1785-P: Drug-Induced Blockade of the Herg-Voltage-Gated Potassium Channel Decreases Glucose-Stimulated Insulin and GLP-1 Secretion in Healthy Participants: A Crossover Study

Background: Patients with Long-QT syndrome (LQTS) due to a loss-of-function mutation in hERG, encoding the hERG-voltage-gated potassium channel (Kv11.1), exhibit increased glucose-stimulated insulin secretion, defective glucagon secretion, and postprandial hypoglycemia. Recently, LQTS has been reported to be associated with an increased risk of type 2 diabetes. We aimed to investigate the effect of drug-induced (moxifloxacin) blockade of the hERG-channel on glucose homeostasis. Methods: Using a double-blinded, randomized, placebo-controlled, crossover design, 40 healthy young participants underwent two 6-hours oral glucose tolerance tests (OGTT). The intervention was a 4-day treatment period with a selective hERG-blocker (the antibiotic moxifloxacin 800 mg/day) or placebo, final dose two hours before the OGTT, separated by a 3-week washout period. Results: Moxifloxacin prolonged the QTc interval by 25 ms. Figure 1 shows the means and 95% CI from the moxifloxacin/placebo 6-hour OGTTs. Insulin and GLP-1 levels were reduced the first 90 min and glucose was reduced the first 15 min with moxifloxacin blockade, thereby increasing the Matsuda-index by 1.16 (95% CI -1.9;-0.4). Conclusion: Moxifloxacin-induced hERG blockade reduced peak postprandial glucose excursions and decreased the secretion of insulin and GLP-1. Disclosure C.R. Juhl: None. J. Burgdorf: None. C. Knudsen: None. S. Veedfald: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp \u0026 Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. J. Kanters: None. S.S. Torekov: Research Support; Self; Novo Nordisk Inc. Funding Independent Research Fund Denmark; Danish Heart Association; Lundbeck Foundation