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Pancreatic neuroendocrine tumors: insulinoma

What is an insulinoma?

An insulinoma is a tumor, usually benign (non-cancerous), made up of specialized beta islet cells (see below) that constantly secrete insulin, causing hypoglycemia (low blood glucose–sugar). Normally, as the glucose rises with eating, the pancreas responds by secreting more insulin, which in turn helps utilize or store the glucose and its blood level drops back down into a safe range. Subsequently, as the glucose level continues to fall toward the lower limit of normal (normal, 60-100mg/dL), the secretion of insulin (by the normal beta cells in the pancreas) stops, and this allows the glucose to remain in the normal range. This type of feedback regulation is the hallmark of endocrine organs (thyroid, parathyroid, endocrine part of the pancreas, pituitary, gonad, and adrenal glands that secrete specific hormones). When an insulinoma is present, insulin regulation is abnormal such that the tumor continues to secrete insulin even though the glucose level may fall to a dangerously low level. Even though insulinoma is the most common pancreatic islet cell tumor, it is very rare, occurring in only 3-4 per million people. Except in very rare familial (occurring in families, transmitted genetically from parent to child) situations, the exact cause is unknown.

Pancreatic neuroendocrine tumors: Actual insulinoma cut in half
Figure 1: Actual insulinoma cut in half, measuring slightly larger than 1 cm (about 1/2 inch).

The average age to develop an insulinoma is the mid-40s (range, 10-82 years), and occurs slightly more frequently in females than males. Most are sporadic (occurring "out of the blue" with no known cause) with about 10% occurring as part of the Multiple Endocrine Neoplasia type 1 (MEN 1) syndrome. At least 90% have single, benign, small (less than 2 cm – 3/4 of an inch) tumors (Figure 1). Hypoglycemic symptoms are experienced by virtually all patients with insulinoma and can be grouped into 2 categories: neurologic (nervous system) and adrenergic (secretion of adrenalin from the adrenal gland). Because the brain requires glucose for normal function, a glucose level below 50 mg/dL often results in abnormal brain-related symptoms (neuroglycopenia, Table 1). When the glucose level drops to about 55 mg/dL, this also triggers release of adrenaline by the adrenal glands with resultant adrenergic symptoms (Table 1). While adrenaline may raise the glucose level in normal patients with modestly low glucose levels, it is insufficient to overcome the effect of the continuously secreted insulin by insulinomas. The patient must be rescued from the hypoglycemia by administration of glucose in some form-often taking sugar-containing food or drinks, or intravenous glucose injection (sometimes by emergency medical technicians!).

Historically, the three components of 1) symptoms of hypoglycemia, 2) documented plasma glucose of less than 50 mg/dL at the time of hypoglycemic symptoms, and 3) relief of these symptoms with administration of glucose has been referred to as Whipple's triad. It remains an excellent starting point for establishing a diagnosis of insulinoma.

Diplopia (double vision)Weakness, warmth
Blurred visionSweating
Confusion, Abnormal behaviorHunger
Amnesia to Symptoms, EventsTremor
SeizuresPalpations (heart pounding)
Loss of consciousnessTachycardia (heart racing)
Table 1. Insulinoma Symptoms

The most common cause of non-insulinoma patient with both low glucose and high insulin is mistakenly taken medication. This typically occurs when 2 people living together get their medications mixed up.
Figure 2: Commonly used medications may appear extremely similar
A. Chlorpropamide (Tolinase™); used in type 2 diabetics to stimulate insulin release from the pancreas to lower blood sugar
B. Metoprolol (Lopressor™) 100 mg tablet, used for blood pressure regulation
C. Tolbutamide (Orinase™), used in type 2 diabetics to stimulate insulin release from the pancreas to lower blood sugar.
D. Metoprolol (Lopressor™) 50 mg tablet, used for blood pressure regulation

Because isolated low levels of either glucose or insulin are not sufficient for the diagnosis of insulinoma, and because the symptoms may be profound and dangerous, the standard method to establish the diagnosis is a supervised fast. This may require hospitalization and fasting rarely needing up to 72 hours (the so-called 72-hour fast). Many times, however, it can be performed as an outpatient if the patient is under careful supervision. With the patient fasting, an IV is inserted, the patient is allowed to drink water and non-caffeine containing drinks. At scheduled intervals and whenever the patient develops the onset of hypoglycemic symptoms, the glucose is checked. When the glucose drops to 50 or below by capillary methods (finger-stick sample—reflectance meter glucose, RMG), a standard venous blood sample is taken (Table 2). When insulin is secreted from the pancreas into the bloodstream, it is broken into 2 components: insulin and C-peptide (connecting peptide, which does not have any clinical effect). Both of these are measured to be sure the insulin is coming from the patient, not from an insulin injection (which does not contain C-peptide). In addition, a blood sample is sent to screen for the presence of drugs that might cause release of insulin from a normal pancreas, to be sure this type of drug (typically sulfonylurea drugs used in the management of diabetes) is not responsible for the low glucose. The most common cause of non-insulinoma patient with both low glucose and high insulin is mistakenly taken medication. This typically occurs when 2 people living together get their medications mixed up (Figure 2). Because measuring insulin in the blood can be difficult, other laboratory studies can also be obtained that indicate high levels of insulin (insulin surrogates). An increase in the glucose level of over 25 mg/dL when glucagon is given IV at the end of the fast when the glucose is low, and a low beta-hydroxybutyrate level are both indicators of high insulin levels with low glucose. Some investigators have noted an insulin to glucose ratio of greater than 0.4 to be helpful. Perhaps most important is to recognize that with a glucose level below 50, no measurable insulin should be present in the bloodstream in a normal individual.

Criteria—Simultaneous blood sample
  1. Blood glucose level at or below 45 mg/dL
  2. Insulin level equal or greater than 3 µU/ml (ICMA technique)
  3. C-peptide levels of 200 pmol/L or more
  4. Absence of sulfonylurea-class drugs in plasma
Table 2. Criteria for Diagnosis of Insulinoma

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