title: Insulin at normal physiological levels does not prolong QT(c)  interval in thorough QT studies performed in healthy volunteers.
abstract: OBJECTIVE
  Food is known to shorten the QT(c) (QT(c)I and QT(c)F) interval and has been proposed as a non-pharmacological method of confirming assay sensitivity in thorough QT (TQT) studies and early phase studies in medicines research. Intake of food leads to a rise in insulin levels together with the release of C-peptide in equimolar amounts. However, it has been reported that euglycaemic hyperinsulinemia can prolong the QT(c) interval, whilst C-peptide has been reported to shorten the QT(c) interval. Currently there is limited information on the effects of insulin and C-peptide on the electrocardiogram (ECG). This study was performed to assess the effect of insulin, glucose and C-peptide on the QT(c) interval under the rigorous conditions of a TQT study.
  
  
  METHODS
  Thirty-two healthy male and female, Caucasian and Japanese subjects were randomized to receive six treatments: (1) placebo, (2) insulin euglycaemic clamp, (3) carbohydrate rich 'continental' breakfast, (4) calorie reduced 'American' FDA breakfast, (5) moxifloxacin without food, and (6) moxifloxacin with food. Measurements of ECG intervals were performed automatically with subsequent adjudication in accordance with the ICH E14 guideline and relevant amendments.
  
  
  RESULTS
  No effect was observed on QT(c)F during the insulin euglycaemic clamp period (maximal shortening of QT(c) F by 2.6 ms, not significant). Following ingestion of a carbohydrate rich 'continental' breakfast or a calorie reduced 'American' FDA standard breakfast, a rapid increase in insulin and C-peptide concentrations were observed. Insulin concentrations showed a peak response after the 'continental' breakfast observed at the first measurement time point (0.25 h) followed by a rapid decline. Insulin concentrations observed with the 'American' breakfast were approximately half of those seen with the 'continental' breakfast and showed a similar pattern. C-peptide concentrations showed a peak response at the first measurement time point (0.25 h) with a steady return to baseline at the 6 h time point. The response to the 'continental' breakfast was approximately double that of the 'American' FDA breakfast. A rapid onset of the effect on QT(c) F was observed with the 'continental' breakfast with shortening by >5 ms in the time interval from 1 to 4 h. After the 'American' FDA breakfast, a similar but smaller effect was seen.
  
  
  CONCLUSIONS
  The findings of this study demonstrate that there was no change in QT(c) during the euglycaemic clamp. Given that insulin was raised to physiological concentrations comparable with those seen after a meal, whilst the release of C-peptide was suppressed, insulin appears to have no effect on the QT(c) interval in either direction. The results suggest a relationship exists between the shortening of QT(c) and C-peptide concentrations and indicate that glucose may have a QT(c) prolonging effect, which will require further research.
authors: Richmond Pharmacology Ltd, St George's University of London, London, UK. j.taubel@richmondpharmacology.com
authors: Jorg
authors: J
authors: Taubel
authors: Ulrike
authors: U
authors: Lorch
authors: Georg
authors: G
authors: Ferber
authors: Jatinder
authors: J
authors: Singh
authors: Velislav N
authors: VN
authors: Batchvarov
authors: Irina
authors: I
authors: Savelieva
authors: A John
authors: AJ
authors: Camm
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D062408:Breakfast / Q000502:physiology; D002096:C-Peptide / Q000494:pharmacology; D018592:Cross-Over Studies; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D015309:Glucose Clamp Technique / Q000379:methods; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D044465:White People; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D004040:Dietary Carbohydrates; D007004:Hypoglycemic Agents; D007328:Insulin