Effects of hyperglycemia on gastric emptying

高血糖对胃排空的影响

• 批准号: 8262612
• 负责人: Toku Takahashi
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262612
• 关键词: Acute; Animal Model; Antibodies; Atropine; Attenuated; Autonomic nervous system; Autonomic nervous system disorders; Blood Glucose; Canis familiaris; Chronic; Conscious; Development; Diabetes Mellitus; Diabetic Autonomic Neuropathy; Diabetic Neuropathies; Disease; Fc Receptor; Feeding behaviors; Fiber; Future; Gastric Emptying; Gastric mucosa; Gastroparesis; Glucose; Human; Hyperglycemia; Hypoglycemia; Infusion procedures; Injection of therapeutic agent; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Ligands; Liquid substance; Masks; Mechanics; Mediating; Mediation; Mediator of activation protein; Motor; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obstruction; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral Nervous System Diseases; Phase; Plasma; Play; Production; Pyloric antrum; Rat-1; Rattus; Role; Sensory; Solid; Staging; Stomach; Streptozocin; Structure of beta Cell of islet; Testing; Type I Insulin; Up-Regulation; Vagotomy; abstracting; autonomic neuropathy; base; cell motility; cholinergic; design; diabetic; diabetic gastroparesis; diabetic rat; feeding; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; insulin secretion; mRNA Expression; prevent; public health relevance

DESCRIPTION (provided by applicant): Abstract Gastroparesis (delayed gastric emptying) occurs in the absence of mechanical obstruction. Although associated with many diseases, the most frequent cause of gastroparesis is diabetes. We have previously showed that acute hyperglycemia induced by glucose infusion significantly delayed solid gastric emptying in normal rats. To study the prolonged effects of hyperglycemia (subacute and chronic effects of hyperglycemia), we utilized streptozotocin (STZ) induced-diabetic rats (animal model of type I diabetes). To the contrary of acute hyperglycemia, gastric emptying was significantly accelerated in rats 2 weeks after STZ injection, compared to that of vehicle-injected rats. Released ghrelin from the gastric mucosa stimulates primarily vagal afferent, accelerating gastric emptying. The elevated plasma ghrelin level has been shown in rats 2-4 weeks after STZ- injection. Our preliminary study also showed that postprandial plasma ghrelin levels and ghrelin mRNA expression of the stomach were significantly increased 2 weeks after STZ injection, compared to that of vehicle injection. We showed that administration of ghrelin antibody and ghrelin receptor antagonists significantly attenuated the accelerated gastric emptying 2 weeks after STZ injection, suggesting that subacute hyperglycemia accelerates gastric emptying via an increased plasma ghrelin level. It has been suggested that insulin suppresses circulating ghrelin levels. STZ destroys beta cells of pancreas and reduces insulin secretion. Thus, it is likely that hypoinsulinemia may increase plasma ghrelin level, which may accelerates gastric emptying in subacute hypoglycemia. In contrast, gastric emptying was significantly delayed 8 weeks after STZ injection. It has been shown that diabetic autonomic neuropathy develops 6-8 weeks after STZ injection. Thus, delayed gastric emptying observed 8 weeks after STZ injection may be explained by the impaired activity of autonomic nervous system. Our preliminary study showed that plasma ghrelin level was no more elevated 8 weeks after STZ injection. As ghrelin release is positively regulated via vagal efferent, the stimulatory effects of hypoinsulinemia on ghrelin release may be masked by the impaired vagal efferent activity in chronic hyperglycemia. This study was designed to investigate the mechanism of accelerated gastric empting in the early phase of diabetes and delayed gastric empting in the late phase of diabetes, from the view point of ghrelin production and autonomic neuropathy. We will study whether insulin treatment alters ghrelin secretion and prevents the development of autonomic neuropathy resulting in normal gastric emptying in chronic hyperglycemia. PUBLIC HEALTH RELEVANCE: Narrative; Gastroparesis is delayed gastric emptying of either solids or liquids, which occurs in the absence of mechanical obstruction. Although associated with many diseases, the most frequent cause of gastroparesis is diabetes mellitus. About one-half of patients with insulin-dependent (type I) or non insulin-dependent (type II) diabetes have delayed gastric emptying of solid or liquid meals. We will focus on the relationship between ghrelin synthesis and autonomic neuropathy in streptozotocin (STZ)-induced diabetic rats. STZ rats are the animal model of type I (insulin deficiency) diabetes. As we will study the hypothesis that insulin deficiency is an important factor for regulating ghrelin synthesis, we will utilize STZ rats. Our study may clarify the mechanism of accelerated gastric emptying in the early phase of diabetes and delayed gastric emptying in the late phase of diabetes. We hope that our study would contribute to the future's better treatment for diabetic gastroparesis of VA patients.

描述（由申请人提供）： 在没有机械阻塞的情况下，会出现抽象的胃轻瘫（延迟胃排空）。尽管与许多疾病有关，但胃轻瘫的最常见原因是糖尿病。我们先前已经表明，葡萄糖输注诱导的急性高血糖症在正常大鼠中显着延迟了固体胃排空。 为了研究高血糖（高血糖的亚急性和慢性作用）的长期作用，我们利用链蛋白酶（STZ）诱导的糖尿病大鼠（I型糖尿病的动物模型）。与急性高血糖相反，与注射媒介物的大鼠相比，在STZ注射后2周，胃排空显着加速。从胃粘膜中释放出生长素释放蛋白，主要是迷走神经传入，加速胃排空。在STZ注射后2-4周，在大鼠中已显示了血浆血清素水平升高。我们的初步研究还表明，与媒介物注射相比，STZ注射后2周，餐后血浆血浆素水平和胃肽mRNA表达显着增加。我们表明，在STZ注射后2周，施用生长素蛋白抗体和生长素蛋白受体拮抗剂可显着衰减加速的胃排空，这表明亚急性高血糖会通过增加的血浆凝血素水平加速胃排空。 已经提出胰岛素抑制循环的生长素素水平。 STZ破坏胰腺的β细胞并减少胰岛素分泌。因此，低胰岛素血症可能会增加血浆生长素素水平，这可能会加速亚急性低血糖中的胃排空。 相比之下，STZ注射8周后，胃排空显着延迟。已经表明，糖尿病自主神经病在STZ注射后6-8周发展。因此，自主神经系统的活性受损，可以解释出在STZ注射后8周观察到的延迟胃排空。我们的初步研究表明，STZ注射后8周不再升高血浆血浆素水平。由于生长素释放的释放是通过迷走神经的释放阳性调节的，因此低胰岛素血症对生长素释放的刺激作用可能会被慢性高血糖的迷走传递活性受损掩盖。这项研究旨在研究糖尿病早期加速胃空的机制，并从糖尿病的后期（从生长素蛋白的产生点和自主神经病的角度来看）在糖尿病的后期延迟胃空。我们将研究胰岛素治疗是否改变了生长素释放素的分泌并防止自主神经病的发展，从而导致慢性高血症的正常胃排空。 公共卫生相关性： 叙述;胃轻瘫是在没有机械障碍物的情况下发生的固体或液体的胃排空。尽管与许多疾病有关，但胃轻瘫的最常见原因是糖尿病。大约一半的患有胰岛素依赖性（I型）或非胰岛素依赖性（II型）糖尿病患者的患者的固体或液体餐延迟胃排空。我们将重点介绍链霉菌素（STZ）诱导的糖尿病大鼠中生长素素合成与自主神经病之间的关系。 STZ大鼠是I型（胰岛素缺乏）糖尿病的动物模型。正如我们将研究胰岛素缺乏症是调节生长素合成的重要因素的假设，我们将利用STZ大鼠。 我们的研究可能会阐明糖尿病早期加速胃排空的机制，并在糖尿病晚期延迟胃排空。我们希望我们的研究将有助于对VA患者的糖尿病性胃轻瘫的未来治疗。