Dataset Information

Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese Type 2 diabetes.

ABSTRACT:

Background and purpose

Thiazolidinediones, acting as PPAR-γ ligands, reduce hepatic steatosis in humans and animals. However, the underlying mechanism of this action remains unclear. The purpose of this study was to investigate changes in hepatic metabolites and lipids in response to treatment with the thiazolidinedione pioglitazone in an animal model of obese Type 2 diabetes.

Experimental approach

Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were orally administered either vehicle (control) or pioglitazone (30 mg·kg^-1 ) and fed a high-fat diet (60% kcal fat) for 12 weeks. Hepatic metabolites were analysed via metabolomic and lipidomic analyses. Gene expression and PLA₂ activity were analysed in livers from pioglitazone-treated and control rats.

Key results

OLETF rats that received pioglitazone showed decreased fat accumulation and improvement of lipid profiles in the liver compared to control rats. Pioglitazone treatment significantly altered levels of hepatic metabolites, including free fatty acids, lysophosphatidylcholines and phosphatidylcholines, in the liver. In addition, pioglitazone significantly reduced the expression of genes involved in hepatic de novo lipogenesis and fatty acid uptake and transport, whereas genes related to fatty acid oxidation were up-regulated. Gene expression and enzyme activity of PLA₂ , which hydrolyzes phosphatidylcholines to release lysophosphatidylcholines and free fatty acids, were significantly decreased in the livers of pioglitazone-treated rats compared to control rats.

Conclusions and implications

Our results present evidence for the ameliorative effect of pioglitazone on hepatic steatosis, largely due to the regulation of lipid metabolism, including fatty acids, lysophosphatidylcholines, phosphatidylcholines and related gene-expression patterns.

SUBMITTER: Yang H

PROVIDER: S-EPMC6086983 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese Type 2 diabetes.

Yang Hyekyung H Suh Dong Ho DH Kim Dae Hee DH Jung Eun Sung ES Liu Kwang-Hyeon KH Lee Choong Hwan CH Park Cheol-Young CY

British journal of pharmacology 20180726 17

<h4>Background and purpose</h4>Thiazolidinediones, acting as PPAR-γ ligands, reduce hepatic steatosis in humans and animals. However, the underlying mechanism of this action remains unclear. The purpose of this study was to investigate changes in hepatic metabolites and lipids in response to treatment with the thiazolidinedione pioglitazone in an animal model of obese Type 2 diabetes.<h4>Experimental approach</h4>Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were orally administered either ...[more]

PMID: 29968381

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Project description:BackgroundThis study aims to identify early metabolomic biomarkers of gestational diabetes mellitus (GDM) and evaluate their association with hepatic steatosis.MethodsWe compared maternal serum metabolomic profiles between women who developed GDM (n = 118) and matched controls (n = 118) during the first (10-14 gestational weeks) and second (24-28 gestational weeks) trimesters using ultra-performance liquid chromatography coupled with mass spectrometry. Mediation analysis was performed to evaluate the mediating role of metabolic dysfunction-associated steatotic liver disease (MASLD) in the relationship between metabolites and subsequent development of GDM. A refined prediction model was developed to predict GDM using established clinical factors and selected metabolites.ResultsSignificant alterations in circulating metabolites, including amino acids, bile acids, and phospholipids, were observed in the GDM group compared to controls during early pregnancy. Mediation analysis revealed that several metabolites, including glycocholic acid (proportion mediated (PM) = 31.9%), butanoyl carnitine (PM = 25.7%), and uric acid (PM = 22.4%), had significant indirect effects on GDM incidence mediated by hepatic steatosis. The refined prediction model composed of clinical factors and selected metabolites in the first trimester demonstrated higher performance in predicting GDM development than the established prediction model composed solely of clinical factors (AUC, 0.85 vs. 0.63, p < 0.001).ConclusionsWomen who developed GDM exhibited altered metabolomic profiles from early pregnancy, which showed a significant correlation with GDM, with MASLD as a mediator. Selected metabolomic biomarkers may serve as predictive markers and potential targets for early risk assessment and intervention in GDM.Research insightsWHAT IS CURRENTLY KNOWN ABOUT THIS TOPIC?: Gestational diabetes mellitus (GDM) is a common pregnancy complication with significant health risks. Early identification of women at high risk for GDM is crucial for timely intervention and improved outcomes. WHAT IS THE KEY RESEARCH QUESTION?: What alterations in circulating metabolites during early pregnancy are associated with subsequent GDM development? Does metabolic dysfunction-associated steatotic liver disease (MASLD) mediate the association between specific metabolites and GDM risk? WHAT IS NEW?: Significant alterations in bile acids, amino acids, phosphatidylethanolamines, and phosphatidylinositols were observed in early pregnancy sera of women who later developed GDM. MASLD significantly mediated the effects of several metabolites on GDM risk, with mediation proportions ranging from 9.7 to 31.9%. A refined prediction model composed of clinical factors and metabolites significantly improved the performance in predicting GDM development. HOW MIGHT THIS STUDY INFLUENCE CLINICAL PRACTICE?: These results provide new insights into early metabolic alterations associated with GDM development and highlight the potential mediating role of MASLD. This comprehensive metabolomic approach may contribute to the development of improved risk prediction models and targeted interventions for GDM prevention.

Project description:BackgroundDiabetes has long been recognised as a strong, independent risk factor for cardiovascular disease, a problem which accounts for approximately 70% of all mortality in people with diabetes. Prospective studies show that compared to their non-diabetic counterparts, the relative risk of cardiovascular mortality for men with diabetes is two to three and for women with diabetes is three to four. The two biggest trials in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study did not reveal a reduction of cardiovascular endpoints through improved metabolic control. Theoretical benefits of the newer peroxisome proliferator activated receptor gamma (PPAR-gamma) activators like pioglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus.ObjectivesTo assess the effects of pioglitazone in the treatment of type 2 diabetes.Search strategyStudies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library. The last search was conducted in August 2006.Selection criteriaStudies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 24 weeks.Data collection and analysisTwo authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analysis could be performed for adverse events only.Main resultsTwenty-two trials which randomised approximately 6200 people to pioglitazone treatment were identified. Longest duration of therapy was 34.5 months. Published studies of at least 24 weeks pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised. The results of the single trial with relevant clinical endpoints (Prospective Pioglitazone Clinical Trial In Macrovascular Events--PROactive study) have to be regarded as hypothesis-generating and need confirmation.Authors' conclusionsUntil new evidence becomes available, the benefit-risk ratio of pioglitazone remains unclear. Different therapeutic indications for pioglitazone of the two big U.S. and European drug agencies should be clarified to reduce uncertainties amongst patients and physicians.

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Dataset Information

Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese Type 2 diabetes.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese Type 2 diabetes.

Similar Datasets

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