Vasu Srividya, Moffett R Charlotte, Thorens Bernard, Flatt Peter R
SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland.
Centre for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
PLoS One. 2014 Jun 26;9(6):e101005. doi: 10.1371/journal.pone.0101005. eCollection 2014.
Role of GLP-1 and GIP in beta cell compensatory responses to beta cell attack and insulin resistance were examined in C57BL/6 mice lacking functional receptors for GLP-1 and GIP. Mice were treated with multiple low dose streptozotocin or hydrocortisone. Islet parameters were assessed by immunohistochemistry and hormone measurements were determined by specific enzyme linked immunoassays. Wild-type streptozotocin controls exhibited severe diabetes, irregularly shaped islets with lymphocytic infiltration, decreased Ki67/TUNEL ratio with decreased beta cell and increased alpha cell areas. GLP-1 and GIP were co-expressed with glucagon and numbers of alpha cells mainly expressing GLP-1 were increased. In contrast, hydrocortisone treatment and induction of insulin resistance increased islet numbers and area, with enhanced beta cell replication, elevated mass of beta and alpha cells, together with co-expression of GLP-1 and GIP with glucagon in islets. The metabolic responses to streptozotocin in GLP-1RKO and GIPRKO mice were broadly similar to C57BL/6 controls, although decreases in islet numbers and size were more severe. In contrast, both groups of mice lacking functional incretin receptors displayed substantially impaired islet adaptations to insulin resistance induced by hydrocortisone, including marked curtailment of expansion of islet area, beta cell mass and islet number. Our observations cannot be explained by simple changes in circulating incretin concentrations, suggesting that intra-islet GLP-1 and GIP make a significant contribution to islet adaptation, particularly expansion of beta cell mass and compensatory islet compensation to hydrocortisone and insulin resistance.
在缺乏GLP-1和GIP功能性受体的C57BL/6小鼠中，研究了GLP-1和GIP在β细胞对β细胞攻击和胰岛素抵抗的代偿反应中的作用。小鼠用多次低剂量链脲佐菌素或氢化可的松处理。通过免疫组织化学评估胰岛参数，通过特异性酶联免疫测定法测定激素水平。野生型链脲佐菌素对照组表现出严重糖尿病，胰岛形状不规则且有淋巴细胞浸润，Ki67/TUNEL比值降低，β细胞面积减小，α细胞面积增加。GLP-1和GIP与胰高血糖素共表达，主要表达GLP-1的α细胞数量增加。相比之下，氢化可的松治疗和胰岛素抵抗的诱导增加了胰岛数量和面积，β细胞复制增强，β细胞和α细胞质量升高，同时胰岛中GLP-1和GIP与胰高血糖素共表达。GLP-1RKO和GIPRKO小鼠对链脲佐菌素的代谢反应与C57BL/6对照组大致相似，尽管胰岛数量和大小的减少更为严重。相比之下，两组缺乏功能性肠促胰岛素受体的小鼠对氢化可的松诱导的胰岛素抵抗的胰岛适应性均显著受损，包括胰岛面积、β细胞质量和胰岛数量的扩张明显受限。我们的观察结果不能用循环肠促胰岛素浓度的简单变化来解释，这表明胰岛内的GLP-1和GIP对胰岛适应性有显著贡献，特别是β细胞质量的扩张以及对氢化可的松和胰岛素抵抗的代偿性胰岛补偿。
