RESUMEN
A rapid increase has been observed in insulin resistance (IR) incidence induced by a long-term olanzapine treatment with no better ways to avoid it. Our study aimed to demonstrate the mechanism underlying the olanzapine-induced insulin resistance and find appropriate drug interventions. In this study, firstly, we constructed rat insulin resistance model using a two-month gavage of olanzapine and used the main active ingredient mixture of Gegen Qinlian Decoction for the treatment. The activity of brown adipose tissue (BAT) was measured using the PET/CT scan, whereas Western blot and quantitative real-time PCR were used to detect the expression of GLUT4 and UCP1. The results showed that the long-term administration of olanzapine impaired glucose tolerance and produced insulin resistance in rats, while Gegen Qinlian Decoction could improve this side effect. The results of the PET/CT scan showed that the BAT activity in the insulin-resistant rats was significantly lower than that of the Gegen Qinlian Decoction treated rats. Also, the expression of GLUT4 and UCP1 in the insulin resistance group showed a significant decrease, which could be up-regulated by Gegen Qinliane Decoction treatment. The results of both in vivo and in vitro experiments were consistent. we demonstrated that the olanzapine could induce IR in vitro and in vivo by decreasing the expression of UCP1; thus, suppressing the thermogenesis of BAT and impairing glucose uptake. More importantly, we demonstrated a possible novel strategy to improve the olanzapine-induced IR by Gegen Qinlian Decoction.
Asunto(s)
Resistencia a la Insulina , Tejido Adiposo , Tejido Adiposo Pardo , Animales , Insulina , Olanzapina , Tomografía Computarizada por Tomografía de Emisión de Positrones , RatasRESUMEN
Olanzapine is commonly used to treat schizophrenia. However, long-term administration of olanzapine causes metabolic side effects, such as insulin resistance (IR), which seriously affects patients' quality of life. Both diagnostic and prognostic markers are urgently needed to increase patient compliance. We applied isobaric tags for relative and absolute quantitation (iTRAQ) labeling combined with 2D LC/MS/MS technology to identify the differentially expressed proteins in olanzapine-induced IR rats. A total of 3194 proteins were identified from rat adipose tissues, and 270 differentially expressed proteins were screened out with a ratio threshold >1.5-fold or <0.67-fold. Based on a bioinformatics analysis and literature search, we selected six candidates (MYH1, MYL2, Cp, FABP4, apoA-IV, and Ywhaz) from a set of 270 proteins and verified these proteins by western blot; the expression of these proteins coincided with the LC-MS/MS results. Finally, the biological roles of FABP4 and apoA-IV, which are two novel IR-related proteins identified in the present study, were verified in 3T3-L1 cells. These data suggest that these two proteins acted on olanzapine-induced IR via the IRS-1/AKT signaling pathway. Our results provide a dataset of potential targets to explore the mechanism in olanzapine-induced IR and reveal the new roles of FABP4 and apoA-IV in olanzapine-induced IR. SIGNIFICANCE: The proteomic analysis of this study revealed the target associated with olanzapine-induced IR and provided relevant insights into the molecular functions, biological processes, and signaling pathways in these targets. Protein MYH1, MYL2, Cp, FABP4, apoA-IV, and Ywhaz may be potential biomarkers, and protein FABP4 and apoA-IV were considered as promising targets in olanzapineinduced IR. Therefore, if the performance of the proposed biomarkers is further confirmed, these proteins can provide powerful targets for exploring the mechanism of olanzapine-induced IR.
Asunto(s)
Tejido Adiposo/metabolismo , Apolipoproteínas A/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Intolerancia a la Glucosa/metabolismo , Resistencia a la Insulina , Olanzapina/toxicidad , Proteómica/métodos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Animales , Antipsicóticos/toxicidad , Biomarcadores/metabolismo , Línea Celular , Biología Computacional/métodos , Femenino , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/patología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Espectrometría de Masas en TándemRESUMEN
PURPOSE: This systematic review aimed to determine whether olanzapine is more likely than other second-generation antipsychotics (SGAs) to induce insulin resistance in patients with schizophrenia in China. METHODS: We reviewed all randomized controlled trials on insulin resistance and metabolic abnormalities caused by SGAs in the PubMed, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang databases. Retrieved articles were published on or before December 2018. Meta-analysis was performed to determine the effect size of the treatment on the insulin resistance index (IRI), fasting blood glucose (FBG), and fasting insulin (FINS). RESULTS: Forty studies (3725 participants in total) were included. All studies contained data suitable for comparing aripiprazole vs. olanzapine, ziprasidone vs. olanzapine, and risperidone vs. olanzapine. Patients treated with olanzapine had higher IRI, FBG, and FINS levels than did patients treated with aripiprazole, ziprasidone, or risperidone, with significant differences (aripiprazole vs. olanzapine: FBG: standardized mean difference [SMD] = 0.72, 95% confidence interval [95%CI] - 0.82, - 0.61; FINS: SMD = - 0.8, 95%CI - 1.00, - 0.61; IRI: SMD = - 0.80, 95%CI - 0.99, - 0.61; ziprasidone vs. olanzapine: FBG: SMD = - 1.19, 95%CI - 1.30, - 1.08; FINS: SMD = - 0.66, 95%CI - 0.85, - 0.47; IRI: SMD = - 0.71, 95%CI - 0.88, - 0.55; risperidone vs. olanzapine: FBG: SMD = - 0.17, 95%CI - 0.34, - 0.00). CONCLUSIONS: Existing data suggest that olanzapine is associated with a significantly greater risk of IRI, FBG, and FINS, while other agents are associated with relatively lower risks. Thus, olanzapine is more likely to induce insulin resistance than are other SGAs in schizophrenic patients in China.
Asunto(s)
Antipsicóticos/efectos adversos , Resistencia a la Insulina , Síndrome Metabólico/inducido químicamente , Olanzapina/efectos adversos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , China , HumanosRESUMEN
BACKGROUND: Olanzapine, a commonly used second-generation antipsychotic, causes severe metabolic adverse effects, such as elevated blood glucose and insulin resistance (IR). Previous studies have proposed that overexpression of CD36, GGPPS, PTP-1B, GRK2, and adipose triglyceride lipase may contribute to the development of metabolic syndrome, and Pueraria could eliminate the metabolic adverse effects. The study aimed to investigate the association between olanzapine-associated IR and IR-related proteins (IRRPs) and determine the role of Pueraria in protection against the metabolic adverse effects of olanzapine. METHODS: The expression levels of IRRPs were examined in schizophrenia patients and rat models with long-term olanzapine treatment. The efficacy of Pueraria on anti-IR by reducing the expression of IRRPs was comprehensively evaluated. RESULTS: Our study demonstrated that in schizophrenia patients chronically treated with olanzapine, the expression levels of IRRPs in patients with a high IR index significantly increased, and these phenomena were further confirmed in a rat model. The expression levels of IRRPs were reduced significantly in Pueraria-treated IR rat models. The body weight, blood glucose, and IR index were restored to levels similar to those of normal controls. CONCLUSIONS: The IRRPs are closely related to IR induced by olanzapine, and Pueraria could interfere with olanzapine-associated IR and revert overexpressed IRRPs. These findings suggest that IRRPs are key players in olanzapine-associated IR and that Pueraria has potential as a clinical drug to prevent the metabolic adverse effects of olanzapine, further improving compliance of schizophrenia patients.
Asunto(s)
Resistencia a la Insulina , Olanzapina/efectos adversos , Extractos Vegetales/farmacología , Pueraria/química , Adulto , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Olanzapina/administración & dosificación , Ratas , Esquizofrenia/tratamiento farmacológico , Factores de TiempoRESUMEN
Olanzapine is a second-generation anti-psychotic drug used to prevent neuroinflammation in patients with schizophrenia. However, the long-term administration of olanzapine leads to insulin resistance (IR); the mechanisms of this effect remains poorly understood. Using cellular and rodent models of IR induced by olanzapine, we found that chronic olanzapine treatment induces differential inflammatory cytokine reactions in peripheral adipose and the central nervous system. Long-term treatment of olanzapine caused metabolic symptoms, including IR, by markedly elevating the plasma levels of pro-inflammatory cytokines, including IL-1ß, IL-6, IL-8 and TNFα; these findings are consistent with observations from schizophrenia patients chronically treated with olanzapine. Our observations of differential inflammatory cytokine responses in white adipose tissues from the prefrontal cortex in the brain indicated cell type-specific effects of the drug. These cytokines induced IR by activating NF-kB through the suppression of IkBα. Functional blockade of the components p50/p65 of NF-kB rescued olanzapine-induced IR in NIH-3T3 L1-derived adipocytes. Our findings demonstrate that olanzapine induces inflammatory cytokine reactions in peripheral tissues without adversely affecting the central nervous system and suggest that chronic olanzapine treatment of schizophrenia patients may cause inflammation-mediated IR with minimal or no adverse effects in the brain.
Asunto(s)
Antipsicóticos/efectos adversos , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Resistencia a la Insulina , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Olanzapina/efectos adversos , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adulto , Animales , Antipsicóticos/administración & dosificación , Glucemia , Modelos Animales de Enfermedad , Duración de la Terapia , Femenino , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Masculino , Ratones , Modelos Biológicos , FN-kappa B/metabolismo , Olanzapina/administración & dosificación , Ratas , Esquizofrenia/complicaciones , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Adulto JovenRESUMEN
In Chinese traditional medicine, the rhizome of Atractylodes lancea (Thunb.) DC. (A. lancea) is used extensively for the treatment of several diseases such as rheumatic diseases, but its actions on rheumatoid arthritis have not been clarified. The purpose of this article was to investigate the pharmacological effect of an A. lancea rhizome extract on collagen-induced arthritis (CIA) in rats. The CIA model was induced by the injection of bovine type II collagen. The rats were orally administered the petroleum ether (PE) fraction of the A. lancea rhizome (0.82 and 1.64 mg/kg), methotrexate (0.3 mg/kg body weight), or a vehicle from day 7 to day 15 after the model was established. The histological examination and radiological observation showed that the PE fraction significantly reduced the inflammatory responses and collagen loss in the joints of the rats with CIA. The PE fraction inhibited the production of tumor necrosis factor-α, interleukin (IL)-1ß, IL-17, and IL-6 in the sera. Moreover, the treatment with the PE fraction in vivo was able to reduce the level of Beclin 1 protein in the synovial tissue of the rats. These results highlight the antiarthritic potential of the PE fraction of the A. lancea rhizome and provide further evidence of the involvement of Beclin 1 inhibition in the effects of the PE fraction of the A. lancea rhizome. Copyright © 2016 John Wiley & Sons, Ltd.