Efficacy and Cardiovascular Safety of Thiazolidinediones

Raveendran, Arkiath Veettil; Fernandez, Cornelius James; Jacob, Koshy

doi:10.2174/1574886315666201026125530

Cited by 8 publications

(9 citation statements)

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“…Diabetes is a well-recognized risk factor for the development of AF ( Xiong et al, 2018 ), adverse cardiovascular events ( Lee et al, 2021a ; Lee et al, 2021b ), complications involving different organs ( Lee et al, 2020 ), and mortality. Of the different classes of antidiabetic drugs, thiazolidinediones act by activating PPAR-γ ( Lebovitz, 2019 ; Veettil et al, 2020 ). Pioglitazone is a thiazolidinedione with favorable effects on insulin sensitivity, blood glucose, lipid metabolism, inflammation, and oxidative stress ( DeFronzo et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway

Zhang

Meng

et al. 2021

Front. Pharmacol.

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Background: Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This remodeling can be prevented by the PPAR-γ agonist pioglitazone via its antioxidant and anti-inflammatory effects. In this study, we examined the molecular mechanisms underlying the protective effects of pioglitazone on atrial remodeling in a rabbit model of diabetes.Methods: Rabbits were randomly divided into control, diabetic, and pioglitazone-treated diabetic groups. Echocardiographic, hemodynamic, and electrophysiological parameters were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of the pro-fibrotic marker TGF-β1, the PPAR-γ coactivator-1α (PGC-1α), and the mitochondrial proteins (biogenesis-, fusion-, and fission-related proteins) was measured. HL-1 cells were transfected with PGC-1α small interfering RNA (siRNA) to determine the underlying mechanisms of pioglitazone improvement of mitochondrial function under oxidative stress.Results: The diabetic group demonstrated a larger left atrial diameter and fibrosis area than the controls, which were associated with a higher incidence of inducible atrial fibrillation (AF). The lower serum PPAR-γ level was associated with lower PGC-1α and higher NF-κB and TGF-β1 expression. Lower mitochondrial biogenesis (PGC-1α, NRF1, and TFAM)-, fusion (Opa1 and Mfn1)-, and fission (Drp1)-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, and lower MMP were observed. The pioglitazone group showed a reversal of structural remodeling and a lower incidence of inducible AF, which were associated with higher PPAR-γ and PGC-1α. The pioglitazone group had lower NF-κB and TGF-β1 expression levels, whereas biogenesis-, fusion-, and fission-related protein expression was higher. Further, mitochondrial structure and function were improved. In HL-1 cells, PGC-1α siRNA transfection blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H2O2-treated cells.Conclusion: Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway.

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Section: Discussionmentioning

confidence: 99%

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway

Zhang

Meng

et al. 2021

Front. Pharmacol.

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“…Rosiglitazone is an agent that targets SCD and is a thiazolidinedione that enhances insulin sensitivity. It was often used in the past for blood glucose control but is now used sparingly due to its significant cardiovascular side effects 50,51 . Animal studies have shown that SCD levels are elevated in obese rats but return to normal levels after rosiglitazone treatment 52 .…”

Section: Discussionmentioning

confidence: 99%

Identification of ferroptosis‐related genes in type 2 diabetes mellitus based on machine learning

Wang,

Lu,

Chi

et al. 2023

Immunity Inflam & Disease

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BackgroundType 2 diabetes mellitus (T2DM), which has a high incidence and several harmful consequences, poses a severe danger to human health. Research on the function of ferroptosis in T2DM is increasing. This study uses bioinformatics techniques identify new diagnostic T2DM biomarkers associated with ferroptosis.MethodsTo identify ferroptosis‐related genes (FRGs) that are differentially expressed between T2DM patients and healthy individuals, we first obtained T2DM sequencing data and FRGs from the Gene Expression Omnibus (GEO) database and FerrDb database. Then, drug‐gene interaction networks and competitive endogenous RNA (ceRNA) networks linked to the marker genes were built after marker genes were filtered by two machine learning algorithms (LASSO and SVM‐RFE algorithms). Finally, to confirm the expression of marker genes, the GSE76895 dataset was utilized. The protein and RNA expression of some marker genes in T2DM and nondiabetic tissues was also examined by Western blotting, immunohistochemistry (IHC), immunofluorescence (IF) and quantitative real‐time PCR (qRT‐PCR).ResultsWe obtained 58 differentially expressed genes (DEGs) associated with ferroptosis. GO and KEGG enrichment analyses showed that these DEGs were significantly enriched in hypoxia and ferroptosis. Subsequently, eight marker genes (SCD, CD44, HIF1A, BCAT2, MTF1, HILPDA, NR1D2, and MYCN) were screened by LASSO and SVM‐RFE machine learning algorithms, and a model was constructed based on these eight genes. This model also has high diagnostic power. In addition, based on these eight genes, we obtained 48 drugs and constructed a complex ceRNA network map. Finally, Western blotting, IHC, IF, and qRT‐PCR results of clinical samples further confirmed the results of public databases.ConclusionsThe diagnosis and aetiology of T2DM can be greatly aided by eight FRGs, providing novel therapeutic avenues.

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“…Significant improvement in NASH without worsening of fibrosis was seen with the use of pioglitazone dose of 45 mg daily (relative risk: 2.64, 95%CI: 1.36; 5.12). An HbA1c reduction ranging from 1%-1.6% has been observed with neutral cardiovascular (CV) safety profile in patients with T2DM treated with pioglitazone though the use of the molecule is now less common owing to the availability of newer antidiabetic medications with better CV benefits[ 40 ]. Weight gain potential, probable risks of worsening heart failure and diabetic maculopathy from fluid retention and elevated fracture risk are the hindrances for widespread use of pioglitazone in clinical practice.…”

Section: Pharmacotherapy For Mafldmentioning

confidence: 99%

Management of metabolic-associated fatty liver disease: The diabetology perspective

Jeeyavudeen¹,

Khan²,

Fouda³

et al. 2023

World J Gastroenterol

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The metabolic syndrome as a consequence of the obesity pandemic resulted in a substantial increase in the prevalence of metabolic-associated fatty live disease (MAFLD) and type 2 diabetes mellitus (T2DM). Because of the similarity in pathobiology shared between T2DM and MAFLD, both disorders coexist in many patients and may potentiate the disease-related outcomes with rapid progression and increased complications of the individual diseases. In fact, awareness about this coexistence and the risk of complications are often overlooked by both hepatologists and diabetologists. Management of these individual disorders in a patient should be addressed wholistically using an appropriate multidisciplinary team approach involving both the specialists and, when necessary, liaising with dieticians and surgeons. This comprehensive review is to compile the current evidence from a diabetologist's perspective on MAFLD and T2DM and to suggest optimal management strategies.

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Efficacy and Cardiovascular Safety of Thiazolidinediones

Cited by 8 publications

References 0 publications

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway

Identification of ferroptosis‐related genes in type 2 diabetes mellitus based on machine learning

Management of metabolic-associated fatty liver disease: The diabetology perspective

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