Testimonial by Dr Anil Kumar (Swami Shantananda) M.D., D.C.H. Kriyayoga Research Institute, Jhunsi, Allahabad, U.P., India I , a U.S. citizen and a medical doctor, has specialized in the care of children and young adults for the last 38 years. After practicing modern medicine mostly in the United States of America and also in England and India, I have returned to India
Bardzo tanie apteki z dostawą w całej Polsce kupic viagra i ogromny wybór pigułek.
Jpn templateResearch Paper
Differential effects of 3 classes of antidiabetic drugs on
olanzapine-induced glucose dysregulation and insulin
resistance in female rats
Heidi N. Boyda, BSc; Ric M. Procyshyn, PharmD, PhD; Lurdes Tse, MSc; Erin Hawkes, MSc;
Chen Helen Jin, MD; Catherine C.Y. Pang, PhD; William G. Honer, MD; Alasdair M. Barr, PhD
Boyda, Tse, Hawkes, Jin, Pang, Barr — Department of Anesthesiology and Pharmacology, University of British Columbia; Procyshyn, Honer — Department of Psychiatry, University of British Columbia; Procyshyn, Honer, Barr — British ColumbiaMental Health & Addictions Research Institute, Vancouver, BC Early-released on May 29, 2012; subject to revision.
Background: The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However,
use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance.
These symptoms have been accurately modelled in rodents. Methods: We compared the effects of 3 distinct classes of anti dia betic
drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapine-
induced metab olic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we
assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assess-
ment of insulin resist ance equation. Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resist -
ance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to
control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels.
Limitations: We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by
anti diabetic treatments. Conclusion: The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metab -
olism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs pri-
marily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose
dysregulation caused by olanzapine and how it can be reversed.
in a metabolic syndrome that substantially increases the riskfor cardiometabolic disorders, such as type II diabetes melli- Second-generation antipsychotics (SGAs; also known as tus and cardiovascular disease.4–6 The identifying characteris- atypical antipsychotics) are effective pharmacological treat- tics of metabolic syndrome are weight gain, hypertension, ments for psychotic conditions, including schizophrenia and hyperlipidemia, hyperglycemia, glucose intolerance and in- bipolar disorder.1 On- and off-label use of SGAs has in- creased in recent years to include additional indications, such Despite the similarity of SGA-induced metabolic syndrome as mood and anxiety disorders.2 The widespread use of these to other forms of prediabetes, the paucity of knowledge drugs has been ascribed to their lower propensity to induce about the underlying physiology of the condition has hin- neurologic side effects, such as extrapyramidal symptoms, dered the development of optimal treatment strategies for compared with first-generation antipsychotics.3 Importantly controlling metabolic dysregulation. Nevertheless, health though, the past decade of clinical research has reported that care providers have recognized the serious nature of SGA- most SGAs can cause serious metabolic side effects, resulting induced metabolic side effects and have sought to ameliorate Correspondence to: A.M. Barr, Department of Anesthesiology and Pharmacology, University of British Columbia, 2176 Health Sciences Mall,
Vancouver BC V6T 1Z3; [email protected]
Submitted Sept. 30, 2011; Revised Feb. 2, Mar. 12, 20, 2012; Accepted Mar. 22, 2012.
J Psychiatry Neurosci
them through various interventions.8 Consistent with the lit- rosiglitazone and glyburide on glucose intolerance and in- erature on type II diabetes mellitus, some success has been sulin resistance caused by acute treatment with olanzapine in obtained through lifestyle changes, including exercise and a rat model that we have used previously.
diet ary modifications.9 However, these changes may be morechallenging in the psychiatric population,10 therefore the mainstay of treatment remains the use of antidiabetic drugs.
A number of different antidiabetic drugs are currently used to treat metabolic syndrome11 and type II diabetes mellitus,but unlike antipsychotic drugs that all work primarily Adult female Sprague-Dawley rats (Charles River) initially through a similar mechanism in regards to clinical efficacy weigh ing 250–275 g were pair-housed and maintained on a 12- (blockade of dopamine D receptors12), the antidiabetic drugs hour light–dark cycle (lights on at 07:00h) in a temperature- operate through diverse physiological pathways. For in- controlled colony (mean 22ºC ± 1ºC). Rats were allowed to ha- stance, the efficacy of metformin (a biguanide) is mediated in bituate to the University of British Columbia (UBC) colony for part by an AMP-dependent kinase (AMPK) signalling path- 1 week before experimental testing. Food and water were way, which does not directly stimulate insulin secretion.13,14 freely available. Animals were treated in accordance with the The main mode of action for rosiglitazone (a thiazolidine- National Institutes of Health Guide for the Care and Use of dione) involves the activation of the peroxisome proliferator- Laboratory Animals. The Animal Care and Use Committee at activated receptor γ (PPARγ), a nuclear transcriptional protein that belongs to the family of PPARs, which regulate genes in-volved in lipid and glucose metabolism.15 Rosiglitazone- induced acute effects are also independent of direct insulinrelease.16 In contrast to both metformin and rosiglitazone, gly- The doses of olanzapine (7.5 and 15 mg/kg, intraperitoneal, buride (a sulfonylurea) directly increases insulin secretion in hereafter referred to as “lower” and “higher” doses, respect - the pancreas by inhibiting the ATP-sensitive potassium chan- ively), which we purchased from Toronto Research Chemicals nel in β cells.17 It is therefore important to determine whether Inc., were carefully chosen to represent the middle-to-upper specific classes of antidiabetic drugs are more efficacious in range of physiologically relevant levels in vivo and were treating SGA-induced metabolic syndrome, as this form of based on doses used in previous behavioural studies.20,31,32 The metabolic dysregulation may be more or less sensitive to in- vehicle solution for olanzapine consisted of 50% polyethylene glycol 400, 40% distilled water and 10% ethanol (PEG solu- The symptoms of metabolic syndrome can be modelled in tion). Olanzapine was administered intraperitoneally in a vol- rodents, and preclinical paradigms have reliably reproduced ume of 1 mL/kg as a single injection 60 minutes before the many of the metabolic symptoms of SGAs observed in hu- glucose challenge (refer to section on Acute antidiabetic treat- mans.18–20 We and others have previously shown that 2 of the ment). The doses of metformin (100 and 500 mg/kg, oral) and key symptoms of SGA-induced metabolic dysregulation (i.e., rosiglitazone (6 and 30 mg/kg, oral), which we purchased glucose intolerance and insulin resistance) are faithfully re- from Toronto Research Chemicals Inc., and of glyburide (2 produced in rats following both acute and chronic treatment and 10 mg/kg, oral), which we purchased from Sigma- with SGAs.21–25 Importantly, these changes in glucose metab - Aldrich Inc., were based on doses used in previous preclinical olism occur rapidly and have been demonstrated repeatedly studies33–35 and represented a 5-fold range from low to high to be independent of changes in body weight, both in the doses in the acute setting of various antidiabetic animal mod- clinical setting and in rodent models.24,26,27 To date, the effects els. The vehicle solutions for metformin and rosiglitazone con- of most of the main classes of antidiabetic drugs on SGA- sisted of heated 0.9% saline (which was allowed to cool before induced metabolic dysregulation remain undetermined in administration), whereas the vehicle for glyburide consisted preclinical models. It is important to perform such studies, as of PEG solution. All hypoglycemic drugs were administered findings may not only provide knowledge about the biologic - orally (gastric gavage) once daily for 2 consecutive days (refer al pathways that are affected, but also offer insights into opti- to section on Acute antidiabetic treatment). The duration of mal treatment approaches in the clinic.
oral hypoglycemic drug treatment was set to 2 consecutive We therefore conducted the present study to determine the days to ensure that baseline fasting metabolic parameters effects of 3 of the most commonly used classes of oral hypo- (measured both before and after olanzapine administration) glycemic drugs (i.e., biguanides, thiazolidinediones and sul- and postprandial measures could be examined under antidia- fonylureas) on the metabolic dysregulation caused by the betic drug exposure. All solutions were compounded fresh SGA olanzapine. Olanzapine is a widely used SGA with a daily, and the use of all other chemical compounds were com- low propensity for neurological side effects that has proven mercially available and of reagent grade.
to be superior in controlling psychosis and preventing rehos-pitalization to other SGAs in a major head-to-head trial.28 Baseline Intraperitoneal Glucose Tolerance Test However, enthusiasm for the use of olanzapine is temperedby evidence that it causes serious metabolic side effects that See Appendix 1, Figure S1, available at cma.ca/jpn, for a rep- may be second only in severity to those associated with resentation of the sequence of events. Prior to the administra- clozapine.29,30 We therefore tested the effects of metformin, tion of the first antidiabetic trial (metformin), all rats were J Psychiatry Neurosci
Olanzapine metabolic side-effects and antidiabetic drugs subjected to a baseline glucose tolerance test (day 1). Briefly, ani - using ultra sensitive rat insulin enzyme-linked immunosor- mals were wrapped in a towel to minimize stress, and a small bent assay (ELISA) kits (Crystal Chem Inc.), as previously drop of saphenous venous blood was procured through the use performed.21,36 Briefly, 5 µL plasma samples were added and of a 25-gauge needle for the baseline blood glucose measure- analyzed, in duplicate, on each 96-well plate according to the ment at t = 0 minutes. Subsequently, all animals received a glu- specific time points studied (t = 60 and t = 90 minutes). Sam- cose challenge (1 g/kg/mL, intraperitoneal) followed by re- ples were incubated at 4°C for 2 hours followed by repeated peated sampling of blood glucose readings at t = 15, 45, 75 and washes. Substrate was added for 40 minutes, and absorbance 105 minutes. All blood glucose measurements were determined was measured at 450–630 nm. Calibrators provided with the by a hand-held glucometer (One Touch Ultra). Rats were left ELISA kit were used to generate a curve to interpolate sam- untreated from days 2–7 before the first antidiabetic drug ad- ple insulin values. In addition, a reference (nonfasted) ani- ministration (day 8) and the subsequent intraperitoneal glucose mal’s plasma added to all plates served as a reference stan- tolerance test (IGTT; day 9). As the present longitudinal study dard; this confirmed a high intraplate reliability, with a mean exposed the rats consecutively to 3 different antidiabetic drugs run-to-run correlation of 0.996 (range 0.994–0.999).
that could theoretically have residual carryover effects, a similar“washout” procedure was performed 1 week after each drug treatment (rats were left untreated during the week after eacholanzapine/antidiabetic drug trial, days 10–14). Any putative To determine acute insulin resistance in drug-treated rats, we carryover effects would be detected as a change in IGTT results calculated the homeostatic model assessment of insulin resist - ance (HOMA-IR). This equation takes into account the prod-uct of both fasting levels of glucose (expressed as mmol/L) and insulin (µU/mL) at 60 minutes postolanzapine treatmentand divides by a constant of 22.5 ([I x G ]/22.5), where I and See Appendix 1, Figure S1 for a representation of the se- G are fasting insulinemia and glycemia. A larger calculated quence of events. Rats (n = 8–10 per group) were rank- HOMA-IR value denotes greater insulin resistance.
ordered based on the baseline IGTT and the initial total bodyweight, and they were then randomized into 1 of 9 treatment groups: higher dose olanzapine (15 mg/kg) and higher dosemetformin (500 mg/kg), higher dose olanzapine and lower We performed a 2-factor analysis of variance (ANOVA), with dose metformin (100 mg/kg), higher dose olanzapine and no antipsychotic drug (2 doses of olanzapine and vehicle) and metformin (0.9% saline vehicle), lower dose olanzapine antidiabetic drug (2 doses and vehicle) as the between-subject (7.5 mg/ kg) and higher dose metformin, lower dose olanza - factors, with an α of p < 0.05. Individual glucose measure- pine and lower dose metformin, lower dose olanzapine and ments at the 8 time points during the IGTT were integrated to 0.9% saline, no olanzapine (PEG vehicle solution) and higher generate a single area under the curve (AUC) value. The vari- dose metformin, no olanzapine and lower dose metformin, ables analyzed included fasting levels of glucose before and and no olanzapine and no metformin (0.9% saline vehicle).
60 min utes after the antipsychotic drug challenge, the AUC Each rat received a single gavage administration of either for the glucose tolerance test, fasting postdrug insulin and metformin or 0.9% saline on day 8 (at 11:00h). On day 9, rats HOMA-IR values. When appropriate, we conducted least that were fasted overnight (mean 16 [SD 2] hr) had their base- significant difference post hoc tests. Data were analyzed with line blood glucose levels measured and then received a single intraperitoneal injection of either olanzapine (7.5 or 15 mg/ kg)or PEG vehicle (t = 0 minutes). After a 60-minute delay, ani- mals were subjected to a 100 µL saphenous blood draw,whereby plasma was centrifuged (10 000 revolutions per minute for 10 minutes at 4°C) and stored at –80°C for theanalysis of insulin levels. The animals then received the second Fasting levels of glucose in the rats before olanzapine admin- dose of metformin or vehicle by gavage (60 min postolanza - istration did not differ between the groups (Table 1). How- pine administration) followed by an intraperitoneal challenge ever, fasting levels of glucose measured 60 minutes after treat- injection of glucose (1 g/mL/kg). Glucose levels were then ment with olanzapine but before the administration of the measured every 15 minutes for a duration of 120 minutes. An second metformin dose and the glucose load showed a highly identical protocol was repeated for the 2 additional antidia- significant effect of antipsychotic drug treatment (F betic drugs, rosiglitazone (6 or 30 mg/kg, oral) and glyburide p < 0.001) but no interaction with antidiabetic drug treatment (2 or 10 mg/kg, oral). For the entirety of the study, each animal (there were no significant interactions between these 2 factors handler was blinded to drug treatment group.
on any variable for any of the 3 antidiabetic drugs). Post hocanalysis indicated that all olanzapine-treated groups had Insulin measurement by enzyme-linked immunosorbent assay higher fasting glucose levels than the vehicle-treated groups(p < 0.001; Table 1). Interestingly, the higher dose olanzapine- Individual plasma samples extracted during day 2 from each treated rats that were not given metformin had higher fasting of the 3 antidiabetic IGTTs were analyzed for insulin content glucose levels than all other groups (p = 0.011), including the J Psychiatry Neurosci
2 other higher dose olanzapine-treated groups that received washout IGTT after metformin treatment (i.e., 1 week before metformin the day before. This suggests that the first day of and 1 week after metformin treatment) indicated no carry- treatment may have had a residual effect on glucose levels af- over effect of drug treatment, so animals were rerandomized ter challenge with the antipsychotic drug.
to 2 days of treatment with rosiglitazone the following week.
Analysis of insulin levels postolanzapine administration but Fasting levels of glucose in the rats on the second day of before the metformin and glucose load indicated a significant rosiglitazone treatment before olanzapine administration did main effect of antipsychotic drug treatment (F not differ between the groups. Olanzapine increased fasting p < 0.001), whereby insulin levels were significantly increased levels of glucose measured 60 minutes after antipsychotic in all groups treated with olanzapine (Table 1). Insulin resist - = 23.29, p < 0.001; Table 1). This reflected ance was calculated using the HOMA-IR equation. The increased glucose levels for the olanzapine-treated groups ANOVA indicated a significant main effect of olanzapine compared with groups not treated with olanzapine (p < 0.001). Fasting insulin levels were similarly increased in whereby they were significantly higher in all groups treated all olanzapine-treated groups compared with vehicle-treated with olanzapine than in those treated with vehicle; HOMA-IR = 17.31, p < 0.001; Table 1). Analysis of HOMA- values were also significantly higher in the 15 mg/kg dose IR values revealed a significant effect of olanzapine (F olanzapine groups than the 7.5 mg/kg dose groups (p = 0.013), 17.29, p < 0.001), whereby HOMA-IR values were signifi- indicating a dose-dependent effect of olanzapine on insulin re- cantly higher in all groups treated with olanzapine. Whereas sistance. The effects of metformin on olanzapine-induced glu- HOMA-IR values were lower in all groups that had received cose dysregulation were directly assessed with the IGTT rosiglitazone on the previous day, this effect did not ap- (Fig. 1A and Appendix 1, Figure S2A). The ANOVA indicated proach significance, unlike with metformin.
significant main effects of both olanzapine (F Analysis of the data from the IGTT indicated that there was p < 0.001) and metformin (F both an effect of treatment with olanzapine (F the IGTT. Post hoc analysis revealed that olanzapine produced p < 0.001) and an effect of treatment with rosiglitazone (F a dose-dependent increase in the glucose values during the 5.43, p = 0.007). Similar to the effects of metformin, both doses IGTT, with the 15 mg/kg dose causing the greatest degree of of rosiglitazone caused a significant reduction in glucose intol- glucose intolerance (p = 0.008). Both doses of metformin erance in olanzapine-treated rats (p = 0.010; Fig. 1B and Appen- caused a significant reduction in olanzapine-induced glucose dix 1, Figure S2B) but did not completely reverse glucose intol- intolerance (p = 0.002); however, this effect did not differ be- erance, as glucose levels still remained significantly higher than tween the 2 doses of metformin. Glucose levels were still those in rats not treated with olanzapine (p = 0.014).
higher in groups that received olanzapine and metformin thanin those that did not receive olanzapine (p = 0.046), reflecting a partial rather than full reversal of glucose intolerance.
Comparison of glucose levels in the washout IGTTs before and after treatment with rosiglitazone indicated no differencein glucose tolerance, therefore the rats were rerandomized to Comparison of glucose levels in the baseline IGTT and the treatment with glyburide the following week.
Table 1: Mean concentration of fasting glucose, insulin and HOMA-IR scores in rats treated with oral hypoglycemic drugs*
H = high-dose hypoglycemic; HOMA-IR = homeostatic model assessment of insulin resistance; L = low-dose hypoglycemic; O = olanzapine; O = olanzapine, 7.5 mg/kg; SEM = standard error of the mean; V = vehicle.
*Rats were treated with vehicle or olanzapine (7.5 or 15 mg/kg) on day 2.
†Significantly different from V – V group, p < 0.05.
‡Significantly different from O J Psychiatry Neurosci
Olanzapine metabolic side-effects and antidiabetic drugs Analysis of fasting glucose levels on the second day of gly- buride treatment revealed a highly significant main effect of A Metformin
with metformin and rosiglitazone. This was due to a large re- duction of about 50% in fasting glucose levels in animalstreated with glyburide, demonstrating that glyburide has hypoglycemic actions even 24 hours after administration (Table 1). Sixty minutes following treatment with olanzapine there was a main effect of treatment with both olanzapine = 29.11, p < 0.001) and glyburide (F fasting glucose levels. Further analysis revealed that olan - zapine had a dose-dependent effect on glucose levels, with both doses of olanzapine causing increases compared with vehicle-treated rats (p < 0.001) and a greater effect of the 15 mg/kg dose compared with the 7.5 mg/kg dose B Rosiglitazone
(p = 0.032). The effect of glyburide, representing residual ef- fects from the first day of treatment, was evident, as de- creased fasting glucose levels compared with rats not treated with the antidiabetic drug: while all glyburide-treated groups showed decreases, this was only significant in the rats not treated with olanzapine. Fasting insulin levels revealed main effects of both olanzapine treatment (F viously (Table 1). Olanzapine, relative to vehicle, caused an increase in insulin levels (p < 0.001). Glyburide treatment 24 hours previously increased insulin levels, but only in the higher dose groups (10 mg/kg; p = 0.017). Insulin resistance, C Glyburide
measured by HOMA-IR, exhibited a main effect of olanza - = 26.65, p < 0.001) but no effect of gly- buride, as olanzapine increased HOMA-IR values. Glucose intolerance during the IGTT following the second dose of glyburide also revealed a main effect of olanzapine treatment = 39.35, p < 0.001) but no effect of glyburide treatment (Fig. 1C and Appendix 1, Fig. S2C). As mentioned previ-ously, olanzapine caused a dose-dependent increase in glu- cose intolerance, regardless of glyburide treatment group,with both doses of olanzapine increasing glucose intolerance significantly (p < 0.001), and a greater effect of the 15 mg/kg olanzapine dose compared with the 7.5 mg/kg dose(p = 0.002). Whereas glyburide decreased glucose levels in the animals not treated with olanzapine, this effect did not quite achieve significance and had no effect in olanzapine-treatedanimals, unlike with metformin and rosiglitazone.
Fig. 1: Animals (n = 8–10 per group) received 2 daily gavages of
Interestingly, the magnitude of the response to olanzapine either (A) metformin (100 and 500 mg/kg, oral), (B) rosiglitazone (6
during the IGTT showed a slight reduction with time across and 30 mg/kg, oral) or (C) glyburide (2 and 10 mg/kg, oral) immedi-
the entire study, as AUC glucose levels modestly (but non- ately after olanzapine treatment (7.5 and 15 mg/kg, intraperitoneal) significantly) declined with both doses of olanzapine be- and overnight fasting. Subsequently, all rats were subjected to a tween the first exposure to olanzapine and the second expos - glucose tolerance test, receiving an intraperitoneal challenge injec- ure (with rosiglitazone), although there was no further drop tion of 1 g/mL/kg of glucose, and blood glucose levels were meas - between the second and third olanzapine exposures.
ured every 15 minutes for the next 2 hours. Total cumulative glu-cose levels for each treatment group are summed as areas under Discussion
the curve (AUC) and are presented as percent change from vehiclecontrol. H = high dose; L = low dose; SEM = standard error of themean; V = vehicle. *Significantly greater than vehicle-treated rats In the present study, we tested the effects of 3 distinct classes (p = 0.010). †Significantly greater than vehicle-only treated rats of oral hypoglycemic drugs on glucose dysregulation and in- (p = 0.009) but lower than rats treated with 7.5 mg/kg olanzapine sulin resistance in adult female rats treated with lower and and no antidiabetic drug (p = 0.045). ‡Significantly greater than higher doses (7.5 mg/kg and 15 mg/kg) of the SGA olanza - vehicle-only treated rats (p = 0.007) but lower than rats treated with pine. The hypoglycemic drugs were administered once daily 15 mg/kg olanzapine and no antidiabetic drug (p = 0.045).
J Psychiatry Neurosci
for 2 consecutive days, and included a biguanide (metformin), The selective effects of metformin and rosiglitazone versus thiazolidinedione (rosiglitazone) and sulfonylurea (glyburide).
glyburide on glucose homeostasis are consistent with the A major conclusion from the present results is that known effects of olanzapine on glucose dysregulation. Evi- olanzapine-induced glucose dysregulation can be alleviated, in dence suggests that the pathogenesis of SGA-induced glu- part, by antidiabetic drug mechanisms that are independent of cose dysregulation stems mainly from inadequate hepatic direct insulin release. Under current experimental conditions, glucose control,24,44,45 reflecting hepatic insulin insensitivity.
improvement of glucose intolerance and hyperglycemia was Hyperinsulinemic-euglycemic clamp studies have demon- demonstrated by both metformin and rosiglitazone, but not strated that olanzapine significantly decreases hepatic insulin glyburide treatment. It is unlikely that the 2 doses of glyburide sensitivity and increases hepatic glucose output (HGO) in ro- used were too low to have an effect, as these are doses com- dent models.22,24,44 For both metformin and rosiglitazone, in monly used efficaciously in other rat models of metabolic dys- vitro evidence indicates that suppression of liver HGO is regulation and type 2 diabetes.33 Furthermore, our 5-fold dose medi ated independently of the effects of insulin.14,46 In compar- range of glyburide reduced fasting glucose levels by almost ison, sulfonylureas, such as glyburide, produce their therapeu- 50% and nearly doubled plasma insulin levels in control ani- tic effects by directly stimulating insulin secretion from the mals, consistent with glyburide’s known insulin-secreting ac- pancreas, giving rise to sustained levels of circulating insulin.17 tion. It appears that increasing insulin levels alone is insuffi- In theory, the increased levels of insulin caused by treatment cient to decrease the glucose dysregulation induced by with glyburide should stimulate type 1 processes that lower olanzapine. Working through mechanisms independent of di- glucose levels in response to a hyperglycemic state, such as rect insulin release, metformin and rosiglitazone were able to hep atic glucose uptake, peripheral glucose disposal and inhibi- cause a respective 39%–54% and 29%–50% decrease in glucose tion of glucogenic responses. However, the clear failure of gly- intolerance in the IGTT. The effects of metformin and rosiglita- buride to affect olanzapine-induced hyperglycemia strongly zone were not dose-dependent, as the higher dose of each suggests that the therapeutic effects of metformin and rosigli- drug did not have a greater effect, so doses might have to be tazone occur via their insulin-independent mechanisms. As substantially higher to produce additional effects on glucose metformin’s pharmacological action involves suppressing dysregulation. It is also unlikely that more extended dosing HGO by curtailing gluconeogenesis in addition to enhancing could produce a greater effect, as our pilot studies found no peripheral glucose utilization,47,48 there are shared physiologic further benefit to extending hypoglycemic drug treatment be- pathways between both antipsychotic and antidiabetic drugs.
yond 1 week (data not shown). It is possible that the inability The “cellular energy sensing” AMPK-signalling pathway has of these drugs to completely reverse olanzapine-induced glu- been proposed as a mechanism of antidiabetic action. Both cose dysregulation reflects the complex physiologic effects of liver and muscle AMPK activity is increased by metformin, the antipsychotics through multiple pathways.
facilitating inhibition of lipogenesis, gluconeogenesis and in- Consistent with previous studies, olanzapine caused signifi - creased glucose uptake.49,50 Metformin also blocks hypothala- cant metabolic dysregulation,22,24,31,37–43 evident as elevated fast- mic AMPK activity, resulting in anorexigenic effects.51,52 Several ing glucose levels, insulin resistance (greater HOMA-IR val- recent studies have documented elevated levels of phosphory- ues) and glucose intolerance in the IGTT. To our knowledge, lated hypothalamic AMPK after chronic olanza pine treat- we assessed the effects of metformin, rosiglitazone and gly- ment,45,53 which were associated with weight gain and in- buride on these metabolic side effects in rats for the first time.
creased food intake.54 Evidence also suggests that metformin Metformin showed an effect on glucose dysregulation after modulates the incretin axis via an AMPK-independent the first day of treatment: fasting glucose levels were de- mech anism. Enhanced plasma levels of the insulinotropic creased after treatment with the higher dose of the antipsy- hormone glucagon-like peptide 1 (GLP-1) have been reported chotic. Importantly, after the second dose, metformin signifi- after metformin treatment in humans and in preclinical cantly reduced glucose intolerance in the IGTT, although models.55–57 Among other beneficial antidiabetic effects, GLP-1 values still remained above those of controls. Rosiglitazone suppresses the hyperglycemic action of glucagon, causing did not exhibit effects after the first day of treatment, but the decreased HGO and lower circulating glucose levels. Recent second dose resulted in a reduction of glucose intolerance in studies by Smith and colleagues41,58 demonstrated that the IGTT similar to metformin, causing a significant reduction olanzapine-, clozapine- and quetiapine-induced glucose dys- of glucose intolerance but, again, not a complete return to con- regulation was associated with decreased GLP-1 production trol values. In contrast, glyburide had a strong hypoglycemic and enhanced glucagon secretion, leading to stimulated effect on fasting glucose levels in rats not treated with olanza- HGO. These studies, together with our present findings, sug- pine. However, the drug did not decrease fasting glucose lev- gest common targets for both metformin and antipsychotic els after olanzapine treatment, and unlike the other 2 antidia- drug action. The opposing effects of SGAs and metformin on betic drugs, glyburide had no effect on glucose intolerance in glucagon, GLP-1 and AMPK may explain why hypoglycemic the IGTT. Previously, we have reported that intermittent drug treatment has been only partially successful in relieving treatment with olanzapine can sensitize glucose intolerance.31 SGA-induced metabolic side effects in the clinic.59 Rosigli - This was not observed in the present study, likely owing to tazone, via activation of PPARγ receptors, causes reduced factors, including the duration of treatment, rerandomization expression of genes required for hepatic gluconeogenesis, of animals after each antidiabetic drug, injection regimen and such as pyruvate carboxylase and glucose-6-phosphatase, potential influence of exposure to antidiabetic drugs.
en hancing suppression of HGO and increasing peripheral J Psychiatry Neurosci
Olanzapine metabolic side-effects and antidiabetic drugs glucose disposal,60 similar to metformin.
zone, but not glyburide, can mitigate glucose intolerance To our knowledge, 4 other studies have determined the ef- caused by olanzapine in female rats. These findings are con- fects of antidiabetic agents on SGA-induced glucose intoler- sistent with those reported in preclinical and clinical studies.
ance. In the study by Lykkegaard and colleagues,61 treatment Our findings indicate that drugs that influence hepatic glu- of female rats with liraglutide, a GLP-1 analogue, alleviated cose metabolism are most effective. Further studies using metabolic indices, including olanzapine-induced glucose in- representative drugs from other classes of antidiabetic drugs tolerance. There was no effect on fasting plasma insulin lev- and different models of SGA-induced metabolic abnormality els, but importantly, only a single dose of both olanzapine are needed to elucidate the biological basis of SGA-induced and liraglutide were tested. In a separate study, treatment metabolic sequelae and how antidiabetic drugs reverse these with the GLP-1 receptor agonist exendin-4 decreased glucose side effects. Future research should also examine multidrug levels in the GTT after treatment with an acute 10 mg/kg antidiabetic combinations, as routinely occurs in the clinical dose of clozapine.58 Arulmozhi and colleagues62 assessed the setting,68 to identify optimal treatment strategies that may effects of 3 different PPARγ modulators (glimepiride, rosigli- tazone and fenofibrate) on ziprasidone-, clozapine- andchlorpromazine-induced hyperglycemia and hyperinsuline- Acknowledgements: The current research was supported by grants
mia in mice. Rosiglitazone and glimepiride reduced hyper- from the British Columbia Provincial Health Services Authority andNational Sciences and Engineering Research Council of Canada glycemia in chlorpromazine-treated animals, whereas all (NSERC) grant 356069-09 to A.M. Barr, and NSERC grant 355912-11 3 antidiabetics reduced clozapine-induced hyperglycemia, to C.C.Y. Pang. A.M. Barr is a Canadian Institutes of Health Research with the greatest effect attributed to rosiglitazone. Adeneye (CIHR) New Investigator, and H.N. Boyda is a CIHR Banting scholar.
and colleagues63 examined the chronic effects of both met- Competing interests: None declared for H.N. Boyda, L. Tse, E. Hawkes
formin (20 mg/kg) and glyburide (0.1 mg/kg) pretreatment and C.C.Y. Pang. R.M. Procyshyn declares having consulted for on risperidone-induced weight gain, hyperglycemia, insulin AstraZeneca, Bristol-Myers Squibb, Janssen, Sunovion and Pfizer; re- resistance and dyslipidemia in male rats. After 60 days of ceived lecture fees from AstraZeneca, Bristol-Myers Squibb, Otsukaand Pfizer; and developed educational presentations for Bristol- pretreatment, metformin reduced weight gain, fasting hyper- Myers Squibb and Pfizer. C.H. Jin declares having received a student glycemia, hyperinsulinemia and dyslipidemia, whereas gly- award from the NSERC to fund a summer research project. W.G. Honer buride had no effect. Our results are therefore consistent with declares advisory board membership with Roche Canada and In those reported in the 2 latter studies, and also mostly consist - Silico Biosciences; having received consultant fees from Novartis and ent with the clinical literature. Human studies have con- the Canadian Agency for Drugs and Technology in Health; receivingroyalties from antibody manufacturers for licenses held by his uni- firmed that metformin alleviates some of the metabolic ef- versity; and having received travel support from multiple academic fects of olanzapine. A recent meta-analysis concluded that and health authorities for presentations. A.M. Barr declares advisory metformin had modest effects on olanzapine-induced weight board membership with Roche Canada; having acted as legal consul- gain,64 whereas another meta-analysis that included multiple tant for Eli Lilly Canada; and having a grant pending with BMSCanada through his institution.
SGAs determined that metformin reduced but did not fullyreverse drug-induced insulin resistance.59 There is less evi- Contributors: H.N. Boyda, R.M. Procyshyn, C.C.Y. Pang and A.M. Barr
dence regarding the clinical efficacy of rosiglitazone, owing designed the study. H.N. Boyda, L. Tse, E. Hawkes, C.H. Jin andA.M. Barr acquired the data, which H.N. Boyda, W.G. Honer and in part to ongoing concern about the cardiovascular side ef- A.M. Barr analyzed. H.N. Boyda, R.M. Procyshyn, C.C.Y. Pang and fects of the drug.65 However, a clinical trial noted that rosigli- A.M. Barr wrote the article, which H.N. Boyda, L. Tse, E. Hawkes, tazone significantly improved glycemic control in patients C.H. Jin, W.G. Honer and A.M. Barr reviewed. All authors approved treated with olanzapine.66 To our knowledge, there has been no reported evaluation of glyburide on the metabolic se -quelae of olanzapine or other SGAs, but given our current References
findings, we would not expect this agent to be efficacious.
Honer WG, Thornton AE, Sherwood M, et al. Conceptual and methodological issues in the design of clinical trials of antipsychoticsfor the treatment of schizophrenia. CNS Drugs 2007;21:699-714.
The principle limitation of the present study is the evaluation Procyshyn RM, Honer WG, Wu TK, et al. Persistent antipsychoticpolypharmacy and excessive dosing in the community psychiatric of only a single SGA, despite testing multiple doses of both treatment setting: a review of medication profiles in 435 Canadian antipsychotic and antidiabetic treatments. Whereas most outpatients. J Clin Psychiatry 2010;71:566-73.
SGAs cause metabolic dysregulation, the extent to which all Rummel-Kluge C, Komossa K, Schwarz S, et al. Second-generationantipsychotic drugs and extrapyramidal side effects: a systematic such drugs produce effects through shared pathways review and meta-analysis of head-to-head comparisons. Schizophr remains unknown. It will therefore be necessary in future studies to determine whether the current findings with olan- Kessing LV, Thomsen AF, Mogensen UB, et al. Treatment with an- zapine generalize across the entire class of SGAs, including tipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry2010;197:266-71.
Newcomer JW. Antipsychotic medications: metabolic and cardio-vascular risk. J Clin Psychiatry 2007;68(Suppl 4):8-13.
Procyshyn RM, Wasan KM, Thornton AE, et al. Changes in serumlipids, independent of weight, are associated with changes in symp-toms during long-term clozapine treatment. J Psychiatry Neurosci The present study shows that both metformin and rosiglita- J Psychiatry Neurosci
Hasnain M, Fredrickson SK, Vieweg WV, et al. Metabolic syn- drome associated with schizophrenia and atypical antipsychotics.
Meyer JM, Davis VG, Goff DC, et al. Change in metabolic syn- Curr Diab Rep 2010;10:209-16.
drome parameters with antipsychotic treatment in the CATIE Sengupta S, Parrilla-Escobar MA, Klink R, et al. Are metabolic in- Schizophrenia Trial: prospective data from phase 1. Schizophr Res dices different between drug-naive first-episode psychosis patients and healthy controls? Schizophr Res 2008;102:329-36.
Boyda HN, Procyshyn RM, Tse L, et al. Intermittent treatment Park T, Usher K, Foster K. Description of a healthy lifestyle inter- with olanzapine causes sensitization of the metabolic side-effects vention for people with serious mental illness taking second- in rats. Neuropharmacology 2012;62:1391-400.
generation antipsychotics. Int J Ment Health Nurs 2011;20:428-37.
Geyer MA, Krebs-Thomson K, Braff DL, et al. Pharmacological von Hausswolff-Juhlin Y, Bjartveit M, Lindstrom E, et al. Schizo- studies of prepulse inhibition models of sensorimotor gating phrenia and physical health problems. Acta Psychiatr Scand Suppl deficits in schizophrenia: a decade in review. Psychopharmacology Hafidh S, Senkottaiyan N, Villarreal D, et al. Management of the Sieber FE, Zakriya KJ, Gottschalk A, et al. Sedation depth during metabolic syndrome. Am J Med Sci 2005;330:343-51.
spinal anesthesia and the development of postoperative delirium Seeman P. Targeting the dopamine D2 receptor in schizophrenia.
in elderly patients undergoing hip fracture repair [published erra- Expert Opin Ther Targets 2006;10:515-31.
tum in Mayo Clin Proc 2010;85:400. Dosage error in article text].
Leclerc I, Woltersdorf WW, da Silva Xavier G, et al. Metformin, but not leptin, regulates AMP-activated protein kinase in pancre- Hauton D. Does long-term metformin treatment increase cardiac atic islets: impact on glucose-stimulated insulin secretion. Am J lipoprotein lipase? Metabolism 2011;60:32-42.
Physiol Endocrinol Metab 2004;286:E1023-31.
Kiss E, Popovic ZV, Bedke J, et al. Peroxisome proliferator- Morioka K, Nakatani K, Matsumoto K, et al. Metformin-induced activated receptor (PPAR)gamma can inhibit chronic renal allo- suppression of glucose-6-phosphatase expression is independent graft damage. Am J Pathol 2010;176:2150-62.
of insulin signaling in rat hepatoma cells. Int J Mol Med 2005;15: Barr AM, Young CE, Sawada K, et al. Abnormalities of presynap- tic protein CDCrel-1 in striatum of rats reared in social isolation: Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic relevance to neural connectivity in schizophrenia. Eur J Neurosci thiazolidinedione is a high affinity ligand for peroxisome prolifer- ator-activated receptor gamma (PPAR gamma). J Biol Chem 1995; Weston-Green K, Huang XF, Deng C. Sensitivity of the female rat to olanzapine-induced weight gain — Far from the clinic? Schizophr Res Irwin N, McKinney JM, Bailey CJ, et al. Acute and long-term ef- fects of peroxisome proliferator-activated receptor-gamma activa- Fell MJ, Anjum N, Dickinson K, et al. The distinct effects of subchronic tion on the function and insulin secretory responsiveness of clonal antipsychotic drug treatment on macronutrient selection, body weight, beta-cells. Horm Metab Res 2011;43:244-9.
adiposity, and metabolism in female rats. Psychopharmacology (Berl) Sturgess NC, Ashford ML, Cook DL, et al. The sulphonylurea re- ceptor may be an ATP-sensitive potassium channel. Lancet 1985; 2: Kalinichev M, Rourke C, Daniels AJ, et al. Characterisation of olanzapine-induced weight gain and effect of aripiprazole vs olan- Park S, Hong SM, Lee JE, et al. Chlorpromazine exacerbates hep - zapine on body weight and prolactin secretion in female rats. atic insulin sensitivity via attenuating insulin and leptin signaling Psychopharmacology (Berl) 2005;182:220-31.
pathway, while exercise partially reverses the adverse effects. Life Minet-Ringuet J, Even PC, Lacroix M, et al. A model for antipsy- chotic-induced obesity in the male rat. Psychopharmacology (Berl) Tulipano G, Rizzetti C, Bianchi I, et al. Clozapine-induced alteration of glucose homeostasis in the rat: the contribution of hypothalamic- Smith GC, Vickers MH, Shepherd PR. Olanzapine effects on body pituitary-adrenal axis activation. Neuroendocrinology 2007; 85: 61-70.
composition, food preference, glucose metabolism and insulin sen- Boyda HN, Tse L, Procyshyn RM, et al. Preclinical models of anti - sitivity in the rat. Arch Physiol Biochem 2011;117:241-9.
psychotic drug-induced metabolic side effects. Trends Pharmacol Cooper GD, Pickavance LC, Wilding JP, et al. A parametric analy- sis of olanzapine-induced weight gain in female rats. Psychophar- Boyda HN, Tse L, Procyshyn RM, et al. A parametric study of the macology (Berl) 2005;181:80-9.
acute effects of antipsychotic drugs on glucose sensitivity in an ani- Wallingford NM, Sinnayah P, Bymaster FP, et al. Zonisamide pre- mal model. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:945-54.
vents olanzapine-associated hyperphagia, weight gain, and elevated Chintoh AF, Mann SW, Lam L, et al. Insulin resistance and secre- blood glucose in rats. Neuropsychopharmacology 2008;33:2922-33.
tion in vivo: effects of different antipsychotics in an animal model.
Chintoh AF, Mann SW, Lam L, et al. Insulin resistance and de- Schizophr Res 2009;108:127-33.
creased glucose-stimulated insulin secretion after acute olanzapine Smith GC, Chaussade C, Vickers M, et al. Atypical antipsychotic administration. J Clin Psychopharmacol 2008;28:494-9.
drugs induce derangements in glucose homeostasis by acutely in- Martins PJ, Haas M, Obici S. Central nervous system delivery of creasing glucagon secretion and hepatic glucose output in the rat.
the antipsychotic olanzapine induces hepatic insulin resistance.
Houseknecht KL, Robertson AS, Zavadoski W, et al. Acute effects of LeBrasseur NK, Kelly M, Tsao TS, et al. Thiazolidinediones can atypical antipsychotics on whole-body insulin resistance in rats: im- rapidly activate AMP-activated protein kinase in mammalian tis- plications for adverse metabolic effects. Neuropsychopharmacology sues. Am J Physiol Endocrinol Metab 2006;291:E175-81.
Boyle JG, Salt IP, McKay GA. Metformin action on AMP-activated Cooper GD, Pickavance LC, Wilding JP, et al. Effects of olanzapine protein kinase: a translational research approach to understanding in male rats: enhanced adiposity in the absence of hyperphagia, a potential new therapeutic target. Diabet Med 2010;27:1097-106.
weight gain or metabolic abnormalities. J Psychopharmacol 2007; Hundal RS, Krssak M, Dufour S, et al. Mechanism by which met- formin reduces glucose production in type 2 diabetes. Diabetes Meyer JM. A retrospective comparison of weight, lipid, and glu- cose changes between risperidone- and olanzapine-treated inpa- Stephenne X, Foretz M, Taleux N, et al. Metformin activates AMP- tients: metabolic outcomes after 1 year. J Clin Psychiatry 2002;63: activated protein kinase in primary human hepatocytes by de- creasing cellular energy status. Diabetologia 2011;54:3101-10.
Smith RC, Lindenmayer JP, Davis JM, et al. Effects of olanzapine and Fryer LG, Parbu-Patel A, Carling D. The anti-diabetic drugs risperidone on glucose metabolism and insulin sensitivity in chronic rosiglitazone and metformin stimulate AMP-activated protein schizophrenic patients with long-term antipsychotic treatment: a kinase through distinct signaling pathways. J Biol Chem 2002; 277: randomized 5-month study. J Clin Psychiatry 2009;70:1501-13.
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of anti - Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular psychotic drugs in patients with chronic schizophrenia. N Engl J mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122: Foussias G, Remington G. Antipsychotics and schizophrenia: from ef- Chau-Van C, Gamba M, Salvi R, et al. Metformin inhibits adeno- ficacy and effectiveness to clinical decision-making. Can J Psychiatry sine 5′-monophosphate-activated kinase activation and prevents J Psychiatry Neurosci
Olanzapine metabolic side-effects and antidiabetic drugs increases in neuropeptide Y expression in cultured hypothalamic activated receptor gamma activation has coordinate effects on gene neurons. Endocrinology 2007;148:507-11.
expression in multiple insulin-sensitive tissues. Endocrinology 2001; Kim SF, Huang AS, Snowman AM, et al. From the cover: Antipsy- chotic drug-induced weight gain mediated by histamine H1 recep- Lykkegaard K, Larsen PJ, Vrang N, et al. The once-daily human tor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance. Schizophr Res 2008;103:94-103.
Sejima E, Yamauchi A, Nishioku T, et al. A role for hypothalamic Arulmozhi DK, Dwyer DS, Bodhankar SL. Antipsychotic induced AMP-activated protein kinase in the mediation of hyperphagia metabolic abnormalities: an interaction study with various PPAR and weight gain induced by chronic treatment with olanzapine in modulators in mice. Life Sci 2006;79:1865-72.
female rats. Cell Mol Neurobiol 2011;31:985-9.
Adeneye AA, Agbaje EO, Olagunju JA. Metformin: an effective at- Molloy AM, Ardill J, Tomkin GH. The effect of metformin treat- tenuator of risperidone-induced insulin resistance hyperglycemia ment on gastric acid secretion and gastrointestinal hormone levels and dyslipidemia in rats. Indian J Exp Biol 2011;49:332-8.
in normal subjects. Diabetologia 1980;19:93-6.
Praharaj SK, Jana AK, Goyal N, et al. Metformin for olanzapine- Mulherin AJ, Oh AH, Kim H, et al. Mechanisms underlying met- induced weight gain: a systematic review and meta-analysis. Br J formin-induced secretion of glucagon-like peptide-1 from the in- Clin Pharmacol 2011;71:377-82.
testinal L cell. Endocrinology 2011;152:4610-9.
Loke YK, Kwok CS, Singh S. Comparative cardiovascular effects of Maida A, Lamont BJ, Cao X, et al. Metformin regulates the incretin thiazolidinediones: systematic review and meta-analysis of obser- receptor axis via a pathway dependent on peroxisome proliferator- vational studies. BMJ 2011;342:d1309.
activated receptor-alpha in mice. Diabetologia 2011;54:339-49.
Baptista T, Rangel N, El Fakih Y, et al. Rosiglitazone in the assist - Smith GC, Vickers MH, Cognard E, et al. Clozapine and quetia pine ance of metabolic control during olanzapine administration in acutely reduce glucagon-like peptide-1 production and increase schizophrenia: a pilot double-blind, placebo-controlled, 12-week glucagon release in obese rats: implications for glucose metab olism trial. Pharmacopsychiatry 2009;42:14-9.
and food choice behaviour. Schizophr Res 2009;115:30-40.
Barr AM, Powell SB, Markou A, et al. Iloperidone reduces sensorimo- Ehret M, Goethe J, Lanosa M, et al. The effect of metformin on an- tor gating deficits in pharmacological models, but not a develop mental thropometrics and insulin resistance in patients receiving atypical model, of disrupted prepulse inhibition in rats. Neuropharmacology antipsychotic agents: a meta-analysis. J Clin Psychiatry 2010; 71: Bain SC. Treatment of type 2 diabetes mellitus with orally admin- Way JM, Harrington WW, Brown KK, et al. Comprehensive messen- istered agents: advances in combination therapy. Endocr Pract ger ribonucleic acid profiling reveals that peroxisome proliferator- J Psychiatry Neurosci
Les systèmes de production animaleau SahelAvec plus de 63 millions de bovins, 83 millions d’ovins, 85 millions de caprins,6,2 millions de dromadaires, 3,5 millions d’ânes et 1,1 million de chevaux, l’éle-vage constitue la première ressource renouvelable du Sahel, outre sa contribution àla subsistance de plus de 20 millions d’éleveurs. Il participe aussi aux fondementsdes valeurs