Del Rey Adriana, Roggero Eduardo, Randolf Anke, Mahuad Carolina, McCann Samuel, Rettori Valeria, Besedovsky Hugo O
Department of Immunophysiology, Institute of Physiology, Medical Faculty, Philipps University, 35037 Marburg, Germany.
Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16039-44. doi: 10.1073/pnas.0607076103. Epub 2006 Oct 11.
Administration of IL-1beta results in a profound and long-lasting hypoglycemia. Here, we show that this effect can be elicited by endogenous IL-1 and is related to not only the capacity of the cytokine to increase glucose uptake in peripheral tissues but also to mechanisms integrated in the brain. We show that (i) blockade of IL-1 receptors in the brain partially counteracted IL-1-induced hypoglycemia; (ii) peripheral administration or induction of IL-1 production resulted in IL-1beta gene expression in the hypothalamus of normal and insulin-resistant, leptin receptor-deficient, diabetic db/db mice; (iii) IL-1-treated normal and db/db mice challenged with glucose did not return to their initial glucose levels but remained hypoglycemic for several hours. This effect was largely antagonized by blockade of IL-1 receptors in the brain; and (iv) when animals with an advanced Type II diabetes were treated with IL-1 and challenged with glucose, they died in hypoglycemia. However, when IL-1 receptors in the brains of these diabetic mice were blocked, they survived, and glucose blood levels approached those that these mice had before IL-1 administration. The prolonged hypoglycemic effect of IL-1 is insulin-independent and develops against increased levels of glucocorticoids, catecholamines, and glucagon. These findings, together with the present demonstration that this effect is integrated in the brain and is paralleled by IL-1beta expression in the hypothalamus, indicate that this cytokine can reset glucose homeostasis at central levels. Such reset, along with the peripheral actions of the cytokine, would favor glucose uptake by immune cells during inflammatory/immune processes.
给予白细胞介素-1β会导致严重且持久的低血糖。在此，我们表明这种效应可由内源性白细胞介素-1引发，不仅与该细胞因子增加外周组织葡萄糖摄取的能力有关，还与大脑中整合的机制有关。我们发现：（i）大脑中白细胞介素-1受体的阻断部分抵消了白细胞介素-1诱导的低血糖；（ii）外周给予或诱导白细胞介素-1产生会导致正常以及胰岛素抵抗、瘦素受体缺陷的糖尿病db/db小鼠下丘脑白细胞介素-1β基因表达；（iii）用葡萄糖刺激经白细胞介素-1处理的正常和db/db小鼠，其血糖水平不会恢复到初始水平，而是会持续低血糖数小时。大脑中白细胞介素-1受体的阻断在很大程度上拮抗了这种效应；（iv）患有晚期II型糖尿病的动物用白细胞介素-1处理并用葡萄糖刺激后，会死于低血糖。然而，当这些糖尿病小鼠大脑中的白细胞介素-1受体被阻断时，它们存活下来，血糖水平接近白细胞介素-1给药前的水平。白细胞介素-1的长期低血糖效应不依赖胰岛素，且在糖皮质激素、儿茶酚胺和胰高血糖素水平升高的情况下仍会出现。这些发现，连同目前关于这种效应整合于大脑且与下丘脑白细胞介素-1β表达平行的证明，表明这种细胞因子可在中枢水平重置葡萄糖稳态。这种重置，连同细胞因子的外周作用，将有利于炎症/免疫过程中免疫细胞摄取葡萄糖。
