Acute Hyperglycemia Induced by Ketamine/Xylazine Anesthesia in Rats: Mechanisms and Implications for Preclinical Models

Abstract

The effects of anesthetic agents, commonly used in animal models, on blood glucose levels in fed and fasted rats were investigated. In fed Sprague-Dawley rats, ketamine (100 mg/kg)/xylazine (10 mg/kg) (KX) produced acute hyperglycemia (blood glucose 178.4 +/- 8.0 mg/dl) within 20 min. The baseline blood glucose levels (104.8 +/- 5.7 mg/dl) reached maximum levels (291.7 +/- 23.8 mg/dl) at 120 min. Ketamine alone did not elevate glucose levels in fed rats. Isoflurane also produced acute hyperglycemia similar to KX. Administration of pentobarbital sodium did not produce hyperglycemia in fed rats. In contrast, none of these anesthetic agents produced hyperglycemia in fasted rats. The acute hyperglycemic effect of KX in fed rats was associated with decreased plasma levels of insulin, adrenocorticotropic hormone (ACTH), and corticosterone and increased levels of glucagon and growth hormone (GH). The acute hyperglycemic response to KX was dose-dependently inhibited by the specific alpha2-adrenergic receptor antagonist yohimbine (1-4 mg/kg). KX-induced changes of glucoregulatory hormone levels such as insulin, GH, ACTH, and corticosterone were significantly altered by yohimbine, whereas the glucagon levels remained unaffected. In conclusion, the present study indicates that both KX and isoflurane produce acute hyperglycemia in fed rats. The effect of KX is mediated by modulation of the glucoregulatory hormones through stimulation of alpha2-adrenergic receptors. Pentobarbital sodium did not produce hyperglycemia in either fed or fasted rats. Based on these findings, it is suggested that caution needs to be taken when selecting anesthetic agents, and fed or fasted state of animals in studies of diabetic disease or other models where glucose and/or glucoregulatory hormone levels may influence outcome and thus interpretation. However, fed animals are of value when exploring the hyperglycemic response to anesthetic agents.

The effect of granulocyte-colony stimulating factor in global cerebral ischemia in rats

“…The global ischemia model used in this study was complicated by transient, statistically equivalent intraoperative hyperglycemia in all experimental groups. This was observed shortly after induction of general anesthesia, and was likely a result of the anesthetic combination used in this study (Ketamine and Xylazine) (Kawai et al, 1997, Saha et al, 2005. Hyperglycemia may have exacerbated blood-brain-barrier breakdown during global ischemia (Dietrich et al, 1993) or possibly increased neuron loss, although we did not study these effects specifically.…”

Use of anesthesia dramatically alters the oral glucose tolerance and insulin secretion in C57Bl/6 mice

“…In a rat study by Saha et al., ketamine alone did not alter BG levels (Saha et al. 2005), and they concluded that xylazine must be the BG increasing factor. Saha et al.…”

“…2005; Saha et al. 2005; Rodrigues et al. 2006); (3) the volatile agent isoflurane increases BG and some have noted a decrease in insulin concentration (Pomplun et al.…”

“…2004; Saha et al. 2005; Zuurbier et al. 2008, 2014), and in humans, isoflurane impairs glucose clearance and decreases insulin secretion during an IVGTT (Intravenous glucose tolerance test) (Tanaka et al.…”

Alpha-chloralose is a suitable anesthetic for chronic focal cerebral ischemia studies in the rat: A comparative study

“…A hyperglycemic response has been observed in several studies using isoflurane (Lattermann et al, 2001;Saha et al, 2005)) potentially due to impaired glucose clearance and increased glucose production. It is important to stress that although there was a significant difference in blood glucose level between the two groups, all animals remained normoglycemic; therefore an effect of glucose on infarct size or outcome is unlikely.…”