shorter hospital stay, and a shorter postoperative recovery period. [53] A large study from Spain showed laparoscopic surgery to be safe and effective in benign and malignant tumor resection. [8]

Laparoscopic enucleation techniques, also in combination with preservation of the spleen for distal pancreatic tumors, have been described. [54] Because of the small likelihood that a tumor that presents without metastatic spread is malignant, insulinomas may be removed by enucleation. [55] 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. This should only rarely be required. When metastatic insulinoma is found on a patient's initial presentation, the organ spread is to liver and sometimes to bone.

Other surgical considerations are as follows:

  • Avoid total pancreatectomy because of its high morbidity and mortality rates.

  • Major resections, such as the Whipple procedure, may become necessary when the tumor is found in the pancreatic head and local excision is not possible.

  • Resect all gross disease when multiple tumors or metastases are present.

  • If insulinoma is associated with type 1 multiple endocrine neoplasia (MEN 1), the management strategy is modified because tumors are often multiple, diffusely spread in the pancreas, and of small size. Definite cure by surgery is rare.

  • Subtotal pancreatectomy with enucleation of tumors from the pancreatic head and uncinate processus often is recommended over simple enucleation because of frequent multiple tumors in MEN 1.

  • Intraoperative serum insulin measurements have been employed to ensure complete tumor removal. This may be important, particularly in patients with MEN 1 who harbor multiple insulinomas.

Metastatic disease

Insulinomas are found to be metastatic at surgery in about 5-10% of patients. It would be extremely uncommon for metastases to develop in a case in which only a solitary lesion was found on initial presentation.

Patients who are responsive to diazoxide should be continued on it while more invasive imaging studies are performed, before repetitive surgery is considered. If the patient is not responsive (5-10%) or if drug intolerance is present and ectopic disease is excluded, a blind distal two-thirds pancreatectomy may be performed. However, this procedure has only a 25% success rate.

Most authorities recommend serial sectioning during resection. Tumors that are not found at surgery normally are located in the pancreatic head (54%), body (20%), and tail (14%).

Even when metastases are found, surgical excision is often feasible before any medical, chemotherapeutic, or other interventional therapy is considered. Resect all gross disease, including wedge resections of hepatic metastases. Avoid ligation of the hepatic artery in case further regional infusion therapy becomes necessary.



Consult with the anesthetist to plan for precise preoperative and intraoperative blood glucose monitoring. The approach should be multidisciplinary, with an endocrinologist, surgeon, and anesthesiologist.


Diet and Activity

Considerations include the following:

  • Because insulin secretion by most insulinomas is not responsive to glucose levels, carbohydrate feedings every 2-3 hours can help maintain euglycemia, although obesity may develop.
  • Glucagon should be available for emergency use.
  • Exercise may aggravate hypoglycemia in patients with insulinoma.