HERG编码的Kv11.1钾通道受损导致长QT综合征患者因反应性低血糖引起的内分泌胰腺和肠降血糖素功能增加
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Patients with Long QT Syndrome Due to Impaired hERG-encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated with Reactive Hypoglycemia
背景与目的
hERG（编码Kv11.1电压门控钾通道）的功能确实突变使心脏复极化延长，导致长QT综合征（LQT2）。然而，Kv11.1也存在于胰腺α和β细胞以及肠L和K细胞中，其分别分泌胰高血糖素、胰岛素和肠促胰岛素胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）。这些激素对葡萄糖调节至关重要，而LQTS可能会导致葡萄糖调节紊乱。我们测量了hERG功能突变的LQT2患者和健康患者中这类激素和心脏复极对葡萄糖摄入的反应，检测了LQT2患者的降血糖素和β细胞功能增加和α细胞功能减弱并因此降低葡萄糖水平的假设。
方 法
纳入11位LQT2患者和性别、年龄和BMI匹配的对照患者，给予口服75g葡萄糖耐量试验6小时，记录心电图（ECG）和采集血液样本检测血糖、胰岛素、C肽、胰高血糖素、GLP-1HE GIP。
结 果
与对照组患者比较，LQT2患者的血清胰岛素、C肽、血浆GLP-1HE GIP增加了56%-78%（P=0.03-0.001），而摄入葡萄糖后的血糖水平降低（P=0.02），出现更明显的低血糖症状（P=0.04）。63%LQT2患者 vs. 36%对照组患者发展为低血糖（<70mg/dl）（P=0.16）,18%LQT2患者发展为严重低血糖（<50mg/dl），而对照组未见。LQT2患者对低血糖缺乏胰高血糖素反应，P=0.008. LQT2患者的β细胞功能（ISSI-2）是对照组患者的2倍（4398 [95% CI 2259；8562] VS. 2156[1961; 3201],P=0.03）。大鼠的药理学Kv11.1阻断剂（多非利特）具有类似的作用，并且β和L-细胞的hERG siRNA抑制作用增加了高达50％的胰岛素和GLP-1分泌。葡萄糖摄入引起患者和对照组如QTc间期延长的心脏复极紊乱，但LQT2患者的QTcF间期延长了122%（P=0.004）。
结 论
LQT2患者除了心脏复极延长外，还表现出GLP-1、GIP和胰岛素分泌增加，胰高血糖素分泌障碍，导致血糖降低，发生低糖血症的风险增加，因此，LQT2患者摄入葡萄糖可延长QT间期，加重心脏复极紊乱。
原始文献摘要
Hyltén-Cavallius L, Iepsen E W, Wewer Albrechtsen N J, et al. Patients With Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia[J]. Circulation, 2017, 135(18):1705-1719.
BACKGROUND:
Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long-QT syndrome type 2 (LQT2) because of prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), respectively. These hormones are crucial for glucose regulation, and long-QT syndrome may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β-cell function and decreased α-cell function, and thus lower glucose levels.
METHODS:
Eleven patients with LQT2 and 22 sex-, age-, and body mass index-matched control participants underwent a 6-hour 75-g oral glucose tolerance test with ECG recording and blood sampling for measurements of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP.
RESULTS:
In comparison with matched control participants, LQT2 patients had 56% to 78% increased serum insulin, serum C-peptide, plasma GLP-1, and plasma GIP responses (P=0.03-0.001) and decreased plasma glucose levels after glucose ingestion (P=0.02) with more symptoms of hypoglycemia (P=0.04). Sixty-three percent of LQT2 patients developed hypoglycemic plasma glucose levels (<70 mg/dL) versus 36% control participants (P=0.16), and 18% patients developed serious hypoglycemia (<50 mg/dL) versus none of the controls. LQT2 patients had defective glucagon responses to low glucose, P=0.008. β-Cell function (Insulin Secretion Sensitivity Index-2) was 2-fold higher in LQT2 patients than in controls (4398 [95% confidence interval, 2259-8562] versus 2156 [1961-3201], P=0.03). Pharmacological Kv11.1 blockade (dofetilide) in rats had similar effect, and small interfering RNA inhibition of hERG in β and L cells increased insulin and GLP-1 secretion up to 50%. Glucose ingestion caused cardiac repolarization disturbances with increased QTc intervals in both patients and controls, but with a 122% greater increase in QTcF interval in LQT2 patients (P=0.004).
CONCLUSIONS:
Besides a prolonged cardiac repolarization phase, LQT2 patients display increased GLP-1, GIP, and insulin secretion and defective glucagon secretion, causing decreased plasma glucose and thus increased risk of hypoglycemia. Furthermore, glucose ingestion increased QT interval and aggravated the cardiac repolarization disturbances in LQT2 patients.
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