Dagogo-Jack S E, Craft S, Cryer P E
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
J Clin Invest. 1993 Mar;91(3):819-28. doi: 10.1172/JCI116302.
We hypothesize that in patients with insulin-dependent diabetes mellitus (IDDM), recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure, a disorder distinct from classical diabetic autonomic neuropathy (CDAN), and that hypoglycemia-associated autonomic failure, by reducing both symptoms of and defense against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. We used the hyperinsulinemic (12.0 pmol.kg-1.min-1) stepped hypoglycemic clamp technique to assess autonomic and symptomatic responses to hypoglycemia and the insulin infusion test (4.0 pmol.kg-1.min-1) to assess defense against hypoglycemia on mornings before and after clamped afternoon hypoglycemia (approximately 2.8 mmol/liter) and hyperglycemia (approximately 11.1 mmol/liter) in patients with IDDM. Compared with nondiabetic subjects, IDDM with or without CDAN exhibited reduced epinephrine (P = 0.0222 and 0.0040) and pancreatic polypeptide (P = 0.0083 and 0.0056) responses to hypoglycemia. After afternoon hypoglycemia, lower plasma glucose concentrations were required to elicit autonomic and symptomatic responses during morning hypoglycemic clamps in patients without CDAN. At the 2.8 mmol/liter step, mean (+/- SE) epinephrine levels were 1,160 +/- 270 and 2,040 +/- 270 pmol/liter (P = 0.0060), pancreatic and total symptom scores were 22 +/- 3 and 41 +/- 7 (P = 0.0475) after afternoon hypoglycemia and hyperglycemia, respectively. During morning insulin infusion tests after afternoon hypoglycemia, nadir plasma glucose concentrations were 2.6 +/- 0.2 mmol/liter compared with 3.3 +/- 0.3 mmol/liter (P < 0.001) at the corresponding time points after afternoon hyperglycemia. Thus, we conclude: (a) elevated glycemic thresholds for autonomic responses to hypoglycemia are a feature of IDDM per se, not classical diabetic autonomic neuropathy; and (b) a single episode of afternoon hypoglycemia results in both elevated glycemic thresholds for autonomic and symptomatic responses to hypoglycemia and impaired physiological defense against hypoglycemia the next morning in IDDM.
我们推测，在胰岛素依赖型糖尿病（IDDM）患者中，近期医源性低血糖是低血糖相关自主神经功能衰竭的主要原因，这是一种有别于经典糖尿病自主神经病变（CDAN）的疾病，且低血糖相关自主神经功能衰竭通过减少低血糖症状及对低血糖发生的防御能力，导致医源性低血糖反复发作，从而形成恶性循环。我们采用高胰岛素血症（12.0 pmol·kg-1·min-1）阶梯式低血糖钳夹技术评估对低血糖的自主神经和症状反应，并采用胰岛素输注试验（4.0 pmol·kg-1·min-1）评估IDDM患者在下午钳夹低血糖（约2.8 mmol/L）和高血糖（约11.1 mmol/L）前后早晨对低血糖的防御能力。与非糖尿病受试者相比，伴有或不伴有CDAN的IDDM患者对低血糖的肾上腺素反应（P = 0.0222和0.0040）及胰多肽反应（P = 0.0083和0.0056）均降低。下午低血糖后，在早晨低血糖钳夹期间，无CDAN的患者引发自主神经和症状反应所需的血糖浓度更低。在2.8 mmol/L这一步骤，下午低血糖和高血糖后，平均（±SE）肾上腺素水平分别为1160±270和2040±270 pmol/L（P = 0.0060），胰腺症状评分和总症状评分分别为22±3和41±7（P = 0.0475）。在下午低血糖后的早晨胰岛素输注试验期间，最低血浆葡萄糖浓度为2.6±0.2 mmol/L，而下午高血糖后相应时间点为3.3±0.3 mmol/L（P < 0.001）。因此，我们得出结论：（a）低血糖自主神经反应的血糖阈值升高是IDDM本身的特征，而非经典糖尿病自主神经病变的特征；（b）单次下午低血糖会导致IDDM患者次日早晨低血糖自主神经和症状反应的血糖阈值升高，以及对低血糖的生理防御受损。
