Insulin resistance and secretion in vivo: Effects of different antipsychotics in an animal model

Chintoh, Araba; Mann, Steve; Lam, Loretta; Giacca, Adria; Fletcher, Paul; Nóbrega, José N.; Remington, Gary

doi:10.1016/j.schres.2008.12.012

Cited by 102 publications

(85 citation statements)

References 33 publications

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“…The explanation that fi ts best with the current data is that OLZ might be acting directly or indirectly to increase glucose level. Accordingly, a study conducted by Chintoh et al (2009) demonstrated that increased glucose was observed in OLZ-treated rats (37). On the other hand, in our study, TQ prevented the increase in fasting plasma glucose, impaired glucose tolerance and alteration in insulin sensitivity.…”

Section: Discussioncontrasting

confidence: 44%

The protective effect of thymoquinone over olanzapine-induced side effects in liver, and metabolic side effects

Bilğiç¹,

Korkmaz²,

Azırak³

et al. 2018

BLL

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OBJECTIVES: The aim of the study was to investigate the possible protective qualities of thymoquinone (TQ) against the side-effects of olanzapine (OLZ) in an experimental model in rat liver with histologic and biochemical assessments. METHODS: Experimental procedures were performed on 35 female Sprague Dawley rats. Rats were randomly divided into fi ve groups as: group 1: control; group 2: OLZ; group 3: OLZ+TQ-1; group 4: OLZ+TQ-2; and group 5: OLZ+TQ-3. RESULTS: The results showed that a 2-week administration of OLZ (4 mg/kg, once a day for the fi rst week, 8 mg/kg once a day for the second week, p.o.) and treatment with TQ (25, 50, 100 mg/kg, once daily, p.o.) signifi cantly reduced weight gain induced by OLZ. In addition, TQ increased the total antioxidant status (TAS), high-density lipoprotein cholesterol (HDL), insulin levels and decreased serum oxidative stress index (OSI), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), low density lipoprotein cholesterol (LDL), glucose, triglycerides (TG) and total cholesterol (CH) levels signifi cantly (p < 0.05). CONCLUSION: This study revealed that treatment with TQ might protect liver tissue against the side-effects of OLZ. TQ could be an effective course of therapy to enhance therapeutic effi cacy (Tab. 4, Fig. 4, Ref. 47). Text in PDF www.elis.sk.

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Section: Discussioncontrasting

confidence: 44%

The protective effect of thymoquinone over olanzapine-induced side effects in liver, and metabolic side effects

Bilğiç¹,

Korkmaz²,

Azırak³

et al. 2018

BLL

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“…S.c. dosing of Ola (3 mg/kg) was based on O70% D 2 brain occupancy, reflecting clinically relevant thresholds for therapeutic efficacy (Kapur et al 2003), as well as established effects on peripheral and hepatic insulin sensitivity (Chintoh et al 2008(Chintoh et al , 2009). Animals were randomly assigned and treated with one of two Met doses (400 mg/kg, nZ11; 150 mg/kg, nZ13) or vehicle (Veh) (nZ11), administered through gavage preceding an overnight fast, followed thereafter by a second dose the morning prior to the HIEC.…”

Section: Drug and Dose Selectionmentioning

confidence: 99%

“…However, their use is also associated with significant concerns in terms of metabolic side effects; high rates of metabolic syndrome, dyslipidemias, weight gain and glucose dysmetabolism have been reported (Goff et al(Pi-Sunyer 1993), there is growing evidence, both clinical and preclinical, indicating increased liability for glucose dysregulation independent of illness-related factors or weight increases (Ader et al 2005, Houseknecht et al 2007, Chintoh et al 2009, Vidarsdottir et al 2010a, Teff et al 2013, Hahn et al 2014. In this regard, our own work from preclinical rodent models consistently supports pronounced, direct effects on insulin sensitivity (peripheral and hepatic) following acute dosing of specific AP agents (e.g., risperidone, olanzapine (Ola) or clozapine) (Chintoh et al 2008(Chintoh et al , 2009. From a clinical perspective, acute or 'direct' effects are supported by reports of diabetic ketoacidosis occurring shortly after initiation of AP drugs in absence of notable weight changes (Guenette et al 2013), as well as studies that suggest a risk of glucose dysregulation independently of weight gain (Newcomer et al 2002, Henderson et al 2005, Ebdrup et al 2014.…”

Section: Introductionmentioning

confidence: 99%

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

Remington

Teo

Wilson

et al. 2015

Journal of Endocrinology

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Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; nZ13, or 400 mg/kg; nZ11) or vehicle (Veh) (nZ11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (R a ) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal R a with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

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“…Although impairments in glucose homeostasis often accompany weight gain itself, there is evidence that OLZ has direct diabetogenic effects independent of changes in body weight. Studies using both humans and rodents have shown increases in blood glucose within minutes to hours of OLZ treatment (Houseknecht et al, 2007;Chintoh et al, 2008;Chintoh et al, 2009;Boyda et al, 2010;Hahn et al, 2013;Ikegami et al, 2013). The acute effects of OLZ are exacerbated in conditions of preexisting obesity and impaired glucose homeostasis (Townsend et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Although the mechanisms are still under investigation, OLZ-induced hyperglycaemia is thought to involve increases in hepatic glucose production (Chintoh et al, 2009;Ikegami et al, 2013), impaired insulin release (Boyda et al, 2010), systemic insulin resistance (Chintoh et al, 2008;Boyda et al, 2010) and an increased reliance on fat oxidation (Klingerman et al, 2014). In This article has not been copyedited and formatted.…”

Section: Introductionmentioning

confidence: 99%

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

Bush

Townsend

Wright

2018

J Pharmacol Exp Ther

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Insulin resistance and secretion in vivo: Effects of different antipsychotics in an animal model

Cited by 102 publications

References 33 publications

The protective effect of thymoquinone over olanzapine-induced side effects in liver, and metabolic side effects

The protective effect of thymoquinone over olanzapine-induced side effects in liver, and metabolic side effects

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

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