Objective

The expression of the interleukin-1 receptor type I (IL-1R) is enriched in pancreatic islet β-cells, signifying that ligands activating this pathway are important for the health and function of the insulin-secreting cell. Using isolated mouse, rat, and human islets, we identified the cytokine IL-1α as a highly inducible gene in response to IL-1R activation. In addition, IL-1α is elevated in mouse and rat models of obesity and Type 2 diabetes. Since less is known about the biology of IL-1α relative to IL-1β in pancreatic tissue, our objective was to investigate the contribution of IL-1α to pancreatic β-cell function and overall glucose homeostasis in vivo.

Methods

We generated a novel mouse line with conditional IL-1α alleles and subsequently produced mice with either pancreatic- or myeloid lineage-specific deletion of IL-1α.

Results

Using this in vivo approach, we discovered that pancreatic (IL-1α^Pdx1−/−), but not myeloid-cell, expression of IL-1α (IL-1α^LysM−/−) was required for the maintenance of whole body glucose homeostasis in both male and female mice. Moreover, pancreatic deletion of IL-1α led to impaired glucose tolerance with no change in insulin sensitivity. This observation was consistent with our finding that glucose-stimulated insulin secretion was reduced in islets isolated from IL-1α^Pdx1−/− mice. Alternatively, IL-1α^LysM−/− mice (male and female) did not have any detectable changes in glucose tolerance, respiratory quotient, physical activity, or food intake when compared with littermate controls.

Conclusions

Taken together, we conclude that there is an important physiological role for pancreatic IL-1α to promote glucose homeostasis by supporting glucose-stimulated insulin secretion and islet β-cell mass in vivo.

中文翻译：

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维持胰岛素分泌和全身葡萄糖稳态需要胰腺（而非骨髓细胞）表达白介素-1α

客观的

I 型白细胞介素 1 受体 (IL-1R) 的表达在胰岛 β 细胞中富集，表明激活该通路的配体对于胰岛素分泌细胞的健康和功能非常重要。使用分离的小鼠、大鼠和人类胰岛，我们将细胞因子 IL-1α 鉴定为响应 IL-1R 激活的高度诱导基因。此外，IL-1α 在肥胖和 2 型糖尿病的小鼠和大鼠模型中升高。由于对胰腺组织中 IL-1α 相对于 IL-1β 的生物学知之甚少，我们的目标是研究 IL-1α 对胰腺 β 细胞功能和体内总体葡萄糖稳态的贡献。

方法

我们培育了一种具有条件性 IL-1α 等位基因的新型小鼠品系，随后又培育出具有胰腺或骨髓谱系特异性 IL-1α 缺失的小鼠。

结果

使用这种体内方法，我们发现胰腺细胞 (IL-1α ^Pdx1−/− ) 而不是骨髓细胞，IL-1α (IL-1α ^LysM−/− ) 的表达是维持全身葡萄糖稳态所必需的在雄性和雌性小鼠中。此外，胰腺IL-1α缺失导致糖耐量受损，但胰岛素敏感性没有变化。这一观察结果与我们的发现一致，即从 IL-1α ^Pdx1−/−小鼠中分离的胰岛中葡萄糖刺激的胰岛素分泌减少。另外，与同窝对照小鼠相比，IL-1α ^LysM−/−小鼠（雄性和雌性）在葡萄糖耐量、呼吸商、体力活动或食物摄入方面没有任何可检测到的变化。

结论

综上所述，我们得出结论，胰腺 IL-1α 通过支持葡萄糖刺激的胰岛素分泌和体内胰岛 β 细胞质量来促进葡萄糖稳态，具有重要的生理作用。