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1.
J Diabetes Res ; 2024: 3470654, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846063

RESUMO

Aims: We compared the glycaemic and cardiorenal effects of combination therapy involving metformin, pioglitazone, sodium-glucose-linked-cotransporter-2 inhibitor (SGLT2i), and glucagon-like peptide-1 receptor agonist (GLP-1RA) versus a more conventional glucocentric treatment approach combining sulphonylureas (SU) and insulin from the point of type 2 diabetes (T2D) diagnosis. Methods: We performed a retrospective cohort study using the Global Collaborative Network in TriNetX. We included individuals prescribed metformin, pioglitazone, an SGLT2i, and a GLP-1 RA for at least 1-year duration, within 3 years of a T2D diagnosis, and compared with individuals prescribed insulin and a SU within the same temporal pattern. Individuals were followed up for 3 years. Results: We propensity score-matched (PSM) for 26 variables. A total of 1762 individuals were included in the final analysis (n = 881 per cohort). At 3-years, compared to the insulin/SU group, the metformin/pioglitazone/SGLT2i/GLP-1 RA group had a lower risk of heart failure (HR 0.34, 95% CI 0.13-0.87, p = 0.018), acute coronary syndrome (HR 0.29, 95% CI 0.12-0.67, p = 0.002), stroke (HR 0.17, 95% CI 0.06-0.49, p < 0.001), chronic kidney disease (HR 0.50, 95% CI 0.25-0.99, p = 0.042), and hospitalisation (HR 0.59, 95% CI 0.46-0.77, p < 0.001). Conclusions: In this real-world study, early, intensive polytherapy, targeting the distinct pathophysiological defects in T2D, is associated with significantly more favourable cardiorenal outcomes, compared to insulin and SU therapy.


Assuntos
Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Insulina , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Compostos de Sulfonilureia , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Masculino , Hipoglicemiantes/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insulina/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Pioglitazona/uso terapêutico , Bases de Dados Factuais , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Resultado do Tratamento
2.
Ulus Travma Acil Cerrahi Derg ; 30(6): 406-414, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38863295

RESUMO

BACKGROUND: This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model. METHODS: Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-ß), and fibronectin levels were measured in serum and peritoneal lavage samples. RESULTS: The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-ß levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005). CONCLUSION: Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.


Assuntos
Modelos Animais de Doenças , Metformina , Pioglitazona , Ratos Wistar , Animais , Pioglitazona/farmacologia , Metformina/farmacologia , Aderências Teciduais/prevenção & controle , Aderências Teciduais/tratamento farmacológico , Ratos , Hipoglicemiantes/farmacologia , Masculino , Tiazolidinedionas/farmacologia , Complicações Pós-Operatórias/prevenção & controle
3.
Theranostics ; 14(8): 3221-3245, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38855177

RESUMO

The availability of non-invasive drug delivery systems capable of efficiently transporting bioactive molecules across the blood-brain barrier to specific cells at the injury site in the brain is currently limited. Delivering drugs to neurons presents an even more formidable challenge due to their lower numbers and less phagocytic nature compared to other brain cells. Additionally, the diverse types of neurons, each performing specific functions, necessitate precise targeting of those implicated in the disease. Moreover, the complex synthetic design of drug delivery systems often hinders their clinical translation. The production of nanomaterials at an industrial scale with high reproducibility and purity is particularly challenging. However, overcoming this challenge is possible by designing nanomaterials through a straightforward, facile, and easily reproducible synthetic process. Methods: In this study, we have developed a third-generation 2-deoxy-glucose functionalized mixed layer dendrimer (2DG-D) utilizing biocompatible and cost-effective materials via a highly facile convergent approach, employing copper-catalyzed click chemistry. We further evaluated the systemic neuronal targeting and biodistribution of 2DG-D, and brain delivery of a neuroprotective agent pioglitazone (Pio) in a pediatric traumatic brain injury (TBI) model. Results: The 2DG-D exhibits favorable characteristics including high water solubility, biocompatibility, biological stability, nanoscale size, and a substantial number of end groups suitable for drug conjugation. Upon systemic administration in a pediatric mouse model of traumatic brain injury (TBI), the 2DG-D localizes in neurons at the injured brain site, clears rapidly from off-target locations, effectively delivers Pio, ameliorates neuroinflammation, and improves behavioral outcomes. Conclusions: The promising in vivo results coupled with a convenient synthetic approach for the construction of 2DG-D makes it a potential nanoplatform for addressing brain diseases.


Assuntos
Dendrímeros , Desoxiglucose , Sistemas de Liberação de Medicamentos , Neurônios , Animais , Dendrímeros/química , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Desoxiglucose/farmacologia , Desoxiglucose/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Camundongos , Pioglitazona/farmacologia , Pioglitazona/administração & dosagem , Pioglitazona/farmacocinética , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encefalopatias/tratamento farmacológico , Humanos , Modelos Animais de Doenças , Distribuição Tecidual , Masculino
4.
Front Endocrinol (Lausanne) ; 15: 1325230, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38818508

RESUMO

Introduction: Polycystic ovary syndrome (PCOS) is often associated with metabolic-associated fatty liver disease (MAFLD). MAFLD has been associated with altered hepatic function, systemic dysmetabolism, and abnormal circulating levels of signaling molecules called organokines. Here, we assessed the effects of two randomized treatments on a set of organokines in adolescent girls with PCOS and without obesity, and report the associations with circulating biomarkers of liver damage, which were assessed longitudinally in the aforementioned studies as safety markers. Materials and methods: Liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT)] were assessed as safety markers in previous randomized pilot studies comparing the effects of an oral contraceptive (OC) with those of a low-dose combination of spironolactone-pioglitazone-metformin (spiomet) for 1 year. As a post hoc endpoint, the organokines fibroblast growth factor-21 (FGF21), diazepam-binding protein-1 (DBI), and meteorin-like protein (METRNL) were assessed by ELISA after 6 months of OC (N = 26) or spiomet (N = 28). Auxological, endocrine-metabolic, body composition (using DXA), and abdominal fat partitioning (using MRI) were also evaluated. Healthy, age-matched adolescent girls (N = 17) served as controls. Results: Circulating ALT and GGT levels increased during OC treatment and returned to baseline concentrations in the post-treatment phase; in contrast, spiomet treatment elicited no detectable changes in ALT and GGT concentrations. In relation to organokines after 6 months of treatment, (1) FGF21 levels were significantly higher in PCOS adolescents than in control girls; (2) DBI levels were lower in OC-treated girls than in controls and spiomet-treated girls; and (3) no differences were observed in METRNL concentrations between PCOS girls and controls. Serum ALT and GGT levels were directly correlated with circulating METRNL levels only in OC-treated girls (R = 0.449, P = 0.036 and R = 0.552, P = 0.004, respectively). Conclusion: The on-treatment increase in ALT and GGT levels occurring only in OC-treated girls is associated with circulating METRNL levels, suggesting enhanced METRNL synthesis as a reaction to the hepatic changes elicited by OC treatment. Clinical Trial Registration: https://doi.org, identifiers 10.1186/ISRCTN29234515, 10.1186/ISRCTN11062950.


Assuntos
Alanina Transaminase , Fatores de Crescimento de Fibroblastos , Fígado , Metformina , Síndrome do Ovário Policístico , Humanos , Feminino , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/sangue , Adolescente , Metformina/uso terapêutico , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Alanina Transaminase/sangue , Alanina Transaminase/metabolismo , Pioglitazona/uso terapêutico , Biomarcadores/sangue , Espironolactona/uso terapêutico , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , gama-Glutamiltransferase/sangue , gama-Glutamiltransferase/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Anticoncepcionais Orais/efeitos adversos , Anticoncepcionais Orais/uso terapêutico , Anticoncepcionais Orais/administração & dosagem , Hipoglicemiantes/uso terapêutico
5.
J Assoc Physicians India ; 72(1): 32-42, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38736072

RESUMO

BACKGROUND: The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India. MATERIALS AND METHODS: In this 16-week randomized, double-blind, and multicenter study, the efficacy and safety of lobeglitazone sulfate 0.5 mg were evaluated with pioglitazone 15 mg. Type 2 diabetes mellitus (T2DM) patients with ≥7.5% glycated hemoglobin (HbA1c) ≤10.5% and on stable metformin dose were assigned to both treatment arms. The primary outcome was a mean change in HbA1c. Safety assessments included adverse events (AE), home-based glucose monitoring, vital parameters, electrocardiogram (ECG), and laboratory assessments. RESULTS: A total of 328 subjects were randomized equally in two groups. A statistically significant reduction in HbA1c at week 16 in the lobeglitazone group with the least square (LS) mean change: 1.01 [standard error (SE): 0.09] (p < 0.0001) was seen. The LS mean difference between the two groups was 0.05 (SE: 0.12) [95% confidence interval (CI): -0.18, 0.27], which was statistically significant (p = 0.0013). Statistically significant reductions were also observed in fasting and postprandial glucose. Treatment-emergent Aes (TEAE) were comparable between both groups. CONCLUSION: Lobeglitazone 0.5 mg once daily was found to be efficacious and safe in the treatment of T2DM in the Indian population. Lobeglitazone significantly improved glycemic parameters and was noninferior to pioglitazone; hence, it could be a promising insulin sensitizer in T2DM management in India.


Assuntos
Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Hemoglobinas Glicadas , Hipoglicemiantes , Metformina , Pioglitazona , Tiazolidinedionas , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Metformina/administração & dosagem , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Feminino , Tiazolidinedionas/uso terapêutico , Tiazolidinedionas/administração & dosagem , Hemoglobinas Glicadas/análise , Índia , Pioglitazona/uso terapêutico , Pioglitazona/administração & dosagem , Glicemia/análise , Glicemia/efeitos dos fármacos , Adulto , Resultado do Tratamento , Idoso , Pirimidinas
6.
Molecules ; 29(9)2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38731628

RESUMO

Fluorescence lifetime imaging microscopy (FLIM) has proven to be a useful method for analyzing various aspects of material science and biology, like the supramolecular organization of (slightly) fluorescent compounds or the metabolic activity in non-labeled cells; in particular, FLIM phasor analysis (phasor-FLIM) has the potential for an intuitive representation of complex fluorescence decays and therefore of the analyzed properties. Here we present and make available tools to fully exploit this potential, in particular by coding via hue, saturation, and intensity the phasor positions and their weights both in the phasor plot and in the microscope image. We apply these tools to analyze FLIM data acquired via two-photon microscopy to visualize: (i) different phases of the drug pioglitazone (PGZ) in solutions and/or crystals, (ii) the position in the phasor plot of non-labelled poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), and (iii) the effect of PGZ or PGZ-containing NPs on the metabolism of insulinoma (INS-1 E) model cells. PGZ is recognized for its efficacy in addressing insulin resistance and hyperglycemia in type 2 diabetes mellitus, and polymeric nanoparticles offer versatile platforms for drug delivery due to their biocompatibility and controlled release kinetics. This study lays the foundation for a better understanding via phasor-FLIM of the organization and effects of drugs, in particular, PGZ, within NPs, aiming at better control of encapsulation and pharmacokinetics, and potentially at novel anti-diabetics theragnostic nanotools.


Assuntos
Nanopartículas , Pioglitazona , Pioglitazona/farmacologia , Pioglitazona/química , Nanopartículas/química , Animais , Linhagem Celular Tumoral , Humanos , Microscopia de Fluorescência/métodos , Ratos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química
7.
Clin Transl Sci ; 17(5): e13834, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38771175

RESUMO

Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone-induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta-alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post-dose. Pioglitazone-dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.


Assuntos
Voluntários Saudáveis , Pioglitazona , Purinas , Tiazolidinedionas , Humanos , Masculino , Pioglitazona/farmacologia , Pioglitazona/administração & dosagem , Purinas/administração & dosagem , Purinas/metabolismo , Adulto , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacologia , Tiazolidinedionas/efeitos adversos , Metabolômica/métodos , Adulto Jovem , Hipoglicemiantes/farmacologia , Hipoglicemiantes/administração & dosagem
8.
Adv Ther ; 41(6): 2168-2195, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38683294

RESUMO

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a complex endocrine condition affecting women of reproductive age. It is characterised by insulin resistance and is a risk for type 2 diabetes mellitus (T2DM). The aim of this study was to review the literature on the effect of pioglitazone and rosiglitazone in women with PCOS. METHODS: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science in April 2020 and updated in March 2023. Studies were deemed eligible if they were randomised controlled trials (RCTs) reporting the effect of pioglitazone and rosiglitazone in PCOS. The study follows the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently extracted data and assessed the risk of bias using the Cochrane risk of bias tool. RESULTS: Out of 814 initially retrieved citations, 24 randomised clinical trials (RCTs) involving 976 participants were deemed eligible. Among women with PCOS, treatment with rosiglitazone compared to metformin resulted in a significant increase in the mean body weight (mean difference (MD) 1.95 kg; 95% CI 0.03-3.87, p = 0.05). Metformin treatment was associated with a reduction in mean body mass index (BMI) compared to pioglitazone (MD 0.85 kg/m2; 95% CI 0.13-1.57, p = 0.02). Both pioglitazone compared to placebo (MD 2.56 kg/m2; 95% CI 1.77-3.34, p < 0.00001) and rosiglitazone compared to metformin (MD 0.74 kg/m2; 95% CI 0.07-1.41, p = 0.03) were associated with a significant increase in BMI. Treatment with pioglitazone compared to placebo showed a significant reduction in triglycerides (MD - 0.20 mmol/L; 95% CI - 0.38 to - 0.03, p = 0.02) and fasting insulin levels (MD - 11.47 mmol/L; 95% CI - 20.20, - 2.27, p = 0.01). Rosiglitazone compared to metformin was marginally significantly associated with a reduction in the luteinising hormone (LH) (MD - 0.62; 95% CI - 1.25-0.00, p = 0.05). CONCLUSION: Both pioglitazone and rosiglitazone were associated with significant increases in body weight and BMI when compared with metformin or placebo. Pioglitazone significantly reduced triglycerides and fasting insulin when compared with placebo while rosiglitazone showed a modest reduction of LH when compared with metformin. PROSPERO REGISTRATION NO: CRD42020178783.


Assuntos
Hipoglicemiantes , Pioglitazona , Síndrome do Ovário Policístico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rosiglitazona , Síndrome do Ovário Policístico/tratamento farmacológico , Humanos , Feminino , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Rosiglitazona/uso terapêutico , Rosiglitazona/farmacologia , Tiazolidinedionas/uso terapêutico , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Índice de Massa Corporal
9.
Diabetes Obes Metab ; 26(7): 2606-2623, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38558280

RESUMO

AIMS: To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta-analysis, and analysis of a large international real-world database. METHODS: We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP-1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane-endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity-score-matched individuals who were treated for at least 1 year with pioglitazone and a GLP-1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP-1RA and SGLT2 inhibitor monotherapy. Outcomes were all-cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack. RESULTS: The average follow-up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP-1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences -1% (95% confidence interval [CI] -1.27, -0.74) and -1.19 kg (95% CI -1.80, -0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference - 1.56 mmHg (95% CI -4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07-1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences -0.48% (95% CI -0.67, -0.28), -2.3 kg (95% CI -2.72, -1.88) and -2.4 mmHg (95% CI -4.1, -0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30-10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real-world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38-0.65; p < 0.001). CONCLUSION: Both our systematic review/meta-analysis and the real-world dataset show that combination of pioglitazone with either GLP-1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy.


Assuntos
Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Pioglitazona , Inibidores do Transportador 2 de Sódio-Glicose , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Humanos , Pioglitazona/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Hipoglicemiantes/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Resultado do Tratamento , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Bases de Dados Factuais , Hemoglobinas Glicadas/análise , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/epidemiologia , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon
10.
Diabetes Obes Metab ; 26(7): 2969-2978, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38685616

RESUMO

AIM: The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain elusive, so we aimed to investigate these issues. METHODS: A 3-year prospective cohort study of 126 Taiwanese patients with SLD treated with pioglitazone (15-30 mg/day) was conducted. Phospholipase domain-containing protein 3 I148M rs738409, methylenetetrahydrofolate reductase rs1801133, aldehyde dehydrogenase 2 (ALDH2) rs671 and lipoprotein lipase rs10099160 single nucleotide polymorphisms were assessed in the patients. RESULTS: Of 126 patients, 78 (61.9%) were men, and the mean and median ages were 54.3 and 56.5 years, respectively. Pioglitazone responders were defined as those with decreased alanine aminotransferase (ALT) levels at 6 months post-treatment, and 105 (83.3%) patients were responders. Compared with non-responders, responders were more frequently women and had higher baseline ALT levels. The proportion of patients with the ALDH2 rs671 GG genotype was lower among responders (38.6% vs. 66.6%, p = .028). Female sex [odds ratio (OR): 4.514, p = .023] and baseline ALT level (OR: 1.015, p = .046; cut-off level: ≥82 U/L) were associated with pioglitazone response. Among responders, the liver biochemistry and homeostasis model assessment of insulin resistance improved from 6 to 24 months post-treatment. The total cholesterol levels decreased within 6 months, while increases in high-density lipoprotein cholesterol levels and decreases in triglyceride levels and fibrosis-4 scores were noted only at 24 months post-treatment. The 2-year cumulative incidences of cardiovascular events, cancers and hepatic events were similar between responders and non-responders. CONCLUSIONS: Regarding liver biochemistry, over 80% of Taiwanese patients with SLD had a pioglitazone response, which was positively associated with female sex and baseline ALT levels. Insulin resistance improved as early as 6 months post-treatment, while liver fibrosis improvement was not observed until 24 months post-treatment. The link between the pioglitazone response and the ALDH2 genotype warrants further investigation.


Assuntos
Aldeído-Desidrogenase Mitocondrial , Hipoglicemiantes , Pioglitazona , Polimorfismo de Nucleotídeo Único , Humanos , Pioglitazona/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Hipoglicemiantes/uso terapêutico , Resultado do Tratamento , Aldeído-Desidrogenase Mitocondrial/genética , Taiwan/epidemiologia , Alanina Transaminase/sangue , Tiazolidinedionas/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Idoso , Lipase Lipoproteica/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Genótipo , Adulto
11.
Am J Physiol Regul Integr Comp Physiol ; 327(1): R25-R34, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38682243

RESUMO

Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer before acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared with placebo (PLA) during aerobic exercise at HA. With the use of a randomized crossover design, native lowlanders (n = 7 males, means ± SD, age: 23 ± 6 yr, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80 min of steady-state (1.43 ± 0.16 V̇o2 L/min) treadmill exercise at HA (460 mmHg; [Formula: see text] 96.6 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes ([13C]glucose and 6,6-[2H2]glucose). Exogenous glucose oxidation was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation (PIO: 1.65 ± 0.22 g/min, PLA: 1.68 ± 0.32 g/min) or fat oxidation (PIO: 0.10 ± 0.0.08 g/min, PLA: 0.09 ± 0.07 g/min) was not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min), disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests that the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues.NEW & NOTEWORTHY Short-term (5 days) use of the oral insulin sensitizer pioglitazone does not alter circulating glucose or insulin responses to enhance exogenous glucose oxidation during steady-state aerobic exercise in young healthy men under simulated acute (8 h) high-altitude (460 mmHg) conditions. These results indicate that dysregulations in glucose metabolism in native lowlanders sojourning at high altitude may not be due to insulin resistance at peripheral tissue.


Assuntos
Altitude , Estudos Cross-Over , Exercício Físico , Glucose , Hipoglicemiantes , Oxirredução , Pioglitazona , Humanos , Pioglitazona/administração & dosagem , Pioglitazona/farmacologia , Masculino , Adulto Jovem , Exercício Físico/fisiologia , Adulto , Glucose/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipoglicemiantes/farmacocinética , Taxa de Depuração Metabólica , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Insulina/sangue , Insulina/metabolismo
12.
Nano Lett ; 24(15): 4354-4361, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38563599

RESUMO

The recent focus of cancer therapeutics research revolves around modulating the immunosuppressive tumor microenvironment (TME) to enhance efficacy. The tumor stroma, primarily composed of cancer-associated fibroblasts (CAFs), poses significant obstacles to therapeutic penetration, influencing resistance and tumor progression. Reprogramming CAFs into an inactivated state has emerged as a promising strategy, necessitating innovative approaches. This study pioneers the design of a nanoformulation using pioglitazone, a Food and Drug Administration-approved anti-diabetic drug, to reprogram CAFs in the breast cancer TME. Glutathione (GSH)-responsive dendritic mesoporous organosilica nanoparticles loaded with pioglitazone (DMON-P) are designed for the delivery of cargo to the GSH-rich cytosol of CAFs. DMON-P facilitates pioglitazone-mediated CAF reprogramming, enhancing the penetration of doxorubicin (Dox), a therapeutic drug. Treatment with DMON-P results in the downregulation of CAF biomarkers and inhibits tumor growth through the effective delivery of Dox. This innovative approach holds promise as an alternative strategy for enhancing therapeutic outcomes in CAF-abundant tumors, particularly in breast cancer.


Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Nanopartículas , Humanos , Feminino , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Microambiente Tumoral
13.
PLoS One ; 19(4): e0297572, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38630788

RESUMO

BACKGROUND: Currently, it is acknowledged that vitamin E, insulin sensitizers and anti-diabetic drugs are used to manage non-alcoholic fatty liver disease (NAFLD), however, these therapeutic interventions harbour adverse side effects. Pioglitazone, an anti-diabetic drug, is currently the most effective therapy to manage NAFLD. The use of natural medicines is widely embraced due to the lack of evidence of their negative side effects. Rooibos has been previously shown to decrease inflammation and oxidative stress in experimental models of diabetes, however, this is yet to be explored in a setting of NAFLD. This study was aimed at investigating the effects of an aspalathin-rich green rooibos extract (Afriplex GRTTM) against markers of hepatic oxidative stress, inflammation and apoptosis in an in vitro model of NAFLD. METHODS: Oleic acid [1 mM] was used to induce hepatic steatosis in C3A liver cells. Thereafter, the therapeutic effect of Afriplex GRTTM, with or without pioglitazone, was determined by assessing its impact on cell viability, changes in mitochondrial membrane potential, intracellular lipid accumulation and the expression of genes and proteins (ChREBP, SREBF1, FASN, IRS1, SOD2, Caspase-3, GSTZ1, IRS1 and TNF-α) that are associated with the development of NAFLD. RESULTS: Key findings showed that Afriplex GRTTM added to the medium alone or combined with pioglitazone, could effectively block hepatic lipid accumulation without inducing cytotoxicity in C3A liver cells exposed oleic acid. This positive outcome was consistent with effective regulation of genes involved in insulin signaling, as well as carbohydrate and lipid metabolism (IRS1, SREBF1 and ChREBP). Interestingly, in addition to reducing protein levels of an inflammatory marker (TNF-α), the Afriplex GRTTM could ameliorate oleic acid-induced hepatic steatotic damage by decreasing the protein expression of oxidative stress and apoptosis related markers such as GSTZ1 and caspase-3. CONCLUSION: Afriplex GRTTM reduced hepatic steatosis in oleic acid induced C3A liver cells by modulating SREBF1, ChREBP and IRS-1 gene expression. The extract may also play a role in alleviating inflammation by reducing TNF-α expression, suggesting that additional experiments are required for its development as a suitable therapeutic option against NAFLD. Importantly, further research is needed to explore its antioxidant role in this model.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Caspase 3/metabolismo , Ácido Oleico/farmacologia , Pioglitazona/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Fígado/metabolismo , Metabolismo dos Lipídeos , Inflamação/metabolismo , Insulina/metabolismo , Dieta Hiperlipídica , Glutationa Transferase/metabolismo
14.
Chem Res Toxicol ; 37(5): 779-790, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38684131

RESUMO

The linagliptin (LIN) and pioglitazone HCl (PIO) combination, currently undergoing phase III clinical trials for diabetes mellitus treatment, demonstrated significant improvements in glycemic control. However, the absence of an analytical method for simultaneous determination in biological fluids highlights a crucial gap. This underscores the pressing need for sensitive bioanalytical methods, emphasizing the paramount importance of developing such tools to advance diabetes management strategies and enhance patient care. Herein, a sensitive reverse-phase high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for simultaneous determination of LIN and PIO in rat plasma using alogliptin as an internal standard. Chromatographic separation was performed on an Agilent Eclipse Plus C18 (4.6 × 100 mm, 3.5 µm) using an isocratic mobile phase system consisting of ammonium formate (pH 4.5) and methanol using an acetonitrile-induced protein precipitation technique for sample preparation. Multiple reaction monitoring in positive ion mode was used for quantitation of the precursor to production at m/z 473.2 → 419.9 for LIN, 357.1 → 134.2 for PIO, and 340.3 → 116.1 for ALO. The linearity range was 0.5 to 100 and 1 to 2000 ng/mL for LIN and PIO, respectively. The developed method was validated as per US-FDA guidelines and successfully applied to clinical pharmacokinetic and drug-drug interaction studies with a single oral administration of LIN and PIO in rat plasma. Pharmacokinetic parameters of LIN were significantly influenced by the concomitant administration of PIO and vice versa. Molecular modeling revealed the significant interaction of LIN and PIO with P-glycoprotein. Therefore, the drug-drug interaction between LIN and PIO deserves further study to improve drug therapy and prevent dangerous adverse effects.


Assuntos
Interações Medicamentosas , Linagliptina , Pioglitazona , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Animais , Linagliptina/sangue , Linagliptina/química , Linagliptina/farmacocinética , Pioglitazona/química , Pioglitazona/sangue , Pioglitazona/farmacocinética , Ratos , Masculino , Cromatografia Líquida de Alta Pressão , Estrutura Molecular , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/química , Espectrometria de Massa com Cromatografia Líquida
15.
Toxicon ; 241: 107687, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38484848

RESUMO

The effects of safranal and pioglitazone alone and their combination on inhaled paraquat (PQ)-induced systemic oxidative stress and inflammation as well as behavioral changes were examined in rats. In this study, animals were exposed to saline (Ctrl) or PQ (PQ groups) aerosols. PQ exposed animals were treated with dexamethasone, 0.8 and 3.2 mg/kg/day safranal (Saf-L and Saf-H), 5 mg/kg/day pioglitazone (Pio), and Saf-L + Pio for 16 days during PQ exposure period. PQ group showed increased numbers of total and differential WBCs in blood and bronchoalveolar lavage fluid (BALF), increased malondialdehyde (MDA), in the serum BALF and brain reduced thiol, catalase (CAT), and superoxide dismutase (SOD) levels compared to the control group (for all, p < 0.001). The escape latency and traveled distance were enhanced, but the time spent in the target quadrant in the probe day and the latency to enter the dark room 3, 24, 48, and 72 h after receiving an electrical shock, (in the shuttle box test) were decreased in the PQ group (p < 0.05 to P < 0.001). In all treated groups, all measure values were improved compared to PQ group (p < 0.05 to p < 0.001). In combination treated group of Saf-L + Pio, most measured values were more improved than the Saf-L and Pio groups (p < 0.05 to p < 0.001). Saf and Pio improved PQ-induced changes similar to dexamethasone but the effects produced by combination treatments of Saf-L + Pio were more prominent than Pio and Saf-L alone, suggesting a potentiating effect for the combination of the two agents.


Assuntos
Lesão Pulmonar Aguda , Cicloexenos , Paraquat , Edema Pulmonar , Terpenos , Ratos , Animais , Paraquat/toxicidade , Pulmão , Pioglitazona/farmacologia , Estresse Oxidativo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Dexametasona/farmacologia , Dexametasona/uso terapêutico
16.
Artigo em Inglês | MEDLINE | ID: mdl-38460447

RESUMO

Human serum albumin (HSA) is known to undergo modifications by glucose during diabetes. This process produces glycated HSA that can have altered binding to some drugs. In this study, high-performance affinity microcolumns and competition studies were used to see how glycation affects the binding by two thiazolidinedione-class drugs (i.e., pioglitazone and rosiglitazone) at specific regions of HSA. These regions included Sudlow sites I and II, the tamoxifen and digitoxin sites, and a drug-binding site located in subdomain IB. At Sudlow site II, the association equilibrium constants (or binding constants) for pioglitazone and rosiglitazone with normal HSA were 1.7 × 105 M-1 and 2.0 × 105 M-1 at pH 7.4 and 37 °C, with values that changed by up to 5.7-fold for glycated HSA. Sudlow site I of normal HSA had binding constants for pioglitazone and rosiglitazone of 3.4 × 105 M-1 and 4.6 × 105 M-1, with these values changing by up to 1.5-fold for glycated HSA. Rosiglitazone was found to also bind a second region that had a positive allosteric effect on Sudlow site I for all the tested preparations of HSA (binding affinity, 1.1-3.2 × 105 M-1; coupling constant for Sudlow site I, 1.20-1.34). Both drugs had a strong positive allosteric effect on the tamoxifen site of HSA (coupling constants, 13.7-19.9 for pioglitazone and 3.7-11.5 for rosiglitazone). Rosiglitazone also had weak interactions at a site in subdomain IB, with a binding constant of 1.4 × 103 M-1 for normal HSA and a value that was altered by up to 6.8-fold with glycated HSA. Neither of the tested drugs had any significant binding at the digitoxin site. The results were used to produce affinity maps that described binding by these thiazolidinediones with HSA and the effects of glycation on these interactions during diabetes.


Assuntos
Diabetes Mellitus , Albumina Sérica Humana , Humanos , Albumina Sérica Humana/química , Hipoglicemiantes/química , Reação de Maillard , Rosiglitazona , Pioglitazona , Ligação Proteica , Albumina Sérica/química , Tamoxifeno , Digitoxina , Cromatografia de Afinidade/métodos , Sítios de Ligação
17.
Eur J Med Chem ; 269: 116279, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38460271

RESUMO

In the current study, two series of novel thiazolidin-4-one benzenesulfonamide arylidene hybrids 9a-l and 10a-f were designed, synthesized and tested in vitro for their PPARÉ£ agonistic activity. The phenethyl thiazolidin-4-one sulphonamide 9l showed the highest PPARÉ£ activation % by 41.7%. Whereas, the 3-methoxy- and 4-methyl-4-benzyloxy thiazolidin-4-one sulphonamides 9i, and 9k revealed moderate PPARÉ£ activation % of 31.7, and 32.8%, respectively, in addition, the 3-methoxy-3-benzyloxy thiazolidin-4-one sulphonamide 10d showed PPARÉ£ activation % of 33.7% compared to pioglitazone. Compounds 9b, 9i, 9k, 9l, and 10d revealed higher selectivity to PPARÉ£ over the PPARδ, and PPARα isoforms. An immunohistochemical study was performed in HepG-2 cells to confirm the PPARÉ£ protein expression for the most active compounds. Compounds 9i, 9k, and 10d showed higher PPARÉ£ expression than that of pioglitazone. Pharmacological studies were also performed to determine the anti-diabetic activity in rats at a dose of 36 mg/kg, and it was revealed that compounds 9i and 10d improved insulin secretion as well as anti-diabetic effects. The 3-methoxy-4-benzyloxy thiazolidin-4-one sulphonamide 9i showed a better anti-diabetic activity than pioglitazone. Moreover, it showed a rise in blood insulin by 4-folds and C-peptide levels by 48.8%, as well as improved insulin sensitivity. Moreover, compound 9i improved diabetic complications as evidenced by decreasing liver serum enzymes, restoration of total protein and kidney functions. Besides, it combated oxidative stress status and exerted anti-hyperlipidemic effect. Compound 9i showed a superior activity by normalizing some parameters and amelioration of pancreatic, hepatic, and renal histopathological alterations caused by STZ-induction of diabetes. Molecular docking studies, molecular dynamic simulations, and protein ligand interaction analysis were also performed for the newly synthesized compounds to investigate their predicted binding pattern and energies in PPARÉ£ binding site.


Assuntos
Benzenossulfonamidas , Diabetes Mellitus Tipo 2 , Ratos , Animais , Pioglitazona/farmacologia , PPAR gama/metabolismo , Simulação de Acoplamento Molecular , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia
18.
Braz J Med Biol Res ; 57: e13235, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38511769

RESUMO

The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1ß, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.


Assuntos
Lesão Pulmonar Aguda , Sepse , Camundongos , Animais , Pioglitazona , Regulação para Cima , PPAR gama/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Sepse/complicações , Lipopolissacarídeos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
19.
Diabetes Obes Metab ; 26(6): 2188-2198, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38425186

RESUMO

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.


Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Glucosídeos , Hemoglobinas Glicadas , Hipoglicemiantes , Metformina , Pioglitazona , Humanos , Glucosídeos/uso terapêutico , Glucosídeos/efeitos adversos , Glucosídeos/administração & dosagem , Pioglitazona/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Metformina/uso terapêutico , Metformina/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Método Duplo-Cego , Masculino , Feminino , Pessoa de Meia-Idade , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Resultado do Tratamento , Tiazolidinedionas/uso terapêutico , Tiazolidinedionas/efeitos adversos , Idoso , Resistência à Insulina , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Circunferência da Cintura/efeitos dos fármacos , República da Coreia , Adulto
20.
Metabolomics ; 20(2): 24, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38393619

RESUMO

INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Tiazolidinedionas , Humanos , Rosiglitazona/uso terapêutico , Pioglitazona , Miócitos Cardíacos , Cardiotoxicidade/complicações , Cardiotoxicidade/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Metabolômica , Tiazolidinedionas/toxicidade , Insuficiência Cardíaca/induzido quimicamente , Aminoácidos , Biomarcadores , Carnitina , Valina
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