Amiel S A, Tamborlane W V, Simonson D C, Sherwin R S
N Engl J Med. 1987 May 28;316(22):1376-83. doi: 10.1056/NEJM198705283162205.
We infused small doses of insulin (0.3 mU per kilogram of body weight per minute; range, 0.9 to 1.7 U per hour) for three hours into 8 subjects who did not have diabetes, 11 patients with well-controlled diabetes (hemoglobin A1, 7.6 +/- 0.7 percent), and 10 patients with poorly controlled diabetes (hemoglobin A1, 11.5 +/- 1.7 percent) to simulate the mild peripheral hyperinsulinemia observed during insulin treatment. Normoglycemia was established in the patients during the night before study. During the insulin infusion, the plasma glucose level stabilized at 60 to 70 mg per deciliter (3.3 to 3.9 mmol per liter) in the subjects without diabetes and the patients with poorly controlled diabetes, because of a rebound increase in hepatic glucose production. In contrast, hypoglycemia developed in the patients with well-controlled diabetes (42 +/- 2 mg of glucose per deciliter, or 2.3 +/- 0.1 mmol per liter, P less than 0.01) as glucose production remained suppressed. The hypoglycemia in the patients with well-controlled diabetes was associated with a lowering of the plasma threshold of glucose that triggered a release of epinephrine (less than 45 mg of glucose per deciliter, or 2.5 mmol per liter, vs. greater than 55 mg per deciliter, or 3.1 mmol per liter, in the other groups, P less than 0.01) as well as an enhanced sensitivity to the suppressive effects of insulin on hepatic glucose production. Nearly identical disturbances in glucose counterregulation and decreased perception of hypoglycemia developed when four of the subjects with poorly controlled diabetes were restudied after intensive treatment. We conclude that strict control of diabetes induces physiologic alterations (delayed release of epinephrine and persistent suppression of glucose production) that impair glucose counterregulation to doses of insulin in the therapeutic range. These defects may contribute to the increased incidence of severe hypoglycemia reported during intensive insulin therapy.
我们对8名非糖尿病受试者、11名血糖控制良好的糖尿病患者（糖化血红蛋白A1，7.6±0.7%）和10名血糖控制不佳的糖尿病患者（糖化血红蛋白A1，11.5±1.7%）持续3小时输注小剂量胰岛素（0.3毫单位/千克体重/分钟；范围为0.9至1.7单位/小时），以模拟胰岛素治疗期间观察到的轻度外周高胰岛素血症。在研究前一晚使患者达到正常血糖水平。在胰岛素输注期间，由于肝葡萄糖生成的反弹增加，非糖尿病受试者和血糖控制不佳的糖尿病患者的血浆葡萄糖水平稳定在60至70毫克/分升（3.3至3.9毫摩尔/升）。相比之下，血糖控制良好的糖尿病患者出现了低血糖（42±2毫克葡萄糖/分升，或2.3±0.1毫摩尔/升，P<0.01），因为葡萄糖生成仍受到抑制。血糖控制良好的糖尿病患者发生低血糖与触发肾上腺素释放的血浆葡萄糖阈值降低有关（低于45毫克葡萄糖/分升，或2.5毫摩尔/升，而其他组高于55毫克葡萄糖/分升，或3.1毫摩尔/升，P<0.01），以及对胰岛素抑制肝葡萄糖生成作用的敏感性增强。当对4名血糖控制不佳的糖尿病受试者进行强化治疗后重新研究时，出现了几乎相同的葡萄糖反调节紊乱和低血糖感知下降。我们得出结论，严格控制糖尿病会引起生理改变（肾上腺素释放延迟和葡萄糖生成持续受到抑制），从而损害对治疗范围内胰岛素剂量的葡萄糖反调节。这些缺陷可能导致强化胰岛素治疗期间严重低血糖发生率增加。
