Role of glucocorticoids in hypoglycemia unawareness

糖皮质激素在低血糖无意识中的作用

基本信息

批准号：
6641137
负责人：
LAUREN JACOBSON
金额：
$ 19.75万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-05 至 2005-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Hypoglycemia unawareness and counterregulatory failure are dangerous complications of intensive insulin therapy in type I diabetes. Hypoglycemia-induced glucocorticoid secretion has been implicated in promoting loss of autonomic responses to hypoglycemia. However, glucocorticoids are both counterregulatory hormones themselves and essential for maintaining secretion of epinephrine, one of the most rapid and effective counterregulatory responses. The relative influence of these opposing glucocorticoid actions on defenses against recurrent hypoglycemia are unknown. In addition, glucocorticoids and their primary neural regulator, corticotropin-releasing hormone (CRH), not only influence one another reciprocally but may also have opposing effects on sympathetic tone. Elucidating the mechanisms and impact of glucocorticoid effects on autonomic activity will aid in preventing hypoglycemia unawareness in diabetic patients. To address these issues, this R21 application proposes to (Aim 1) refine a mouse model of hypoglycemia-induced counterregulatory failure, working closely with investigators at the Mouse Metabolic Physiology Core of Vanderbilt University to use hypoglycemic clamp techniques in protocols for recurrent hypoglycemia in mice. Focusing on adrenomedullary epinephrine secretion as a key, glucocorticoid-dependent aspect of counterregulation, we will (Aim 2) use physiological glucocorticoid replacement in CRH knockout mice (CRH KO) to define the relative influence of glucocorticoids vs. CRH on counterregulatory hormone secretion and adrenomedullary activation induced by acute hypoglycemia. We will then (Aim 3) combine the recurrent hypoglycemia procedures defined in Aim 1 with the glucocorticoid manipulations of Aim 2 to test the hypothesis that glucocorticoids inhibit sympathoadrenal responses to recurrent hypoglycemia independently of CRH. Lastly, to identify potential neural mechanisms for the opposing effects of glucocorticoids on epinephrine secretion, we will (Aim 4) map glucocorticoid-dependent changes in expression of marker genes for neuronal activity (c-fos) and specific neurotransmitters in brains of acutely and recurrently hypoglycemic WT and CRH KU mice from Aim 3. These experiments will establish a mouse model for hypoglycemia unawareness, resolve the conflicting effects of glucocorticoids on sympathoadrenal activity, and reveal potential mechanisms for hypoglycemia-induced counterregulatory failure.

描述（由申请人提供）：低血糖意识和反调节失败是 I 型糖尿病强化胰岛素治疗的危险并发症。低血糖诱导的糖皮质激素分泌与促进低血糖自主反应的丧失有关。然而，糖皮质激素本身都是反调节激素，对于维持肾上腺素的分泌至关重要，肾上腺素是最快速、最有效的反调节反应之一。这些相反的糖皮质激素作用对预防复发性低血糖的相对影响尚不清楚。此外，糖皮质激素及其主要神经调节剂促肾上腺皮质激素释放激素（CRH）不仅相互影响，而且还可能对交感神经张力产生相反的影响。阐明糖皮质激素对自主神经活动的影响机制和影响将有助于预防糖尿病患者无意识地发生低血糖。为了解决这些问题，该 R21 申请建议（目标 1）完善低血糖引起的反调节失败的小鼠模型，与范德比尔特大学小鼠代谢生理学核心的研究人员密切合作，在小鼠复发性低血糖的方案中使用低血糖钳技术。重点关注肾上腺髓质肾上腺素分泌作为反调节的关键、糖皮质激素依赖性方面，我们将（目标 2）在 CRH 敲除小鼠 (CRH KO) 中使用生理性糖皮质激素替代，以确定糖皮质激素与 CRH 对反调节激素分泌和肾上腺髓质的相对影响急性低血糖引起的激活。然后（目标 3）将目标 1 中定义的复发性低血糖程序与目标 2 中的糖皮质激素操作结合起来，以检验糖皮质激素独立于 CRH 抑制交感肾上腺对复发性低血糖反应的假设。最后，为了确定糖皮质激素对肾上腺素分泌的相反作用的潜在神经机制，我们将（目标 4）绘制急性和复发性脑损伤患者大脑中神经元活动标记基因（c-fos）和特定神经递质表达的糖皮质激素依赖性变化。来自目标 3 的低血糖 WT 和 CRH KU 小鼠。这些实验将建立低血糖无意识小鼠模型，解决相互矛盾的问题糖皮质激素对交感肾上腺活性的影响，并揭示低血糖引起的反调节失败的潜在机制。