HYPOGLYCEMIA AND EXERCISE IN CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES

患有 1 型糖尿病的儿童和青少年的低血糖与运动

• 批准号: 7606612
• 负责人: PIETRO R GALASSETTI
• 金额: $ 1.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7606612
• 关键词: Acute; Adolescent; Adoption; Adult; Affect; Anabolism; Attenuated; Catecholamines; Child; Chronic stress; Clinical; Competence; Complex; Complication; Computer Retrieval of Information on Scientific Projects Database; Daily; Development; Diabetes Mellitus; Diabetic Coma; Epinephrine; Event; Exercise; Exposure to; Failure; Funding; Glucagon; Glucose; Grant; Growth Factor; High Prevalence; Hour; Hydrocortisone; Hypoglycemia; In Vitro; Incidence; Inflammatory; Institution; Insulin; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor I; Interleukin-6; Life; Mediating; Norepinephrine; Patients; Play; Production; Property; Range; Recurrence; Research; Research Personnel; Resources; Risk; Role; Seizures; Series; Skeletal Muscle; Sleep; Somatomedins; Somatotropin; Source; Stress; Time; Treatment Protocols; United States National Institutes of Health; age group; base; blood glucose regulation; blood pressure regulation; cardiovascular disorder prevention; cognitive function; concept; cytokine; experience; fetal; follow-up; glucose production; glucose uptake; glycemic control; improved; insulin sensitivity; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The specific aim of this project is to determine whether in children/adolescents with Type 1 Diabetes, the adaptive glucoregulatory response to exercise is attenuated, contributing to the high incidence of hypoglycemia occurring in this group of patients. In the management of patients with Type 1 diabetes mellitus (T1DM), hypoglycemia is a major clinical problem. Hypoglycemia may disrupt daily activities, cause life-threatening events, induce fetal damage, alter cognitive function in children, and exert long-term negative effects on intellectual function. Hypoglycemia often occurs in association with physical exercise, often forcing patients to renounce several beneficial effects of exercise, including improved insulin sensitivity and glycemic control, and improved control of blood pressure and prevention of cardiovascular disease, for which these patients are at elevated risk. The causes of the recent increase in the indidence of hypoglycemia in patients with T1DM are incompletely understood. Although the recent adoption of more aggressive insulin regimens certainly play a role, it has become clear that a more complex alteration of the patients' ability to react against hypoglycemia is also present. The underlying mechanisms of this phenomenon are still unclear. When hypoglycemia occurs, a series of responses (defined as counter-regulatory responses) are activated, including secretion of glucagon, epinephrine, norepinephrine, cortisol, and growth hormone, which stimulate endogenous glucose production, and can correct hypoglycemia. Activation of these responses, however, may become acutely inadequate if an episode of stress (including hypoglycemia itself) occurred recently before. Patients with T1DM, therefore, who experience frequent, recurrent hypoglycemia, are trapped in a vicious cycle in which each episodes of hypoglycemia weakens responses to a later episode, including more hypoglycemia and so on. Although reversible, this phenomenon practically often results in continuous loss of counter-regulatory competence. During exercise, the skeletal muscle increases its glucose uptake for energy production. As a result, circulating levels of glucose may rapidly decrease. This does not occur, however, over a broad range of exercise intensities and durations, because counter-regulatory responses (similar to those elicited by hypoglycemia) are activated, stimulating endogenous glucose production. Hypoglycemia during exercise, however, may supervene if counter-regulatory responses become acutely inadequate. Acute failure of counter-regulatory responses during exercise may be induced by antecedent hypoglycemia in healthy adults and in adult patients with Type 1 diabetes. Further, exercise is also known to acutely increase insulin sensitivity. Modulation of the exercise-induced increase in insulin-sensitivity may be a mechanism by which exercise-associated hypoglycemia is favored by a prior stress. The above blunting effects of prior stress on subsequent exercise have only been observed in adults. It is important, however, to determining whether these concepts also apply to children who, among patients with T1DM, display the highest incidence of hypoglycemia. A 6.5 year follow-up in the Diabetes Control and Complication Trial showed that severe hypoglycemia occurred 27.8 times/100 patients/year in conventionally treated adolescents 18.7 times in conventionally treated adults, and 85.7 times in intensively treated adolescents. In the same study, hypoglycemic coma or seizures occurred 5.4 times/100 patients/year in conventionally treated adolescents and 16.3 times in intensively treated adolescents. Children/adolescents are also the most physically active age group, and not surprisingly T1DM children present with a high prevalence of exercise-related hypoglycemia. Hypoglycemia may occur during, 1-2 hours after, or 10-17 hours after exercise. Often hypoglycemia occurs during sleep in the night following the exercise activity. Adaptation to exercise also elicits a broader series of responses, including secretion of inflammatory cytokines and growth factors. Although many of these agents often display glucoregulatory activity, their role as possible regulators of glucose homeostasis during stress has not been studied. The pro-inflammatory IL-6 is the most abundantly elevated cytokine during exercise. Beyond its immunoregulatory properties, IL-6 can also stimulate secretion of catecholamines, cortisol, GH and glucagon, and may have also direct glucoregulatory effect, as proven in several in vitro studies. It was therefore recently hypothesized that the IL-6 produced by active skeletal muscle may partly mediate glucose homeostasis during exercise. The growth hormone --> insulin-like growth factor I (GH --> IGF-I) axis is a key regulator of systemic anabolism. During exercise GH increases, but IGF-I levels remain substantially constant, despite significant changes in most of its regulatory factors (insulin, GH, IL-6, IGF BP-1). In children this may be viewed as an attempt to preserve the anabolic/developmental effects of IGF-1, while avoiding perturbations in glucose homeostasis due to its insulin-like effects. Although both GH (which stimulates IGF-I), and insulin (whose reduction stimulates IGF BP-1), which in turn inhibits IGF-I responses to exercise are markedly affected by prior hypoglycemia, it is currently unknown whether prior stress affects IGF-I or IGF BP-1 responses in exercise, niether in adults or children. Based on the above considerations, our hypotheses are: a) The adaptive response aimed a maintaining glucose homeostatis during exericse, in addition to neuroendrocrine components (glucagon, catecholamines, cortisol, growth hormone), also includes cytokines (IL-6) and growth factors (IGF-I, IGF BP-1). b) Alterations of this adaptive response may be induced by a prior stress, such as prior hypoglycemia, resulting in inadequate endogenous glucose production (EGP) during exercise and/or changes in the exercise-induced increase in insulin sensitivity. c) In children with T1DM, in particular, exposure to frequent, recurrent hypoglycemia and other chronic stress results in an attenuated adaptive response to exercise, as compared to healthy control children.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的具体目的是确定在患有1型糖尿病的儿童/青少年中是否会减弱对运动的适应性葡萄糖调节反应，从而导致这组患者发生低血糖的高发病率。 在1型糖尿病（T1DM）患者的治疗中，低血糖是一个主要的临床问题。 低血糖可能会破坏日常活动，引起威胁生命的事件，诱发胎儿损害，改变儿童的认知功能，并对智力功能产生长期负面影响。 低血糖通常与体育锻炼有关，通常迫使患者放弃运动的几种有益作用，包括提高胰岛素敏感性和血糖控制，并改善对血压和预防心血管疾病的控制，这些患者的风险升高。 T1DM患者降低血糖的最近增加的原因是尚不完全了解。 尽管最近采用更具侵略性的胰岛素方案肯定起着作用，但很明显，患者对低血糖症的反应能力的变化也更为复杂。 这种现象的基本机制仍不清楚。 当发生低血糖时，激活了一系列反应（定义为反调节反应），包括胰高血糖素，肾上腺素，去甲肾上腺素，皮质醇和生长激素的分泌，它们刺激内源性葡萄糖产生，并可以纠正低血糖症。 但是，如果最近发生的压力（包括低血糖本身）发生，这些反应的激活可能会严重不足。 因此，患有T1DM的患者经历了频繁，复发性低血糖的患者被困在一个恶性循环中，其中每次低血糖症会削弱对以后发作的反应，包括更多的低血糖症等。 尽管可逆，但这种现象实际上通常会导致反调节能力的持续丧失。 在运动过程中，骨骼肌增加了其葡萄糖吸收以产生能源。 结果，循环水平的葡萄糖可能会迅速降低。 但是，在广泛的运动强度和持续时间内，这并没有发生，因为反调节反应（与低血糖引起的反应相似）被激活，刺激了内源性葡萄糖的产生。 但是，如果反调节反应变得严重不足，运动过程中的低血糖可能会监管。 健康成年人和1型糖尿病的成年患者的先决性低血糖症可能会引起反调节反应的急性衰竭。 此外，还知道运动可以急性提高胰岛素敏感性。 运动引起的胰岛素敏感性增加的调节可能是一种机制，通过这种机制，与运动相关的低血糖受到先前的压力有利的机制。 先前的压力对随后的运动的上述钝化作用仅在成年人中观察到。 但是，重要的是要确定这些概念是否也适用于在T1DM患者中表现出最高发病率最高的儿童。 在糖尿病控制和并发症试验中进行了6。5年的随访表明，常规治疗的青少年在常规治疗的成年人中发生了27.8次/100名患者/年/年，在经常治疗的成年人中发生了18.7次，在经过敏感治疗的青少年中发生了85.7次。 在同一项研究中，降血糖昏迷或癫痫发作发生在常规治疗的青少年中5.4次/100名患者/年，在经过严格治疗的青少年中发生了16.3次。 儿童/青少年也是最活跃的年龄组，并不奇怪的是，T1DM儿童患有与运动有关的低血糖患病率很高。 运动后1-2小时或运动后10-17小时可能发生低血糖。 运动活动后夜晚的睡眠期间通常发生低血糖。 适应运动还引起了更广泛的反应，包括分泌炎症性细胞因子和生长因子。 尽管这些药物中的许多经常表现出葡萄糖调节活性，但尚未研究其在压力期间的作用作为葡萄糖稳态的调节剂。 促炎性IL-6是运动过程中升高的细胞因子。 除了其免疫调节特性外，IL-6还可以刺激儿茶酚胺，皮质醇，GH和胰高血糖素的分泌，并且在几项体外研究中证明，也可能具有直接的葡萄糖调节作用。 因此，最近假设由活性骨骼肌产生的IL-6可能在运动过程中部分介导葡萄糖稳态。 生长激素 - >胰岛素样生长因子I（GH-> IGF-I）轴是全身性合物的关键调节剂。 在运动期间，尽管其大多数调节因素发生了显着变化（胰岛素，GH，IL-6，IGF BP-1），但IGF-I水平仍然显着稳定。 在儿童中，这可能被视为试图保留IGF-1的合成代谢/发育作用，同时避免由于其胰岛素样作用而避免葡萄糖稳态扰动。 尽管GH（刺激IGF-I）和胰岛素（其还原刺激IGF BP-1）均均均抑制IGF-I对运动的反应受到先前低血糖的反应显着影响，但目前尚不清楚先前的压力是否会影响IGF-I或IGF BP-1在运动中是否会影响IGF-I或IGF BP-1的反应，而成人或儿童中的儿童或儿童。 基于上述考虑，我们的假设是： a）自适应反应还针对地球过程中维持葡萄糖稳态的，除了神经内分泌成分（胰高血糖素，儿茶酚胺，皮质醇，生长激素），还包括细胞因子（IL-6）和生长因子（IGF-I，IGF-I，IGF BP-1）。 b）这种适应性反应的改变可能是由先前的压力（例如先前的低血糖）引起的，导致运动过程中内源性葡萄糖产生不足和/或运动诱导的胰岛素敏感性增加的变化。 c）在患有T1DM的儿童中，与健康对照儿童相比，在暴露于频繁，复发性低血糖和其他慢性应激的频繁暴露会导致对运动的适应性反应。