Pathophysiology of Diabetic Gastroparesis

糖尿病胃轻瘫的病理生理学

• 批准号: 8922590
• 负责人: Raj K Goyal
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922590
• 关键词: Adherence; Affect; Age; Age-Years; Anatomy; Animal Model; Animals; Attenuated; Caring; Characteristics; Chronic Disease; Comorbidity; Complex; Complications of Diabetes Mellitus; Data; Defect; Diabetes Mellitus; Diabetic mouse; Diagnosis; Disease; Elderly; Enteral; Etiology; Expenditure; Experimental Designs; Food; Functional disorder; Fundus; Gastric Emptying; Gastroparesis; Guidelines; Human; Hyperglycemia; Inbred DBA Mice; Individual; Interstitial Cell of Cajal; Liquid substance; Mechanics; Mediating; Medical; Modeling; Modification; Molecular; Morbidity - disease rate; Motor; Mus; Muscle; Myosin ATPase; Nature; Nerve; Neurons; Neurotransmitters; PI3 gene; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Play; Population; Post-Traumatic Stress Disorders; Prevalence; Process; Pyloric antrum; Pyloric sphincter structure; Pylorus; Regulation; Relaxation; Reporting; Role; Rosa; Signal Pathway; Smooth Muscle; Solid; Staging; Stomach; Symptoms; System; Techniques; Testing; Therapeutic; Varicosity; Veterans; base; care systems; cell motility; cell type; cholinergic; cost; design; diabetes management; diabetic; diabetic gastroparesis; gastric fundus; gastrointestinal; human disease; improved; innovation; neuromuscular; neuromuscular transmission; neurotransmission; new therapeutic target; novel; premature; public health relevance; research study; response; statistics; transmission process

 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.

 描述（由申请人提供）： 糖尿病是一种日益常见的疾病，最近估计影响 9.3% 的美国人口和 25.9% 的 65 岁以上人群（国家糖尿病统计报告，2014 年 6 月）。因为 VHA 是一个持续的护理系统，所以糖尿病的所有短期和长期并发症都会在不断扩大的退伍军人群体中遇到（Miller，2004）。此外，VHA 系统中的糖尿病护理很复杂，因为患者经常患有年龄增长和创伤后应激障碍等并发症。糖尿病对胃功能的有害影响非常普遍，并且与相当大的发病率相关。然而，尽管在遵守公认的治疗指南方面有着良好的记录，但糖尿病胃并发症的治疗仍然不能令人满意，部分原因是人们对胃排空异常的机制知之甚少。因此，对个别病例潜在的病理生理学进行诊断很困难，并且由于目前的治疗方法主要是经验性的而不是理性设计的，因此往往缺乏有效的治疗选择。糖尿病胃异常的发病机制和治疗研究很复杂，因为：1）胃排空快或慢可能引起症状； 2）胃排空是由胃的独立调节的解剖和功能区域的综合反应决定的，因此类似的缺陷可能会导致胃排空快速或缓慢，具体取决于所涉及的区域和/或细胞类型； 3）不同的胃运动模式在消化期间和消化间期调节胃排空固体和液体； 4）最后，尚不完全清楚如何最好地使用糖尿病动物模型来研究糖尿病性胃轻瘫。虽然有许多糖尿病动物模型可用，但尚不清楚哪种模型最能代表人类疾病的特征。胃排空由胃底、胃体/胃窦和幽门的不同活动调节。快速胃排空通常是由于胃底抑制性神经传递丧失所致，胃底由强直肌组成，在抑制性神经的影响下通过放松来储存和容纳摄入的食物。胃排空缓慢通常是由于幽门体/幽门推进活动缺陷或幽门松弛缺陷造成的。缺陷 在糖尿病动物的胃中，平滑肌、卡哈尔间质细胞 (ICC) 和神经肌肉神经传递均已被描述，其中 ICC 丧失以及硝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了，这表明囊泡和非囊泡神经传递都受损。该提案的目的是研究糖尿病相关胃排空变化的发病机制。在目标 1 中，我们将研究具有预定义的快速和慢速胃排空的糖尿病小鼠不同胃区域的神经传递缺陷谱。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。这些研究将明确快速和缓慢胃排空的发病机制，并产生糖尿病胃功能紊乱的可靠、可重复的数据。在目标 2 中，我们将系统地检验这样的假设：细胞内货物运动肌球蛋白 5a (myo5a) 的功能障碍是糖尿病胃部神经递质缺陷的重要原因。这一假设基于我们的研究，该研究表明 myo5a 功能障碍会导致多种神经递质的释放受损。目标 3 将检验以下假设：高血糖会导致 myo5a O-GlcNAcNA 酰化升高，抑制其活性并抑制神经传递，并使其过早降解。阐明参与抑制肠神经传递的途径可能会确定糖尿病胃治疗的新靶点。