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Cureus Dec 2023Non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated liver disease (MASLD), is a spectrum of liver disease. It can be identified by... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated liver disease (MASLD), is a spectrum of liver disease. It can be identified by the fact that considerable amount of hepatocytes with minimal or no alcohol use have steatosisBecause of its rising incidence along with increasing rates of obesity, metabolic syndromes, and diabetes mellitus type 2, NAFLD is expected to overtake all other causes of cirrhosis over the next decade, necessitating liver transplantation. Nevertheless, heart disease persists as the most prevalent manifestation of mortality, with only a small percentage experiencing fibrosis and complications associated with the liver. Pathologically, NAFLD is linked to lipid toxicity, oxidative stress, lipid deposits, and endoplasmic reticulum stress. A healthy diet, physical exercise, and a decrease in weight are advised by current international guidelines for the treatment of NAFLD, along with a limited number of medicinal therapies, including vitamin E and pioglitazone. Various natural substances have also been identified as NAFLD in vivo and in vitro regulators. The frequency, complexity of the pathophysiology, lack of authorised medications, and difficulty in interpretation of NAFLD have made it a major problem. This article assesses MASLD's pathophysiology, diagnosis, treatment, and epidemiology. This study also reviews a few natural substances that have been shown to have therapeutic advantages for NAFLD.
PubMed: 38186528
DOI: 10.7759/cureus.50159 -
Biomolecules Jul 2023Despite the increasing prevalence rate of nonalcoholic fatty liver disease (NAFLD) worldwide, efficient pharmacotherapeutic regimens against NAFLD still need to be...
BACKGROUND
Despite the increasing prevalence rate of nonalcoholic fatty liver disease (NAFLD) worldwide, efficient pharmacotherapeutic regimens against NAFLD still need to be explored. Previous studies found that pioglitazone and metformin therapy could partly ameliorate NAFLD, but their combination therapy effects have not been researched. In the present study, we assessed the protective effects of metformin and pioglitazone combination therapy on liver lipid metabolism in high-fat diet (HFD)-fed mice and investigated the molecular mechanism.
METHODS
Male C57BL/6 mice were divided into five groups: normal control; HFD control; metformin monotherapy; pioglitazone monotherapy and combined therapy. After 8 weeks of pharmacological intervention, glucose and lipid metabolism characteristics, hepatic histology, lipidomics profiling and RNA-seq analysis were performed.
RESULTS
The combination of pioglitazone and metformin significantly ameliorated HFD-induced metabolic disturbance and the hepatic oil red O area. A lipidomics analysis showed that combined therapy could significantly reduce the high levels of free fatty acids (FFA), diacylglycerol and triglycerides, while a set of glycerophospholipids and sphingolipids were increased in the combined therapy group. Consistently, an RNA-seq analysis also showed a remarkable reduction in genes associated with FFA uptake and de novo lipogenesis, including , , , , , and in the combined therapy group.
CONCLUSIONS
Pioglitazone and metformin might have a synergistic protective effect on NAFLD by improving hepatic lipid profiles in HFD-induced mice. Further studies are needed to verify the clinical effects.
Topics: Male; Animals; Mice; Mice, Inbred C57BL; Lipid Metabolism; Mice, Obese; Pioglitazone; Non-alcoholic Fatty Liver Disease
PubMed: 37627267
DOI: 10.3390/biom13081199 -
Expert Opinion on Emerging Drugs Mar 2024Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million.... (Review)
Review
INTRODUCTION
Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient.
AREAS COVERED
After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action.
EXPERT OPINION
Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.
Topics: Child; Humans; Risperidone; Antipsychotic Agents; Autism Spectrum Disorder; Aripiprazole; Riluzole
PubMed: 38296815
DOI: 10.1080/14728214.2024.2313650 -
BMC Gastroenterology Sep 2023Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic disorder that increases the risk for cardiovascular disease in patients with type 2 diabetes mellitus... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Empagliflozin and Pioglitazone on left ventricular function in patients with type two diabetes and nonalcoholic fatty liver disease without established cardiovascular disease: a randomized single-blind clinical trial.
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic disorder that increases the risk for cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). Global longitudinal strain (GLS) is an indicator of left ventricular (LV) mechanics and can detect subclinical myocardial dysfunction. We compared the effects of pioglitazone and empagliflozin on GLS in patients with T2DM and NAFLD without established atherosclerotic cardiovascular disease.
METHODS
This study was a 24-week randomized, single-blind, and parallel-group (1: 1 ratio) clinical trial. Seventy-three participants with T2DM (being treated with metformin) and NAFLD but without established atherosclerotic cardiovascular disease (ASCVD) were randomized to empagliflozin or pioglitazone. Liver steatosis and fibrosis were measured using transient elastography, and GLS was measured by echocardiography. The primary endpoint was the change in GLS from baseline to week 24. Secondary end points include changes in controlled attenuation parameter (CAP) and Liver stiffness measure (LSM).
RESULTS
In this study, GLS improved by 1.56 ± 2.34% (P < 0.01) in the pioglitazone group and 1.06 ± 1.83% (P < 0.01) in the empagliflozin group without a significant difference between the two groups (P = 0.31). At baseline, GLS was inversely associated with the severity of liver fibrosis: r = - 0.311, P = 0.007. LSM in the pioglitazone and empagliflozin group [(-0.73 ± 1.59) and (-1.11 ± 1.33)] kpa (P < 0.01) decreased significantly. It was without substantial difference between the two groups (P = 0.26). Empagliflozin and pioglitazone both improved controlled attenuation parameter. The improvement was more critical in the empagliflozin group: -48.22 + 35.02 dB/m vs. -25.67 + 41.50 dB/m, P = 0.01.
CONCLUSION
Subclinical cardiac dysfunction is highly important in patients with T2DM and with NAFLD. Empagliflozin and Pioglitazone improve LV mechanics and fibrosis in patients without established ASCVD. This has a prognostic importance on cardiovascular outcomes in high-risk patients with T2DM. Moreover, empagliflozin ameliorates liver steatosis more effectively them pioglitazone. This study can serve as a start point hypothesis for the future. Further studies are needed to explore the concept in larger populations.
TRIAL REGISTRATION
This trial was registered in the Iranian Registry of Clinical Trials (IRCT): "A Comparison between the Effect of Empagliflozin and Pioglitazone on Echocardiographic Indices in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease" IRCT20190122042450N5, 29 November 2020. https://www.irct.ir/search/result?query=IRCT20190122042450N5 .
Topics: Humans; Pioglitazone; Non-alcoholic Fatty Liver Disease; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Ventricular Function, Left; Iran; Single-Blind Method
PubMed: 37742004
DOI: 10.1186/s12876-023-02948-4 -
European Review For Medical and... Aug 2023Changes in hormone levels, improper lipid metabolism, and oxidative stress all significantly contribute to the pathogenic process of polycystic ovarian syndrome (PCOS)....
OBJECTIVE
Changes in hormone levels, improper lipid metabolism, and oxidative stress all significantly contribute to the pathogenic process of polycystic ovarian syndrome (PCOS). According to earlier research, pioglitazone and alpha-lipoic acid are crucial in the emergence of PCOS. The beneficial effects of pioglitazone and alpha-lipoic acid on PCOS were examined in the current study.
PATIENTS AND METHODS
The 120 patients with PCOS received three months of treatment in pioglitazone groups (n=40 case, 30 mg/time, 1 time/day), α-lipoic acid (n=40 case, 0.6 g/time, 1 time/day), and combination therapy (n=40 case, pioglitazone 30 mg/time, 1 time/day and α-lipoic acid, 0.6 g/time, 1 time/day). Before and after therapy, the following factors were evaluated: the hormonal profile, fasting serum insulin, body weight, body mass index (BMI), menstruation status, oxidative stress, and indications of lipid metabolism.
RESULTS
The combination of pioglitazone and α-lipoic acid has a significantly improving effect on BMI, body weight, oxidative stress levels, lipid metabolism, and menstrual status. A significant increase in body weight, BMI, and follicle-stimulating hormone (FSH) levels were found in mice after being treated with α-lipoic acid alone. However, the use pioglitazone alone improves body weight, BMI, the calculation of insulin resistance index (HOMA-IR), Area under the curve (AUC)-insulin, fasting glucose/insulin (G/I) ratio, total testosterone, and malondialdehyde (MDA) levels in post-treatment than pre-treatment.
CONCLUSIONS
These findings suggest that pioglitazone alone has a better effect than alpha-lipoic acid in improving oxidative stress levels, BMI, and menstrual cyclicity. Additionally, treatment with pioglitazone and alpha-lipoic acid did demonstrate a greater effect than monotherapy with each medication alone.
Topics: Female; Humans; Animals; Mice; Thioctic Acid; Polycystic Ovary Syndrome; Pioglitazone; Body Weight; Insulin
PubMed: 37606122
DOI: 10.26355/eurrev_202308_33285 -
International Journal of Nanomedicine 2023Hyaluronic acid (HA) is a popular biological material for osteoarthritis (OA) treatment. Pioglitazone, a PPAR-γ agonist, has been found to inhibit OA, but its use is...
BACKGROUND
Hyaluronic acid (HA) is a popular biological material for osteoarthritis (OA) treatment. Pioglitazone, a PPAR-γ agonist, has been found to inhibit OA, but its use is limited because achieving the desired local drug concentration after administration is challenging.
PURPOSE
Herein, we constructed HA-based cartilage-targeted nanomicelles (C-HA-DOs) to deliver pioglitazone in a sustained manner and evaluated their efficacy in vitro and in vivo.
METHODS
C-HA-DOs were chemically synthesized with HA and the WYRGRL peptide and dodecylamine. The products were characterized by FT-IR, H NMR, zeta potential and TEM. The drug loading rate and cumulative, sustained drug release from Pio@C-HA-DOs were determined, and their biocompatibility and effect on oxidative stress in chondrocytes were evaluated. The uptake of C-HA-DOs by chondrocytes and their effect on OA-related genes were examined in vitro. The nanomicelle distribution in the joint cavity was observed by in vivo small animal fluorescence imaging (IVIS). The therapeutic effects of C-HA-DOs and Pio@C-HA-DOs in OA rats were analysed histologically.
RESULTS
The C-HA-DOs had a particle size of 198.4±2.431 nm, a surface charge of -8.290±0.308 mV, and a critical micelle concentration of 25.66 mg/Land were stable in solution. The cumulative drug release from the Pio@C-HA-DOs was approximately 40% at pH 7.4 over 24 hours and approximately 50% at pH 6.4 over 4 hours. Chondrocytes rapidly take up C-HA-DOs, and the uptake efficiency is higher under oxidative stress. In chondrocytes, C-HA-DOs, and Pio@C-HA-DOs inhibited HO-induced death, reduced intracellular ROS levels, and restored the mitochondrial membrane potential. The IVIS images confirmed that the micelles target cartilage. Pio@C-HA-DOs reduced the degradation of collagen II and proteoglycans by inhibiting the expression of MMP and ADAMTS, ultimately delaying OA progression in vitro and in vivo.
CONCLUSION
Herein, C-HA-DOs provided targeted drug delivery to articular cartilage and improved the role of pioglitazone in the treatment of OA.
Topics: Rats; Animals; Hyaluronic Acid; Pioglitazone; Hydrogen Peroxide; Spectroscopy, Fourier Transform Infrared; Osteoarthritis; Chondrocytes; Cartilage, Articular
PubMed: 37873552
DOI: 10.2147/IJN.S428938 -
Scientific Reports Nov 2023The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose-lowering action,...
The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose-lowering action, pioglitazone exerts pleiotropic effects including amelioration of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). The mechanism by which pioglitazone achieves this latter effect has remained unclear, however. We here show that pioglitazone administration increases the amount of linoleic acid (LA) metabolites in adipose tissue of KK-Ay mice. These metabolites are produced by lactic acid bacteria in the gut, and pioglitazone also increased the fraction of Lactobacillus in the gut microbiota. Administration of the LA metabolite HYA (10-hydroxy-cis-12-octadecenoic acid) to C57BL/6 J mice fed a high-fat diet improved liver histology including steatosis, inflammatory cell infiltration, and fibrosis. Gene ontology analysis of RNA-sequencing data for the liver revealed that the top category for genes downregulated by HYA treatment was related to extracellular matrix, and the expression of individual genes related to fibrosis was confirmed to be attenuated by HYA treatment. Mechanistically, HYA suppressed TGF-β-induced Smad3 phosphorylation and fibrosis-related gene expression in human hepatic stellate cells (LX-2). Our results implicate LA metabolites in the mechanism by which pioglitazone ameliorates liver fibrosis, and they suggest that HYA is a potential therapeutic for NAFLD/NASH.
Topics: Mice; Humans; Animals; Non-alcoholic Fatty Liver Disease; Pioglitazone; Linoleic Acid; Hepatic Stellate Cells; Gastrointestinal Microbiome; Mice, Inbred C57BL; Liver; Liver Cirrhosis; Fibrosis; Diet, High-Fat; Transforming Growth Factor beta
PubMed: 37923895
DOI: 10.1038/s41598-023-46404-5 -
Cureus Aug 2023Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, especially in people with obesity, dyslipidemia, type 2 diabetes mellitus (T2DM),... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, especially in people with obesity, dyslipidemia, type 2 diabetes mellitus (T2DM), and metabolic syndrome. Weight loss and dietary modifications are established first-line treatments for NAFLD. Currently, there is no approved drug for NAFLD; however, pioglitazone and vitamin E have shown some beneficial effects. This systematic review covers the comparative efficacies of vitamin E, pioglitazone, and vitamin E plus pioglitazone. As of December 2022, the sources for prior literature review included PubMed, PubMed Central, and Medline. We included studies assessing the efficacy of pioglitazone, vitamin E, and vitamin E plus pioglitazone in improving liver histology, liver markers, and lipid profile when compared to other interventions in patients with NAFLD/non-alcoholic steatohepatitis (NASH). Review materials include randomized control trials (RCTs), traditional reviews, systematic reviews, meta-analyses, and observational studies on human participants published within the last five years in the English language. Studies on animals, pediatric populations, and with insufficient data were excluded from the review. Two authors scanned and filtered articles independently and later performed quality checks. A third reviewer resolved any conflicts. The risk of bias was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines for systematic reviews, the Cochrane Risk of Bias Tool for RCTs, and the Scale for the Assessment of Narrative Review Articles for Traditional Reviews. A total of 21 articles were shortlisted. The results showed that pioglitazone and vitamin E are effective in reducing steatosis, inflammation, and ballooning, reducing liver markers, but there seem to be conflicting data on fibrosis resolution. Pioglitazone decreases triglycerides and increases high-density lipoproteins. One study has suggested that pioglitazone has superior efficacy to vitamin E in fibrosis reduction and vitamin E plus pioglitazone has superior efficacy than pioglitazone alone for NASH resolution. However, these conclusions require further validation through extensive analysis and additional research. In conclusion, diabetic patients with NAFLD can be given pioglitazone, and non-diabetic patients with NAFLD can be given vitamin E.
PubMed: 37719477
DOI: 10.7759/cureus.43635 -
The Journal of Clinical Endocrinology... Dec 2023The management of solid-organ transplantation is rapidly evolving, and posttransplant diabetes mellitus (PTDM), which is increasingly common, is a barrier to transplant... (Review)
Review
CONTEXT
The management of solid-organ transplantation is rapidly evolving, and posttransplant diabetes mellitus (PTDM), which is increasingly common, is a barrier to transplant success, adversely impacting infection rates, allograft survival, cardiovascular disease, quality of life, and overall mortality. Currently, the management of PTDM relies primarily on intensified insulin therapy. However, emerging studies report that several noninsulin glucose-lowering agents are safe and effective in improving metabolic control and enhancing treatment adherence. More importantly, their use in PTDM can potentially transform the long-term management of these complex patients, as some glucose-lowering agents may provide benefits beyond glycemic control. For instance, glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors may offer cardiorenal protection, and pioglitazone may treat nonalcoholic fatty liver disease (NAFLD). This review will focus on the pharmacological management of PTDM and the emerging evidence for noninsulin glucose-lowering agents in this population.
EVIDENCE ACQUISITION
Evidence from observational studies, randomized controlled trials, and meta-analyses.
EVIDENCE SYNTHESIS
PTDM adversely affects the outcomes of infection, organ survival, cardiovascular events, and mortality. Insulin therapy has been the drug of choice but is associated with weight gain and hypoglycemia. In contrast, noninsulin agents appear safe and may provide additional benefits, such as cardiorenal protection with SGLT-2 inhibitors and GLP-1 RA, and cardiometabolic benefits with pioglitazone, in patients undergoing solid-organ transplantation.
CONCLUSIONS
Optimal care of patients with PTDM requires close monitoring and the early involvement of the endocrinologist as part of a multidisciplinary team. Noninsulin glucose-lowering agents will likely play an increasing role as more long-term, controlled studies become available in this setting.
Topics: Humans; Pioglitazone; Quality of Life; Glycated Hemoglobin; Diabetes Mellitus; Insulin; Hyperglycemia; Glucose; Glucagon-Like Peptide 1; Diabetes Mellitus, Type 2; Hypoglycemic Agents
PubMed: 37410930
DOI: 10.1210/clinem/dgad395 -
Experimental and Clinical Endocrinology... Nov 2023Pioglitazone is an insulin sensitizer used for the treatment of type 2 diabetes mellitus (T2DM) by activating peroxisome proliferator-activated receptor gamma. This...
INTRODUCTION
Pioglitazone is an insulin sensitizer used for the treatment of type 2 diabetes mellitus (T2DM) by activating peroxisome proliferator-activated receptor gamma. This study aimed to investigate the effects of pioglitazone on white adipose tissue (WAT) and brown adipose tissue (BAT) in diet-induced obese (DIO) mice.
METHODS
C57BL/6 mice were treated with pioglitazone (30 mg/kg/day) for 4 weeks after a 16-week high-fat diet (HFD) challenge. Body weight gain, body fat mass, energy intake, and glucose homeostasis were measured during or after the treatment. Histopathology was observed by hematoxylin and eosin, oil red O, immunohistochemistry, and immunofluorescence staining. Expression of thermogenic and mitochondrial biogenesis-related genes was detected by quantitative real-time PCR and western blotting.
RESULTS
After 4-week pioglitazone treatment, the fasting blood glucose levels, glucose tolerance, and insulin sensitivity were significantly improved, but the body weight gain and fat mass were increased in DIO mice. Compared with the HFD group, pioglitazone did not significantly affect the weights of liver and WAT in both subcutaneous and epididymal regions. Unexpectedly, the weight of BAT was increased after pioglitazone treatment. Histological staining revealed that pioglitazone ameliorated hepatic steatosis, reduced the adipocyte size in WAT, but increased the adipocyte size in BAT.
CONCLUSION
Though pioglitazone can promote lipolysis, thermogenesis, and mitochondrial function in WAT, it leads to impaired thermogenesis, and mitochondrial dysfunction in BAT. In conclusion, pioglitazone could promote the browning of WAT but led to the whitening of BAT; the latter might be a new potential mechanism of pioglitazone-induced weight gain during T2DM treatment.
Topics: Mice; Animals; Adipose Tissue, Brown; Pioglitazone; Obesity; Mice, Obese; Diabetes Mellitus, Type 2; Mice, Inbred C57BL; Weight Gain; Adipose Tissue, White; Diet, High-Fat; Glucose
PubMed: 37729949
DOI: 10.1055/a-2178-9113