Abstract

Purpose of Study: Islet amyloid deposition and β-cell loss are pathological hallmarks of the pancreatic islet in type 2 diabetes mellitus (T2DM). Studies in animal models of T2DM have shown that islet amyloid deposition is associated with reduced β-cell mass, increased β-cell apoptosis, and decreased β-cell replication. We have shown that islet amyloid deposition occurs in human T2DM and is associated with a reduction in β-cell area. As part of this ongoing study, we sought to determine whether a similar relationship between islet amyloid deposition and β-cell apoptosis and/or replication exists in human T2DM. Methods Used: Human autopsy samples of pancreas from subjects with and without T2DM (n=18 and 20, respectively) were studied. Age and body mass index did not differ, but as expected, random blood glucose was significantly higher in subjects with T2DM (148.0±6.9 vs. 100.0±2.1 mg/dl, p<0.001; data are mean±SEM). Amyloid and β-cell area were quantified using thioflavin S-staining and insulin-immunostaining respectively. Apoptotic β-cells were identified as the percentage of insulin-positive cells with TUNEL-positive nuclei, while replicating β-cells were similarly identified as insulin-positive cells having Ki-67-positive nuclei. Summary of Results: Islet amyloid deposition was significantly higher (12.6±3.1 vs. 0.59±0.32%, p<0.001) and β-cell area significantly lower (36.0±3.7 vs. 45.6±2.1%, p=0.05) in T2DM than control subjects. In T2DM subjects, the rate of β-cell apoptosis was 2.8-fold higher than in control subjects (2.31±0.38 vs. 0.84±0.28%, n=14-16, p=0.006). In contrast, the rate of β-cell replication did not differ between subjects with and without T2DM (0.16±0.06 vs. 0.14±0.05%, n=15-17, p=0.71). Among subjects with T2DM, there was a strong inverse correlation between β-cell area and amyloid deposition (r=0.84, p<0.001); however, no correlation was observed between the increased rate of β-cell apoptosis and either amyloid deposition (r=0.06, p=0.85) or β-cell area (r=0.15, p=0.62). Conclusions: Human T2DM is associated with islet amyloid deposition, decreased β-cell area, and increased β-cell apoptosis. While islet amyloid is strongly associated with decreased β-cell area, neither islet amyloid deposition nor β-cell area is correlated with β-cell apoptosis.