Mechanisms underlying gastric motor disturbances associated with diabetes

 描述(申请人提供)：在美国大约有2000万人被诊断为1型或2型糖尿病(DM)。2型糖尿病占95%。世界卫生组织估计，到2030年，美国将有超过3000万人被诊断为2型糖尿病。糖尿病患者经常出现胃肠道(GI)并发症，包括胃瘫、便秘和大便失禁。糖尿病胃轻瘫的定义是在没有机械性梗阻的情况下胃排空延迟，可与胃食道反流、恶心、呕吐、腹胀和腹痛等症状相关。胃瘫使胃排空变得不可预测，因此血糖水平可能很难控制。糖尿病胃病对生活质量有负面影响。以前的研究主要是利用2型糖尿病的动物模型，认为胃肠道症状是由肠道神经病变引起的，但最近的研究表明，血管平滑肌细胞的缺陷以及Cajal间质细胞(ICC)和PDGFRA+细胞(SIP细胞)的网络发生了变化。对糖尿病患者的人体肌肉的解剖学评估，包括NIDDK胃轻瘫临床研究联盟(GpCRC)的评估，支持了这一假设，即在2型糖尿病中，SIP细胞被破坏或减少。然而，临床研究一直是描述性的，对ICC丢失的影响和DM胃病的其他机制的调查还不够深入。该项目将使用多方面的方法来测试胃运动活动的变化是否与SIP细胞网络和功能的变化、起搏器和神经效应体关键基因细胞特异性表达的变化(重构)、起搏器和神经效应器反应的细胞缺陷和/或影响胃肌肉电和机械活动的环氧合酶通路的变化相关。初步数据为DM胃病的基本机制提供了新的见解，而特定目标的完成将为DM运动功能障碍的正常化提供新的治疗理论依据。

 DESCRIPTION (provided by applicant): Approximately 20 million people in the USA have been diagnosed with type 1 or 2 diabetes mellitus (DM). Type 2 DM accounts for 95% cases. The World Health Organization has estimated that more than 30 million people in the USA will be diagnosed with type 2 DM by 2030. DM patients often develop gastrointestinal (GI) complications, including gastroparesis, constipation and fecal incontinence. DM gastroparesis is defined as delayed gastric emptying in the absence of a mechanical obstruction and can be associated with symptoms such as gastro-esophageal reflux, nausea, vomiting bloating and abdominal pain. Gastroparesis makes gastric empting unpredictable, so blood glucose levels may be difficult to control. Diabetic gastropathy has a negative impact on quality of life. Previou studies, primarily utilizing animal models of type 2 DM have suggested that the GI symptoms result from enteric neuropathy, however recent studies have suggested defects in smooth muscle cells and changes in networks of interstitial cells of Cajal (ICC) and PDGFRa+ cells (SIP cells). Anatomical evaluations of human muscles from DM patients, including those of the NIDDK Gastroparesis Clinical Research Consortium (GpCRC), support the hypothesis that SIP cells are disrupted or reduced in type 2 DM. Clinical studies have been descriptive, however, and investigations into the impact of ICC loss and other mechanisms of DM gastropathy have not been performed in adequate depth. This project will use a multifaceted approach to test whether changes in gastric motor activity correlate with changes in SIP cell networks and function, changes in cell-specific expression of key genes of the pacemakersome and neuroeffectorsomes (remodeling), cellular defects in pacemaker and neuroeffector responses, and/or alterations in cyclooxygenase pathways that affect gastric muscle electrical and mechanical activities. Preliminary data provide novel insights into the basic mechanisms of DM gastropathy, and completion of the specific aims will provide new therapeutic rationales for normalization of DM motor dysfunction.