Pathophysiology of Diabetic Gastroparesis

 描述（由申请人提供）： 糖尿病是一种越来越常见的疾病，最近估计影响9.3%的美国人口和25.9%的65岁以上的个体（国家糖尿病统计报告，2014年6月）。由于VHA是一个持续的护理系统，糖尿病的所有短期和长期并发症都发生在不断扩大的退伍军人群体中（米勒，2004）。此外，VHA系统中的糖尿病护理是复杂的，因为患者经常患有并发症，如年龄增长和创伤后应激障碍。糖尿病对胃功能的有害影响非常普遍，并与相当大的发病率相关。然而，糖尿病胃并发症的管理仍然不能令人满意，尽管有良好的记录，遵守公认的治疗指南，部分原因是胃排空异常的机制知之甚少。因此，个体病例的潜在病理生理学诊断是困难的，并且由于目前的治疗方法在很大程度上是经验性的，而不是合理设计的，因此通常缺乏有效的治疗选择。糖尿病胃异常的发病机制和治疗的研究是复杂的，因为：1）症状可能由快速或缓慢的胃排空引起; 2）胃排空由胃的独立调节的解剖和功能区域的综合反应决定，因此类似的缺陷可能导致快速或缓慢的胃排空，这取决于所涉及的区域和/或细胞类型;和3）在消化和消化间期，不同的胃运动模式调节固体和液体的胃排空; 4）最后，在研究糖尿病胃轻瘫中如何最好地使用糖尿病动物模型还不完全清楚。虽然有许多糖尿病动物模型，但尚不清楚哪种模型最能代表人类疾病的特征。胃排空受胃底、胃体/胃窦和幽门的不同活动调节。快速胃排空最常由胃底中抑制性神经传递的丧失引起，胃底由紧张性肌肉组成，并且通过在抑制性神经的影响下放松来储存和调节摄入的食物。胃排空缓慢通常是由于胃体/幽门的推进活动缺陷或幽门松弛缺陷所致。缺陷 在平滑肌中，Cajal间质细胞（ICC）和神经肌肉神经传递都在糖尿病动物的胃中被描述，ICC的丧失和氮能和胆碱能神经传递受损是最一致的发现。然而，我们发现嘌呤能神经传递也丢失，这表明囊泡和非囊泡神经传递受损。本研究旨在探讨糖尿病相关胃排空改变的发病机制。在目的1中，我们将研究具有预定义的快速和缓慢胃排空的糖尿病小鼠的不同胃区域中的神经传递缺陷谱。这些研究将在不同的糖尿病动物模型中进行，以确定这些模型具有共同病理生理学的程度。这些研究将确定胃排空快和慢的发病机制，并在糖尿病胃紊乱中产生可靠的、可重复的数据。在目标2中，我们将系统地研究这一假设，即细胞内货物马达，肌球蛋白5a（myo 5a）的功能障碍，是糖尿病胃神经递质缺乏的重要原因。这一假设是基于我们的研究，表明myo 5a功能障碍导致多种神经递质的释放受损。目的3将检验以下假设：高血糖导致myo 5a O-GlcNAc化升高，抑制其活性并抑制神经传递，以及使其过早降解。阐明参与抑制肠道神经传递的途径可能会发现治疗糖尿病胃的新靶点。

 DESCRIPTION (provided by applicant): Diabetes is an increasingly common disorder, recently estimated to affect 9.3% of the US population and 25.9% of individuals over 65 years of age (National Diabetes Statistics Report, June 2014). Because the VHA is a continuing system of care, all short- and long-term complications of diabetes are encountered in an expanding veteran group (Miller, 2004). Moreover, diabetes care in the VHA system is complex, since patients frequently have co-morbidities such as advancing age and post-traumatic stress disorder. Deleterious effects of diabetes on gastric function are highly prevalent and associated with considerable morbidity. However, the management of diabetic gastric complications remains unsatisfactory, despite an excellent record of adherence to accepted treatment guidelines, in part because mechanisms of gastric emptying abnormalities are so poorly understood. As a result, diagnosis of the underlying pathophysiology in individual cases is difficult, and since current treatment approaches are largely empirical rather than rationally designed, effective therapeutic options are often lacking. The study of the pathogenesis and treatment of gastric abnormalities in diabetes is complicated because: 1) symptoms may arise from either fast or slow gastric emptying; 2) gastric emptying is determined by the integrated response of independently regulated anatomic and functional regions of the stomach, so similar defects may result in either fast or slow gastric emptying depending on the region and/or cell type that is involved; and 3) different patterns of gastric motility regulate gastric emptying of solids and liquids during the digestive and inter-digestive periods; 4) finally, it is not entirely clear how best to use diabeti animal models in investigating diabetic gastroparesis. While many animal models of diabetes are available, it is unknown which of them most closely represents the features of human disease. Gastric emptying is regulated by distinct activities in gastric fundus, corpus/antrum and pylorus. Fast gastric emptying most often results from loss of inhibitory neurotransmission in the fundus, which is composed of tonic muscle and serves to store and accommodate ingested food by relaxing under the influence of inhibitory nerves. Slow gastric emptying often results from defective propulsive activity in the corpus/pylorus or defective relaxation of the pylorus. Defects in smooth muscle, interstitial cells of Cajal (ICC) and neuromuscular neurotransmission have all been described in the stomach of diabetic animals, with loss of ICC and impaired nitrergic and cholinergic neurotransmission being the most consistent findings. However, we find that purinergic neurotransmission is also lost, suggesting that both vesicular and non-vesicular neurotransmission are impaired. The purpose of this proposal is to investigate the pathogenesis of diabetes-associated changes in gastric emptying. In Aim 1, we will investigate the spectrum of neurotransmission deficits in different stomach regions of diabetic mice with predefined fast and slow gastric emptying. These studies will be performed in different animal models of diabetes to determine the degree to which these models share a common pathophysiology. These studies will define the pathogenesis of fast and slow gastric emptying, and generate reliable, reproducible data in disordered diabetic stomach. In Aim 2, we will systematically examine the hypothesis that dysfunction of the intracellular cargo motor, myosin 5a (myo5a), is an important cause of neurotransmitter deficit in diabetic stomach. This hypothesis is based on our studies showing myo5a dysfunction results in impaired release of multiple neurotransmitters. Aim 3 will test the hypothesis that hyperglycemia leads to elevated myo5a O-GlcNAcylation, suppressing its activity and inhibiting neurotransmission, as well as enabling its premature degradation. Elucidation of the pathway involved in suppression of enteric neurotransmission may identify novel targets of therapy for diabetic stomach.