Islet amyloid polypeptide/amylin messenger RNA and protein expression in human insulinomas in relation to amyloid formation

Abstract

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

Giant Insulinoma: Case Report and Review of the Literature

“…Amyloid deposits have been demonstrated in more than 50% of insulinomas, but not to the extent present in our patient's tumor (12,13). The major component of the amyloid of an insulinoma is a 37-amino acid polypeptide known as islet amyloid polypeptide or amylin.…”

“…The major component of the amyloid of an insulinoma is a 37-amino acid polypeptide known as islet amyloid polypeptide or amylin. Islet amyloid polypeptide has been observed within the tumor cells and the stroma surrounding the islet cells of patients with an insulinoma as well as in the stroma surrounding the islet cells of patients with insulinomas and patients with type II diabetes mellitus (12,13). Overexpression of islet amyloid polypeptide, with aberrant processing and secretion by abnormal ␤-cells of the insulinoma, is postulated to be the cause of amyloidogenesis (13).…”

Extensive islet amyloid formation is induced by development of Type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model

“…This notion is supported by the findings that 1) islet amyloid was detected only in hIAPP transgenic mice from line No18, with higher plasma IAPP concentrations than mice from line No14; 2) islet amyloid developed mainly in homozygous transgenic mice [19]; 3) among the ob/ob mice, there was a positive correlation between the degree of amyloid deposition (Amyloid Index at t3) and the plasma IAPP concentrations at t1 and t2; 4) hIAPP amyloid develops in approximately 50 % of human beta-cell tumours (insulinomas), which overproduce IAPP in addition to insulin [24], i. e. in patients who are hypoglycaemic rather than hyperglycaemic. Amyloid is detected particularly in those insulinomas which have a high IAPP content [25]. Although these data strongly indicate that high hIAPP production rather than hyperglycaemia as such is an amyloidogenic factor, it cannot be excluded that the diabetic state might enhance islet amyloid deposition.…”

High plasma amylin/islet amyloid polypeptide levels in patients with residual medullary thyroid carcinoma after total thyroidectomy

“…It has been suggested that in those cases IAPP is probably retained in tumour cells and not secreted (16). In addition, although IAPP mRNA has been found in the gastrointestinal tract, dorsal root ganglia, and lung (17), circulating IAPP levels were not increased in patients with gastrointestinal tumours, where the peptide was detected in the respective tissues using immunohistochemistry (14).…”