Inflammation in Pancreatic Islets
Janice Pang
Pinetree Secondary School
Floor Location : M 019 H

Type 2 diabetes mellitus is a chronic disease that is brought about by metabolic events such as insulin resistance and progressive impairment of insulin-secreting beta cell function. Islet amyloid polypeptide (IAPP), a peptide that aggregates to form amyloid plaques, is also found in the pancreatic islets of diabetic patients. In recent years, inflammation has been thought to impair insulin actions in tissues and lead to beta cell dysfunction. Particularly, IL-1 beta has been found to be the key mediator of inflammation and inducer of insulin resistance. The cleaved mature form of IL-1 beta is induced by caspase-1, found in an intracellular protein complex known as the inflammasome. However, how caspase-1 is activated in pancreatic islets, and which cell types, still needs further elucidation. In this study, pancreatic islets were treated with IAPP to identify whether it activates caspase-1 and impairs insulin secretion in islet macrophages. As well, the survival of macrophages in cultured islets was investigated. Flow cytometry revealed that MHC Class II markers were reduced in macrophages after culturing, which is consistent to previous studies. However, the percentage of cells with CD11b (a cell surface marker for macrophages) remained relatively the same after 5 days of culture. Thus, previous studies that concluded that macrophages deplete after culturing may be incorrect, as they looked at markers that alter over time. Results revealed that islets treated with IAPP had active caspase-1 in both macrophages and beta cells. However, the activation was not significantly different, and therefore suggests that IAPP may not be a major stimulus of caspase-1 in islet cells. Further, insulin secretion was increased with human IAPP treatment in both low (1.67 mM) and high (16.7 mM) glucose. In contrast the stimulation index of insulin secretion (fold secretion at high vs. low glucose) was decreased with human IAPP, supporting the hypothesis human IAPP may impair stimulation of insulin secretion, and islet function. Depletion of macrophages from the islets using clodronate liposomes decreased insulin secretion. Thus, macrophages may play an important role in regulating islet function. Collectively, these results suggests that macrophages in cultured islets survive but express less MHC Class II after being cultured. Human IAPP may not be a major stimulus for caspase-1 in islets and could impair islet function. By understanding how caspase-1 is activated, the specific stimulus can be targeted and thereby decreasing inflammation. Furthermore, this could improve insulin sensitivity and lessen beta cell dysfunction in diabetic patients.