Department of Medicine, Albert Einstein College of Medicine, Belfer 702, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
J Clin Endocrinol Metab. 2011 Nov;96(11):3424-31. doi: 10.1210/jc.2011-1723. Epub 2011 Sep 14.
Recurrent hypoglycemia induces hypoglycemia-associated autonomic failure (HAAF), characterized by deterioration in counterregulatory responses. Endogenous opioids may mediate the development of HAAF, and blockade of opioid receptors with naloxone prevented HAAF in nondiabetic subjects.
We hypothesized that opioid receptor blockade with naloxone during antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM) would prevent the development of HAAF.
DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Eight subjects with T1DM (three women, aged 34 ± 7.4 yr, hemoglobin A1c 7.3 ± 1.1%) were studied on 2 consecutive days on three separate occasions. Day 1 consisted of: 1) two 90-min hypoglycemic clamps (60 mg/dl, N-); 2) two 90-min hypoglycemic clamps (60 mg/dl) with concomitant naloxone infusion (N+); or 3) two 90-min euglycemic clamps (90 mg/dl) with concomitant naloxone infusion (control). Day 2 consisted of hyperinsulinemic stepped hypoglycemic clamps (90, 80, 70, and 60 mg/dl plasma glucose steps).
Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover [(3-(3)H)-glucose] as indicators of recovery from hypoglycemia.
Antecedent hypoglycemia in N- group resulted in a markedly decreased epinephrine response and a lower rate of endogenous glucose production (EGP) during subsequent hypoglycemia compared with control (75 ± 17 vs. 187 ± 21 pg/ml, P < 0.05 and 0.8 ± 0.1 vs. 1.4 ± 0.2 mg/kg · min, P < 0.05, respectively). In contrast, in the N+ studies, plasma epinephrine was 164 ± 18 pg/ml and EGP was 1.3 ± 0.2 mg/kg · min during subsequent hypoglycemia, both levels similar to those seen in control studies (P = NS vs. control). Plasma glucagon did not increase with hypoglycemia.
Blockade of endogenous opioids with naloxone during antecedent hypoglycemia improves HAAF in patients with T1DM by ameliorating the epinephrine response and restoring EGP.
反复低血糖会导致低血糖相关自主神经衰竭（HAAF），其特征是代偿反应恶化。内源性阿片类物质可能介导 HAAF 的发生，纳洛酮阻断阿片受体可预防非糖尿病患者的 HAAF。
我们假设在 1 型糖尿病（T1DM）患者的前驱性低血糖期间，用纳洛酮阻断阿片受体可预防 HAAF 的发生。
设计、地点、参与者和干预措施：8 名 T1DM 患者（3 名女性，年龄 34 ± 7.4 岁，糖化血红蛋白 7.3 ± 1.1%）在 3 个不同时间点连续 2 天进行了 3 项研究。第 1 天包括：1）2 次 90 分钟低血糖钳夹（60mg/dl，N-）；2）2 次 90 分钟低血糖钳夹（60mg/dl）同时输注纳洛酮（N+）；或 3）2 次 90 分钟正常血糖钳夹（90mg/dl）同时输注纳洛酮（对照）。第 2 天进行高胰岛素递增性低血糖钳夹（90、80、70 和 60mg/dl 血糖步长）。
第 2 天低血糖时的激素反应和葡萄糖周转（[3-（3）H]-葡萄糖）作为低血糖恢复的指标。
N-组的前驱性低血糖导致随后低血糖时的肾上腺素反应明显降低，内源性葡萄糖生成率（EGP）降低，与对照相比（75 ± 17 与 187 ± 21pg/ml，P < 0.05 和 0.8 ± 0.1 与 1.4 ± 0.2mg/kg·min，P < 0.05）。相比之下，在 N+研究中，随后低血糖时的血浆肾上腺素为 164 ± 18pg/ml，EGP 为 1.3 ± 0.2mg/kg·min，均与对照研究相似（与对照相比，P=NS）。血浆胰高血糖素在低血糖时没有增加。
在前驱性低血糖期间用纳洛酮阻断内源性阿片类物质可通过改善肾上腺素反应和恢复 EGP 来改善 T1DM 患者的 HAAF。
