碘过量对胰岛β细胞的损伤及其机制研究

Looking for the pathogenies and preventing diabetes is controling the prevalence of diabetes is a key point.It was observed that pancreatitis occured in the animal model with excessive iodine and the patients using amiodarone with excessive iodine，but till now there is no research about the the damage of iodine excess in pancreas and its mechanism. We previously reported that iodine excess caused hyperlipemia ,oxidative stress,which may lead to endoplasmic reticulum stress（ERS）through ATF6,PERK and IRE1 signal pathway.ERS can induce pancreaticβcell impairment.In view of the above, we hypothese that excessive iodine may induce oxidative stress and ERS, which may lead to pancreatic β cell impairment.To verify this hypothesis, this project is designed to observe the morphology and function of islet by light microscope, electron microscope and flow cytometry and to measure ERS signal molecules in pancreas by real time PCR and Western Blot in animal model with excessive iodine,ERS blocking experiment and vitro experiment. A cross-section investigation will be used to explore the relation between the pancreas disease, blood glucose and insulin level and excessive iodine.We will determine whether iodine excess induces β cell dysfunction and clarify its time-effect and dose-effect. Furthermore, we will aim to explore the mechanisms underlying the impairment of pancreatic β cell function by the way of ERS, lipid metabolism and thyroid hormones metabolism . The results of this project will clarify the association between iodine excess and damage of β cell, and its mechanism.Further more, the results can provide new ideas for the research of pathogeny of type 2 diabetes and the metabolic diseases induced by excessive iodine.

寻找病因、预防糖尿病是控制糖尿病流行的关键环节。碘过量动物模型和使用富含碘的胺碘酮引起胰腺炎，提示碘过量可能损伤胰腺。前期研究发现，碘过量引起高脂血症、氧化应激等，而氧化应激可通过ATF6、PERK和IRE1信号通路引起胰腺内质网应激，从而导致胰岛β细胞损伤。据此推测：碘过量通过内质网应激、氧化应激、甲状腺激素代谢、脂代谢异常等导致胰岛损伤。本项目拟通过碘过量动物实验、内质网应激阻断实验以及胰腺离体刺激实验，运用光镜、电镜及流式细胞术观察碘过量对胰岛β细胞形态及功能的影响及时间、剂量效应关系；并运用定量PCR、Western Blot等分子生物学技术检测胰腺内质网应激信号分子的改变；通过人群现况调查探索碘过量与胰腺疾病、血糖、血胰岛素水平之间的相关性，以阐明人群碘过量对胰岛β细胞的影响，从内质网应激、脂代谢、甲状腺激素角度揭示作用机制，为探索糖尿病病因及碘过量对代谢性疾病的影响提供依据

寻找病因、预防糖尿病是控制糖尿病流行的关键环节。碘过量动物模型和使用富含碘的胺碘酮引起胰腺炎，提示碘过量可能损伤胰腺。前期研究发现，碘过量引起高脂血症、氧化应激等，而氧化应激可通过ATF6、PERK和IRE1信号通路引起胰腺内质网应激，从而导致胰岛β细胞损伤。本项目通过碘过量动物实验、细胞实验和人群调查，研究碘过量对胰岛β细胞形态及功能的影响及时间、剂量效应关系；从胰腺内质网应激角度研究β细胞损伤的机制。研究发现，（1）高碘组300ug/L，600ug/L、1200 ug/L、2400 ug/L和4800ug/L小鼠饲养1个月起，小鼠胰岛增生肥大、萎缩、坏死等损伤，随着时间和剂量增加而加重；（2）高碘组小鼠分泌胰岛素的β细胞数目相对减少，α细胞增加明显；（3）从电镜超微结构观察，高碘水饲养1个月起，最低水碘剂量300μg/L组线粒体增多、肿胀，嵴消失、空泡化，胞浆脱颗粒，内质网减少，核膜皱缩；（4）高碘水饲养小鼠3个月时，从600 ug/L起各个高碘组小鼠的空腹胰岛素水平逐渐下降，与正常对照组相比有统计学意义（P<0.05，0.89±0.15，0.56±0.09，0.55±0.15,0.56±0.11,0.40±0.11 vs 1.05±0.16）；饲养6个月起，600ug/L剂量组开始空腹血糖高于正常对照组（P<0.05，6.41±0.89, 6.05±0.74, 8.06±0.76，11.11±0.80 vs 4.95±0.47 mM）；（5）糖耐量试验和细胞实验显示碘过量导致糖耐量降低，肝脏胰岛素敏感性降低，其机制是碘过量引起了β细胞的内质网应激， 高碘组GRP78和IRE1α蛋白表达量均显著高于对照组， P-PERK、ATF6α、P-EIF2α的表达变化不显著。（6）人群调查：随机选择成年农村和城镇居民各200人和300人，农村尿碘中位数为 268.00μg/L，碘超足量和碘过量所占比例达76.5%，碘水平处于较高状态，低胰岛素血症检出率为45.5%, 农村和城区空腹血糖受损率分别为32.0%和38.3%；城区成年人尿碘中位数数为206.2，碘超足量和碘过量所占比例合计达52.7%。多元线性回归分析显示尿碘可能与空腹血糖和胰岛素水平有关，需进一步验证。本研究从内质网应激角度揭示了碘过量对胰岛β细胞的损伤，为探索糖尿病病因及碘过量对代谢性疾病的影响提供了依据。