Diabetic patients show elevated plasma IL18 concentrations. IL18 has two receptors: the IL18 receptor (IL18r) and the Na-Cl co-transporter (NCC). Here, we report that IL18 is expressed on islet α cells, NCC on β cells, and IL18r on acinar cells in human and mouse pancreases. The deficiency of these receptors reduces islet size, β cell proliferation, and insulin secretion but increases β cell apoptosis and exocrine macrophage accumulation after diet-induced glucose intolerance or streptozotocin-induced hyperglycemia. Together with the glucagon-like peptide-1 (GLP1), IL18 uses the NCC and GLP1 receptors on β cells to trigger β cell development and insulin secretion. IL18 also uses the IL18r on acinar cells to block hyperglycemic pancreas macrophage expansion. The β cell-selective depletion of the NCC or acinar-cell-selective IL18r depletion reduces glucose tolerance and insulin sensitivity with impaired β cell proliferation, enhanced β cell apoptosis and macrophage expansion, and inflammation in mouse hyperglycemic pancreas. IL18 uses NCC, GLP1r, and IL18r to maintain islet β cell function and homeostasis.

糖尿病患者血浆 IL18 浓度升高。IL18 有两种受体：IL18 受体 (IL18r) 和 Na-Cl 协同转运蛋白 (NCC)。在此，我们报道在人和小鼠胰腺中，IL18 在胰岛 α 细胞上表达，NCC 在 β 细胞上表达，IL18r 在腺泡细胞上表达。这些受体的缺乏会减少胰岛大小、β细胞增殖和胰岛素分泌，但在饮食引起的葡萄糖不耐症或链脲佐菌素引起的高血糖后会增加β细胞凋亡和外分泌巨噬细胞的积累。IL18 与胰高血糖素样肽 1 (GLP1) 一起使用 β 细胞上的 NCC 和 GLP1 受体来触发 β 细胞发育和胰岛素分泌。IL18 还利用腺泡细胞上的 IL18r 来阻止高血糖胰腺巨噬细胞的扩张。NCC 的 β 细胞选择性耗竭或腺泡细胞选择性 IL18r 耗竭会降低葡萄糖耐量和胰岛素敏感性，并导致 β 细胞增殖受损、β 细胞凋亡和巨噬细胞扩张增强，以及小鼠高血糖胰腺中的炎症。IL18 使用 NCC、GLP1r 和 IL18r 来维持胰岛 β 细胞功能和稳态。