Islet amyloid polypeptide/amylin messenger RNA and protein expression in human insulinomas in relation to amyloid formation.
OBJECTIVE
Islet amyloid polypeptide (IAPP), also named amylin, is the predominant protein component of amyloid deposits in human islet beta cell tumours of the pancreas (insulinomas). IAPP is co-produced with insulin by islet beta cells. We investigated IAPP expression in relation to insulin expression and to amyloid formation in eleven insulinomas.


METHODS
RNA and protein extracts were prepared from the same pieces of tumour tissue, and from specimens of two normal human pancreata. IAPP and insulin mRNA and peptide content were quantified using Northern blot analysis and radioimmunoassay (RIA) respectively. Molecular forms of IAPP immunoreactivity were analysed by reversed-phase high-performance liquid chromatography (HPLC). The presence of islet hormones and of amyloid was assessed by (immuno)histochemical staining of paraffin sections. Plasma levels of IAPP and insulin prior to tumour resection were determined by RIA.


RESULTS
IAPP and insulin mRNA and peptide content varied widely between the tumour specimens, and there was considerable intratumour heterogeneity of peptide content. HPLC analysis indicated correct proteolytic processing of the IAPP precursor protein. Amyloid deposits were detected only in the three tumours with the highest IAPP content. In contrast to insulin, plasma levels of IAPP were not elevated in the insulinoma patients.


CONCLUSIONS
The spectrum of hormone production by insulinomas cannot be inferred from only a few tissue sections due to intratumour heterogeneity. Expression of the IAPP and insulin genes is not coupled in insulinomas, which produce properly processed mature IAPP. In addition to IAPP overproduction, additional factors such as intracellular accumulation of IAPP are involved in amyloidogenesis in insulinomas.
Department of Internal Medicine, University Hospital Utrecht, The Netherlands.
K L
KL
van Hulst
C
C
Oosterwijk
W
W
Born
T M
TM
Vroom
M G
MG
Nieuwenhuis
M A
MA
Blankenstein
C J
CJ
Lips
J A
JA
Fischer
J W
JW
Höppener
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D053379:Chromogranin A; D002864:Chromogranins / Q000032:analysis; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis / Q000235:genetics; D007340:Insulinoma / Q000378:metabolism* / Q000473:pathology; D058228:Islet Amyloid Polypeptide; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis*
D000682:Amyloid; D053379:Chromogranin A; D002864:Chromogranins; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D011498:Protein Precursors; D012333:RNA, Messenger