Benzodiazepines induce hyperglycemia in rats by affecting peripheral disposal of glucose

Abstract

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 f ve 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). Results (1) Diazepam was associated with higher levels of blood glucose in a dose-response fashion: DZP0 128 ± 7 mg/dl, DZP5 166 ± 7.3, DZP15 197 ± 7 (P <0.05). (2) The acute insulin response to intravenous glucose tolerance test was similar in DZP0 and DZP5 (DZP0 3.97 ± 0.42 ng/ml, DZP5 3.68 ± 0.44, P = 0.68), while blood glucose levels were different (DZP0 192 ± 5 mg/dl, DZP5 217 ± 5, P <0.05). (3) During hyperinsulinemic euglycemic clamp, blood glucose levels were similar (109 ± 3 mg/dl, P = 0.2), but the DZP5 group showed a trend through lower values of GIR (DZP0 30.8 ± 2 mg/kg/minute, DZP5 24.7 ± 2, P = 0.08). (4) Infusion of midazolam was associated with higher blood glucose levels (DZP0 128 ± 5 mg/dl, M5 151 ± 6, P <0.05). 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.