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Effects of olanzapine and haloperidol on the metabolic status of healthy men

Effects of Olanzapine and Haloperidol on the
Metabolic Status of Healthy Men
Solrun Vidarsdottir, Judith E. de Leeuw van Weenen, Marijke Fro¨lich,Ferdinand Roelfsema, Johannes A. Romijn, and Hanno Pijl Department of Endocrinology and Metabolism, Leiden University Medical Center, 2300 RC Leiden,The Netherlands Background: A large body of evidence suggests that antipsychotic drugs cause body weight gain
and type 2 diabetes mellitus, and atypical (new generation) drugs appear to be most harmful. The
aim of this study was to determine the effect of short-term olanzapine (atypical antipsychotic drug)
and haloperidol (conventional antipsychotic drug) treatment on glucose and lipid metabolism.
Research Design and Methods: Healthy normal-weight men were treated with olanzapine (10
mg/d; n ⫽ 7) or haloperidol (3 mg/d, n ⫽ 7) for 8 d. Endogenous glucose production, whole body
glucose disposal (by [6,6-2H ]glucose dilution), lipolysis (by [2H ]glycerol dilution), and substrate
oxidation rates (by indirect calorimetry) were measured before and after intervention in basal andhyperinsulinemic condition.
Results: Olanzapine hampered insulin-mediated glucose disposal (by 1.3 mg 䡠 kg⫺1 䡠 min⫺1),
whereas haloperidol did not have a significant effect. Endogenous glucose production was not
affected by either drug. Also, the glycerol rate of appearance (a measure of lipolysis rate) was not
affected by either drug. Olanzapine, but not haloperidol, blunted the insulin-induced decline of
plasma free fatty acid and triglyceride concentrations. Fasting free fatty acid concentrations de-
clined during olanzapine treatment, whereas they did not during treatment with haloperidol.
Conclusions: Short-term treatment with olanzapine reduces fasting plasma free fatty acid con-
centrations and hampers insulin action on glucose disposal in healthy men, whereas haloperidol
has less clear effects. Moreover, olanzapine, but not haloperidol, blunts the insulin-induced decline
of plasma free fatty acids and triglyceride concentrations. Notably, these effects come about
without a measurable change of body fat mass. (J Clin Endocrinol Metab 95: 118 –125, 2010)
Typicalantipsychotic(AP)drugshavebeenthecorner- Treatment with atypical AP drugs appears to be more
stone of the medical management of patients with harmful for glucose/lipid metabolism than treatment with schizophrenia for a long time. The advent of atypical AP conventional AP drugs (5, 7).
drugs has brought clear benefits for schizophrenic patients Because obesity is a major risk factor for insulin resis- because these compounds have less extrapyramidal side tance and type 2 diabetes (8), it is tempting to postulate effects and ameliorate negative symptoms (1). However, a that weight gain induced by atypical AP drugs is primarily large body of evidence suggests that the use of these drugs responsible for their unfavorable impact on these pathol- is associated with obesity (2, 3) and diabetes mellitus (4).
ogies. However, this does not appear to be the case in Several studies have looked at the metabolic effects of AP studies evaluating this possibility (2, 9). Moreover, in a drugs in nondiabetic schizophrenic patients. The results review of case reports, diabetes often developed after a consistently show that these drugs induce (euglycemic) short treatment period, in some cases without significant hyperinsulinemia and impaired glucose tolerance (5, 6).
weight gain (10). The metabolic profile often improved ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: AP, Antipsychotic; EGP, endogenous glucose production; FFA, free fatty Printed in U.S.A.
acid(s); GIR, glucose infusion rate; LPL, lipoprotein lipase; Ra, rate of appearance; Rd, rate Copyright 2010 by The Endocrine Society of disappearance; RQ, respiratory quotient; t, time; TG, triglycerides.
doi: 10.1210/jc.2008-1815 Received August 18, 2008. Accepted October 19, 2009.
First Published Online November 11, 2009 J Clin Endocrinol Metab, January 2010, 95(1):118 –125 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 07 October 2016. at 09:31 For personal use only. No other uses without permission. All rights reserved.
J Clin Endocrinol Metab, January 2010, 95(1):118 –125 upon drug discontinuation, whereas rechallenge with the measured according to World Health Organization recommen- same drug resulted in recurrence of hyperglycemia (10).
dations. The subjects were asked to refrain from vigorous phys- Thus, AP drugs may act directly to induce insulin resis- ical exercise for 1 wk before each clamp. When the study drugwas not tolerated, treatment was discontinued. Food intake was tance and diabetes. Atypical AP drugs antagonize a broad not monitored.
range of monoamine neurotransmitter receptors. In addi-tion to their relatively weak affinity for dopamine D2 re- Hyperinsulinemic, euglycemic clamp
ceptors, they have a strong affinity for serotonin 5-HT2, [6,6-2H ]glucose was infused in the basal state and during a histamine H1, ␣-1 adrenergic, and muscarinic M3 recep- hyperinsulinemic, euglycemic clamp to determine the effect of tors, whereas typical AP drugs particularly antagonize do- insulin on peripheral glucose disposal and endogenous glucose pamine D2 receptors. Indeed, various neurotransmitters, production (EGP). Lipolysis was monitored by primed contin- whose signals are blocked by atypical but not typical AP uous infusion of [2H ]glycerol. At 0730 h, after an overnight (10 h) fast, subjects were admitted to the clinical research unit and drugs, are involved in the control of glucose metabolism asked to lie down in a semirecumbent position. An iv catheter (11–15), which could mechanistically explain direct ac- was placed in an antecubital vein for infusions. Another catheter tions of olanzapine on insulin sensitivity.
was placed in the contralateral hand for blood sampling. This We hypothesized that short-term treatment with AP hand was placed in a heated box (60 C) to obtain arterialized drugs induces insulin resistance through a mechanistic venous blood samples. The subjects were asked to take their last route that is independent of weight gain and that atypical drug dose at 0800 h. Thereafter, basal blood samples for glucose,insulin, free fatty acids (FFA), lipid spectrum, and background drugs exert stronger effects than typical compounds in this isotope enrichment of [6,6-2H ]glucose and [2H ]glycerol were respect. To evaluate this hypothesis, we treated healthy taken. At time (t) ⫽ 0, primed (26.4 ␮mol/kg) continuous (0.33 nonobese men with olanzapine (atypical AP) or haloper- ␮mol/kg 䡠 min) infusion of [6,6-2H ]glucose (enrichment 99.9%; idol (typical AP) for 8 d and studied the impact of these Cambridge Isotopes, Cambridge, MA) was started and contin- interventions on glucose and lipid metabolism by hyper- ued throughout the clamp (4 h) to monitor glucose metabolism.
At 0900 h (t ⫽ 60), a primed (1.6 ␮mol/kg) continuous (0.11 insulinemic euglycemic clamp, isotope dilution technol- ␮mol/kg 䡠 min) infusion of [2H ]glycerol (Cambridge Isotopes) ogy, and indirect calorimetry.
began and continued throughout the clamp (3 h) to monitorlipolysis. At t ⫽ 90 –120 min, four blood samples were taken with10-min intervals for determination of plasma glucose, insulin,glycerol, and enrichment of [6,6-2H ]glucose and [2H ]glycerol.
Subjects and Methods
Subsequently (t ⫽ 120), a primed continuous (40 mU 䡠 m⫺2 䡠min⫺1) infusion of insulin (Actrapid; Novo Nordisk Pharma BV, Alphen aan de Rijn, The Netherlands) was started. Insulin was Fourteen healthy men between the ages of 20 and 40 yr were infused for 2 h. Blood glucose concentrations were measured recruited through advertisements in local newspapers. Subjects every 5 min, and a variable infusion of 20% glucose (enriched were required to have a normal weight, normal fasting plasma with 3% [6,6-2H ]glucose) was adjusted to maintain a stable glucose concentration (⬍6.0 mmol/liter), and normal physical blood glucose concentration (⬃5.0 mmol/liter). By the end of the examination. Subjects who had ever used AP medication and hyperinsulinemic clamp (t ⫽ 210 –240), blood was drawn every subjects who where currently smoking or using medication af- 10 min for determination of plasma glucose, insulin, glycerol, fecting the central nervous system were excluded. Subjects who and enrichment of [6,6-2H ]glucose and [2H ]glycerol. Indirect dropped out (because of side effects) were replaced by other calorimetry was performed for determination of resting energy volunteers. All subjects provided written informed consent after expenditure, respiratory quotient (RQ), glucose, and fat oxida- the study procedures and possible adverse effects of the treat- tion in basal condition (t ⫽ 60 –90) and during hyperinsulinemia ment had been explained. The protocol was approved by the (t ⫽ 180 –210).
medical ethics committee of the Leiden University MedicalCenter.
Each tube, except the serum tubes, was immediately chilled on ice. Samples were centrifuged at 4000 rpm at 4 C for 20 min.
Subjects underwent a hyperinsulinemic, euglycemic clamp at Subsequently, plasma was divided into separate aliquots and baseline and on the last day (d 8) of treatment with either olan- frozen at ⫺80 C until assays were performed.
zapine (10 mg once daily) or haloperidol (3 mg once daily). The Serum glucose, total cholesterol, and high-density lipopro- drugs were taken at 0800 h. The drug doses prescribed are in the tein-cholesterol were measured in the laboratory for Clinical low range of doses used for the treatment of patients with schizo- Chemistry at Leiden University Medical Center, using a fully phrenia. On both study days, substrate oxidation was measured automated Hitachi Modular P800 system (Hitachi Ltd., Tokyo, by indirect calorimetry (Oxycon Beta; Jaeger Toennies, Breda, Japan). Low-density lipoprotein-cholesterol was measured The Netherlands) in basal (after a 10-h overnight fast) and hy- with COBAS INTEGRA 800 (Roche Diagnostics, Mannheim, perinsulinemic conditions. Body fat percentage was determined by bioelectrical impedance analysis (Bodystat 1500; Bodystat Serum insulin was measured by immunoradiometric assay (INS- Limited, Dougles, Isle of Man, United Kingdom). Body mass IRMA; BioSource Europe S.A., Nivelles, Belgium), and serum glu- index (BMI; weight/length2) and waist/hip circumference were cagon was measured by RIA (Medgenix, Fleurus, Belgium). Serum The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 07 October 2016. at 09:31 For personal use only. No other uses without permission. All rights reserved.
Vidarsdottir et al.
Olanzapine Induces Insulin Resistance J Clin Endocrinol Metab, January 2010, 95(1):118 –125 prolactin concentrations were measured with a sensitive time-re- solved fluoroimmunoassay with a detection limit of 0.04 ␮g/liter(Delfia, Wallac Oy, Turku, Finland).
Subjects, anthropometric measures, and plasma
Plasma levels of FFA and triglycerides (TG) were determined using commercially available kits (Wako Pure Chemical Indus- Fourteen subjects were included in the study. Four sub- tries, Osaka, Japan; and Roche Diagnostics).
Glucose and [6,6-2H ]glucose enrichment as well as glycerol jects discontinued haloperidol treatment: one subject be- and [2H ]glycerol enrichment were determined in a single ana- cause of a vasovagal reaction when basal blood samples lytical run, using gas chromatography coupled to mass spec- where taken at the first study day, and three subjects be- trometry (Hewlett-Packard, Palo Alto, CA) as previously de- cause of the occurrence of side effects. Of those subjects, scribed (16, 17).
two had acute dystonia, which was treated with anticho-linergic drugs (Akineton im) and one subject discontinued In isotopic steady-state condition, the rate of glucose disappear- treatment because of restlessness. All of these subjects ance (Rd) equals the rate of glucose appearance (Ra). Ra, which were replaced by other volunteers. None of the subjects represents EGP, was calculated by dividing the [6,6-2H ]glucose using olanzapine had major side effects. Five were some- infusion rate (milligrams per minute) by the steady-state plasma what drowsy during the first day of treatment only. The [6,6-2H ]glucose tracer/tracee ratio. During insulin infusion, Rd father of one subject in the haloperidol group was of Med- was calculated by adding the rate of exogenous glucose infusion tothe Ra. The Ra of glycerol was calculated by dividing the iterranean origin (ethnicity may have impact on insulin [2H ]glycerol infusion rate (micromoles per minute) by the steady- sensitivity); all other subjects were of Caucasian origin. In state plasma [2H ]glycerol tracer/tracee ratio. Total lipid and car- the haloperidol group, one subject had a father with type bohydrate oxidation rates were calculated as previously described 2 diabetes, and in the olanzapine group one subject had a (18). Data are expressed per kilogram body weight.
second-degree family member with type 2 diabetes.
Table 1 summarizes anthropometric measurements and biochemical parameters in fasting condition on d 0 The study was powered to detect a difference in glucose in- fusion rate before and after treatment with either drug. Eight and d 8 in both groups. Baseline characteristics, including subjects per group allowed detection of a 30% difference with risk factors for insulin resistance (i.e. anthropometrics, 80% power at a two-sided significance level of 0.05. Data are ethnicity, family history of type 2 diabetes, fasting insulin presented as mean ⫾ SEM. Data were logarithmically trans- and glucose levels), did not differ between the treatment formed when appropriate. Comparisons were made within groups. Body weight and waist-hip ratio did not change groups with two-tailed dependent Student's t test. To comparethe effect of olanzapine and haloperidol treatment (between from d 0 to d 8 in either group. Fat percentage decreased groups), an independent Student's t test was used; the difference slightly during treatment with haloperidol. Fasting plasma of the values before and after each intervention was compared.
insulin and glucose levels did not change during treatment When the distribution of data was not normal after logarith- in either group. FFA concentrations significantly declined mic transformation, data were analyzed using non-parametric during olanzapine treatment (P ⫽ 0.03). This effect did not Wilcoxon signed-rank test. Significance level was set at 0.05.
All analyses were performed using SPSS for Windows, version differ significantly from the effect of haloperidol treat- 12.0 (SPSS Inc., Chicago, IL).
ment. Serum glucagon concentrations were significantly TABLE 1. Subject characteristics, before and after treatment with olanzapine or haloperidol
Olanzapine (n ⴝ 7)
Haloperidol (n ⴝ 7)
8.9 ⫾ 1.5a Glucose (mmol/liter) Insulin (mU/liter) 68.5 ⫾ 6.6a Prolactin (␮g/liter) 16.3 ⫾ 3.1b 15.2 ⫾ 1.9a 0.43 ⫾ 0.10a Total cholesterol (mmol/liter) Values are expressed as mean ⫾ SEM. BMI, Body mass index; WHR, waist-hip ratio.
a P ⬍ 0.05 vs. baseline.
b P ⬍ 0.01 vs. baseline.
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J Clin Endocrinol Metab, January 2010, 95(1):118 –125 TABLE 2. Metabolic variables during hyperinsulinemic euglycemic clamp
Olanzapine (n ⴝ 7)
Haloperidol (n ⴝ 7)
Glucose (mmol/liter) Insulin (mU/liter) Background enrichment of 关6,6-2H 兴 1.33 ⫻ 10⫺2 ⫾ 1.29 ⫻ 10⫺2 ⫾ 1.31 ⫻ 10⫺2 ⫾ 1.32 ⫻ 10⫺2 ⫾ glucose (% of total glucose) GIR (mg 䡠 kg⫺1 䡠 min⫺1) 4.9 ⫾ 0.9a Glucose disposal (mg 䡠 kg⫺1 䡠 min⫺1) 6.9 ⫾ 0.8a EGP basal (mg 䡠 kg⫺1 䡠 min⫺1) EGP hyperinsulinemic (mg 䡠 kg⫺1 䡠 min⫺1) Ra glycerol basal (␮mol 䡠 kg⫺1 䡠 min⫺1) Ra glycerol hyperinsulinemic (␮mol 䡠 kg⫺1 䡠 min⫺1) Ra glycerol % decline 65.3 ⫾ 6.9a 8.1 ⫾ 3.6b Values are expressed as mean ⫾ SEM. EGP % inhibition, Decline of EGP during hyperinsulinemia expressed as percentage of basal value; FFA %decline, decline of circulating FFA during hyperinsulinemia expressed as percentage of basal value; Ra, rate of appearance; TG % decline, declineof circulating TG during hyperinsulinemia expressed as percentage of basal value.
a P ⬍ 0.05 vs. d 0.
b P ⬍ 0.01 vs. d 0.
elevated by olanzapine treatment, but the difference with affected by either treatment (Fig. 1). Glucose disposal dur- the effect of haloperidol did not reach statistical signifi- ing hyperinsulinemia was significantly blunted by olan- cance. Plasma prolactin concentrations were increased zapine treatment (Fig. 1). Again, although haloperidol did during treatment in both groups (olanzapine, P ⫽ 0.002; not affect glucose disposal to a significant extent, the mag- haloperidol, P ⫽ 0.01), which indicates that the drugs nitude of its effect did not differ significantly from that of were properly taken.
EGP and whole body glucose disposal
Serum glucose and insulin concentrations in basal con- dition did not change in response to either treatment (Ta- In fasting condition, plasma FFA concentrations sig- ble 1). Accordingly, EGP was not affected by olanzapine nificantly decreased during olanzapine treatment, and this or haloperidol (Table 2 and Fig. 1).
effect did not differ from that of haloperidol althoughhaloperidol's impact did not reach statistical significance.
Fasting TG concentrations (Table 1) and basal glycerol Ra Data on glucose metabolism during insulin infusion are (Table 2) were not affected by either drug.
shown in Table 2. Serum glucose concentrations wereclamped at similar levels on both study days. Also, plasma insulin concentrations during insulin infusion were in the Data on lipid metabolism during insulin infusion are postprandial range and similar on both days (Table 2).
Background enrichment of [6,6-2H shown in Table 2. Insulin significantly suppressed the glyc- 2]glucose (% of total glucose) was similar on both study occasions (olanzapine erol Ra in the haloperidol (P ⫽ 0.028 on d 0; P ⫽ 0.018 d 0, 1.33 ⫻ 10⫺2 ⫾ 0.07 ⫻ 10⫺2; d 8, 1.29 ⫻ 10⫺2 ⫾ on d 8) -treated group, but not in the olanzapine-treated 0.04 ⫻ 10⫺2; haloperidol d 0, 1.31 ⫻ 10⫺2 ⫾ 0.02 ⫻ 10⫺2; group (P ⫽ 0.071 on d 0; P ⫽ 0.379 on d 8). During d 8, 1.32 ⫻ 10⫺2 ⫾ 0.03 ⫻ 10⫺2).
hyperinsulinemia, the decline of circulating FFA and TG The glucose infusion rate (GIR) required to maintain levels, expressed as percentage of basal value, was signif- euglycemia during hyperinsulinemia was reduced after icantly blunted by olanzapine, whereas the decline of cir- olanzapine treatment (Fig. 1). Although haloperidol did culating FFA and TG was not affected by treatment with not affect the GIR to a significant extent, the magnitude of haloperidol. Thus, the propensity of olanzapine to blunt its effect did not differ significantly from that of olanza- the decline of circulating FFA and TG by hyperinsulinemia pine. The capacity of insulin to suppress EGP was not differed significantly from the effect of haloperidol.
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Vidarsdottir et al.
Olanzapine Induces Insulin Resistance J Clin Endocrinol Metab, January 2010, 95(1):118 –125 RQ, and lipid and glucose oxidation rate were not affectedby either drug.
To establish the early effects of AP drugs on glucose andlipid metabolism, we treated healthy young men with 10mg olanzapine or 3 mg haloperidol once daily for only 8 d.
Olanzapine significantly reduced the glucose infusion raterequired to maintain euglycemia during insulin infusion,indicating that the drug induces whole body insulin resis-tance. Specifically, olanzapine reduced insulin-mediatedglucose disposal, whereas it did not affect insulin's capac-ity to suppress EGP. These effects did not differ from thoseof haloperidol to a significant extent, although the glucoseinfusion rate and disposal during haloperidol treatmentwere not significantly different from baseline. Olanzapinealso curtailed the decline of circulating FFA and TG duringhyperinsulinemia, whereas it did not affect the glycerol Raor the ability of insulin to inhibit this measure of the rateof lipolysis. Notably, these metabolic effects occurredwithout a measurable effect on body weight or body fatmass, although the waist circumference increased slightlyin response to olanzapine treatment. In clear contrast, hal-operidol did not affect the insulin-induced decline of FFAand TG concentrations.
Effects on glucose metabolism
FIG. 1. GIR, EGP basal, and EGP hyperinsulinemic (hyperins), and
These data indicate that olanzapine hampers insulin glucose disposal (Rd) before and after 8-d treatment with olanzapine action on glucose disposal, whereas the effect of haloper- and haloperidol. Values are expressed as mean ⫾ SD. *, P ⬍ 0.05.
idol was less clear. This inference is consistent with datafrom large epidemiological studies (19 –21), showing that Glucose and lipid oxidation rate
patients treated with atypical AP drugs are more likely to Table 3 provides an overview of the effects of both develop diabetes mellitus than patients treated with typ- drugs on substrate oxidation. Resting energy expenditure, ical AP drugs. Also in line with our data, Newcomer et al. TABLE 3. Fuel oxidation before and after treatment with olanzapine or haloperidol
Olanzapine (n ⴝ 7)
Haloperidol (n ⴝ 7)
Glucose oxidation (mg 䡠 kg⫺1 䡠 min⫺1) Lipid oxidation (mg 䡠 kg⫺1 䡠 min⫺1) Values are expressed as mean ⫾ SEM. There were no significant differences in fuel oxidation after treatment with olanzapine or haloperidol. REE,Resting energy expenditure.
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J Clin Endocrinol Metab, January 2010, 95(1):118 –125 (7) reported that schizophrenic patients treated with olan- rinic M3 receptors (28). Activation of all of these receptor zapine are more insulin resistant than patients treated with (sub)types, including the D2 receptors (29), generally in- typical AP drugs, as estimated by iv glucose tolerance test.
hibits food intake, reduces body weight, and/or enhances Relatively few studies have looked at the metabolic effects insulin secretion (30 –33). Notably, various receptors of AP drugs in healthy subjects. Sowell et al. (22) assessed blocked by olanzapine appear to be directly (i.e. indepen- meal tolerance and insulin sensitivity, using a two-step dent of their effects on body weight) involved in the reg- hyperinsulinemic euglycemic clamp and a mixed meal tol- ulation of glucose metabolism. Indeed, imipramine in- erance test, in normal subjects after 3 wk of olanzapine (10 duces hyperglycemia in mice by blocking 5-HT2 receptors mg/d; n ⫽ 22), risperidone (4 mg/d; n ⫽ 14), or placebo (14), and a single dose of ketanserin, a 5-HT2 receptor (n ⫽ 19) treatment. The glucose infusion rate required to antagonist, impairs insulin action on glucose metabolism maintain euglycemia during hyperinsulinemia was not af- in healthy humans (12). Blocking H1 receptors in cardiac fected by either treatment, suggesting that the drugs did muscle tissue impairs glucose uptake (15), whereas, in ap- not impact on insulin action. However, treatment with parent contradiction, activation of H1 receptors in the olanzapine significantly increased fasting insulin and glu- brain acutely elevates plasma glucose levels (34). Thus, the cose levels, whereas treatment with risperidone or placebo H1 receptor has multiple, apparently opposite roles in did not. Also, there was a significant increase of the glu- the control of glucose metabolism. Activation of dopa- cose area under the plasma concentration curve in re- mine D2 receptors ameliorates insulin resistance in obese sponse to the mixed meal tolerance test in the group women through a mechanism that is independent of body treated with olanzapine. These data are quite difficult to weight (13), and D2 receptor binding sites are reduced in reconcile. Moreover, glucose disposal and EGP were not the brain of obese animal models and humans (29). Fi- determined in these studies. In full agreement with our nally, ␣1-adrenergic receptor knockout mice are glucose data, 10 d of olanzapine treatment were recently reported intolerant (11), and ␣1-adrenergic receptors stimulate glu- to decrease the glucose infusion rate required to maintain cose uptake in muscle cells (35). Thus, antagonism of ei- euglycemia in healthy men (23). EGP and glucose disposal ther one of these receptors, alone or in combination, by were not determined in this study.
olanzapine may hamper insulin action and explain our The (sub)acute nature of the inhibitory impact of olan- zapine treatment on glucose disposal is consistent withclinical data indicating that atypical AP drugs can induce Effects on lipid metabolism
hyperglycemia within a couple of weeks, before significant Neither drug affected insulin's capacity to suppress li- weight gain has occurred (10). Moreover, it corroborates polysis. Olanzapine, but not haloperidol decreased FFA papers reporting that proximate measures of insulin re- concentrations in fasting condition (although group dif- sistance do not correlate with BMI in schizophrenic pa- ferences did not reach statistical significance). Moreover, tients treated with atypical AP drugs (2, 9). Also, Dwyer it curtailed the decline of circulating FFA and TG concen- and Donohoe (24) reported that atypical AP drugs acutely trations during hyperinsulinemia, which indeed clearly (⬍3 h) induce hyperglycemia in mice, whereas typical AP differed from the effect of haloperidol. In agreement with drugs do not. The ability of these medications to induce our findings, olanzapine was shown to reduce FFA con- hyperglycemia in vivo was tightly correlated with their centration in a recent comprehensive evaluation of lipid effect on glucose transport in pheochromocytoma (PC12) changes in schizophrenia (36). The cause of these changes cells in vitro (24). However, PC12 cells do not express the in lipid metabolism remains to be established. We specu- GLUT-4 transporter, which is abundant in muscle and late that olanzapine inhibits lipoprotein lipase (LPL) ac- responsive to insulin (25), and the concentration of drugs tivity in muscles and impairs the stimulatory action of required to block glucose uptake in these cell systems is insulin on LPL in adipose tissue. LPL hydrolyzes the tri- generally very high (26). Thus, although clozapine and acylglycerol component of circulating lipoprotein parti- fluphenazine were shown to also block glucose transport cles, chylomicrons, and very low-density lipoprotein to in a rat muscle cell line in vitro (27), the relevance of these provide FFA for tissue utilization. In fasting condition, findings for the mechanistic explanation of our data re- LPL is active in muscle and inhibited in adipose tissue, mains uncertain.
whereas (postprandial) hyperinsulinemia stimulates LPL Alternatively, our observations may be explained by in adipose tissue and inhibits LPL activity in muscle (37, the distinct receptor affinity profiles of olanzapine and 38). Reduced LPL activity in muscles may therefore reduce haloperidol. Haloperidol particularly antagonizes dopa- plasma FFA concentrations and impair fatty acid oxida- mine D2 receptors, whereas olanzapine also blocks sero- tion in fasting condition. Reduced LPL activity in adipose tonin 5-HT2, histamine H1, ␣-1 adrenergic, and musca- tissue would explain the blunted decline of plasma FFA The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 07 October 2016. at 09:31 For personal use only. No other uses without permission. All rights reserved.
Vidarsdottir et al.
Olanzapine Induces Insulin Resistance J Clin Endocrinol Metab, January 2010, 95(1):118 –125 and TG during hyperinsulinemia. Inhibition of LPL activ- 7. Newcomer JW, Haupt DW, Fucetola R, Melson AK, Schweiger JA,
ity could either result from direct effects of the drug or be Cooper BP, Selke G 2002 Abnormalities in glucose regulation during
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9. Popli AP, Konicki PE, Jurjus GJ, Fuller MA, Jaskiw GE 1997
In aggregate, these data suggest that olanzapine impairs Clozapine and associated diabetes mellitus. J Clin Psychiatry 58: insulin action on glucose and lipid disposal in muscle and adipose tissue, whereas it does not affect insulin's capacity 10. Liebzeit KA, Markowitz JS, Caley CF 2001 New onset diabetes and
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are early metabolic effects of olanzapine that occur with- Tosato M, Seydoux J, Cotecchia S, Thorens B 2004 Impaired glu-
out a measurable change of body fat mass. Our findings cose homeostasis in mice lacking the ␣1b-adrenergic receptor sub- may explain the property of olanzapine to induce dyslip- type. J Biol Chem 279:1108 –1115 12. Gilles M, Wilke A, Kopf D, Nonell A, Lehnert H, Deuschle M 2005
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14. Sugimoto Y, Inoue K, Yamada J 2003 Involvement of 5-HT(2) re-
ceptor in imipramine-induced hyperglycemia in mice. Horm MetabRes 35:511–516 We thank Trea Streefland for the determination of stable isotope 15. Thomas J, Linssen M, van der Vusse GJ, Hirsch B, Ro¨sen P,
enrichments and the research assistants of the Clinical Research Kammermeier H, Fischer Y 1995 Acute stimulation of glucose trans-
Center of the General Internal Medicine Department of Leiden port by histamine in cardiac microvascular endothelial cells. Bio-chim Biophys Acta 1268:88 –96 University Medical Center, E. J. M. Ladan-Eijgenraam and I. A.
16. Ackermans MT, Ruiter AF, Endert E 1998 Determination of glyc-
Sierat-van der Steen, for their assistance during the study.
erol concentrations and glycerol isotopic enrichments in humanplasma by gas chromatography/mass spectrometry. Anal Biochem Address all correspondence and requests for reprints to: Hanno Pijl, M.D., Ph.D., Department of Endocrinology and Me- 17. Reinauer H, Gries FA, Hu¨binger A, Knode O, Severing K, Susanto
tabolism, Leiden University Medical Center, Leiden, The Neth- F 1990 Determination of glucose turnover and glucose oxidation
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rates in man with stable isotope tracers. J Clin Chem Clin Biochem The research described in this article is supported by the 18. Simonson DC, DeFronzo RA 1990 Indirect calorimetry: method-
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