Insulinoma is a rare neuroendocrine tumor with an incidence of 4 cases per million per year. It is more commonly seen in individuals 40-50 years old and in females (~ 60%). It is the most common functioning pancreatic neuroendocrine tumor and is typically solitary and small (less than 2 cm in diameter). It is generally well circumscribed, benign and may occur in any part of the pancreas. The usual presenting feature is hypoglycemia, classically in the fasting state although sometimes postprandially. The symptoms of hypoglycemia frequently differ from the classic neurogenic pattern of tachycardia, faintness and sweating. Atypical symptoms of hypoglycemia may for example include personality change or bizarre behavior resulting in referral to a psychiatrist. The first and most important step in diagnosis is to consider the possibility of insulinoma. Inappropriately raised insulin levels in the presence of fasting hypoglycemia is an important initial clue, and may be confirmed by eliciting Whipple's triad in the course of a controlled fast. The triad is hypoglycemia associated with symptoms typical for the patient and relieved by glucose; relative hyperinsulinemia can usefully be added to these. Localization is sometimes difficult, and treatment is by surgical resection or medical management where this proves impractical.
The diagnosis of hypoglycemia is confirmed when the venous glucose is less than 3 mmol/l and symptoms present consistent with Whipple's triad. These are signs and symptoms, as experienced by the patient and consistent with low blood glucose, low plasma glucose concentration and resolution of signs and symptoms after the glucose is increased.  
Signs and Symptoms
In most cases, signs and symptoms related to insulinoma or inappropriate secretion of insulin are present in the fasting state. Rarely, presentation can be in a postprandial or mixed fasting and postprandial state.  Symptoms can be neurogenic in nature such as: hunger, sweating, parethesias, palpitations, anxiety and tremors. They can also be neuroglycopenic along a wide range which includes: confusion, visual disturbances, behavioral changes, seizures or epileptic like movements, confusion or frank coma. 
Due to the non-specific nature and presentation of signs and symptoms, diagnosis may be difficulty and delayed for several months or years. In some cases, the patient may be diagnosed with a neuropsychiatric or neurologic etiology. 
- Symptoms known or likely to be caused by hypoglycemia especially after fasting or heavy exercise
- A low plasma glucose measured at the time of the symptoms
- Relief of symptoms when the glucose is raised to normal
The above Triad must be confirmed by biochemical studies:
- Fast glucose less than 3.o mmol/l (< 55 mg/dl);
- Insulin levels greater than 18 pmol/l (>3 mcgU/ml);
- C-peptide greater than 0.2 nmol/l (>0.6 ng/ml);
- Beta hydroxybuterate levels less than 2.7 mmol/l;
- Change in blood glucose greater than 1.4 mmol/l (> 25 mg/dl) after 1 mg glucagon IV;
- Negative sulfonylurea screen;
- Negative insulin antibody studies.
If symptoms are non diagnostic, but clinical evidence points towards diagnosis of insulinoma, a supervised 72 hour fast should be considered in the attempt to induce hypoglycemia.
It is important to consider the possibility of factitious hypoglycemia, and there are several examples of this in the literature. Suspicion may be raised if there is no evidence of an anatomical lesion, especially if the patient is connected to the medical profession or has access to glucose-lowering medication. C-peptide measurement distinguishes between endogenous and exogenous insulin (the latter contains no C-peptide), and plasma chromatography can detect ingested sulfonylureas.
MRI of Pancreas demonstrating insulinoma with both T1 weighted and T2 weighted images
 Localization of the neoplasm or tumor can by accomplished via conventional imaging such as CT scan, Ultrasound or MRI. MRI at present, may be the radiological procedure of choice. It is non-invasive, rapid and can facilitate the detection of metastatic disease. Insulinomas generally have low signal intensity on T1 weighted imaging and high signal intensity on T2 weighted imaging.
Invasive techniques include endoscopic ultrasound (EUS), intra-arterial calcium stimulation with hepatic vein sampling (associated with or without angiography) and arterial stimulation venous sampling (ASVS).
Management of Insulinomas
Surgery is the procedure of choice for all localized tumors. The decision regarding which approach will be considered is dependent on various factors: features of the tumor, size, cell type, localized vs. diffuse.
Various techniques include enucleation, partial pancreatectomy, total pancreatectomy or laparoscopic approach. Laparoscopic resection has been, in the past, performed for smaller, probable benign tumors located in the body or tail of the pancreas. Radical resection in generally the procedure of choice in those individuals with larger (>3-4 cm) tumors, not well encapsulated, those with multiple tumors and tumors which involve or are near the pancreatic duct. 
Though surgery is generally the treatment of initial choice in patients with insulinomas, medical treatment is appropriate in the preoperative state to attempt to normalize blood glucoses, also for those who cannot be cured with surgery or have contraindications to surgery and those who refuse surgical intervention.
Earlier attempts utilizing diazoxide and calcium channel blockers have had limited success. Somatostatin analogs such as Octreotide and mTOR inhibitors sucah as Temsirolimus and Everolimus have demonstrated efficacy in controlling hypoglycemic and reducing tumor burden. 
The use of CGM (Continuous Glucose Monitoring) has been considered in patients to detect and monitor hypoglycemia, assess response to various chemotherapeutic and medical treatments and to confirm a "cure" from surgical intervention. Several studies have reported that CGM is a useful addition to the therapeutic regimen in order to prevent hypoglycemia. It allows patient to respond promptly to hypoglycemia and institute appropriate treatment.
Insulinomas are the most common neuroendocrine tumors of the pancreas. Most are benign, small and respond to surgical intervention for possible cure. Those that are not operable, malignant or aggressive in etiology may respond to a combination of treatment modalities.
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