HYPOGLYCEMIA AND EXERCISE IN CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。该项目的具体目的是确定儿童/青少年1型糖尿病患者对运动的适应性血糖调节反应是否减弱，从而导致该组患者高发低血糖。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。低血糖可扰乱日常活动，引起危及生命的事件，诱发胎儿损伤，改变儿童认知功能，并对智力功能产生长期的负面影响。低血糖的发生往往与体育锻炼有关，常常迫使患者放弃运动的一些有益效果，包括改善胰岛素敏感性和血糖控制，改善血压控制和预防心血管疾病，这些患者的风险较高。最近T1DM患者低血糖发生率增加的原因尚不完全清楚。虽然最近采用更积极的胰岛素治疗方案肯定起了作用，但很明显，患者对低血糖的反应能力也发生了更复杂的变化。这一现象的潜在机制尚不清楚。当低血糖发生时，一系列反应（定义为反调节反应）被激活，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的产生，并能纠正低血糖。然而，如果最近发生过应激事件（包括低血糖本身），这些反应的激活可能会变得严重不足。因此，经常发生反复低血糖的T1DM患者陷入了一个恶性循环，每次低血糖发作都会削弱对后一次低血糖发作的反应，包括更多的低血糖，等等。虽然这种现象是可逆的，但实际上往往导致反监管能力的持续丧失。在运动过程中，骨骼肌增加葡萄糖的摄取以产生能量。因此，循环中的葡萄糖水平可能会迅速下降。然而，在大范围的运动强度和持续时间内，这种情况不会发生，因为反调节反应（类似于低血糖引起的反应）被激活，刺激内源性葡萄糖的产生。然而，如果反调节反应严重不足，运动期间可能会发生低血糖。在健康成人和1型糖尿病成人患者中，运动过程中反调节反应的急性失效可能由先前的低血糖引起。此外，运动还会急剧增加胰岛素敏感性。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，先前的应激有利于运动相关的低血糖。上述先前压力对随后运动的钝化作用仅在成人中观察到。然而，重要的是要确定这些概念是否也适用于T1DM患者中低血糖发生率最高的儿童。在糖尿病控制和并发症试验中，一项为期6.5年的随访显示，在常规治疗的青少年中，严重低血糖发生率为27.8次/100例/年，在常规治疗的成人中为18.7次，在强化治疗的青少年中为85.7次。在同一项研究中，低血糖昏迷或癫痫发作在常规治疗的青少年中发生5.4次/100例/年，在强化治疗的青少年中发生16.3次。儿童/青少年也是身体活动最多的年龄组，因此T1DM儿童出现与运动相关的低血糖的高发并不奇怪。低血糖可在运动后1-2小时或10-17小时发生。低血糖常发生在运动后的夜间睡眠中。对运动的适应还会引发一系列更广泛的反应，包括炎症细胞因子和生长因子的分泌。尽管许多这些药物经常表现出血糖调节活性，但它们在应激过程中可能调节葡萄糖稳态的作用尚未得到研究。促炎因子IL-6是运动中升高最多的细胞因子。除了其免疫调节特性，IL-6还可以刺激儿茶酚胺、皮质醇、生长激素和胰高血糖素的分泌，并可能具有直接的血糖调节作用，已被多项体外研究证实。因此，最近有人假设，活动骨骼肌产生的IL-6可能在一定程度上介导运动期间的葡萄糖稳态。生长激素->胰岛素样生长因子I （GH -> IGF-I）轴是全身合成代谢的关键调节因子。运动时生长激素增加，但IGF- 1水平基本保持不变，尽管其大多数调节因子（胰岛素、生长激素、IL-6、IGF BP-1）发生了显著变化。在儿童中，这可能被视为一种保留IGF-1合成代谢/发育作用的尝试，同时避免因其胰岛素样作用而扰乱葡萄糖稳态。虽然生长激素（刺激IGF- i）和胰岛素（其减少刺激IGF- BP-1）（反过来抑制IGF- i对运动的反应）都明显受到先前低血糖的影响，但目前尚不清楚在成人或儿童中，先前的应激是否会影响运动中的IGF- i或IGF- BP-1反应。基于上述考虑，我们的假设是：a)适应性反应旨在维持运动期间的葡萄糖稳态，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）外，还包括细胞因子（IL-6）和生长因子（IGF- i、IGF BP-1）。b)这种适应性反应的改变可能是由先前的应激引起的，例如先前的低血糖，导致运动期间内源性葡萄糖生成（EGP）不足和/或运动引起的胰岛素敏感性增加的变化。c)特别是在T1DM儿童中，与健康对照儿童相比，暴露于频繁、复发性低血糖和其他慢性应激会导致对运动的适应性反应减弱。

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.