Dagogo-Jack S, Rattarasarn C, Cryer P E
Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, St. Louis, Missouri 63110.
Diabetes. 1994 Dec;43(12):1426-34. doi: 10.2337/diab.43.12.1426.
To test the hypothesis that the neuroendocrine (including autonomic) responses to hypoglycemia are dissociated from the symptomatic responses to hypoglycemia in insulin-dependent diabetes mellitus (IDDM) patients with hypoglycemia awareness and during reversal of hypoglycemia unawareness in IDDM, we used the hyperinsulinemic stepped hypoglycemic (5.0, 4.4, 3.9, 3.3, 2.8, and 2.2 mmol/l) clamp technique to quantitate these responses in nondiabetic control subjects and IDDM patients with hypoglycemia awareness and with hypoglycemia unawareness. The latter were restudied after 3 days, 3-4 weeks, and 3 months of scrupulous avoidance of iatrogenic hypoglycemia. At baseline, symptom responses were virtually nil in unaware patients (P = 0.0001 vs. nondiabetic); these were increased in aware patients (P = 0.0183 vs. nondiabetic). In contrast, several neuroendocrine responses were comparably reduced in both unaware and aware patients: epinephrine (P = 0.0222 and 0.0156), pancreatic polypeptide (P = 0.0004 and 0.0003), glucagon (P = 0.0112 and 0.0109), and cortisol (P = 0.0214 and 0.0450). In initially unaware patients, symptom responses increased (P = 0.0001) during avoidance of hypoglycemia. Demonstrable after 3 days, these were entirely normal after 3-4 weeks and 3 months. In contrast, none of the neuroendocrine responses increased. Thus, we conclude that several neuroendocrine responses to hypoglycemia (including the adrenomedullary and parasympathetic components of the autonomic response) can be dissociated from symptomatic responses in IDDM patients with hypoglycemia awareness and during reversal of hypoglycemia unawareness in IDDM. Avoidance of iatrogenic hypoglycemia sufficient to reverse the clinical syndrome of hypoglycemia unawareness did not reverse the key elements (deficient glucagon and epinephrine responses) of the clinical syndrome of defective glucose counterregulation. This implies that the mechanisms of hypoglycemia unawareness and of defective glucose counterregulation are, at least in part, different in IDDM.
在有低血糖感知的胰岛素依赖型糖尿病（IDDM）患者以及IDDM低血糖无感知状态逆转过程中，对低血糖的神经内分泌（包括自主神经）反应与对低血糖的症状反应是分离的，我们采用高胰岛素阶梯式低血糖（5.0、4.4、3.9、3.3、2.8和2.2 mmol/l）钳夹技术，对非糖尿病对照受试者以及有低血糖感知和无低血糖感知的IDDM患者的这些反应进行定量分析。后者在严格避免医源性低血糖3天、3 - 4周和3个月后再次接受研究。在基线时，无感知患者的症状反应几乎为零（与非糖尿病患者相比，P = 0.0001）；有感知患者的症状反应有所增加（与非糖尿病患者相比，P = 0.0183）。相比之下，无感知和有感知患者的几种神经内分泌反应均有相应降低：肾上腺素（P = 0.0222和0.0156）、胰多肽（P = 0.0004和0.0003）、胰高血糖素（P = 0.0112和0.0109）以及皮质醇（P = 0.0214和0.0450）。在最初无感知的患者中，避免低血糖期间症状反应增加（P = 0.0001）。3天后可显现，3 - 4周和3个月后这些反应完全正常。相比之下，神经内分泌反应均未增加。因此，我们得出结论：在有低血糖感知的IDDM患者以及IDDM低血糖无感知状态逆转过程中，对低血糖的几种神经内分泌反应（包括自主神经反应的肾上腺髓质和副交感神经成分）可与症状反应相分离。避免足以逆转低血糖无感知临床综合征的医源性低血糖，并未逆转葡萄糖反向调节缺陷临床综合征的关键要素（胰高血糖素和肾上腺素反应不足）。这意味着在IDDM中，低血糖无感知机制和葡萄糖反向调节缺陷机制至少部分不同。
