Visceral Afferent Dysfunction in Diabetic Gastropathy

描述(由申请人提供)： 糖尿病胃病表现为恶心、呕吐、腹胀和疼痛，被认为是胃轻瘫的代名词，因为许多患者表现出胃排空延迟。然而，排空率与症状的相关性很差，治疗的改善与正常化的排空无关。因此，其他因素也是糖尿病胃病症状的致病因素。功能障碍的内脏传入被认为是功能性肠病症状的基础。最近的研究表明，一些伴有恶心和腹胀的糖尿病患者存在痛觉过敏。我们假设：(1)胃感觉改变在糖尿病胃病变中普遍存在，并与症状相关，(2)感觉异常与其他糖尿病神经病变有关，(3)感觉改变与胃病的自然病史平行，(4)治疗反应与传入功能改善有关。我们建议由胃轻瘫临床研究联盟实施2个多中心方案。有6个月恶心、呕吐、腹胀、早饱或不适的糖尿病患者将被招募。第一个方案将通过饱腹感和恒压测试来测量胃感觉和适应缺陷，将其与特定的胃病症状、糖尿病并发症、心理社会参数、生活质量测量、胃排空以及外周和自主神经病变测量相关联。这些研究将量化糖尿病胃病中传入功能障碍的患病率，并评估其在这种情况下症状发展的潜在致病作用。第二个方案将纵向跟踪患有胃病的糖尿病患者。系列饱腹感、稳压和胃排空试验将与周围神经和自主神经病变的临床参数和测量方法相关，以比较糖尿病自然病史中胃感觉和运动功能异常的情况。这项纵向研究中的部分患者将参加治疗试验。在使用纯促动力药物红霉素与安慰剂进行双盲治疗12周之前和12周时，将量化饱腹感、适应能力、知觉和排空。在单独的个体中，将在植入胃刺激器(Enterra)之前和24周后进行胃测试，该刺激器几乎没有促进运动的作用。双盲测试将以假刺激控制的方式进行，有一半的患者在测试前4周关闭设备。每种疗法的胃功能改善将与症状的减少相关，以测试选择性地针对运动功能障碍或增强内脏感觉的疗法是否产生更大的好处。平常人描述：恶心、呕吐和腹胀是长期糖尿病患者的常见症状，严重影响生活质量。这些研究将为糖尿病胃病的症状发病机制提供洞察力，并将指导未来的研究，以纠正这种情况下内脏感觉而不是运动缺陷的治疗方法。

DESCRIPTION (provided by applicant): Diabetic gastropathy, presenting as nausea, vomiting, bloating, and pain, has been considered synonymous with gastroparesis as many patients exhibit delayed gastric emptying. Yet, emptying rates correlate poorly with symptoms and improvements on therapy do not associate with normalized emptying. Thus, other factors are pathogenic of gastropathic symptoms in diabetes. Dysfunctional visceral afferent transmission purportedly underlies symptoms in functional bowel disorders. Recent studies have shown that hyperalgesia is present in some diabetics with nausea and bloating. We hypothesize: (1) altered gastric sensation is prevalent in diabetic gastropathy and correlates with symptoms, (2) sensory abnormalities relate to other diabetic neuropathies, (3) altered sensation parallels the natural history of gastropathy, and (4) responses to therapy relate to improved afferent function. We propose 2 multicenter protocols to be conducted by the Gastroparesis Clinical Research Consortium. Diabetics with >6 months of nausea, vomiting, bloating, early satiety, or discomfort will be recruited. The first protocol will relate gastric sensory and accommodation defects, measured by satiety and barostat tests, to specific gastropathy symptoms, diabetic complications, psychosocial parameters, quality of life measures, gastric emptying, and measures of peripheral and autonomic neuropathy. These studies will quantify the prevalence of afferent dysfunction in diabetic gastropathy and assess its potential pathogenic role in symptom development in this condition. The second protocol will follow diabetics with gastropathy longitudinally. Serial satiety, barostat, and gastric, emptying tests will be correlated with clinical parameters and measures of peripheral and autonomic neuropathy to compare when abnormal gastric sensory vs. motor function develop in the natural history of diabetes. Subsets of patients in this longitudinal study will enroll in treatment trials. Satiety, accommodation, perception, and emptying will be quantified before and at 12 weeks of double-blind therapy with the pure prokinetic drug erythromycin vs. placebo. In separate individuals, gastric testing will be performed before and 24 weeks after implantation of the gastric stimulator (Enterra)-which has little prokinetic action. Double-blind testing will occur in sham-stimulation controlled fashion with the device turned OFF in half of patients 4 weeks before testing. Gastric function improvements with each therapy will be correlated with symptom reductions to test if therapies that selectively target motor dysfunction or heightened visceral sensation produce greater benefits. Lay description: Nausea, vomiting and bloating are prevalent in patients with long-standing diabetes and markedly impair quality of life. These studies will provide insight into symptom pathogenesis in diabetic gastropathy and will direct future research into therapies that correct visceral sensory rather than motor defects in this condition