Effects of a beta 3-adrenoceptor agonist, BRL 26830A, on insulin and glucagon release in mice.

The beta 3-adrenoceptor agonist, BRL 26830A, which is not inhibited by either beta 1 or beta 2-selective antagonists, has been shown to possess anti-obesity and anti-diabetic actions. However, the effects of this agent on insulin and glucagon release have not yet been substantiated. Therefore, we tested the hypothesis that BRL 26830A promotes insulin and glucagon secretion via beta 3 receptors on pancreatic islet B and A cells. In ICR mice fasted for 48 h, BRL 26830A significantly stimulated insulin secretion from 5 min after administration, markedly decreased blood glucose levels from 30 min after administration, and significantly increased glucagon secretion from 30 min after administration. The administration of a non-selective beta-receptor antagonist, at a dose of 50 mg/kg, 30 min prior to BRL 26830A injection completely abolished the effects induced by BRL 26830A. However, the administration of a beta 1-selective antagonist at doses of 50 or 100 mg/kg did not produce any significant effects. On the action of BRL 26830A, whereas the administration of a beta 2-selective antagonist at 50 mg/kg, a near maximal effective dose, partially abolished the effects of BRL 26830A. BRL 26830A had no effect on insulin, glucagon, or glucose levels in streptozocin (STZ) diabetic mice fasted for 48 h. These results suggest that, in mice, BRL 26830A may promote insulin secretion mainly via beta 3 receptors and partially via beta 2 receptors on pancreatic-islet B cells, and that glucagon may be secreted as the result of hypoglycemia induced by this agent.     

The roles of glucagon and adrenal epinephrine in mediating hyperglycemia induced by third cerebroventricular injection of bombesin

The roles of glucagon and adrenal epinephrine in mediating bombesin-induced central hyperglycemia were further studied in anesthetized rats. Bombesin (10(-9) mol) injected into the third cerebral ventricle produced an increase in plasma concentrations of glucose, glucagon, and epinephrine. Prior bilateral adrenalectomy completely prevented the hyperglucagonemic and hyperglycemic responses to third cerebral ventricle injection of bombesin. These results support the view that bombesin-induced increases in plasma glucose and glucagon are fully dependent on adrenal epinephrine secretion. Furthermore, during constant intravenous infusion of somatostatin, the hyperglycemic response to third cerebral ventricle injection of bombesin was not significantly influenced despite complete inhibition of the increase in plasma glucagon. Therefore, it is suggested that bombesin-induced central hyperglycemia is mainly mediated by epinephrine itself rather than via epinephrine-stimulated glucagon secretion.     

Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanisms and implications for preclinical models

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.     

Catecholamine-induced hyperglycemia in dogs: independence from alterations in pancreatic hormone release

Although isoproterenol is a very effective hyperglycemic agent in dogs, other species such as rats, baboons and man are resistant to this effect. In each of these species catecholamines exert pronounced effects on insulin and glucagon release from the pancreas. In man, baboons, and rats catecholamine-induced alterations in pancreatic hormone release indirectly influence the hyperglycemic response to these amines: glucagon release supports and insulin release limits hyperglycemic responses. In contrast, the present study demonstrates that in dogs catecholamine-induced hyperglycemic responses are relatively independent of concurrent alterations in pancreatic hormone release. In dogs isoproterenol produces hyperglycemia equal to or greater than responses to epinephrine despite large increases in insulin release produced by isoproterenol. Moreover, catecholamine-induced hyperglycemia is not significantly altered when insulin and glucagon release are blocked with somatostatin.     

Dissociation of somatostatin effects. Peptides inhibiting the release of growth hormone but not glucagon or insulin in rats

Two analogs of somatostatin were tested for their effects on release of growth hormone, glucagon, and insulin after subcutaneous injection into rats. These peptides significantly suppressed pentobarbital-stimulated growth hormone release but showed no effect on arginine-stimulated glucagon or insulin release at dosages greater than 2 mg/kg. Somotostatin acts on all three secretions at dosages below 200 μg/kg.     

Ghrelin is suppressed by glucagon and does not mediate glucagon-related growth hormone release

BACKGROUND: Glucagon stimulation is routinely used as a provocative test to assess growth hormone (GH) sufficiency in pediatrics. Ghrelin also markedly stimulates GH secretion. Because glucagon stimulates the promoter of the ghrelin gene in vitro as well as ghrelin secretion by the perfused rat stomach, we sought to determine whether ghrelin mediates glucagon-induced GH secretion. METHODS: We compared ghrelin, GH, insulin and glucose responses following administration of 0.03 mg/kg intravenously (iv; max. 1 mg) and 0.1 mg/kg intramuscularly (im; max. 2 mg) of glucagon in two groups (n = 10-11/group) of GH-sufficient children. We also measured ghrelin before and 6 min after iv administration of 1 mg glucagon in 21 adult subjects. RESULTS: In children, glucagon caused a 26% decrease in ghrelin and a 72% increase in glucose concentrations that were independent of the dose or administration route of glucagon. In contrast, the insulin response was 2-3 times higher following administration of 0.1 mg/kg im compared to 0.03 mg/kg of glucagon iv. There was a significant correlation between the maximum decrease in ghrelin and increases in glucose (p = 0.03) but not in insulin. There was a significant correlation between ghrelin and GH area under the curve after controlling for the dose of glucagon (p = 0.03) but not for the maximum increase in glucose.In normal adults, glucagon administration caused a 7% decrease in ghrelin concentrations after 6 min (p = 0.0002). CONCLUSION: Ghrelin does not play a causal role in the GH response to pharmacological glucagon administration, which suppresses ghrelin levels starting a few minutes after injection.     

Insulin and glucagon response during hemorrhage induced hyperglycemia

Rapid hemorrhage to 50 mmHg (1 mmHg = 133.322 Pa) in the pentobarbital-anesthetized cat leads to severe hyperglycemia which declines only slightly by 90 min of hemorrhage. Insulin levels decline to less than one-half of control levels and remain low throughout, despite the hyperglycemia. Glucagon levels decline at 15 min but are significantly elevated by 90 min. These data confirm that the hepatic glycogenolysis is controlled almost entirely by hepatic sympathetic nerves and adrenal secretions with no role for elevated glucagon levels at the early stages in hemorrhage. Hepatic denervation leads to lesser insulin suppression and greater glucagon elevation at later times (45 and 90 min), suggesting that intact hepatic nerves are required for a normal pancreatic response. Hepatic sympathectomy did not produce these effects. Insulin responses remained normal, but glucagon levels were suppressed throughout the entire experiment in sympathectomized cats. The data suggest that hepatic nerves may modulate insulin and glucagon levels during hemorrhage in an unknown manner.     

四种胃肠激素对链佐霉素诱发的小鼠高血糖的影响

本实验用腹腔注射链佐霉素(Streptozotocin简称STZ)方法破坏小鼠胰岛B细胞以诱发高血糖,观察生长抑素(Somatostatin,SS)、神经降压素(neurotensin,NT)、胰高血糖素(glucagon,GC)和促甲状腺素释放激素(TRH)4种胃肠激素对小鼠高血糖的影响。在每天腹腔注射STZ(60mg/kg)前10分钟分别经皮下注射上述4种胃肠激素,连续注射5天,在实验的第1,6,8,10,15天取血测血清葡萄糖浓度,对照组注射生理盐水(NS)。结果发现:(1)预先注射SS和NT可不同程度地抑制由STZ引起的实验性高血糖,并呈剂量一效应关系,(2)预先注射GC和TRH,血糖浓度仍明显升高,与NS对照组比较无显著差异,(3)取注射STZ后第15天的高血糖小鼠(血糖高于350mg％者)分为8组,分别以SS和NT作治疗性注射,每天一次共5日,并未见对小鼠高血糖有缓解效果;(4)正常小鼠单独皮下注射NS、SS、NT、GC、和TRH,每天一次连续5天,在注射后15天内未见对血糖水平有明显影响。以上结果提示:预防性注射SS和NT可显著抑制由STZ诱发的高血糖的产生。     

Increments in glucose, glucagon and insulin after morphine in rats, and naloxone blocking of this effect.

In awake rats adapted to experimental conditions and allowed food ad libitum, hyperglycemia was induced by the administration of morphine 10 mg/kg through indwelling catheters in the external jugular vein. High glucose values were measured at 5, 15 and 25 min. Glucagon values were high at 5 and 15 min, and again at basal level at 25 min. Insulin was increased after morphine both at 5, 15 and 25 min, whereas somatostatin levels did not change after morphine. When morphine was administered together with naloxone after an initial 10 min period of naloxone administration, there was no increment in glucose, insulin or somatostatin values; neither at 5, 15 or 25 min. There was a remarkable glucagon decrease after naloxone and morphine remaining from 5 to 25 min. Then, one of the possible mechanisms for the hyperglycemic response after morphine may be an opioid effect on pancreas, stimulating glucagon and thereby causing hepatic glucose output.     

Interactions between oxytocin, glucagon and glucose in normal and streptozotocin-induced diabetic rats

Oxytocin has been suggested to have glucoregulatory functions in rats, man and other mammals. The hyperglycemic actions of oxytocin are believed to be mediated indirectly through changes in pancreatic function. The present study examined the interaction between glucose and oxytocin in normal and streptozotocin (STZ)-induced diabetic rats, under basal conditions and after injections of oxytocin. Plasma glucose and endogenous oxytocin levels were significantly correlated in cannulated lactating rats (r = 0.44, P less than 0.01). To test the hypothesis that oxytocin was acting to elevate plasma glucose, adult male rats were injected with 10 micrograms/kg oxytocin and killed 60 min later. Oxytocin increased plasma glucose from 6.1 +/- 0.1 to 6.8 +/- 0.2 mM (P less than 0.05), and glucagon from 179 +/- 12 to 259 +/- 32 pg/ml (P less than 0.01, n = 18). There was no significant effect of oxytocin on plasma insulin, although the levels were increased by 30%. A lower dose (1 microgram/kg) of oxytocin had no significant effect on plasma glucose or glucagon. To eliminate putative local inhibitory effects of insulin on glucagon secretion, male rats were made diabetic by i.p. injection of 100 mg/kg STZ, which increased glucose to greater than 18 mM and glucagon to 249 +/- 25 pg/ml (P less than 0.05). In these rats, 10 micrograms/kg oxytocin failed to further increase plasma glucose, but caused a much greater increase in glucagon (to 828 +/- 248 pg/ml) and also increased plasma ACTH. A specific oxytocin analog, Thr4,Gly7-oxytocin, mimicked the effect of oxytocin on glucagon secretion in diabetic rats. The lower dose of oxytocin also increased glucagon levels (to 1300 +/- 250 pg/ml), but the effect was not significant. A 3 h i.v. infusion of 1 nmol/kg per h oxytocin in conscious male rats significantly increased glucagon levels by 30 min in normal and STZ-rats; levels returned to baseline by 30 min after stopping the infusion. Plasma glucose increased in the normal, but not STZ-rats. The relative magnitude of the increase in glucagon was identical for normal and diabetic rats, but the absolute levels of glucagon during the infusion were twice as high in the diabetics. To test whether hypoglycemia could elevate plasma levels of oxytocin, male rats were injected i.p. with insulin and killed from 15-180 min later. Plasma glucose levels dropped to less than 2.5 mM by 15 min. Oxytocin levels increased by 150-200% at 30 min; however, the effect was not statistically significant.(ABSTRACT TRUNCATED AT 400 WORDS)     

Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.     

Progressive loss of sensitivity of the A cell to insulin in geese made diabetic by subtotal pancreatectomy

The effects of insulin deficiency on pancreatic A cell responsiveness to glucose was studied in subtotally depancreatized geese. In geese operated for 3 to 5 days and receiving insulin therapy (I.M.: 0.5-1.0 U/kg/24 h), A cell response to glucose (I.V. injection: 0.5 g/kg) was abolished, but could be restored to normal range by insulin (I.V. injection: 0.025-0.2 U/kg) together with glucose. After 5 weeks of therapy, A cell sensitivity declined: the physiological amount of insulin (0.025 U/kg) was insufficient to suppress glucagon during the glucose load, whereas the large dose (0.2 U/kg) partially restored A cell response. In addition, daily insulin treatment prevented a severe increase of fasting plasma glucose and glucagon. Geese receiving no insulin therapy showed "total blindness" to glucose, even when given insulin at the time of the test. These data suggest a progressive loss of sensitivity of the A cell to insulin. Endocrine and/or panacrine insulin deficiency may play a role on the dysfuncion of the glucose-glucagon feedback mechanism.     

Changes in plasma glucagon, pancreatic polypeptide and insulin during development of alloxan diabetes mellitus in dog

Changes in canine plasma glucose, immunoreactive glucagon (IRG), pancreatic polypeptide (PP) and insulin (IRI) were studied during the acute development of diabetes mellitus after iv alloxan injection. 100 mg or 75 mg/kg body weight of alloxan was injected iv and blood was taken successively till one or two days later. Plasma glucose showed four phases: first immediate and moderate decrease appeared 30 min after injection, second initial hyperglycemic phase, third hypoglycemic and fourth diabetic ones. Plasma IRI had already increased to 182 +/- 60 microU/ml 10 min after injection and again began to increase after about 6 h, peaking to 134 +/- 49 microU/ml at 18 h. Plasma IRG began increasing gradually soon after alloxan injection. The initial value was 196 +/- 26 pg/ml and it increased to 534 +/- 144 pg/ml at 4 h during the initial hyperglycemic phase, then reached a higher level through the hypoglycemic and diabetic phases. The change in plasma PP was similar to that in IRG. The initial value was 256 +/- 95 pg/ml at 12 h after injection, peaking to 840 +/- 100 pg/ml in the hypoglycemic phase. Similar blunted values were obtained following 75 mg/kg alloxan injection. Thus not only plasma IRI but also plasma IRG and PP varied greatly during the acute development of alloxan diabetes and some contribution of IRG to the initial hyperglycemic phase was suggested.     

Multiple subcutaneous injections of somatostatin induce tachyphylaxis of the suppression of plasma insulin, but not glucagon, in the rat

The time course of pancreatic effects of somatostatin was studied over a period of 2 h in unanesthetized unrestrained rats after administration of the peptide by intravenous infusion and by single and multiple subcutaneous injections. During infusion of 10 and 30 micrograms/kg per min, somatostatin continuously suppressed plasma insulin and plasma glucagon. Plasma glucose was significantly increased at the lower dose, but not affected at the higher dose. Single subcutaneous injections of 0.3 and 3 mg/kg decreased plasma insulin and glucagon dose-dependently for 20-60 min without affecting plasma glucose. Multiple subcutaneous injections of somatostatin (one to four doses of 3 mg/kg, administered at intervals of 30 min) caused an initial decrease of plasma insulin (at 30 min), a rebound-increase at 60 and 90 min, and a final return to control values by 120 min. Plasma glucagon remained continuously suppressed. Plasma glucose increased significantly at 60 and 90 min and tended to return towards control values thereafter. In conclusion, pancreatic B cells - but not A cells - of the rat develop tachyphylaxis to somatostatin within 2 h after multiple subcutaneous injections of the peptide. By this mode of administration, 'selective' suppression of plasma glucagon can be achieved with somatostatin in the rat.     

Pharmacological doses of oxytocin affect plasma hormone levels modulating glucose homeostasis in normal man

Pharmacological doses of oxytocin administered in basal conditions evoked a rapid surge in plasma glucose and glucagon levels followed by a later increase in plasma insulin and adrenaline levels. The effects of oxytocin on plasma glucagon and adrenaline levels were potentiated by hypoglycemia. When the endogenous pancreas secretion was suppressed by cyclic somatostatin (150 micrograms/h) and exogenous glucagon (3.5 micrograms/h) and insulin (0.2 mU/kg.min) were both replaced, oxytocin (0.2 U/min) evoked a transient but significant increase in plasma glucose levels suppressing the glucose infusion rate (GIR) in the first 60 min. On the contrary at higher insulin infusion rate (0.6 mU/kg.min) plasma glucose levels and GIR remained unaffected throughout the study. Oxytocin seems also to potentiate glucose-induced insulin secretion as evidenced by hyperglycemic glucose clamp. In conclusion, pharmacological doses of oxytocin seem to exert a prevalent hyperglycemic effect by a combined action at the liver site (as glycogenolytic agent) and at the endocrine pancreas (as a stimulatory agent of A cell secretion).     

Basal insulin, glucagon, and growth hormone replacement

Conclusions drawn from the pancreatic (or islet) clamp technique (suppression of endogenous insulin, glucagon, and growth hormone secretion with somatostatin and replacement of basal hormone levels by intravenous infusion) are critically dependent on the biological appropriateness of the selected doses of the replaced hormones. To assess the appropriateness of representative doses we infused saline alone, insulin (initially 0.20 mU.kg(-1).min(-1)) alone, glucagon (1.0 ng.kg(-1).min(-1)) alone, and growth hormone (3.0 ng.kg(-1).min(-1)) alone intravenously for 4 h in 13 healthy individuals. That dose of insulin raised plasma insulin concentrations approximately threefold, suppressed glucose production, and drove plasma glucose concentrations down to subphysiological levels (65 +/- 3 mg/dl, P < 0.0001 vs. saline), resulting in nearly complete suppression of insulin secretion (P < 0.0001) and stimulation of glucagon (P = 0.0059) and epinephrine (P = 0.0009) secretion. An insulin dose of 0.15 mU.kg(-1).min(-1) caused similar effects, but a dose of 0.10 mU.kg(-1).min(-1) did not. The glucagon and growth hormone infusions did not alter plasma glucose levels or those of glucoregulatory factors. Thus, insulin "replacement" doses of 0.20 and even 0.15 mU.kg(-1).min(-1) are excessive, and conclusions drawn from the pancreatic clamp technique using such doses may need to be reassessed.     

The effect of hyperglycemia on acid-base and sympathoadrenal responses in the hypoxemic fetal monkey.

We investigated the influence of hyperglycemia on the fetal acid-base and sympathoadrenal responses to hypoxemia (maternal FIO2 9%) in rhesus monkey fetuses. In chronic preparations, we determined PO2, O2 content, PCO2, pH, lactate, glucose, insulin, catecholamines, heart rate, and arterial pressure. Combined hyperglycemia and hypoxemia resulted in a decrease in fetal pH and an increase in lactate; however, the magnitude of these changes was only modestly, and not significantly, greater than those observed during euglycemic hypoxemia. These effects were much less striking than expected, based on earlier work in sheep (Shelley, Bassett & Milner, 1975; Robillard, Sessions, Kennedy & Smith, 1978). Although catecholamines increased significantly in response to hypoxemia both in hyperglycemic and euglycemic fetuses, the increase was less in the hyperglycemic group, possibly resulting from a modulating effect of the high glucose concentration on catecholamine release from the adrenal medulla. Finally, a significant fetal insulin response to hyperglycemia was seen which, suggestively, was partially inhibited in the presence of hypoxemia and its associated increase in sympathoadrenal activity.     

Insulin and glucagon in rats with islet cell tumors induced by small doses of streptozotocin

Plasma insulin and glucagon responses to oral glucose loading were examined in rats with islet cell tumors induced by a single intravenous injection of streptozotocin (30 or 40 mg/kg body weight). Twenty-four macroscopic and six microscopic tumors occurred in 21 rats. In 15 of 21 tumor-bearing rats, there was exaggerated insulin release in response to oral glucose. Plasma glucose levels did not rise with the oral glucose load and were comparable to those seen in normal animals. Hence these rats are described as having "responsive tumors." In six rats with "nonresponsive tumors" there was no insulin response and the plasma glucose levels rose. No significant differences in plasma levels were observed between the two groups. Nonresponsive tumors as well as responsive tumors contained a significant amount of extractable insulin (17.68 +/- 8.60 and 35.07 +/- 10.05 mg/g wet weight, respectively) and detectable amounts of immunoreactive glucagon (1.47 +/- 0.61 and 2.24 +/- 0.67 micrograms/g wet weight, respectively). These results suggest that a small dose of streptozotocin produces two types of islet cell tumors. One is insulin producing and insulin secreting whereas the other is insulin producing but not insulin secreting.     

Resistance of cats to the diabetogenic effect of alloxan

Experimental diabetes mellitus can be induced chemically in many species of animals with streptozotocin or alloxan. However, the cat is known to be resistant to the diabetogenic effect of streptozotocin. The purpose of this study was to find the optimal dose and rate of injection of alloxan to consistently produce hyperglycemia (blood sugar levels greater than 300 mg/dl) in cats. Alloxan was administered to 22 cats at various concentrations (50, 100 and 150 mg/kg) and different rates of injection (0.5, 1.0 and 1.5 ml/min). No hyperglycemic effect was observed at any of the concentrations or different rates of injection. Cats receiving high concentrations and/or high rates of injection of alloxan died due to kidney damage. The results of this study suggest that the cat is resistant to the diabetogenic effect of alloxan, but is susceptible to its toxic side effects.