Wright J R, Lefkowith J B, Schreiner G, Lacy P E
Department of Pathology, Washington University School of Medicine, Saint Louis, MO 63110.
Proc Natl Acad Sci U S A. 1988 Aug;85(16):6137-41. doi: 10.1073/pnas.85.16.6137.
Multiple i.p. injections of low-dose streptozotocin (40 mg/kg) produce insulitis, beta cell destruction, and diabetes in male CD-1 mice. Recent data also suggest that macrophages figure in the low-dose streptozotocin model. Because other recent studies have shown that essential fatty acid deficiency prevents autoimmune nephritis in mice, decreases the number of resident Ia-positive glomerular macrophages, and decreases the elicitation of macrophages into the glomerulus in inflammation, we examined the effect of essential fatty acid deficiency on the incidence and severity of insulitis and diabetes in CD-1 mice treated with low-dose streptozotocin. Streptozotocin-treated mice on the control diet uniformly developed diabetes (19/19). Essential fatty acid-deficient mice treated with streptozotocin did not develop diabetes (1/13). Mean plasma glucose levels for the control and essential fatty acid-deficient mice were 384.5 +/- 23.6 and 129.1 +/- 15.5 mg/dl, respectively, at the end of 1 month. To discern whether essential fatty acid deficiency prevented the streptozotocin-induced beta cell injury or the inflammatory response to injured beta cells, mice were repleted with daily injections of 99% pure methyl linoleate beginning 3 days after the last streptozotocin injection. These mice also quickly developed severe (3/4) or mild (1/4) diabetes. Histologic examination of the pancreata of control mice or repleted mice showed marked insulitis and beta cell destruction; in contrast, the pancreata of essential fatty acid-deficient mice showed preservation of beta cells and only focal mild peri-insulitis. Essential fatty acid deficiency thus prevents the insulitis and resultant diabetes in low-dose streptozotocin-treated CD-1 mice, suggesting a central role for macrophages and lipid mediators in this autoimmunity model.
多次腹腔注射低剂量链脲佐菌素（40毫克/千克）可使雄性CD-1小鼠发生胰岛炎、β细胞破坏及糖尿病。近期数据还表明巨噬细胞在低剂量链脲佐菌素模型中起作用。由于其他近期研究显示必需脂肪酸缺乏可预防小鼠自身免疫性肾炎，减少肾小球中驻留的Ia阳性巨噬细胞数量，并减少炎症时巨噬细胞向肾小球的募集，我们研究了必需脂肪酸缺乏对低剂量链脲佐菌素处理的CD-1小鼠胰岛炎发病率和严重程度以及糖尿病的影响。用对照饮食喂养的经链脲佐菌素处理的小鼠均发生了糖尿病（19/19）。用链脲佐菌素处理的必需脂肪酸缺乏小鼠未发生糖尿病（1/13）。在1个月末，对照小鼠和必需脂肪酸缺乏小鼠的平均血浆葡萄糖水平分别为384.5±23.6和129.1±15.5毫克/分升。为了确定必需脂肪酸缺乏是预防了链脲佐菌素诱导的β细胞损伤还是对受损β细胞的炎症反应，在最后一次链脲佐菌素注射后3天开始，每天给小鼠注射99%纯亚油酸甲酯进行补充。这些小鼠也很快发展为重度（3/4）或轻度（1/4）糖尿病。对照小鼠或补充小鼠胰腺的组织学检查显示有明显的胰岛炎和β细胞破坏；相比之下，必需脂肪酸缺乏小鼠的胰腺显示β细胞保存，仅局灶性轻度胰岛周围炎。因此，必需脂肪酸缺乏可预防低剂量链脲佐菌素处理的CD-1小鼠发生胰岛炎及由此导致的糖尿病，提示巨噬细胞和脂质介质在该自身免疫模型中起核心作用。
