Abnormalities of proinsulin processing in functioning insulinomas: clinical implications.
OBJECTIVE
Abnormal proinsulin processing in insulinomas may result in secretory granules containing both insulin and proinsulin, a finding not encountered in healthy beta-cells. The aim of this study was to test whether such abnormalities in the proinsulin to insulin conversion have clinical implications in patients with hypoglycaemic disorders.


METHODS
Case-series.


METHODS
Fifteen patients with histologically confirmed insulinoma and two patients with islet cell hyperplasia were included. The immunohistochemical distribution pattern of proinsulin within the tumour cells was classified as Golgi pattern (predominantly perinuclear immunolabelling) or diffuse pattern (immunolabelling in the periphery of the cells, indicating the presence of proinsulin in secretory granules). Data obtained from the 72-h fast and arterial calcium stimulation and hepatic venous sampling (ASVS) test were related to the morphological classification.


RESULTS
Six insulinomas exhibited a diffuse proinsulin distribution pattern, while nine insulinomas and two islet cell hyperplasias disclosed a Golgi pattern. Median proinsulin concentrations at the termination of the fast tended to be higher in patients with the diffuse proinsulin distribution pattern than in patients with the Golgi pattern (86.9 vs. 18.8 pmol/l, P = 0.07). Higher insulin (P < 0.005) and proinsulin (P < 0.05) concentrations were significantly correlated with earlier occurrence of hypoglycaemia during the prolonged fast. During the ASVS test, tumours with the diffuse proinsulin distribution pattern exhibited a higher increase in both insulin (median, 37.3- vs. 10.5-fold, P < 0.05) and proinsulin (6.3- vs. 1.6 fold, P < 0.005) concentrations following calcium stimulation than the tumours with the Golgi pattern.


CONCLUSIONS
Abnormalities in the proinsulin to insulin conversion in patients with insulinomas and islet cell hyperplasia correlate with impaired regulation of both insulin and proinsulin secretion during the prolonged fast as well as the ASVS test.
Department of Internal Medicine, Division of Endocrinology and Diabetes, Institute for Diagnostic Radiology, University Hospital of Zurich, Switzerland. peter.wiesli@DIM.usz.ch
Peter
P
Wiesli
Aurel
A
Perren
Parvin
P
Saremaslani
Thomas
T
Pfammatter
Giatgen A
GA
Spinas
Christoph
C
Schmid
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium; D005215:Fasting; D005260:Female; D006499:Hepatic Artery; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism* / Q000601:surgery; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000601:surgery; D011384:Proinsulin / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism
D007328:Insulin; D011384:Proinsulin; D002118:Calcium