AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

Bush, Natasha; Townsend, Logan K.; Wright, David C.

doi:10.1124/jpet.118.248393

Cited by 21 publications

(26 citation statements)

References 55 publications

(76 reference statements)

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“…As measured by a hyperinsulinemic-euglycemic (HIEC) clamp, the gold standard technique to assess whole body insulin sensitivity, acute exposure to a subcutaneous bolus of olanzapine significantly decreased insulin sensitivity in male rats [60,81,85,86] (Table 4B). This aligns with work demonstrating worsened insulin tolerance following a bolus of olanzapine in male mice [82,83] and rats [81]. Interestingly, some [79], but not all [88] have shown that central administration of olanzapine also worsens insulin sensitivity in male rats during a HIEC.…”

Section: Resultssupporting

confidence: 86%

“…A single treatment of olanzapine has been shown to rapidly and significantly increase blood glucose in male mice [61,82–84,89,91] and rats [48,81,85,87,88,92], with peak blood glucose occurring approximately 1–2 h post treatment (Table 4B). Indeed, both a single dose of olanzapine (administered via subcutaneous injection [85], intravenous infusion [79,94], intragastric infusion [87], oral gavage [85]) as well as a twice daily dose via oral gavage (one dose in the evening, one dose one hour preceding measures) [48,81] increased blood glucose in male rats.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, both a single dose of olanzapine (administered via subcutaneous injection [85], intravenous infusion [79,94], intragastric infusion [87], oral gavage [85]) as well as a twice daily dose via oral gavage (one dose in the evening, one dose one hour preceding measures) [48,81] increased blood glucose in male rats. Similarly, a single injection of olanzapine (intraperitoneal injection [82–84,89] or intracerebral ventricular infusion [79,89,91]) in male mice significantly increased blood glucose levels compared to vehicle treated mice. Interestingly, olanzapine-induced hyperglycemia is more pronounced in the fed compared to the fasted state.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Preclinical and Clinical Sex Differences in Antipsychotic-Induced Metabolic Disturbances: A Narrative Review of Adiposity and Glucose Metabolism

Castellani

Costa-Dookhan

McIntyre

et al. 2019

J Psychiatry Brain Sci

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Antipsychotic (AP) medications are associated with an increased risk of developing metabolic side effects including weight gain, type 2 diabetes (T2D), dyslipidemia, and hypertension. In the majority of clinical studies, females on APs are noted to gain more weight, and are more likely to be diagnosed with metabolic syndrome when compared to males. However, the data is less clear when comparing sex disparities associated with other specific AP-induced metabolic risk factors. Accumulating evidence has demonstrated a role for AP-induced adipose tissue accumulation as well as whole body glucose dysregulation in male models that is independent of changes in body weight. The purpose of this narrative review is to explore the susceptibility of males and females to changes in adiposity and glucose metabolism across clinical and preclinical models of AP treatment. It is important that future research examining AP-induced metabolic side effects analyzes outcomes by sex to help clarify risk and identify the mechanisms of adverse event development to improve safe prescribing of medications.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical and Clinical Sex Differences in Antipsychotic-Induced Metabolic Disturbances: A Narrative Review of Adiposity and Glucose Metabolism

Castellani

Costa-Dookhan

McIntyre

et al. 2019

J Psychiatry Brain Sci

View full text Add to dashboard Cite

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“…Central activation of AMPK in the hypothalamus increases hepatic glucose production and hyperglycemia [8,40]. In contrast, the peripheral administration of AMPK analog AICAR and hepatic activation of AMPK show improvement in olanzapine-induced hyperglycemia and hyperlipidemia [22,41]. This is to say that the effects of AMPK vary and show tissue difference.…”

Section: Discussionmentioning

confidence: 99%

Olanzapine Induced Dysmetabolic Changes Involving Tissue Chromium Mobilization in Female Rats

Yang

Wang

Lin

et al. 2019

IJMS

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Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

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“…As noted above, the oxidation of amine substrates generates hydrogen peroxide, irrespective of the amine oxidase catalyzing the oxidative deamination. It was of interest to study the influence of opipramol and of antipsychotics on the fate of H 2 O 2 in human adipose tissue because the adverse effects of the latter have been reported to be mitigated by antioxidants [50] or AMP-activated protein kinase (AMPK) activators [51].…”

Section: Interactions Of Opipramol and Other Psychotropes With Adiposmentioning

confidence: 99%

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

et al. 2020

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Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.

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AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

Cited by 21 publications

References 55 publications

Preclinical and Clinical Sex Differences in Antipsychotic-Induced Metabolic Disturbances: A Narrative Review of Adiposity and Glucose Metabolism

Preclinical and Clinical Sex Differences in Antipsychotic-Induced Metabolic Disturbances: A Narrative Review of Adiposity and Glucose Metabolism

Olanzapine Induced Dysmetabolic Changes Involving Tissue Chromium Mobilization in Female Rats

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

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