In human type 2 diabetes islet amyloid deposition is associated with B-cell loss and increased B-cell apoptosis. Islet amyloid polypeptide (IAPP), a normal secretory product of the B-cell, is the unique peptide component of these amyloid deposits. Amyloid-laden islets in humans and human IAPP (hIAPP) transgenic mice contain increased numbers of macrophages. Further, incubation of macrophages with hIAPP results in increased IL-1B production. Whether this production of IL-1B then feeds back to further increase islet amyloid deposition has not previously been determined. Thus, we sought to determine whether exposure of islets to physiological levels of IL-1B exacerbates islet amyloid deposition.
Isolated islets from hIAPP transgenic and wild-type mice were cultured for 48 hours in 16.7 mmol/l glucose with or without a physiological concentration of IL-1B (4 pg/ml), after which islet amyloid deposition and mRNA levels of Iapp and Ins2 were quantified by histomorphometric analysis and qRT-PCR, respectively.
As expected, in the absence of IL-1B, hIAPP transgenic islets developed amyloid, while wild-type mice did not. Exposure of hIAPP transgenic mouse islets to IL-1B resulted in an increase in amyloid severity (% islet area occupied by amyloid; 3.85±0.9 vs. 0.6±0.23%; p=0.02, n=5). IL-1B did not change Iapp mRNA expression in hIAPP transgenic islets (0.58±0.02 vs. 0.72±0.17; n=7). In contrast, IL-1B decreased Ins2 mRNA expression in these islets (0.60±0.04 vs. 1.11±0.17, p=0.01; n=7), so that the ratio of Iapp/Ins2 mRNA was increased (1.59±0.11 vs. 1±0.12, p=0.003; n=7).
We conclude that physiological levels of IL-1B increase islet amyloid formation. Further, IL-1B reduces insulin but not IAPP gene expression, thus producing an imbalance in the normal ratio of Iapp:Ins2, and an islet environment which could favor islet amyloid formation. Thus, antagonizing the effects of islet IL-1B may be beneficial to improve B-cell function and reduce B-cell mass in type 2 diabetes.