背景:低血糖相关性自主神经衰竭(HAAF),定义为对复发性低血糖的反调节激素和症状反应的钝化,仍然是糖尿病治疗的治疗挑战。阿片样物质系统可能在HAAF发病机制中起作用,因为阿片样物质受体的激活诱导HAAF。静脉内纳洛酮阻断阿片受体可通过实验改善HAAF,但在治疗上不可行。
目的:研究鼻内纳洛酮阻断阿片受体对实验性HAAF的影响。
方法:随机化,双盲,安慰剂对照交叉研究。
方法:学术研究中心。
方法:健康非糖尿病志愿者。
方法:配对的为期两天的研究,相隔5-10周,每个包括三个连续的低血糖发作(高胰岛素低血糖钳夹,葡萄糖最低点:54mg/dL):第1天两次,鼻内纳洛酮与安慰剂,接着是第2天的第三集.
方法:纳洛酮第一次和第三次低血糖发作之间的反调节激素反应和低血糖症状的差异安慰剂研究。
结果:在17名参与者中,9开发的HAAF,确认可变的个体间易感性。在对HAAF易感的参与者中,纳洛酮维持了对低血糖的一些激素和症状反应,并阻止了增加葡萄糖输注的相关需求。出乎意料的是,纳洛酮降低了血浆肾上腺素和生长激素对首次低血糖发作的反应,但阻止了随后低血糖的进一步降低。
结论:这是第一个报告鼻内纳洛酮,广泛使用的阿片受体拮抗剂,可以改善HAAF的一些特征。有必要进一步研究不同个体间对HAAF易感性的机制以及鼻内纳洛酮对有HAAF风险的糖尿病患者的影响。
BACKGROUND: Hypoglycemia-associated autonomic failure (
HAAF), defined as blunting of counter-regulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in
HAAF pathogenesis since activation of opioid receptors induces
HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates
HAAF experimentally, yet is not feasible therapeutically.
OBJECTIVE: To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally-induced HAAF.
METHODS: Randomized, double-blinded, placebo-controlled crossover study.
METHODS: Academic research center.
METHODS: Healthy non-diabetic volunteers.
METHODS: Paired two-day studies, 5-10 weeks apart, each consisting of three consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): two on day 1 with administration of intranasal naloxone vs. placebo, followed by the third episode on day 2.
METHODS: Differences in counter-regulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs. placebo studies.
RESULTS: Out of 17 participants, 9 developed HAAF, confirming variable inter-individual susceptibility. Among participants susceptible to
HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and growth hormone responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia.
CONCLUSIONS: This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable inter-individual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for
HAAF.