Aim: The voltage-gated potassium channel K v 11.1 is important for repolarizing the membrane potential in excitable cells such as myocytes, pancreatic αand β-cells.Moxifloxacin blocks the K v 11.1 channel and increases the risk of hypoglycaemia in patients with diabetes. We investigated glucose regulation and secretion of glucoregulatory hormones in young people with and without moxifloxacin, a drug known to block the K v 11.1 channel. Materials and Methods:The effect of moxifloxacin (800 mg/day for 4 days) or placebo on glucose regulation was assessed in a randomized, double-blind, crossover study of young men and women (age 20-40 years and body mass index 18.5-27.5 kg/m 2 ) without chronic disease, using 6-h oral glucose tolerance tests and continuous glucose monitoring.Results: Thirty-eight participants completed the study. Moxifloxacin prolonged the QTcF interval and increased heart rate. Hypoglycaemia was more frequently observed with moxifloxacin, both during the 8 days of continuous glucose monitoring and during the oral glucose tolerance tests. Hypoglycaemia questionnaire scores were higher after intake of moxifloxacin. Moxifloxacin reduced the early plasmaglucose response (AUC 0-30 min ) by 7% (95% CI: À9% to À4%, p < .01), and overall insulin response (AUC 0-360 min ) decreased by 18% (95% CI: À24% to À11%, p < .01) and plasma glucagon increased by 17% (95% CI: 4%-33%, p = .03). Insulin sensitivity calculated as the Matsuda index increased by 11%, and MISI, an index of muscle insulin sensitivity, increased by 34%. Conclusions:In young men and women, moxifloxacin, a drug known to block the K v 11.1 channel, increased QT interval, decreased glucose levels and was associated

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 & 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

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