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）： 摘要 胃轻瘫（胃排空延迟）发生在没有机械性梗阻的情况下。尽管胃轻瘫与许多疾病有关，但最常见的原因是糖尿病。我们之前已经表明，葡萄糖输注引起的急性高血糖显着延迟正常大鼠的固体胃排空。 为了研究高血糖的长期影响（高血糖的亚急性和慢性影响），我们利用链脲佐菌素 (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，与注射载体的大鼠相比，注射 STZ 2 周后大鼠的胃排空显着加速。从胃粘膜释放的生长素释放肽主要刺激迷走神经传入，加速胃排空。注射 STZ 后 2-4 周，大鼠血浆生长素释放肽水平升高。我们的初步研究还表明，与注射赋形剂相比，注射 STZ 2 周后餐后血浆 ghrelin 水平和胃 ghrelin mRNA 表达显着增加。我们发现，注射 STZ 后 2 周，给予生长素释放肽抗体和生长素释放肽受体拮抗剂显着减弱胃排空加速，表明亚急性高血糖通过血浆生长素释放肽水平增加而加速胃排空。 有人认为胰岛素会抑制循环中的生长素释放肽水平。 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释放肽水平，这可能会加速亚急性低血糖时的胃排空。 相反，注射 STZ 后 8 周，胃排空明显延迟。研究表明，注射 STZ 后 6-8 周会出现糖尿病自主神经病变。因此，注射 STZ 后 8 周观察到的胃排空延迟可能是由于自主神经系统活动受损所致。我们的初步研究表明，注射 STZ 后 8 周，血浆生长素释放肽水平不再升高。由于生长素释放肽的释放通过迷走神经传出受到正向调节，因此低胰岛素血症对生长素释放肽释放的刺激作用可能被慢性高血糖中迷走神经传出活动受损所掩盖。本研究旨在从ghrelin产生和自主神经病变的角度探讨糖尿病早期胃排空加速和糖尿病晚期胃排空延迟的机制。我们将研究胰岛素治疗是否会改变生长素释放肽的分泌并防止自主神经病变的发展，从而导致慢性高血糖患者胃排空正常。 公共卫生相关性： 叙述;胃轻瘫是固体或液体的胃排空延迟，发生在没有机械性梗阻的情况下。尽管胃轻瘫与许多疾病有关，但最常见的原因是糖尿病。大约一半的胰岛素依赖型（I 型）或非胰岛素依赖型（II 型）糖尿病患者固体或液体食物的胃排空延迟。我们将重点关注链脲佐菌素 (STZ) 诱导的糖尿病大鼠中生长素释放肽合成与自主神经病变之间的关系。 STZ大鼠是I型（胰岛素缺乏）糖尿病的动物模型。由于我们将研究胰岛素缺乏是调节生长素释放肽合成的重要因素这一假设，因此我们将利用 STZ 大鼠。 我们的研究可能阐明糖尿病早期胃排空加速和糖尿病晚期胃排空延迟的机制。我们希望我们的研究能够为未来更好地治疗 VA 患者的糖尿病胃轻瘫做出贡献。