Carlsson P O, Sandler S, Jansson L
Department of Medical Cell Biology, Uppsala University, Sweden.
Endocrinology. 1998 Aug;139(8):3534-41. doi: 10.1210/endo.139.8.6153.
The present study tested the hypothesis that changes in pancreatic islet blood flow correlate with the difference in diabetes incidence between male and female nonobese diabetic (NOD) mice. The blood flows were determined by a microsphere technique. In animals aged 10 and 14 weeks, the islet blood perfusion was 3-fold higher in female NOD mice compared with that in either age-matched male NOD mice or age- and sex-matched control ICR mice. At 5 weeks of age islet blood flow was similar in all groups. No differences between male and female NOD mice in whole pancreatic, duodenal, ileal, or colonic blood flows were observed at any time point. Administration of a bolus dose of aminoguanidine (a blocker of inducible nitric oxide synthase) to 10-week-old animals selectively and markedly decreased islet blood flow in female NOD mice, whereas islet blood flow in ICR mice and male NOD mice remained unaffected. Aminoguanidine did not affect mean arterial blood pressure or whole pancreatic blood flow in any of the groups. Injection of N(G)-methyl-L-arginine, an unspecific inhibitor of both constitutive and inducible nitric oxide synthase, markedly decreased whole pancreatic and islet blood flow to the same level in both male and female NOD mice. These combined findings suggest that diabetes-prone female NOD mice have an increased islet blood flow, which is mediated by an excessive production of nitric oxide formed by inducible nitric oxide synthase. The islet blood hyperperfusion may augment homing to the pancreatic islets of inflammatory cells and soluble factors involved in beta-cell destruction during the development of insulin-dependent diabetes mellitus in this animal model. The presently observed gender difference in the blood flow response could, therefore, at least partially explain why female NOD mice are more prone to develop hyperglycemia than the males.
胰岛血流的变化与非肥胖糖尿病（NOD）雄性和雌性小鼠糖尿病发病率的差异相关。血流通过微球技术测定。在10周龄和14周龄的动物中，雌性NOD小鼠的胰岛血流灌注比年龄匹配的雄性NOD小鼠或年龄和性别匹配的对照ICR小鼠高3倍。在5周龄时，所有组的胰岛血流相似。在任何时间点，均未观察到雄性和雌性NOD小鼠在整个胰腺、十二指肠、回肠或结肠血流方面存在差异。对10周龄的动物给予大剂量氨基胍（诱导型一氧化氮合酶的抑制剂），可选择性且显著降低雌性NOD小鼠的胰岛血流，而ICR小鼠和雄性NOD小鼠的胰岛血流不受影响。氨基胍对任何组的平均动脉血压或整个胰腺血流均无影响。注射N（G）-甲基-L-精氨酸（一种组成型和诱导型一氧化氮合酶的非特异性抑制剂）可使雄性和雌性NOD小鼠的整个胰腺和胰岛血流显著降低至相同水平。这些综合研究结果表明，易患糖尿病的雌性NOD小鼠胰岛血流增加，这是由诱导型一氧化氮合酶产生的过量一氧化氮介导的。在该动物模型中，胰岛素依赖型糖尿病发展过程中，胰岛血流过度灌注可能会增加炎症细胞和参与β细胞破坏的可溶性因子向胰岛的归巢。因此，目前观察到的血流反应性别差异至少可以部分解释为什么雌性NOD小鼠比雄性更容易发生高血糖。
