Islet Amyloid Deposition Occurs In Residual Insulin-Positive Islets In Type 1 Diabetes
Dixon, Graham   (University of Washington)
Mentor: Hull, Rebecca L. (University of Washington)
Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic islet ß cells, although some subjects exhibit residual ß-cell mass and secretory function that can persist for years after diagnosis. In addition to insulin, ß cells produce and secrete islet amyloid polypeptide (IAPP), which under conditions of ß-cell dysfunction can aggregate into islet amyloid and destroy ß cells. Islet amyloid is typically observed in type 2 diabetes (T2D), where it is associated with increased ß-cell apoptosis. We hypothesized that individuals with long-term T1D who have residual insulin-positive (insulin+) islets will also exhibit islet amyloid deposition. Specimens were collected from subjects with T1D during autopsy (n=7, age: 44±10 y, gender: 3F/4M, BMI: 27.8±8.2 kg/m2, diabetes duration: 29±5 y) and immunostained for insulin to visualize ß cells and stained for thioflavin S to visualize islet amyloid. Islets (defined as clusters of =6 insulin+ cells) were counted and designated positive or negative for islet amyloid. Pancreas section area was measured to determine insulin+ islet density. Data were compared to a cohort of non-diabetic control subjects matched for gender and age (ND: n=7, 45±11 y, 3F/4M, 27.4±5.1 kg/m2) and T2D subjects with the longest known diabetes duration (n=7, 68±7 y, 3F/4M, 30.6±7.3 kg/m2, diabetes duration: 15±6 y). Diabetes classification and matching were performed from medical records by an observer blinded to the islet pathology. Within the T1D cohort, 29% of subjects were found to have insulin+ islets, although as expected insulin+ islet density was significantly lower than in ND and T2D subjects (0.03±0.05 vs. 3.21±1.40 and 5.97±2.72, respectively; p<0.001). All T1D subjects with insulin+ islets also exhibited islet amyloid deposition, whereas none of the insulin-negative T1D subjects showed evidence of islet amyloid. Amyloid deposition was absent in ND controls but was present in all T2D subjects. In summary, T1D subjects with residual insulin-positive islets demonstrate coincident islet amyloid deposition. Thus, the toxic effects of islet amyloid deposition could contribute to ß-cell dysfunction and death in long-standing T1D.