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Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys.

Xiao YF, Wang B, Wang X, Du F, Benzinou M, Wang YX - BMC Anesthesiol (2013)

Bottom Line: Xylazine-induced hyperglycemia declined slowly in diabetic animals.In addition, after clamping blood glucose level in a range of 55 to 75 mg/dL for 40 min with constant glucose infusion, xylazine administration still increased blood glucose concentration.We conclude that xylazine administration induces hyperglycemia in normoglycemic and insulin-dependent diabetic monkeys potentially via stimulation of α2-adrenoceptors and then reducing tissue sensitivity to insulin and glucose uptake.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cardiovascular and Metabolic Disease Research, Crown Bioscience Inc, Science and Technology Park, 6 Beijing West Road, Taicang Economic Development Area, Jiangsu Province 215400, The People's Republic of China. xiaoyongfu@crownbio.com.

ABSTRACT

Background: The α2-adrenoceptor agonist xylazine as an anesthetic has been widely used either alone or in combination with other anesthetics, such as ketamine, in veterinary clinic and research. In the last decade xylazine has been used in drug abusers in certain geographic area. This study investigated the effects of xylazine on blood glucose level and insulin secretion in normoglycemic and insulin-dependent diabetic monkeys.

Methods: Both adult cynomolgus (n = 10) and rhesus (n = 8) monkeys with either sex were used in the study. Xylazine (1-2 mg/kg) was administrated intramuscularly. Blood glucose, insulin, glucagon and glucagon-like peptide 1 in overnight-fasted monkeys were measured immediately before and after xylazine administration. The hyperinsulinemic-euglycemic clamp method was used in the study for assessing the potential mechanism of xylazine-induced hyperglycemia.

Results: Xylazine administration increased the blood glucose levels from 58 ± 3 to 108 ± 12 mg/dL in normoglycemic (n = 5, p < 0.01) and from 158 ± 9 to 221 ± 13 mg/dL in insulin-dependent diabetic (n = 5, p < 0.01) monkeys and was not accompanied by any significant changes in blood insulin, glucagon, and glucagon-like peptide-1. Xylazine-induced hyperglycemia occurred within 10 min and reached the peak at 35 min after injection. Xylazine-induced hyperglycemia declined slowly in diabetic animals. The α2-adrenoceptor antagonist yohimbine was administrated to bring down the elevated glucose level to the pre-xylazine one in 4 out of 5 diabetic animals. To assess the potential mechanism, the hyperinsulinemic-euglycemic clamp was used to maintain a nearly saturated and constant insulin level for minimizing endogenous insulin glucoregulation. Xylazine administration decreased glucose infusion rate, from 14.3 ± 1.4 to 8.3 ± 0.8 mg/min/kg (n = 6, p < 0.01) in normoglycemic rhesus monkeys, which indicates that the glucose metabolic rate (M rate) was decreased by xylazine. In addition, after clamping blood glucose level in a range of 55 to 75 mg/dL for 40 min with constant glucose infusion, xylazine administration still increased blood glucose concentration.

Conclusions: We conclude that xylazine administration induces hyperglycemia in normoglycemic and insulin-dependent diabetic monkeys potentially via stimulation of α2-adrenoceptors and then reducing tissue sensitivity to insulin and glucose uptake.

No MeSH data available.


Related in: MedlinePlus

Effects of xylazine on blood glucose concentrations in two fasted normoglycemic rhesus monkeys during the hyperinsulinemic-euglycemic clamp. Insulin was given with an initial bolus infusion to reduce blood glucose close to a targeted level followed by a constant infusion rate of 40 mU/m2 Surface Area*min (open squares) for maintaining hyperinsulinemia. Glucose was infused simultaneously with adjustable rates to clamp blood glucose in the euglycemic range of 55 – 75 mg/dL (open triangles). Xylazine (2 mg/kg) was injected intramuscularly after 40-min euglycemia stabilization to observe its effects on blood glucose when glucose was infused at a constant rate.
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Figure 3: Effects of xylazine on blood glucose concentrations in two fasted normoglycemic rhesus monkeys during the hyperinsulinemic-euglycemic clamp. Insulin was given with an initial bolus infusion to reduce blood glucose close to a targeted level followed by a constant infusion rate of 40 mU/m2 Surface Area*min (open squares) for maintaining hyperinsulinemia. Glucose was infused simultaneously with adjustable rates to clamp blood glucose in the euglycemic range of 55 – 75 mg/dL (open triangles). Xylazine (2 mg/kg) was injected intramuscularly after 40-min euglycemia stabilization to observe its effects on blood glucose when glucose was infused at a constant rate.

Mentions: To exclude or minimize the influence of endogenous insulin on xylazine-induced hyperglycemia and also to see the effects of xylazine on blood glucose in another monkey strain (rhesus), the hyperinsulinemic-euglycemic clamp was performed in normoglycemic rhesus monkeys of either sex (n = 8). Their mean age was 10.7 ± 1.1 years with the body weight of 7.7 ± 0.8 kg. Compared with the normoglycemic cynomolgus monkeys (Table 1, 47.9 ± 5.4 mg/dL), their blood glucose was significantly higher (86 ± 4.6 mg/dL) probably due to their older ages. They were intravenously infused with a constant dose of insulin following an initial bolus infusion in the 1st 10 min (Figure 3, open square). Glucose was simultaneously infused with rates adjusted until blood glucose was maintained in a range of 55 to 75 mg/dL under a constant infusion rate (Figure 3, open triangle). Prior to xylazine injection, a 40 min period (from 150–190 min after the initiation of the clamp, Figure 3) of stable blood glucose ranging from 55 to 75 mg/dL was reached (Figure 3). Administration of xylazine (2 mg/kg) significantly increased blood glucose level, from 55 mg/dL (left panel) and 64 mg/dL (right panel) for pre-xylazine to the peak of 83 mg/dL (left panel) and 99 mg/dL (right panel), respectively, despite the glucose infusion rate being unchanged. These results indicate that xylazine still produced hyperglycemia in the presence of clamp-maintained hyperinsulinemia which maximally inhibited endogenous negligible insulin secretion.


Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys.

Xiao YF, Wang B, Wang X, Du F, Benzinou M, Wang YX - BMC Anesthesiol (2013)

Effects of xylazine on blood glucose concentrations in two fasted normoglycemic rhesus monkeys during the hyperinsulinemic-euglycemic clamp. Insulin was given with an initial bolus infusion to reduce blood glucose close to a targeted level followed by a constant infusion rate of 40 mU/m2 Surface Area*min (open squares) for maintaining hyperinsulinemia. Glucose was infused simultaneously with adjustable rates to clamp blood glucose in the euglycemic range of 55 – 75 mg/dL (open triangles). Xylazine (2 mg/kg) was injected intramuscularly after 40-min euglycemia stabilization to observe its effects on blood glucose when glucose was infused at a constant rate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016475&req=5

Figure 3: Effects of xylazine on blood glucose concentrations in two fasted normoglycemic rhesus monkeys during the hyperinsulinemic-euglycemic clamp. Insulin was given with an initial bolus infusion to reduce blood glucose close to a targeted level followed by a constant infusion rate of 40 mU/m2 Surface Area*min (open squares) for maintaining hyperinsulinemia. Glucose was infused simultaneously with adjustable rates to clamp blood glucose in the euglycemic range of 55 – 75 mg/dL (open triangles). Xylazine (2 mg/kg) was injected intramuscularly after 40-min euglycemia stabilization to observe its effects on blood glucose when glucose was infused at a constant rate.
Mentions: To exclude or minimize the influence of endogenous insulin on xylazine-induced hyperglycemia and also to see the effects of xylazine on blood glucose in another monkey strain (rhesus), the hyperinsulinemic-euglycemic clamp was performed in normoglycemic rhesus monkeys of either sex (n = 8). Their mean age was 10.7 ± 1.1 years with the body weight of 7.7 ± 0.8 kg. Compared with the normoglycemic cynomolgus monkeys (Table 1, 47.9 ± 5.4 mg/dL), their blood glucose was significantly higher (86 ± 4.6 mg/dL) probably due to their older ages. They were intravenously infused with a constant dose of insulin following an initial bolus infusion in the 1st 10 min (Figure 3, open square). Glucose was simultaneously infused with rates adjusted until blood glucose was maintained in a range of 55 to 75 mg/dL under a constant infusion rate (Figure 3, open triangle). Prior to xylazine injection, a 40 min period (from 150–190 min after the initiation of the clamp, Figure 3) of stable blood glucose ranging from 55 to 75 mg/dL was reached (Figure 3). Administration of xylazine (2 mg/kg) significantly increased blood glucose level, from 55 mg/dL (left panel) and 64 mg/dL (right panel) for pre-xylazine to the peak of 83 mg/dL (left panel) and 99 mg/dL (right panel), respectively, despite the glucose infusion rate being unchanged. These results indicate that xylazine still produced hyperglycemia in the presence of clamp-maintained hyperinsulinemia which maximally inhibited endogenous negligible insulin secretion.

Bottom Line: Xylazine-induced hyperglycemia declined slowly in diabetic animals.In addition, after clamping blood glucose level in a range of 55 to 75 mg/dL for 40 min with constant glucose infusion, xylazine administration still increased blood glucose concentration.We conclude that xylazine administration induces hyperglycemia in normoglycemic and insulin-dependent diabetic monkeys potentially via stimulation of α2-adrenoceptors and then reducing tissue sensitivity to insulin and glucose uptake.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cardiovascular and Metabolic Disease Research, Crown Bioscience Inc, Science and Technology Park, 6 Beijing West Road, Taicang Economic Development Area, Jiangsu Province 215400, The People's Republic of China. xiaoyongfu@crownbio.com.

ABSTRACT

Background: The α2-adrenoceptor agonist xylazine as an anesthetic has been widely used either alone or in combination with other anesthetics, such as ketamine, in veterinary clinic and research. In the last decade xylazine has been used in drug abusers in certain geographic area. This study investigated the effects of xylazine on blood glucose level and insulin secretion in normoglycemic and insulin-dependent diabetic monkeys.

Methods: Both adult cynomolgus (n = 10) and rhesus (n = 8) monkeys with either sex were used in the study. Xylazine (1-2 mg/kg) was administrated intramuscularly. Blood glucose, insulin, glucagon and glucagon-like peptide 1 in overnight-fasted monkeys were measured immediately before and after xylazine administration. The hyperinsulinemic-euglycemic clamp method was used in the study for assessing the potential mechanism of xylazine-induced hyperglycemia.

Results: Xylazine administration increased the blood glucose levels from 58 ± 3 to 108 ± 12 mg/dL in normoglycemic (n = 5, p < 0.01) and from 158 ± 9 to 221 ± 13 mg/dL in insulin-dependent diabetic (n = 5, p < 0.01) monkeys and was not accompanied by any significant changes in blood insulin, glucagon, and glucagon-like peptide-1. Xylazine-induced hyperglycemia occurred within 10 min and reached the peak at 35 min after injection. Xylazine-induced hyperglycemia declined slowly in diabetic animals. The α2-adrenoceptor antagonist yohimbine was administrated to bring down the elevated glucose level to the pre-xylazine one in 4 out of 5 diabetic animals. To assess the potential mechanism, the hyperinsulinemic-euglycemic clamp was used to maintain a nearly saturated and constant insulin level for minimizing endogenous insulin glucoregulation. Xylazine administration decreased glucose infusion rate, from 14.3 ± 1.4 to 8.3 ± 0.8 mg/min/kg (n = 6, p < 0.01) in normoglycemic rhesus monkeys, which indicates that the glucose metabolic rate (M rate) was decreased by xylazine. In addition, after clamping blood glucose level in a range of 55 to 75 mg/dL for 40 min with constant glucose infusion, xylazine administration still increased blood glucose concentration.

Conclusions: We conclude that xylazine administration induces hyperglycemia in normoglycemic and insulin-dependent diabetic monkeys potentially via stimulation of α2-adrenoceptors and then reducing tissue sensitivity to insulin and glucose uptake.

No MeSH data available.


Related in: MedlinePlus