Benzodiazepines induce hyperglycemia in rats by affecting peripheral disposal of glucose

Introduction : In light of the interest in the relationship between glycemia control in critically ill subjects and outcome, we set up a study to investigate whether benzodiazepine, commonly used in anesthesia and ICUs, interferes with glucose metabolism and to explore the mechanism. Methods : A total of 40 sedated and paralyzed Sprague-Dawley rats (301 ± 55 g) were investigated in four consecutive studies. (1) To investigate the effects of diazepam on blood glucose, 15 rats were randomly assigned to intraperitoneal anesthesia with tiopenthal 80 mg/kg (DZP0), tiopenthal 40 mg/kg + diazepam 5 mg/kg (DPZ5) or tiopenthal 40 mg/kg + diazepam 15 mg/kg (DZP15). Blood levels of glucose (GEM premier 3000; IL) were measured at time intervals over 2 hours. (2) Ten animals randomized to DZP0 or DZP5 underwent an intravenous glucose tolerance test with glucose bolus (0.5 g/kg). Acute insulin response, the mean value of blood insulin (Insulin ELISA kit; Millipore) from 2 to 10 minutes after glucose bolus, was measured as index of insulin secretion. (3) A hyperinsulinemic euglycemic clamp obtained by a continuous intravenous infusion of insulin (130 mUI/kg/minute) was run in 10 animals randomized to DZP0 or DZP5 and the glucose infusion rate (GIR, mg/kg/minute) was assessed [1]. (4) The effect of midazolam on blood glucose was tested in five additional animals (M5: tiophental 40 mg/kg + midazolam 5 mg/kg). Data are presented as mean ± SEM. Statistical analysis (ANOVA, t test) was conducted with Sigma Stat 3.1 (Systat Software). Conclusion : Both diazepam and midazolam significantly alter plasma glucose levels in rats. Peripheral disposal of glucose rather than altered pancreas secretion of insulin explains the benzodiazepine-associated hyperglycemia.