GLP1 receptor agonism protects against acute olanzapine-induced hyperglycemia

2020 ◽  
Vol 319 (6) ◽  
pp. E1101-E1111 ◽  
Author(s):  
Kyle D. Medak ◽  
Hesham Shamshoum ◽  
Willem T. Peppler ◽  
David C. Wright
Keyword(s):  
Lipid Metabolism ◽  
Side Effects ◽  
Antipsychotic Drug ◽  
Antipsychotic Drugs ◽  
Glucose And Lipid Metabolism ◽  
Metabolic Dysregulation ◽  
Metabolic Side Effects ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Effective Adjunct

Antipsychotic drugs cause rapid perturbations in glucose and lipid metabolism. In the present study we have demonstrated that cotreatment with glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, protects against metabolic dysregulation caused by the antipsychotic drug olanzapine. These findings suggest that pharmacological targeting of the GLP1 receptor could be an effective adjunct approach to mitigate the harmful acute metabolic side effects of antipsychotic drugs.

A systematic review of metabolic side effects related to the use of antipsychotic drugs in dementia

2013 ◽  
Vol 26 (1) ◽  
pp. 19-37 ◽  
Author(s):  
A.R. Atti ◽  
B. Ferrari Gozzi ◽  
G. Zuliani ◽  
V. Bernabei ◽  
P. Scudellari ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Weight Gain ◽  
Side Effects ◽  
Glucose Homeostasis ◽  
Older Patients ◽  
Antipsychotic Drugs ◽  
Old Patients ◽  
Metabolic Side Effects ◽  
Moderate Dementia ◽  
Increased Risk

ABSTRACTBackground:In clinical practice, Second Generation Antipsychotics (SGAs) are often used as first-line treatment for the Behavioral and Psychological Symptoms of Dementia (BPSD) in older adults due to their fewer neurological adverse events and similar effectiveness compared with First Generation Antipsychotics (FGAs). SGAs, however, are associated with more severe metabolic side effects (weight gain, hyperglycemia, diabetes risk, and hyperlipidemia) than FGAs are. In general, older patients, especially those affected by dementia, are at increased risk for malnutrition, and tend to have lower basal metabolism and reduced liver and kidney function. However, little is known about the metabolic side effects of antipsychotic drugs in this population.Methods:A comprehensive review of the literature published between January 1996 and December 2012 investigating the metabolic side effects related to FGAs and SGAs use in old patients affected by dementia.Results:Antipsychotic drugs currently used to treat BPSD in subjects with mild to moderate dementia are associated with weight gain. Currently, there are insufficient data to support a causal relationship between the use of FGAs and SGAs and changes in glucose homeostasis or lipid metabolism in older persons affected by severe dementia (MMSE <14).Conclusion:A possible association between antipsychotic drugs use and weight gain might exist, in particular in subjects with mild to moderate dementia whereas no significant effects are demonstrated regarding glucose homeostasis and lipid metabolism. The antipsychotic drugs potential for causing metabolic abnormalities in older patients requires further specifically designed studies. Clinicians must be aware of this possibility even if the shorter periods of treatment administered in late-life might not be as harmful as it is in younger individuals.

scholarly journals Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Chuanjun Zhuo ◽  
Yong Xu ◽  
Weihong Hou ◽  
Jiayue Chen ◽  
Qianchen Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Weight Gain ◽  
Side Effects ◽  
Antipsychotic Drugs ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Glucose And Lipid Metabolism ◽  
Pathway Activation ◽  
Extrapyramidal Motor

AbstractAntipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

scholarly journals Liraglutide prevents metabolic side-effects and improves recognition and working memory during antipsychotic treatment in rats

2018 ◽  
Vol 32 (5) ◽  
pp. 578-590 ◽  
Author(s):  
Ilijana Babic ◽  
Ashleigh Gorak ◽  
Martin Engel ◽  
Dominic Sellers ◽  
Paul Else ◽  
...  
Keyword(s):  
Working Memory ◽  
Weight Gain ◽  
Locomotor Activity ◽  
Side Effects ◽  
Antipsychotic Treatment ◽  
Clozapine Treatment ◽  
Metabolic Side Effects ◽  
Glucagon Like Peptide ◽  
Test Discrimination ◽  
Glucagon Like Peptide 1

Background: Antipsychotic drugs (APDs), olanzapine and clozapine, do not effectively address the cognitive symptoms of schizophrenia and can cause serious metabolic side-effects. Liraglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist with anti-obesity and neuroprotective properties. The aim of this study was to examine whether liraglutide prevents weight gain/hyperglycaemia side-effects and cognitive deficits when co-administered from the commencement of olanzapine and clozapine treatment. Methods: Rats were administered olanzapine (2 mg/kg, three times daily (t.i.d.)), clozapine (12 mg/kg, t.i.d.), liraglutide (0.2 mg/kg, twice daily (b.i.d.)), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle (Control) ( n = 12/group, 6 weeks). Recognition and working memory were examined using Novel Object Recognition (NOR) and T-Maze tests. Body weight, food intake, adiposity, locomotor activity and glucose tolerance were examined. Results: Liraglutide co-treatment prevented olanzapine- and clozapine-induced reductions in the NOR test discrimination ratio ( p < 0.001). Olanzapine, but not clozapine, reduced correct entries in the T-Maze test ( p < 0.05 versus Control) while liraglutide prevented this deficit. Liraglutide reduced olanzapine-induced weight gain and adiposity. Olanzapine significantly decreased voluntary locomotor activity and liraglutide co-treatment partially reversed this effect. Liraglutide improved clozapine-induced glucose intolerance. Conclusion: Liraglutide co-treatment improved aspects of cognition, prevented obesity side-effects of olanzapine, and the hyperglycaemia caused by clozapine, when administered from the start of APD treatment. The results demonstrate a potential treatment for individuals at a high risk of experiencing adverse effects of APDs.

scholarly journals Targeting the GPR119/incretin axis: a promising new therapy for metabolic-associated fatty liver disease

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Jianan Zhao ◽  
Yu Zhao ◽  
Yiyang Hu ◽  
Jinghua Peng
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Drug Targets ◽  
Metabolic Dysfunction ◽  
Multiple Organs ◽  
Glucose And Lipid Metabolism ◽  
Potential Therapeutic Role ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

AbstractIn the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological effects have been extensively studied. Among these receptors, GPR119 is expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting inflammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.

Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

2021 ◽  
Vol 35 (3) ◽  
pp. 284-302
Author(s):  
Ilijana Babic ◽  
Dominic Sellers ◽  
Paul L Else ◽  
Jessica Nealon ◽  
Ashleigh L Osborne ◽  
...  
Keyword(s):  
Side Effects ◽  
Chronic Treatment ◽  
Antipsychotic Treatment ◽  
Metabolic Markers ◽  
Metabolic Side Effects ◽  
Feeding Efficiency ◽  
Adaptive Mechanisms ◽  
Liver And Kidney ◽  
Glucagon Like Peptide 1 ◽  
Peripheral Markers

Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that prevents metabolic side effects of the antipsychotic drugs (APDs) olanzapine and clozapine through unknown mechanisms. Aim: This study aimed to investigate the effect of chronic APD and liraglutide co-treatment on key neural and peripheral metabolic signals, and acute liraglutide co-treatment on clozapine-induced hyperglycaemia. Methods: In study 1, rats were administered olanzapine (2 mg/kg), clozapine (12 mg/kg), liraglutide (0.2 mg/kg), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle for six weeks. Feeding efficiency was examined weekly. Examination of brain tissue (dorsal vagal complex (DVC) and mediobasal hypothalamus (MBH)), plasma metabolic hormones and peripheral (liver and kidney) cellular metabolism and oxidative stress was conducted. In study 2, rats were administered a single dose of clozapine (12 mg/kg), liraglutide (0.4 mg/kg), clozapine + liraglutide co-treatment or vehicle. Glucose tolerance and plasma hormone levels were assessed. Results: Liraglutide co-treatment prevented the time-dependent increase in feeding efficiency caused by olanzapine, which plateaued by six weeks. There was no effect of chronic treatment on melanocortinergic, GABAergic, glutamatergic or endocannabionoid markers in the MBH or DVC. Peripheral hormones and cellular metabolic markers were unaltered by chronic APD treatment. Acute liraglutide co-treatment was unable to prevent clozapine-induced hyperglycaemia, but it did alter catecholamine levels. Conclusion: The unexpected lack of change to central and peripheral markers following chronic treatment, despite the presence of weight gain, may reflect adaptive mechanisms. Further studies examining alterations across different time points are required to continue to elucidate the mechanisms underlying the benefits of liraglutide on APD-induced metabolic side effects.

scholarly journals The key role of a glucagon-like peptide-1 receptor agonist in body fat redistribution

2019 ◽  
Vol 240 (2) ◽  
pp. 271-286 ◽  
Author(s):  
Li Zhao ◽  
Chunfang Zhu ◽  
Meng Lu ◽  
Chi Chen ◽  
Xiaomin Nie ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Body Fat ◽  
Visceral Fat ◽  
Subcutaneous Fat ◽  
Control Group ◽  
Acid Oxidation ◽  
High Dose ◽  
Fat Depots ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an ideal therapy for type 2 diabetes and, as of recently, for obesity. In contrast to visceral fat, subcutaneous fat appears to be protective against metabolic diseases. Here, we aimed to explore whether liraglutide, a GLP-1RA, could redistribute body fat via regulating lipid metabolism in different fat depots. After being fed a high-fat diet for 8 weeks, 50 male Wistar and Goto-Kakizaki rats were randomly divided into a normal control group, a diabetic control group, low- and high-dose liraglutide-treated groups and a diet-control group. Different doses of liraglutide (400 μg/kg/day or 1200 μg/kg/day) or an equal volume of normal saline were administered to the rats subcutaneously once a day for 12 weeks. Body composition and body fat deposition were measured by dual-energy X-ray absorptiometry and MRI. Isotope tracers were infused to explore lipid metabolism in different fat depots. Quantitative real-time PCR and Western blot analyses were conducted to evaluate the expression of adipose-related genes. The results showed that liraglutide decreased visceral fat and relatively increased subcutaneous fat. Lipogenesis was reduced in visceral white adipose tissue (WAT) but was elevated in subcutaneous WAT. Lipolysis was also attenuated, and fatty acid oxidation was enhanced. The mRNA expression levels of adipose-related genes in different tissues displayed similar trends after liraglutide treatment. In addition, the expression of browning-related genes was upregulated in subcutaneous WAT. Taken together, the results suggested that liraglutide potentially redistributes body fat and promotes browning remodeling in subcutaneous WAT to improve metabolic disorders.

scholarly journals Predictors of Effectiveness of Glucagon-Like Peptide-1 Receptor Agonist Therapy in Patients with Type 2 Diabetes and Obesity

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Alina Yu. Babenko ◽  
Daria A. Savitskaya ◽  
Yulia A. Kononova ◽  
Aleksandra Yu. Trofimova ◽  
Anna V. Simanenkova ◽  
...  
Keyword(s):  
Lipid Profile ◽  
Response To Treatment ◽  
Glucose And Lipid Metabolism ◽  
Lower Baseline ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Peptide ◽  
Diabetes And Obesity ◽  
Hba1c Levels

Rationale. It is well known that diabetes mellitus (DM) exacerbates the mechanisms underlying atherosclerosis. Currently, glucagon-like peptide-1 receptor agonists (aGLP-1) have one of the most prominent cardioprotective effects among the antidiabetic agents. However, the treatment with aGLP-1 is effective only in 50-70% of the cases. Taking into account the high cost of these medications, discovery of the predictors of optimal response to treatment is required. Purpose. To identify the predictors of the greater impact of aGLP-1 on HbA1c levels, weight reduction, and improvement in lipid profile. Methods. The study group consisted of 40 patients with type 2 DM (T2DM) and obesity who were treated with aGLP-1. The follow-up period was 24 weeks. Patients’ evaluation was conducted at baseline and after 24 weeks. In addition, it included the assessment of the hormones involved in glucose and lipid metabolism and appetite regulation. Results. Patients who have initially higher BMI (body mass index), glycemia, and triglycerides (TG) had better improvement in these parameters undergoing aGLP-1 treatment. In patients with a BMI loss≥5%, GLP-1 and fasting ghrelin levels were higher and ghrelin level in postnutritional status was lower. The HbA1c levels decreased more intensively in participants with higher GLP-1 levels. TG responders had lower baseline fasting glucose-dependent insulinotropic peptide (GIP) and postprandial ghrelin levels. Conclusion. The evaluation of the glycemic control, lipid profile, and GLP-1, GIP, and ghrelin levels are useable for estimating the expected efficacy of aGLP-1.

scholarly journals JTT-130, a Novel Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein, Improves Hyperglycemia and Dyslipidemia Independent of Suppression of Food Intake in Diabetic Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Shohei Sakata ◽  
Makoto Ito ◽  
Yasuko Mera ◽  
Tomohiko Sasase ◽  
Hiromi Yamamoto ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Treatment Group ◽  
Food Intake ◽  
Plasma Cholesterol ◽  
Specific Inhibitor ◽  
Microsomal Triglyceride Transfer Protein ◽  
Diabetic Rats ◽  
Glucose And Lipid Metabolism ◽  
Zdf Rats ◽  
Glucagon Like Peptide 1

We investigated the effects of JTT-130 on glucose and lipid metabolism independent of the suppression of feeding by comparing with pair-fed animals. Male Zucker diabetic fatty (ZDF) rats were divided into control, JTT-130 treatment, and pair-fed groups. The rats were fed with a regular powdered diet with or without JTT-130 as a food admixture for 6 weeks. We compared the effects on glucose and lipid metabolism in JTT-130 treatment group with those in pair-fed group.Results. Hyperglycemia in ZDF rats was prevented in both JTT-130 treatment and pair-fed groups, but the prevention in pair-fed group became poor with time. Moreover, reduction in plasma cholesterol levels was observed only in JTT-130 treatment group. JTT-130 treatment group showed improved glucose tolerance at 5 weeks after treatment and significant elevation of portal glucagon-like peptide-1 (GLP-1) levels. The hepatic lipid content in JTT-130 treatment group was decreased as compared with pair-fed group. Furthermore, pancreatic protection effects, such as an increase in pancreatic weight and an elevation of insulin-positive area in islets, were observed after JTT-130 treatment.Conclusions. JTT-130 improves hyperglycemia and dyslipidemia via a mechanism independent of suppression of food intake, which is ascribed to an enhancement of GLP-1 secretion and a reduction of lipotoxicity.

scholarly journals Metabolic Side-Effects of the Novel Second-Generation Antipsychotic Drugs Asenapine and Iloperidone: A Comparison with Olanzapine

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e53459 ◽  
Author(s):  
Heidi N. Boyda ◽  
Ric M. Procyshyn ◽  
Catherine C. Y. Pang ◽  
Erin Hawkes ◽  
Daniel Wong ◽  
...  
Keyword(s):  
Side Effects ◽  
Antipsychotic Drugs ◽  
Second Generation ◽  
The Novel ◽  
Metabolic Side Effects ◽  
Second Generation Antipsychotic
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