Insulinoma

"endogenous hyperinsulinism"
"organic hyperinsulinism, autonomous inadaequate hyperinsulinemia"


 

Insulin Secretion 

Physiological range of insulin secretion and concentration

The physiological insulin secretion (suppression) and thus insulin levels in serum by means of complex regulatory mechanisms of glucose homoeostasis effectively prevent fasting or spontaneous hypoglycemia, e.g. the lowering of blood glucose concentrations below the critical level of 50 mg/dL, required for "normal" function of the central nervous system, the brain.

This minimal concentration of blood glucose is required by the brain in order to meet energetic and caloric needs consuming an hourly average of 6 grams of glucose.
Between meals insulin levels demonstrate a highly variable sharp rise of short duration (30 to 60 minutes postprandially) dependent upon the amount and quality of carbohydrates consumed. A concentration range of 50 - 100 µU/mL (300 - 600 pmol/L) is regularly found, thus insulin belongs to the few hormones demonstrating a physiological range of concentrations by a factor of 20-30.
In parallel the blood glucose concentration fluctuates between 60 mg/dL and 180 mg/dL maximally (3.3 - 10 mM) clearly dependent upon the highly variable individual insulin sensitivity.

 

Normal suppression of insulin secretion

Adaequate suppression of insulin secretion during prolonged fasting is achieved when the insulin concentration in serum samples drops below 5 µU/mL ( < 30 pmol/L ) during normal blood glucose levels in the range of 50 mg/dL.

In case of adaequate suppression of insulin secretion the concentration of proinsulin should be measured in the range of a few pmol/l close to the detection limit: < 5 pmol/l

Adaequate suppression of the C-peptide concentration is achieved with parallel levels < 0.6 ng/ml
(= < 0.2 nmol/l or < 200 pmol/l)

If the blood glucose concentration during assured fasting (positive acetonuria) definitely is > 50 mg/dL (55-70 mg/dL), the insulin levels may be higher than 5 µU/mL (6-10 µU/mL / 36-60 pmol/L).

If the blood glucose concentration is found in the range of 40-45 mg/dL, insulin levels
should be < 3 µU/mL (< 18 pmol/L).

For a long time the above mentioned ranges were equivalent with the lower limit of detection estimated by means of commercially available radioimmunoassays and non-radioactive elisa`s (enzyme-linked immunosorbent assay).
Insulin levels < 3 µU/mL physiologically represent suppressed zero values (no detectable insulin concentration) despite development of very sensitive assays which lowered the detection limit into the range below 1 µU/mL. Such an "accuracy" is unnecessary and without consequences in the diagnosis of hypoglycemia.

 

Pathological suppression of insulin secretion

Patients with an insulinoma demonstrate a lack of the physiological and adaequate suppression of insulin concentrations after meals when blood glucose is falling to basal pre-meal levels.

Starting off with suspiciously low or lower than normal fasting blood glucose levels in the range of 50 to 60 mg/dL (or even below) the ingestion of pure glucose or dextrose (100 grams orally) normally results in regular early postprandial insulin secretion dependent upon the secretory behaviour of the normal endocrine pancreatic tissue mass.
Principally a tendency towards slightly impaired glucose tolerance is seen, which is due to the physiological attenuation of insulin sensitivity in patients adapted to chronically reduced blood glucose levels.
During the late postprandial phase ( 3 to 15 hours after glucose ingestion) inadaequate suppression of insulin secretion will result in hypoglycemia, which is regularly found in patients with an insulinoma with reproducible low blood glucose concentrations below 40 mg/dL (< 2.2 mmol/L).
Hypoglycemia sometimes occurs as late as 24-30 hours after the last meal, rarely in 2-3% of the patients as late as more than 48 hours. Thus, claims to reduce the duration of fasting tests from 72 to 48 hours would result in a loss of diagnostic accuracy.

Insulin concentrations > 6 µU/mL ( > 36 pmol/L) have to be considered as pathologically elevated if the simultaneous blood glucose concentration is < 40 mg/dL (< 2.2 mmol/L). This reflected by simultaneously elevated proinsulin concentrations of > 5 - 10 pmol/L, and C-peptide concentrations > 200 pmolL = > 0.6 ng/ml.

However, concentrations 10 to 25 times higher within the range of 60 - 150 µU/mL (360 - 900 pmol/L) may be measured.

These ranges are meant to resemble the total insulin concentration including crossreacting proinsulin as measured with an unspecific insulin assay.
Normative values for the level of insulin concentrations during a combined OGTT - fasting test do not exist in insulinoma.

Increased stimulation of insulin secretion as a consequence of glucose ingestion does not occur in insulinoma. Afraid of such a reaction the initial administration of glucose often is omitted from the test procedure, thus fasting tests are started in patients already fasting overnight for 10-12 hours without representative and diagnostic samples being drawn. This might lead to a premature discontinuation of the fasting test and difficult interpretation of a few available samples.

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