Effects of hyperglycemia on gastric emptying

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。虽然与许多疾病有关，但胃轻瘫最常见的原因是糖尿病。我们先前已经表明，急性高血糖诱导的葡萄糖输注显着延迟固体胃排空正常大鼠。 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型糖尿病动物模型）。与急性高血糖相反，STZ注射后2周大鼠的胃排空显著加速，与注射溶媒的大鼠相比。从胃粘膜释放的ghrelin主要刺激迷走神经传入，加速胃排空。在STZ注射后2-4周，大鼠的血浆胃饥饿素水平升高。我们的初步研究还表明，与注射溶剂相比，STZ注射后2周，餐后血浆ghrelin水平和胃ghrelin mRNA表达显著增加。我们发现，胃饥饿素抗体和胃饥饿素受体拮抗剂的管理显着衰减STZ注射后2周的胃排空加速，表明亚急性高血糖通过增加血浆胃饥饿素水平加速胃排空。 已经表明胰岛素抑制循环胃饥饿素水平。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ghrelin水平，这可能会加速亚急性低血糖症的胃排空。 相比之下，胃排空显着延迟8周后STZ注射。已经表明，糖尿病自主神经病变在STZ注射后6-8周发展。因此，STZ注射后8周观察到的胃排空延迟可能是由自主神经系统活动受损所致。我们的初步研究显示，注射STZ后8周，血浆ghrelin水平不再升高。由于ghrelin的释放是通过迷走神经传出神经正调控的，因此低胰岛素血症对ghrelin释放的刺激作用可能被慢性高血糖症中迷走神经传出神经活动受损所掩盖。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快和晚期胃排空延迟的机制。我们将研究胰岛素治疗是否能改变胃饥饿素的分泌，并阻止慢性高血糖患者自主神经病变的发展，从而导致正常的胃排空。 公共卫生相关性： 叙述;胃轻瘫是固体或液体胃排空延迟，发生在没有机械性梗阻的情况下。虽然与许多疾病有关，但胃轻瘫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）糖尿病患者存在固体或液体食物胃排空延迟。我们将集中研究链脲佐菌素（STZ）诱导的糖尿病大鼠生长素释放肽的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ghrelin合成的重要因素的假设，我们将使用STZ大鼠。 本研究为阐明糖尿病早期胃排空加快和晚期胃排空延迟的机制提供了理论依据。希望本研究能为今后更好地治疗糖尿病性胃轻瘫患者做出贡献。

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.