Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice
Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice
复制标题
口服皮质酮可减少雄性非肥胖糖尿病小鼠的胰岛素抵抗，但会促进胰岛素抵抗和高血糖
DOI：
10.1016/j.ajpath.2016.11.009
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发表时间：
2017-03-01
影响因子：
6
通讯作者：
Collier, J. Jason
中科院分区：
文献类型：
--
作者：
Burke, Susan J.;Batdorf, Heidi M.;Collier, J. Jason
类固醇诱导的糖尿病是最常见的药物诱导的高血糖。因此，使用雄性非肥胖型糖尿病小鼠研究了与慢性口服皮质酮相关的代谢和免疫学变化。皮质酮注射三周后，通过胰岛素耐量试验测量，对胰岛素作用的敏感性降低。身体成分测量显示脂肪质量增加，瘦质量减少。在开始使用糖皮质激素6周后，出现明显的高血糖(250 mg/dL)，而接受赋形剂对照的小鼠100%保持正常血糖。这一表型在淘汰阶段被完全逆转，并很容易在机构中复制。与赋形剂对照组相比，皮质酮治疗的小鼠胰腺胰岛素阳性面积显著增加，但CD3(+)细胞浸润明显减少。此外，与赋形剂对照组相比，皮质酮组小鼠骨骼肌柠檬酸合成酶基因表达和酶活性均显著增加。此外，糖原合成酶的表达显著增强，这与皮质酮治疗的小鼠肌肉糖原储存的增加一致。皮质酮诱导的高血糖、胰岛素抵抗和肌肉基因表达的变化在洗脱阶段结束时都被逆转，表明代谢变化不是永久性的。因此，雄性非肥胖型糖尿病小鼠可以在具有自身免疫性疾病遗传易感性的小鼠模型中，对糖皮质激素相关干预的代谢和免疫学后果进行翻译研究。
Steroid-induced diabetes is the most common form of drug-induced hyperglycemia. Therefore, metabolic and immunological alterations associated with chronic oral corticosterone were investigated using male nonobese diabetic mice. Three weeks after corticosterone delivery, there was reduced sensitivity to insulin action measured by insulin tolerance test. Body composition measurements revealed increased fat mass and decreased lean mass. Overt hyperglycemia (>250 mg/dL) manifested 6 weeks after the start of glucocorticoid administration, whereas 100% of the mice receiving the vehicle control remained normoglycemic. This phenotype was fully reversed during the washout phase and readily reproducible across institutions. Relative to the vehicle control group, mice receiving corticosterone had a significant enhancement in pancreatic insulin-positive area, but a marked decrease in CD3(+) cell infiltration. In addition, there were striking increases in both citrate synthase gene expression and enzymatic activity in skeletal muscle of mice in the corticosterone group relative to vehicle control. Moreover, glycogen synthase expression was greatly enhanced, consistent with elevations in muscle glycogen storage in mice receiving corticosterone. Corticosterone-induced hyperglycemia, insulin resistance, and changes in muscle gene expression were all reversed by the end of the washout phase, indicating that the metabolic alterations were not permanent. Thus, male nonobese diabetic mice allow for translational studies on the metabolic and immunological consequences of glucocorticoid-associated interventions in a mouse model with genetic susceptibility to autoimmune disease.