The main finding of this study is that xylazine administration produced an acute hyperglycemia without significant changes in blood insulin, glucagon, and GLP-1 in both insulin-dependent diabetic and normoglycemic monkeys. As xylazine is widely used either alone or combined with other anesthetics, such as ketamine, in various animal research, its hyperglycemia can have an obvious impact on experimental results, especially in diabetic and metabolic research. Xylazine is commonly used as an anesthetic and analgesic in veterinary clinics [5, 6]. Also, due to increasing amongst drug abusers [20–22], xylazine-induced hyperglycemia potentially becomes a clinically relevant issue, especially in diabetic subjects.
Xylazine-induced hyperglycemia was reported previously in various species, including dogs , cattle [33, 34], and rats [12, 35]. However, these studies were performed in normoglycemic animals. These studies led to the hypothesis that the inhibition of insulin secretion plays a critical role in the hyperglycemia. The present study attempts to test this hypothesis in a series of 3 experiments. First, we used naturally developed diabetic monkeys who required insulin treatment because their insulin secretory function was greatly diminished. Our data clearly demonstrate that xylazine not only produced profound hyperglycemia in the normoglycemic monkeys, but also in the diabetic animals (Figure 2). Secondly, blood insulin, glucagon, and GLP-1 exhibited no significant changes during the xylazine-induced hyperglycemic period (Figure 2). Thirdly, xylazine still caused hyperglycemia (Figure 3) and decreased glucose uptake (M rate, Figure 4) during hyperinsulinemic-euglycemic clamp. These results are consistent with those reported in foals that insulin was not significantly changed during xylazine-produced hyperglycemia . However, xylazine-induced hyperglycemia in rats, sheep, cattle, and dogs is associated with a reduction of insulin secretion [35, 37–41], while a significant rise in plasma insulin levels occurs in horses . These inconsistent results may be due to different animal species used. Our results suggest that xylazine-induced hyperglycemia results from the decrease of tissue sensitivity to insulin, which leads to the reduction of tissue glucose uptake and utilization.
Xylazine is an analogue of the α2-adrenergic agonist clonidine. The effects of activation of α2-adrenoceptors on blood glucagon are inconsistent and whether the hyperglycemic effect of xylazine involves glucagon is not clear [37, 43]. Previous studies in rats showed that xylazine significantly increased blood glucagon, which was not affected by the α2-adrenergic antagonist yohimbine [1, 12, 35]. The unchanged glucagon level found in our present study is consistent with the results previously reported in dogs . Glucagon thus seems not so critical for xylazine-induced hyperglycemia at least in NHPs in this study. Furthermore, blood GLP-1 was also not altered after xylazine administration in the present study. Therefore, it is possible that the cause of xylazine-induced hyperglycemia results from stimulation of α2-adrenoceptors and then modifying other stress hormones, such as ACTH and GH, which were not measured in our study. However, xylazine has been reported to increase the release of ACTH and GH in cattle and dogs [3, 39].
It is unclear whether xylazine itself could increase hepatic glucose production (glycogenolysis and gluconeogenesis) and then cause hyperglycemia. However, as xylazine-induced hyperglycemia observed in the present study was conducted in fasted monkeys which had reduced glycogen stores , the contribution of glycogenolysis to the hyperglycemia was very unlikely, especially in fasted insulin-dependent diabetic monkeys. In addition, the level of blood glucagon (the stimulating hormone of glycogenolysis and gluconeogenesis) was not increased in the presence of xylazine (Figure 2C). Therefore, xylazine-induced hyperglycemia was unlikely via an increase in hepatic glucose production.
Compared with the insulin-dependent diabetic monkeys, the decline of xylazine-induced hyperglycemia was faster and blood glucose returned to the pre-xylazine level within 90 min in normoglycemic monkeys (Figure 2A). In contrast, blood glucose remained elevated during the entire observation period of 120 min in the diabetic monkeys. The specific α2-adrenoceptor antagonist yohimbine had to be given in 4 out of 5 insulin dependent diabetic monkeys to decrease their blood glucose to the pre-xylazine level for animal safety reason. These results suggest that xylazine-induced hyperglycemia is mediated, at least partially, via stimulation of α2-adrenoceptors. Lattermann and colleagues reported that blood glucose concentrations were significantly increased in patients during and after lower abdominal surgery . However, compared with control patients (saline), intraoperative glucose plasma concentrations were even higher in the patients who received clonidine (1 μg/kg) 30 min before induction of general anesthesia. The adverse effects of hyperglycemia can be reflected in animal models of myocardial infarction  and in patients after acute myocardial infarction , stroke , and cardiac surgery . Therefore, great care should be taken to avoid using an agent which causes hyperglycemia and influences outcome.
Due to the difficulty of obtaining traditional illicit drugs, consumption in drug abusers is turning towards less restricted compounds. Xylazine, the veterinary sedative anesthetic, was confirmed as the anesthetic substance used in Puerto Rico by testing exchanged needles in 29 sites in 11 municipalities . Xylazine used as adulterants in heroin was also found in drug related deaths in Philadelphia, Pennsylvania [20, 50]. An 18-year-old man after inhaling xylazine showed chills and dizziness followed by sweating, gait instability, palpitations and syncope with bradycardia and hypotension. More cases of toxicity caused by xylazine consumption have been documented in humans, occasionally resulting in death [18, 20, 28]. Xylazine users could become apneic and require intubation and mechanical ventilation. Two critical issues about chronic use of xylazine are the physical dependence and the noticeable open skin ulcers . These ulcers are referred to as abscesses and are a serious health concern. The pain caused by the ulcers promotes further injections of xylazine because of its sedative/anesthetic effects. These open skin ulcers emit a strong odor, ooze, and in severe cases limit the mobility of the extremities with a possibility of amputation . In xylazine abusers (generally male with a mean age of 30 years) 35% have skin lesions, which leads to more social exclusion. It is unclear whether the skin ulcers result from the hyperglycemic effect of xylazine in abusers, because extremity infection in diabetic patients is common and severe, sometimes difficult to cure . More experiments are thus required to elucidate how xylazine induces hyperglycemia at the cellular and molecular levels, which may have clinical relevance.