Islet Amyloid Develops Diffusely Throughout the Pancreas Before Becoming Severe and Replacing Endocrine Cells

Abstract

Islet amyloid occurs in >90% of type 2 diabetic patients and may play a role in the pathogenesis of this disease. To determine whether islet amyloid occurs diffusely throughout the pancreas, whether it affects islets equally, and whether it decreases islet endocrine cells, we characterized islet amyloidosis by computerized fluorescence microscopy in transgenic mice that develop typical islet amyloid. These mice produce the unique amyloidogenic component of human islet amyloid, human islet amyloid polypeptide (hIAPP). The prevalence of amyloid (number of islets containing amyloid/total number of islets ؋ 100) and the severity of amyloid (⌺amyloid area/⌺islet area ؋ 100) were found to be uniform throughout the pancreas. Furthermore, a high prevalence of amyloid was observed in islets when the severity of amyloid was only 1.5% of the islet area, suggesting a diffuse distribution of amyloid from the very early stages of islet amyloidosis. In 12 hIAPP transgenic mice with an amyloid severity of 9.6 ؎ 3.4%, the proportion of islets composed of ␤-and ␦-cells was reduced in the transgenic mice compared with 6 nontransgenic mice that do not develop amyloid (␤-cells: 62.9 ؎ 3.1% vs. 75.5 ؎ 0.9%, P ‫؍‬ 0.02; ␦-cells: 2.8 ؎ 0.5% vs. 4.4 ؎ 0.4%, P ‫؍‬ 0.05), whereas the proportion of islets composed of ␣-cells did not significantly differ between the two groups of mice. In the individual islets in these transgenic mice, amyloid severity was inversely correlated with ␤-cell, (r ‫؍‬ ؊0.59, P < 0.0001), ␣-cell (r ‫؍‬ ؊0.32, P < 0.0001), and ␦-cell (r ‫؍‬ ؊0.25, P < 0.0001) areas. In conclusion, islet amyloidosis occurs uniformly throughout the pancreas, affecting all islets before becoming severe. A reduction in islet endocrine mass starts at this early stage of islet amyloid development and progresses as amyloid mass increases.

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

“…However, very small perivascular deposits, whilst not apparently cytotoxic, could compromise transfer of nutrients and insulin across the pericapillary space in affected islets and contribute to glucose intolerance in these models. As the deposition progresses more islets become affected (increased islet prevalence) and when most islets are affected there is a substantial increase in severity (larger deposits in islets); careful measurements in transgenic mice have shown that a prevalence of 80% was associated with 1.5% of islet space occupied by amyloid [114]. Using similar calculations, a similar progressive relationship between prevalence and severity has been identified in Macaca mulatta islets (Fig.…”

“…6). Similarly, hIAPP TM possessing moderate islet replacement with amyloid (~10% islet mass filled with amyloid and 100% islets affected) did not exhibit fasting hyperglycaemia but had slightly impaired glucose stimulated insulin secretory response [114] implicating islet amyloid (and the associated destruction of islet cells) directly with impaired insulin secretion. The later stages in mice, when there is extensive replacement of cells, is similar to that observed in man when insulin therapy is required [1,2,11].…”

“…1b). In these non-human species and in transgenic hIAPP, fat-fed mice [114], initial fibril formation accompanies or precedes obesity and/or glucose intolerance and, at this stage, only a few islets are affected (low prevalence) with no significant change in islet-cell mass [114]. However, very small perivascular deposits, whilst not apparently cytotoxic, could compromise transfer of nutrients and insulin across the pericapillary space in affected islets and contribute to glucose intolerance in these models.…”

Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMR

“…Studies with transgenic mice that express human amylin suggest that amyloid could develop uniformly throughout the islets of the pancreas from an early stage of the disease (8). In a mouse model for type 2 diabetes, development of persistent hyperglycemia and insulin deficiency was found to require expression of human amylin and to correlate positively with islet amyloid formation (9).…”

“…to be toxic to cultured β-cells (4), and has been proposed to play a significant role in the pathogenesis of type 2 diabetes by contributing to the destruction of β-cells in the later stages of the disease (5-7). Studies with transgenic mice that express human amylin suggest that amyloid could develop uniformly throughout the islets of the pancreas from an early stage of the disease (8). In a mouse model for type 2 diabetes, development of persistent hyperglycemia and insulin deficiency was found to require expression of human amylin and to correlate positively with islet amyloid formation (9).…”