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 (Σamyloid area/Σislet 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 β- and δ-cells was reduced in the transgenic mice compared with 6 nontransgenic mice that do not develop amyloid (β-cells: 62.9 ± 3.1% vs. 75.5 ± 0.9%, P = 0.02; δ-cells: 2.8 ± 0.5% vs. 4.4 ± 0.4%, P = 0.05), whereas the proportion of islets composed of α-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 β-cell, (r = −0.59, P < 0.0001), α-cell (r = −0.32, P < 0.0001), and δ-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.