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1.
Sci Rep ; 12(1): 13220, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918386

RESUMO

Imeglimin is a new anti-diabetic drug commercialized in Japan (Twymeeg®) and has been drawing much attention in diabetes research area as well as in clinical practice. In this study, we evaluated the effect of imeglimin on pancreatic ß-cells. First, single-dose administration of imeglimin enhanced insulin secretion from ß-cells and decreased blood glucose levels in type 2 diabetic db/db mice. In addition, single-dose administration of imeglimin significantly augmented insulin secretion in response to glucose from islets isolated from non-diabetic db/m mice. Second, during an oral glucose tolerance test 4-week chronic treatment with imeglimin enhanced insulin secretion and ameliorated glycemic control in diabetic db/db mice. Furthermore, the examination with electron microscope image showed that imeglimin exerted favorable effects on morphology in ß-cell mitochondria and substantially increased the number of insulin granules in type 2 diabetic db/db and KK-Ay mice. Finally, imeglimin reduced the percentage of apoptotic ß-cell death which was accompanied by reduced expression levels of various genes related to apoptosis and inflammation in ß-cells. Taken together, imeglimin directly enhances insulin secretion in response to glucose from ß-cells, increases the number of insulin granules, exerts favorable effects on morphology in ß-cell mitochondria, and reduces apoptotic ß-cell death in type 2 diabetic mice, which finally leads to amelioration of glycemic control.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Mitocôndrias/metabolismo , Triazinas
2.
Front Endocrinol (Lausanne) ; 13: 881256, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909530

RESUMO

As mitochondrial metabolism is a major determinant of ß-cell insulin secretion, mitochondrial dysfunction underlies ß-cell failure and type 2 diabetes mellitus progression. An algal polysaccharide of Laminaria japonica, sulfated fucogalactan (SFG) displays various pharmacological effects in a variety of conditions, including metabolic disease. We investigated the protective effects of SFG against hydrogen peroxide (H2O2)-induced ß-cell failure in MIN6 cells and islets. SFG significantly promoted the H2O2-inhibited proliferation in the cells and ameliorated their senescence, and potentiated ß-cell function by regulating ß-cell identity and the insulin exocytosis-related genes and proteins in H2O2-induced ß-cells. SFG also attenuated mitochondrial dysfunction, including alterations in ATP content, mitochondrial respiratory chain genes and proteins expression, and reactive oxygen species and superoxide dismutase levels. Furthermore, SFG resulted in SIRT1-PGC1-α pathway activation and upregulated the downstream Nrf2 and Tfam. Taken together, the results show that SFG attenuates H2O2-induced ß-cell failure by improving mitochondrial function via SIRT1-PGC1-α signaling pathway activation. Therefore, SFG is implicated as a potential agent for treating pancreatic ß-cell failure.


Assuntos
Diabetes Mellitus Tipo 2 , Laminaria , Animais , Diabetes Mellitus Tipo 2/metabolismo , Galactanos , Humanos , Peróxido de Hidrogênio/farmacologia , Laminaria/metabolismo , Camundongos , Mitocôndrias/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Sulfatos/metabolismo , Sulfatos/farmacologia
3.
Front Endocrinol (Lausanne) ; 13: 930919, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909524

RESUMO

Autophagy is a cellular process involved in the selective degradation and recycling of dysfunctional intracellular components. It plays a crucial role in maintaining cellular homeostasis and survival by removing damaged and harmful proteins, lipids, and organelles. SIRT1, an NAD+-dependent multifunctional enzyme, is a key regulator of the autophagy process. Through its deacetylase activity, SIRT1 participates in the regulation of different steps of autophagy, from initiation to degradation. The levels and function of SIRT1 are also regulated by the autophagy process. Dysregulation in SIRT1-mediated autophagy hinders the proper functioning of the endocrine system, contributing to the onset and progression of endocrine disorders. This review provides an overview of the crosstalk between SIRT1 and autophagy and their implications in obesity, type-2 diabetes mellitus, diabetic cardiomyopathy, and hepatic steatosis.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Autofagia/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/metabolismo , Humanos , Obesidade/metabolismo , Sirtuína 1/metabolismo
4.
Front Endocrinol (Lausanne) ; 13: 873699, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909571

RESUMO

Chronic low-grade inflammation in adipose tissue (AT) is a hallmark of obesity and contributes to various metabolic disorders, such as type 2 diabetes and cardiovascular diseases. Inflammation in ATs is characterized by macrophage infiltration and the activation of inflammatory pathways mediated by NF-κB, JNK, and NLRP3 inflammasomes. Adipokines, hepatokines and myokines - proteins secreted from AT, the liver and skeletal muscle play regulatory roles in AT inflammation via endocrine, paracrine, and autocrine pathways. For example, obesity is associated with elevated levels of pro-inflammatory adipokines (e.g., leptin, resistin, chemerin, progranulin, RBP4, WISP1, FABP4, PAI-1, Follistatin-like1, MCP-1, SPARC, SPARCL1, and SAA) and reduced levels of anti-inflammatory adipokines such as adiponectin, omentin, ZAG, SFRP5, CTRP3, vaspin, and IL-10. Moreover, some hepatokines (Fetuin A, DPP4, FGF21, GDF15, and MANF) and myokines (irisin, IL-6, and DEL-1) also play pro- or anti-inflammatory roles in AT inflammation. This review aims to provide an updated understanding of these organokines and their role in AT inflammation and related metabolic abnormalities. It serves to highlight the molecular mechanisms underlying the effects of these organokines and their clinical significance. Insights into the roles and mechanisms of these organokines could provide novel and potential therapeutic targets for obesity-induced inflammation.


Assuntos
Adipocinas , Tecido Adiposo , Inflamação , Obesidade , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo
5.
Nutr Diabetes ; 12(1): 35, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931683

RESUMO

Branched-chain amino acid (BCAA) catabolism has been considered to have an emerging role in the pathogenesis of metabolic disturbances in obesity and type 2 diabetes (T2D). Several studies showed elevated plasma BCAA levels in humans with insulin resistance and patients with T2D, although the underlying reason is unknown. Dysfunctional BCAA catabolism could theoretically be an underlying factor. In vitro and animal work collectively show that modulation of the BCAA catabolic pathway alters key metabolic processes affecting glucose homeostasis, although an integrated understanding of tissue-specific BCAA catabolism remains largely unknown, especially in humans. Proof-of-concept studies in rodents -and to a lesser extent in humans - strongly suggest that enhancing BCAA catabolism improves glucose homeostasis in metabolic disorders, such as obesity and T2D. In this review, we discuss several hypothesized mechanistic links between BCAA catabolism and insulin resistance and overview current available tools to modulate BCAA catabolism in vivo. Furthermore, this review considers whether enhancing BCAA catabolism forms a potential future treatment strategy to promote metabolic health in insulin resistance and T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Aminoácidos de Cadeia Ramificada , Animais , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Humanos , Obesidade/metabolismo
6.
Oxid Med Cell Longev ; 2022: 8255550, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936218

RESUMO

Type 2 diabetes mellitus (T2DM) is a metabolic disease with increasing prevalence and mortality year by year. The purpose of this study was to explore new therapeutic targets and candidate drugs for multitargets by single-cell RNA expression profile analysis, network pharmacology, and molecular docking. Single-cell RNA expression profiling of islet ß cell samples between T2DM patients and nondiabetic controls was conducted to identify important subpopulations and the marker genes. The potential therapeutic targets of T2DM were identified by the overlap analysis of insulin-related genes and diabetes-related genes, the construction of protein-protein interaction network, and the molecular complex detection (MCODE) algorithm. The network distance method was employed to determine the potential drugs of the target. Molecular docking and molecular dynamic simulations were carried out using AutoDock Vina and Gromacs2019, respectively. Eleven cell clusters were identified by single-cell RNA sequencing (scRNA-seq) data, and three of them (C2, C8, and C10) showed significant differences between T2DM samples and normal samples. Eight genes from differential cell clusters were found from differential cell clusters to be associated with insulin activity and T2DM. The MCODE algorithm built six key subnetworks, with five of them correlating with inflammatory pathways and immune cell infiltration. Importantly, CCR5 was a gene within the key subnetworks and was differentially expressed between normal samples and T2DM samples, with the highest area under the ROC curve (AUC) of 82.5% for the diagnosis model. A total of 49 CCR5-related genes were screened, and DB05494 was identified as the most potential drug with the shortest distance to CCR5-related genes. Molecular docking illustrated that DB05494 stably bound with CCR5 (-8.0 kcal/mol) through multiple hydrogen bonds (LYS26, TYR37, TYR89, CYS178, and GLN280) and hydrophobic bonds (TRP86, PHE112, ILE198, TRP248, and TYR251). This study identified CCR5 as a potential therapeutic target and screened DB05494 as a potential drug for T2DM treatment.


Assuntos
Diabetes Mellitus Tipo 2 , Insulinas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulinas/uso terapêutico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , RNA
7.
Biomater Adv ; 136: 212793, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35929325

RESUMO

Chronic nonhealing wounds are one of the most common and serious complications of diabetes, which can lead to disability of patients. Adipose-derived stem cells (ADSCs) have emerged as a promising tool for skin wound healing, but the therapeutic potential depends considerably on the cell delivery system. Small intestinal submucosa (SIS) is an extracellular matrix-based membranous scaffold with outstanding repair potential for skin wounds. In this study, we first fabricated a bioactive wound dressing, termed the SIS+ADSCs composite, by using human ADSCs as the seed cell and porcine SIS as the cell delivery vehicle. Then, we systematically investigated, for the first time, the healing potential of this wound dressing in a rat model of type 2 diabetes. In vitro studies revealed that SIS provided a favorable microenvironment for ADSCs and significantly promoted the expression of growth factors critical for chronic wound healing. After implantation in the full-thickness skin wounds of diabetic rats, the SIS+ADSCs composite showed a higher wound healing rate and wound healing quality than those in the PBS, ADSCs, and SIS groups. Along with the ability to modulate the polarization of macrophages in vivo, the SIS+ADSCs composite was potent at promoting wound angiogenesis, reepithelialization, and skin appendage regeneration. Taken together, these results indicate that the SIS+ADSCs composite has good therapeutic potential and high translational value for diabetic wound treatment.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Bandagens , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Ratos , Células-Tronco/metabolismo , Suínos , Cicatrização
8.
Front Endocrinol (Lausanne) ; 13: 955070, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937828

RESUMO

Diurnal oscillation persists throughout the body and plays an essential role in maintaining physiological homeostasis. Disruption of diurnal rhythm contributes to many diseases including type 2 diabetes. The regulatory mechanism of the transcription-translation feedback loop (TTFL) of core clock genes is well-established, while a systematic study across all regulatory layers of gene expression, including gene transcription, RNA translation, and DNA binding protein (DBP) activities, is still lacking. We comprehensively bioinformatics analyzed the rhythmicity of gene transcription, mature RNA abundance, protein abundance and DBP activity using publicly available omic-datasets from mouse livers. We found that the core clock genes, Bmal1 and Rev-erbα, persistently retained rhythmicity in all stages, which supported the essential rhythmic function along with the TTFL. Interestingly, there were many layer-specific rhythmic genes playing layer-specific rhythmic functions. The systematic analysis of gene transcription rate, RNA translation efficiency, and post-translation modification of DBP were incorporated to determine the potential mechanisms for layer-specific rhythmic genes. We observed the gene with rhythmic expression in both mature RNA and protein layers were largely due to relatively consistent translation rate. In addition, rhythmic translation rate induced the rhythms of protein whose mature RNA levels were not rhythmic. Further analysis revealed a phosphorylation-mediated and an enhancer RNA-mediated cycling regulation between the corresponding layers. This study presents a global view of the oscillating genes in multiple layers via a systematical analysis and indicates the complexity of regulatory mechanisms across different layers for further functional study.


Assuntos
Diabetes Mellitus Tipo 2 , Animais , Ritmo Circadiano/genética , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/metabolismo , Expressão Gênica , Fígado/metabolismo , Camundongos , RNA
9.
Methods Mol Biol ; 2538: 165-188, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35951300

RESUMO

Amyloid aggregation is linked to a number of human disorders that range from non-neurological illnesses such as type 2 diabetes to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The formation of insoluble protein aggregates with amyloid conformation inside bacteria, namely, in bacterial inclusion bodies, offers the possibility to use bacteria as simple models to study amyloid aggregation processes and potential effects of both anti-amyloid drugs and/or pro-aggregative compounds. This chapter describes fast, simple, inexpensive, highly reproducible, and tunable in vitro and in cellulo methods that use bacterial inclusion bodies as preliminary screening tools for anti-amyloid drugs.


Assuntos
Amiloidose , Diabetes Mellitus Tipo 2 , Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Amiloidose/metabolismo , Bactérias/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Corpos de Inclusão/metabolismo
10.
Cells ; 11(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35954211

RESUMO

Osteoarthritis (OA) is a degenerative joint disease resulting in limited mobility and severe disability. Type II diabetes mellitus (T2D) is a weight-independent risk factor for OA, but a link between the two diseases has not been elucidated. Adipose stem cells (ASCs) isolated from the infrapatellar fat pad (IPFP) may be a viable regenerative cell for OA treatment. This study analyzed the expression profiles of inflammatory and adipokine-related genes in IPFP-ASCs of non-diabetic (Non-T2D), pre-diabetic (Pre-T2D), and T2D donors. Pre-T2D ASCs exhibited a substantial decrease in levels of mesenchymal markers CD90 and CD105 with no change in adipogenic differentiation compared to Non-T2D and T2D IPFP-ASCs. In addition, Cyclooxygenase-2 (COX-2), Forkhead box G1 (FOXG1) expression and prostaglandin E2 (PGE2) secretion were significantly increased in Pre-T2D IPFP-ASCs upon stimulation by interleukin-1 beta (IL-1ß). Interestingly, M1 macrophages exhibited a significant reduction in expression of pro-inflammatory markers TNFα and IL-6 when co-cultured with Pre-T2D IPFP-ASCs. These data suggest that the heightened systemic inflammation associated with untreated T2D may prime the IPFP-ASCs to exhibit enhanced anti-inflammatory characteristics via suppressing the IL-6/COX-2 signaling pathway. In addition, the elevated production of PGE2 by the Pre-T2D IPFP-ASCs may also suggest the contribution of pre-diabetic conditions to the onset and progression of OA.


Assuntos
Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Tecido Adiposo/metabolismo , Biomarcadores/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dinoprostona/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-6/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco
11.
Cells ; 11(15)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35954247

RESUMO

Advanced glycation end products (AGEs) and the cognate receptor, named RAGE, are involved in metabolic disorders characterized by hyperglycemia, type 2 diabetes mellitus (T2DM) and obesity. Moreover, the AGEs/RAGE transduction pathway prompts a dysfunctional interaction between breast cancer cells and tumor stroma toward the acquisition of malignant features. However, the action of the AGEs/RAGE axis in the main players of the tumor microenvironment, named breast cancer-associated fibroblasts (CAFs), remains to be fully explored. In the present study, by chemokine array, we first assessed that interleukin-8 (IL-8) is the most up-regulated pro-inflammatory chemokine upon AGEs/RAGE activation in primary CAFs, obtained from breast tumors. Thereafter, we ascertained that the AGEs/RAGE signaling promotes a network cascade in CAFs, leading to the c-Fos-dependent regulation of IL-8. Next, using a conditioned medium from AGEs-exposed CAFs, we determined that IL-8/CXCR1/2 paracrine activation induces the acquisition of migratory and invasive features in MDA-MB-231 breast cancer cells. Altogether, our data provide new insights on the involvement of IL-8 in the AGEs/RAGE transduction pathway among the intricate connections linking breast cancer cells to the surrounding stroma. Hence, our findings may pave the way for further investigations to define the role of IL-8 as useful target for the better management of breast cancer patients exhibiting metabolic disorders.


Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Diabetes Mellitus Tipo 2 , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Interleucina-8/metabolismo , Transdução de Sinais , Microambiente Tumoral
12.
Cells ; 11(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35954309

RESUMO

Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human ß-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human ß-cell stress induced by pro-inflammatory cytokines (which mediate ß-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1ß plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human ß-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for ß-cell protection in other types of diabetes, possibly including early T1D.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Metformina , Caspase 3/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glucose/toxicidade , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Metformina/farmacologia
13.
Int J Mol Sci ; 23(15)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35955482

RESUMO

The interaction between the mitochondria and the endoplasmic reticulum (ER) is essential for hepatocyte function. An increase in ER-mitochondria contacts (ERMCs) is associated with various metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and its progressive form non-alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. However, the role of ERMCs in the progression of NAFL to NASH is still unclear. We assessed whether ERMCs could correlate with NAFLD severity. We used a proximity ligation assay to measure the abundance of ERMCs in liver biopsies from patients with biopsy-proven NAFLD (n = 48) and correlated the results with histological and metabolic syndrome (MetS) features. NAFLD patients were included according to inclusion and exclusion criteria, and then assigned to NAFL (n = 9) and NASH (n = 39) groups. ERMCs density could discriminate NASH from NAFL (sensitivity 61.5%, specificity 100%). ERMCs abundance correlated with hepatocellular ballooning. Moreover, the density of ERMCs increased with an increase in the number of MetS features. In conclusion, ERMCs increased from NAFL to NASH, in parallel with the number of MetS features, supporting a role for this interaction in the pathophysiology of NASH.


Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Síndrome Metabólica/metabolismo , Mitocôndrias/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo
14.
Int J Mol Sci ; 23(15)2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35955709

RESUMO

High doses of ionizing radiation can cause cardiovascular diseases (CVDs); however, the effects of <100 mGy radiation on CVD remain underreported. Endothelial cells (ECs) play major roles in cardiovascular health and disease, and their function is reduced by stimuli such as chronic disease, metabolic disorders, and smoking. However, whether exposure to low-dose radiation results in the disruption of similar molecular mechanisms in ECs under diabetic and non-diabetic states remains largely unknown; we aimed to address this gap in knowledge through the molecular and functional characterization of primary human aortic endothelial cells (HAECs) derived from patients with type 2 diabetes (T2D-HAECs) and normal HAECs in response to low-dose radiation. To address these limitations, we performed RNA sequencing on HAECs and T2D-HAECs following exposure to 100 mGy of ionizing radiation and examined the transcriptome changes associated with the low-dose radiation. Compared with that in the non-irradiation group, low-dose irradiation induced 243 differentially expressed genes (DEGs) (133 down-regulated and 110 up-regulated) in HAECs and 378 DEGs (195 down-regulated and 183 up-regulated) in T2D-HAECs. We also discovered a significant association between the DEGs and the interferon (IFN)-I signaling pathway, which is associated with CVD by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein network analysis, and module analysis. Our findings demonstrate the potential impact of low-dose radiation on EC functions that are related to the risk of CVD.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Aorta/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Perfilação da Expressão Gênica , Humanos , Transcriptoma
15.
Int J Mol Sci ; 23(15)2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35955784

RESUMO

Despite the constant improvement of therapeutical options, heart failure (HF) remains associated with high mortality and morbidity. While new developments in guideline-recommended therapies can prolong survival and postpone HF hospitalizations, impaired exercise capacity remains one of the most debilitating symptoms of HF. Exercise intolerance in HF is multifactorial in origin, as the underlying cardiovascular pathology and reactive changes in skeletal muscle composition and metabolism both contribute. Recently, sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly. Whilst much effort has been devoted to untangling the mechanisms responsible for these cardiovascular benefits of SGLT2 inhibitors, little is known about the effect of SGLT2 inhibitors on exercise performance in HF. This review provides an overview of the pathophysiological mechanisms that are responsible for exercise intolerance in HF, elaborates on the potential SGLT2-inhibitor-mediated effects on these phenomena, and provides an up-to-date overview of existing studies on the effect of SGLT2 inhibitors on clinical outcome parameters that are relevant to the assessment of exercise capacity. Finally, current gaps in the evidence and potential future perspectives on the effects of SGLT2 inhibitors on exercise intolerance in chronic HF are discussed.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Doença Crônica , Diabetes Mellitus Tipo 2/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Músculo Esquelético/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
16.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955910

RESUMO

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). Studies have also shown that canagliflozin directly acts on endothelial cells (ECs). Since heme oxygenase-1 (HO-1) is an established modulator of EC function, we investigated if canagliflozin regulates the endothelial expression of HO-1, and if this enzyme influences the biological actions of canagliflozin in these cells. Treatment of human ECs with canagliflozin stimulated a concentration- and time-dependent increase in HO-1 that was associated with a significant increase in HO activity. Canagliflozin also evoked a concentration-dependent blockade of EC proliferation, DNA synthesis, and migration that was unaffected by inhibition of HO-1 activity and/or expression. Exposure of ECs to a diabetic environment increased the adhesion of monocytes to ECs, and this was attenuated by canagliflozin. Knockdown of HO-1 reduced the anti-inflammatory effect of canagliflozin which was restored by bilirubin but not carbon monoxide. In conclusion, this study identified canagliflozin as a novel inducer of HO-1 in human ECs. It also found that HO-1-derived bilirubin contributed to the anti-inflammatory action of canagliflozin, but not the anti-proliferative and antimigratory effects of the drug. The ability of canagliflozin to regulate HO-1 expression and EC function may contribute to the clinical profile of the drug.


Assuntos
Diabetes Mellitus Tipo 2 , Heme Oxigenase-1 , Bilirrubina/metabolismo , Canagliflozina/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo
17.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955916

RESUMO

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia, IH), and it is a risk factor for cardiovascular disease (CVD) and insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes to experimental IH or normoxia for 24 h to analyze the mRNA expression of the components of Cd38-cyclic ADP-ribose (cADPR) signaling. We found that the mRNA levels of cluster of differentiation 38 (Cd38), type 2 ryanodine receptor (Ryr2), and FK506-binding protein 12.6 (Fkbp12.6) in H9c2 and P19.CL6 cardiomyocytes were significantly decreased by IH, whereas the promoter activities of these genes were not decreased. By contrast, the expression of phosphatase and tensin homolog deleted from chromosome 10 (Pten) was upregulated in IH-treated cells. The small interfering RNA for Pten (siPten) and a non-specific control RNA were introduced into the H9c2 cells. The IH-induced downregulation of Cd38, Ryr2, and Fkbp12.6 was abolished by the introduction of the siPten, but not by the control RNA. These results indicate that IH stress upregulated the Pten in cardiomyocytes, resulting in the decreased mRNA levels of Cd38, Ryr2, and Fkbp12.6, leading to the inhibition of cardiomyocyte functions in SAS patients.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , ADP-Ribosil Ciclase/genética , ADP-Ribosil Ciclase 1 , Animais , Sinalização do Cálcio , Doenças Cardiovasculares/metabolismo , ADP-Ribose Cíclica/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulação para Baixo , Hipóxia/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Regulação para Cima
18.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955920

RESUMO

BACKGROUND: We report that myocardial insulin resistance (mIR) occurs in around 60% of patients with type 2 diabetes (T2D) and was associated with higher cardiovascular risk in comparison with patients with insulin-sensitive myocardium (mIS). These two phenotypes (mIR vs. mIS) can only be assessed using time-consuming and expensive methods. The aim of the present study is to search a simple and reliable surrogate to identify both phenotypes. METHODS: Forty-seven patients with T2D underwent myocardial [18F]FDG PET/CT at baseline and after a hyperinsulinemic-euglycemic clamp (HEC) to determine mIR were prospectively recruited. Biochemical assessments were performed before and after the HEC. Baseline hepatic steatosis index and index of hepatic fibrosis (FIB-4) were calculated. Furthermore, liver stiffness measurement was performed using transient elastography. RESULTS: The best model to predict the presence of mIR was the combination of transaminases, protein levels, FIB-4 score and HOMA (AUC = 0.95; sensibility: 0.81; specificity: 0.95). We observed significantly higher levels of fibrosis in patients with mIR than in those with mIS (p = 0.034). In addition, we found that patients with mIR presented a reduced glucose uptake by the liver in comparison with patients with mIS. CONCLUSIONS: The combination of HOMA, protein, transaminases and FIB-4 is a simple and reliable tool for identifying mIR in patients with T2D. This information will be useful to improve the stratification of cardiovascular risk in T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/metabolismo , Fibrose , Humanos , Fígado/metabolismo , Miocárdio/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Transaminases/metabolismo
19.
Stem Cell Res Ther ; 13(1): 395, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35922870

RESUMO

BACKGROUND: In diabetes, delayed wound healing was considered as the result of excessive recruitment and retention of pro-inflammatory cells and factors. Hematopoietic prostaglandin D synthase (HPGDS) was identified from differently expressed genes of diabetic human foot skin. HPGDS is responsible for the production of prostaglandin D2 (PGD2), an inflammatory mediator. Therefore, we aim to explore whether HPGDS could be a therapeutic target in the diabetic wound (DW). METHOD: In this study, we compared gene expression profilings of diabetic human foot skin and non-diabetic human foot skin from the Gene Expression Omnibus database. We detected the characteristics of immune components in diabetic mice wound and investigated the role and underlying mechanism of the differently expressed Hpgds for the diabetic wound healing. For in vivo studies, we engineered ADSC to overexpress Hpgds (ADSCHpgds) and evaluated its effects on diabetic wound healing using a full-thickness skin wound model. For in vitro studies, we evaluated the role of ADSCHpgds conditioned medium and PGD2 on Lipopolysaccharide (LPS) induced macrophage. RESULTS: Hpgds was significantly down-regulated in type 2 diabetic mice wound and its deficiency delayed normal wound healing. ADSCHpgds accelerated DW healing by reducing neutrophil and CD8T cell recruitment, promoting M2 macrophage polarization and increasing the production of growth factors. ADSCHpgds conditioned medium showed superior capability in promoting M2 macrophage transition than conditioned medium derived from ADSC alone. CONCLUSION: Our results demonstrated that Hpgds is required for wound healing, and ADSCHpgds could accelerate DW healing by improving anti-inflammatory state and normalizing the proliferation phase of wound healing in mice. These findings provide a new insight in the therapeutic strategy of diabetic wound.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Células-Tronco Mesenquimais , Animais , Meios de Cultivo Condicionados/farmacologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Humanos , Oxirredutases Intramoleculares/metabolismo , Camundongos , Prostaglandina D2/metabolismo , Prostaglandina D2/farmacologia , Células-Tronco/metabolismo , Cicatrização/genética
20.
Cell Rep ; 40(6): 111170, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35947949

RESUMO

The glucagon-like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential in type 2 diabetes (T2D) treatment, notably by improving ß cell functions. The cell-cycle regulator and transcription factor E2f1 is involved in glucose homeostasis by modulating ß cell mass and function. Here, we report that ß cell-specific genetic ablation of E2f1 (E2f1ß-/-) impairs glucose homeostasis associated with decreased expression of the Glp-1 receptor (Glp1r) in E2f1ß-/- pancreatic islets. Pharmacological inhibition of E2F1 transcriptional activity in nondiabetic human islets decreases GLP1R levels and blunts the incretin effect of GLP1R agonist exendin-4 (ex-4) on insulin secretion. Overexpressing E2f1 in pancreatic ß cells increases Glp1r expression associated with enhanced insulin secretion mediated by ex-4. Interestingly, ex-4 induces retinoblastoma protein (pRb) phosphorylation and E2f1 transcriptional activity. Our findings reveal critical roles for E2f1 in ß cell function and suggest molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Diabetes Mellitus Tipo 2/metabolismo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo
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