Davis S N, Shavers C, Costa F
Department of Medicine, Vanderbilt University School of Medicine and Veterans Affairs Medical Center, Nashville, Tennessee 37232-6303, USA.
J Clin Endocrinol Metab. 2000 Jun;85(6):2148-57. doi: 10.1210/jcem.85.6.6641.
Compared to men, inherent counterregulatory responses are reduced in healthy and type 1 diabetic women. Despite this, the prevalence of hypoglycemia in patients with type 1 diabetes (type 1 DM) is gender neutral. The aim of this study was to determine the in vivo mechanism(s) responsible for this apparent clinical paradox. The central importance of antecedent hypoglycemia in causing subsequent counterregulatory failure is now established. We, therefore, hypothesized that a gender-related difference to the blunting effects of prior hypoglycemia may exist, and this could explain why type 1 DM women do not have an increased prevalence of hypoglycemia despite reduced counterregulatory responses. Fifteen healthy male and female individuals (eight men and seven women) underwent four separate 2-day experimental protocols in a randomized fashion. Day 1 involved identical morning and afternoon 2-h hyperinsulinemic (9 pmol/kg x min) glucose clamp studies with 5.1 +/- 0.1, 3.9 +/- 0.1, 3.3 +/- 0.1, or 2.9 +/- 0.1 mmol/L. Day 2 consisted of a single 2-h hypoglycemic clamp of 2.9 +/- 0.1 mmol/L. Insulin levels were similar on both days of each protocol in men and women. After day 1 euglycemia (5.1 +/- 0.1 mmol/L), day 2 counterregulatory responses were significantly increased (P < 0.01) in men relative to women. In women, counterregulatory responses were resistant to the effects of day 1 hypoglycemia. Antecedent hypoglycemia of 3.9, 3.3, and 2.9 +/- 0.1 mmol/L produced 3 +/- 2%, 5 +/- 2%, and 25 +/- 4% aggregate reductions in day 2 neuroendocrine, muscle sympathetic nerve activity, and metabolic counterregulatory responses. In marked contrast, identical day 1 hypoglycemia of 3.9, 3.3, and 2.9 +/- 0.1 mmol/L in men produced significantly greater reductions in day 2 counterregulatory responses of 30 +/- 6%, 39 +/- 6%, and 52 +/- 6%, respectively. The net effect of the differential gender effects of antecedent hypoglycemia was to overcome the usually increased (50%) sympathetic nervous system (SNS) counterregulatory responses to hypoglycemia found in men. We conclude that 1) antecedent hypoglycemia produces less blunting of counterregulatory responses to subsequent hypoglycemia in women relative to men; 2) two episodes of antecedent hypoglycemia can overcome the greater SNS response to hypoglycemia usually found in men; and 3) the reduced susceptibility of women to the blunting effects of antecedent hypoglycemia may be the mechanism explaining why, despite inherently reduced SNS counterregulatory responses, female type 1 DM patients have a similar prevalence of hypoglycemia compared to men.
与男性相比，健康女性和1型糖尿病女性的内源性对抗调节反应有所减弱。尽管如此，1型糖尿病（T1DM）患者低血糖的患病率在性别上并无差异。本研究的目的是确定导致这一明显临床矛盾现象的体内机制。先前低血糖在导致随后对抗调节功能衰竭中的核心重要性现已明确。因此，我们推测可能存在与性别相关的对先前低血糖钝化作用的差异，这可以解释为什么1型糖尿病女性尽管对抗调节反应减弱，但低血糖患病率并未增加。15名健康男性和女性个体（8名男性和7名女性）以随机方式接受了4个独立的为期2天的实验方案。第1天包括相同的上午和下午2小时高胰岛素血症（9 pmol/kg·min）血糖钳夹研究，血糖水平分别为5.1±0.1、3.9±0.1、3.3±0.1或2.9±0.1 mmol/L。第2天包括一次2小时的2.9±0.1 mmol/L低血糖钳夹。在每个方案的两天中，男性和女性的胰岛素水平相似。在第1天血糖正常（5.1±0.1 mmol/L）后，第2天男性的对抗调节反应相对于女性显著增加（P<0.01）。在女性中，对抗调节反应对第1天低血糖的影响具有抗性。3.9、3.3和2.9±0.1 mmol/L的先前低血糖分别使第2天神经内分泌、肌肉交感神经活动和代谢对抗调节反应的总和降低3±2%、5±2%和25±4%。形成鲜明对比的是，男性中相同的第1天3.9、3.3和2.9±0.1 mmol/L低血糖分别使第2天的对抗调节反应显著降低30±6%、39±6%和52±6%。先前低血糖的性别差异效应的净结果是克服了男性中通常增加的（50%）对低血糖的交感神经系统（SNS）对抗调节反应。我们得出结论：1）相对于男性，先前低血糖对女性随后低血糖的对抗调节反应的钝化作用较小；2）两次先前低血糖发作可以克服男性中通常出现的对低血糖更大的SNS反应；3）女性对先前低血糖钝化作用的敏感性降低可能是解释为什么尽管女性1型糖尿病患者的SNS对抗调节反应固有地降低，但与男性相比低血糖患病率相似的机制。
