Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans
Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans
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DOI：
10.2337/db16-1478
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发表时间：
2017-11-01
期刊：
影响因子：
7.7
通讯作者：
Hawkins, Meredith
中科院分区：
文献类型：
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作者：
Carey, Michelle;Gospin, Rebekah;Hawkins, Meredith
尽管强化血糖控制可以改善 1 型糖尿病 (T1DM) 的预后，但医源性低血糖限制了其实现。复发性和/或既往低血糖会导致保护性反调节反应减弱，称为低血糖相关自主神经衰竭（HAAF）。为了确定阿片受体激活是否以及如何诱发人类 HAAF，12 名无糖尿病的健康受试者（7 名男性，年龄 32.3 +/- 2.2 岁，BMI 25.1 +/- 1.0 kg/m(2)）连续两天随机参加了两项研究方案。第一天，受试者接受两次 120 分钟的生理盐水或吗啡输注（0.1 μg/kg/min），中间间隔 120 分钟（均为血糖正常）。第 2 天，受试者接受阶梯式降血糖钳夹（最低点 60 mg/dL），评估反调节激素反应、内源性葡萄糖产生（EGP，使用 6,6-D2-葡萄糖）和低血糖症状。吗啡在第 2 天诱导血浆肾上腺素反应降低约 30%，同时 EGP 和低血糖相关症状降低。因此，我们报告了第一项人体研究，证明药理学阿片受体激活可诱导 HAAF 的一些临床和生化特征，从而阐明参与 HAAF 发展的各种受体的个体作用，并提出在 T1DM 中更安全地强化血糖控制的新药理学方法。
Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 +/- 2.2 years, BMI 25.1 +/- 1.0 kg/m(2)) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 mu g/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an similar to 30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF's development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.