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Definition	- 2nd frequent NET of pancreas with inadaequate insulin-(proinsulin) secretion - first described as Langerhans - adenoma: Nichols 1902 (J Med Res) + Warren 1926 (Am J Pathol) : ass "Insulinoma": Wilder et al 1927 (JAMA)
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Incidence	1 - 4 per 1 Mill. / year more frequent in women > men / median age > 50 years
Pathology - Pathophysiology	Insulin secretion: inadaequately elevated during hypoglycemia ( < 40 mg/dl) as a cause of predominantly neuroglycopenic (neurological) symptoms due to a shortage of glucose supply in the brain, in addition a variety of unspecific adrenergical warning symptoms through activation of the sympathetic adrenergic nervous system (epinephrine) - mostly small and benign tumors (1-2 cm), evenly distributed over the entire pancreatic organ (extrapancreatic localization an absolute rarity - tumors may protrude from the pancreas), often localized in the processus uncinatus - malignant tumors often identified only on the basis of metastases, more frequent larger tumors (but also < 1 cm ! ), metastases in local lymph nodes and liver, suspicverdächtig bei jahrelanger Anamnese, Tendenz steigend (10 - < 20 %)
Clinical	typical clinical syndrome 1. Whipple Trias - biochemical hypoglycemia (blood glucose <50 mg/dl) - simultaneous compatible adrenergic and/or neurological symptoms - amelioration of symptoms after carbohydrate intake 2. adrenergic unspecific symptoms and / or 3. neurological (=neuroglucopenic) symptoms frequent-symptoms: dizziness, disturbance or loss of consciousness, weight gain, sweating, seizures
Diagnosis	Test: standardized fasting test, start in the morning, preferentially after oral intake of 100 g of gluocse. ! Interpretation of fasting tests requires knowledge of normal limits pointing towards or against an insulinoma diagnosis (not to be confused with "normal values for insulin" - these require a simultaneous normal blood glucose level) Laboratory: insufficiently suppressed insulin secretion at reproducible ( ! ) biochemical hypoglycemia ( < 40 mg/dl ) - laboratory method ! no"test strip" ! blood glucose Insulin Proinsulin C-Peptide < 40 mg/dl > 6 µU/ml or > 36 pmol/l > 10 pmol/l > 0.6 ng/ml or > 200 pmol/l !! beware of "specific" insulin assays: these might miss frequently or singularly elevated proinsulin concentrations !!
Therapy-Strategies	always surgical resection (also in case of rare "malignant" insulinoma if possible), danger of malignant transformation if usual benign tumors are left, no safe symptomatic therapy available Symptoms : Glucose or rapidly absorbed carbohydrates intravenously or orally Somatostatin subcutaneously: frequently unsuccessful - many insulinomas do not express the necessary somatostatin receptors in contrast to other GEP-NETs, paradox aggravation of hypoglycemia possible due to inhibiton of glucagon Diazoxide: due to severe side effects no alternative treatment for longer periods
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