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.
Showing the most recent 10 out of 1825 publications
