NEUROENDOCRINE ETIOLOGY OF DIABETIC GASTROPATHY

糖尿病胃病的神经内分泌病因

• 批准号: 2518304
• 负责人: THOMAS V NOWAK
• 金额: $ 8.24万
• 依托单位: ST. VINCENT HOSP/HLTH CARE CTR (INDNPLS)
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518304
• 关键词: adenosinetriphosphatase; aldehyde reductase; drug related diabetes mellitus; fructose; gastrointestinal motility /pressure; glucose; glucose metabolism; insulin; isozymes; laboratory rat; messenger RNA; neuroendocrine system; overeating; pancreas transplantation; paralysis; pathologic process; phosphatidylinositols; sciatic nerve; sorbitol; starvation; stomach; streptozotocin; vagus nerve; vasoactive intestinal peptide

Clinical studies of human diabetic gastroparesis support the notion of autonomic neural dysfunction as a causative factor. Vagal nerve dysfunction has been documented in patients with diabetic gastropathy, but it is unclear whether this is an etiologic factor or an associated phenomenon. Although neuropeptides such as vasoactive intestinal polypeptide (VIP) and cholecystokinin (CCK) have been shown to influence neuromuscular transmission, the role of endocrine factors in the pathophysiology of diabetic gastroparesis has remained unexamined. The aim of this research proposal is to study the neural and endocrine controls of gastric emptying in experimental diabetes. The proposed investigations examine the influence of the duration of diabetes, the effects of hyperphagia and caloric malnutrition, and the influence of glycemic control with insulin on gastric emptying. Studies will determine whether the observed changes in gastric emptying are associated with altered gastric tissue levels of neuropeptides (VIP,CCK,neurotensin) or neuropeptide release. These studies examine the influence of the duration of the diabetic state on vagal and sciatic nerve concentrations of glucose, fructose, sorbitol, myoinositol, and Na+-K+-ATPase activity. Since the Principal Investigator's preliminary studies show that diabetes acutely reduces sciatic and vagus nerve Na+- K+-ATPase activities, experiments will examine the temporal effect of diabetes mellitus on the expression of 1) isoforms of Na+-K+-ATPase and 2) mRNA for the Na+-K+-ATPase isoforms in vagus and sciatic nerve. Studies will also examine whether identified abnormalities in diabetic vagus nerve can be improved by dietary myoinositol supplementation or aldose reductase inhibition in a manner similar to that observed in the diabetic sciatic nerve. These investigations will determine whether abnormalities in glucose metabolism and polyol pathway activity evident in diabetic peripheral nerve are also operant in the autonomic vagus nerve. In vitro studies will examine the influence of the vagus nerves and intrinsic nervous system on the compliance properties of the diabetic stomach as well as the influence of diabetes on distension-induced gastric neuropeptide release. Finally, a separate group of streptozotocin-treated diabetic rodents will undergo heterotopic pancreas transplantation to determine how well pancreas transplantation compares with conventional insulin treatment in preventing the complications of diabetes mellitus. It is anticipated that these studies will help define the neural mechanisms associated with diabetic gastropathy. Ultimately, the results of these investigations will improve not only the understanding of diabetic gastropathy, but also the treatment of patients with this disorder.

人类糖尿病性胃轻瘫的临床研究支持 自主神经功能障碍是病因。迷走神经 糖尿病胃病患者已记录了功能障碍， 但是目前尚不清楚这是病因学因素还是相关因素 现象。虽然神经肽如血管活性肠道 多肽（VIP）和胆囊动蛋白（CCK）已显示出影响 神经肌肉传播，内分泌因子在 糖尿病性胃癌的病理生理尚未审查。这 该研究建议的目的是研究神经和内分泌 实验性糖尿病中胃排空的控制。 拟议的调查检查了持续时间的影响 糖尿病，倍率和热量营养不良的作用，以及 胰岛素血糖控制对胃排空的影响。研究 将确定观察到的胃排空变化是 与神经肽的胃组织水平改变有关 （VIP，CCK，神经素）或神经肽释放。这些研究检查了 糖尿病状态持续时间对迷走神经和坐骨神经的影响 神经浓度的葡萄糖，果糖，山梨糖醇，肌醇和肌醇的浓度 Na+-K+-ATPase活性。由于首席研究员的初步 研究表明，糖尿病急性减少坐骨神经和迷走神经Na+ - K+-ATPase活动，实验将检查 Na+-k+-ATPase和 2）MRNA用于迷走神经和坐骨神经中的Na+-K+-ATPase同工型。 研究还将检查是否发现糖尿病的异常 通过补充饮食中的肌醇或 醛糖还原酶抑制的方式与在 糖尿病坐骨神经。这些调查将确定是否 葡萄糖代谢和多元醇途径活性的异常 在糖尿病外周神经中也是自主神经中的操作者 神经。体外研究将检查迷走神经的影响 以及糖尿病患者合规性的内在神经系统 胃以及糖尿病对延伸引起的影响 胃神经肽释放。最后，一组单独 链蛋白酶治疗的糖尿病啮齿动物会发生异位胰腺 移植以确定胰腺移植的比较程度 进行常规的胰岛素治疗以防止 糖尿病。 预计这些研究将有助于定义神经 与糖尿病性胃病相关的机制。最终，结果 这些调查不仅会改善对的理解 糖尿病性胃病，但也对患者进行治疗 紊乱。