Carey Michelle, Gospin Rebekah, Goyal Akankasha, Tomuta Nora, Sandu Oana, Mbanya Armand, Lontchi-Yimagou Eric, Hulkower Raphael, Shamoon Harry, Gabriely Ilan, Hawkins Meredith
Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY.
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD.
Diabetes. 2017 Nov;66(11):2764-2773. doi: 10.2337/db16-1478. Epub 2017 Aug 31.
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) 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 μg/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 ∼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.
尽管强化血糖控制可改善1型糖尿病（T1DM）的预后，但医源性低血糖限制了这一目标的实现。反复和/或先前的低血糖会导致保护性反调节反应减弱，即低血糖相关自主神经功能衰竭（HAAF）。为了确定阿片受体激活是否以及如何在人类中诱发HAAF，12名无糖尿病的健康受试者（7名男性，年龄32.3±2.2岁，体重指数25.1±1.0kg/m）在连续两天内随机顺序参与两项研究方案。在第1天，受试者接受两次120分钟的生理盐水或吗啡（0.1μg/kg/分钟）输注，中间间隔120分钟休息（均为血糖正常）。在第2天，受试者接受逐步低血糖钳夹（最低点60mg/dL），评估反调节激素反应、内源性葡萄糖生成（EGP，使用6,6-D2-葡萄糖）和低血糖症状。吗啡导致第2天血浆肾上腺素反应降低约30%，同时EGP和低血糖相关症状减少。因此，我们报告了首次在人类中的研究，证明药物性阿片受体激活诱发了HAAF的一些临床和生化特征，从而阐明了参与HAAF发展的各种受体的个体作用，并为T1DM中更安全的强化血糖控制提出了新的药物学方法。
