Pro Islet Amyloid Polypeptide (ProIAPP) Immunoreactivity in the Islets of Langerhans

Abstract

Islet amyloid is typically found in type 2 diabetes mellitus and is believed to participate in the beta cell deterioration. The islet amyloid fibril consists of the 37-amino-acid islet amyloid polypeptide (IAPP) but its pathogenesis is only partly understood. We developed several different rabbit antisera against the flanking peptides of the IAPP precursor (proIAPP) and the proIAPP processing sites in order to study the possible occurrence of unprocessed proIAPP or parts thereof in islet amyloid. We applied these antisera in an immunohistochemical study on islet amyloid deposits present in a newly generated mouse strain that over-expresses human IAPP but is devoid of mouse IAPP. Male mice of this strain develop severe islet amyloidosis when given a high fat diet. Generally, the antisera showed no immunoreactivity with the amyloid. However, in scattered single beta cells, where amyloid could be seen intracellularly, immunoreactivity with one or more of the antisera colocalized with the amyloid. Although virtually all amyloid in human islets of Langerhans is found extracellularly, we propose that the initial amyloid formation occurs intracellularly, perhaps by not fully processed or folded (pro)IAPP. This amyloid, which may develop rapidly under certain circumstances, probably leads to cell death. If not degraded these amyloid spots may then act as nidus for further amyloid formation from fully processed IAPP, secreted from surrounding beta cells.

Dietary fat modulation of apoA-II metabolism and prevention of senile amyloidosis in the senescence- accelerated mouse

“…A fish oil diet may modify the prostaglandin profile of macrophages and may change cellular immune function and/or enhance the processing of serum amyloid A (18). A high-fat diet has been associated with the development of severe islet amyloidosis in mice (43). We evaluated whether AA amyloid protein could serve as a nidus for the deposition of AApoAII fibrils; however, we did not identify serum amyloid A protein in SAMP1 mice fed the three dietary fats in this study or detect AA amyloid deposition associated with AApoAII deposition in their organs.…”

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

“…In T2DM [71] and in patients with insulinoma (both conditions associated with amyloid) there is increased secretion of incompletely processed proinsulin, [72,73]. Islet studies in vitro indicate increased production of N-terminal intact proIAPP under stimulated secretory conditions [74] and immunoreactivity for the N-terminal peptide of proIAPP has been identified in islet amyloid deposits in insulinomas and T2DM [75]. N-terminal intact proIAPP has been identified in a PC2 knockout, hIAPP transgenic mouse model [76].…”

Formation of amyloid in human pancreatic islets transplanted to the liver and spleen of nude mice

“…Deposition of islet amyloid is the most consistent morphological alteration found present in type 2 diabetes and is seen, to some degree, in the pancreas in more than 95% of individuals with this disease (1). Although islet amyloid was described more than 100 years ago (2,3), its possible importance for the development of diabetes has only recently become accepted.…”

“…First, individuals who have failed on oral antidiabetic drugs have a more severe islet amyloidosis than those who respond well to these drugs (1,14). Second, in a spontaneous monkey form of diabetes, islet amyloid develops before diabetes becomes manifest (15).…”