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2.
Front Endocrinol (Lausanne) ; 13: 801260, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35242109

RESUMO

Type 2 diabetes (T2D) patients with SARS-CoV-2 infection hospitalized develop an acute cardiovascular syndrome. It is urgent to elucidate underlying mechanisms associated with the acute cardiac injury in T2D hearts. We performed bioinformatic analysis on the expression profiles of public datasets to identify the pathogenic and prognostic genes in T2D hearts. Cardiac RNA-sequencing datasets from db/db or BKS mice (GSE161931) were updated to NCBI-Gene Expression Omnibus (NCBI-GEO), and used for the transcriptomics analyses with public datasets from NCBI-GEO of autopsy heart specimens with COVID-19 (5/6 with T2D, GSE150316), or dead healthy persons (GSE133054). Differentially expressed genes (DEGs) and overlapping homologous DEGs among the three datasets were identified using DESeq2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were conducted for event enrichment through clusterProfile. The protein-protein interaction (PPI) network of DEGs was established and visualized by Cytoscape. The transcriptions and functions of crucial genes were further validated in db/db hearts. In total, 542 up-regulated and 485 down-regulated DEGs in mice, and 811 up-regulated and 1399 down-regulated DEGs in human were identified, respectively. There were 74 overlapping homologous DEGs among all datasets. Mitochondria inner membrane and serine-type endopeptidase activity were further identified as the top-10 GO events for overlapping DEGs. Cardiac CAPNS1 (calpain small subunit 1) was the unique crucial gene shared by both enriched events. Its transcriptional level significantly increased in T2D mice, but surprisingly decreased in T2D patients with SARS-CoV-2 infection. PPI network was constructed with 30 interactions in overlapping DEGs, including CAPNS1. The substrates Junctophilin2 (Jp2), Tnni3, and Mybpc3 in cardiac calpain/CAPNS1 pathway showed less transcriptional change, although Capns1 increased in transcription in db/db mice. Instead, cytoplasmic JP2 significantly reduced and its hydrolyzed product JP2NT exhibited nuclear translocation in myocardium. This study suggests CAPNS1 is a crucial gene in T2D hearts. Its transcriptional upregulation leads to calpain/CAPNS1-associated JP2 hydrolysis and JP2NT nuclear translocation. Therefore, attenuated cardiac CAPNS1 transcription in T2D patients with SARS-CoV-2 infection highlights a novel target in adverse prognostics and comprehensive therapy. CAPNS1 can also be explored for the molecular signaling involving the onset, progression and prognostic in T2D patients with SARS-CoV-2 infection.


Assuntos
COVID-19/epidemiologia , Biologia Computacional , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Cardiomiopatias Diabéticas/epidemiologia , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Calpaína/genética , Calpaína/fisiologia , Comorbidade , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/fisiopatologia , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/ultraestrutura , Proteínas Musculares/metabolismo , Miocárdio/química , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Prognóstico , Análise de Sequência de RNA , Transcriptoma
3.
Med Sci Monit ; 28: e935615, 2022 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35306503

RESUMO

BACKGROUND It is well established that primary aldosteronism (PA) and aldosterone-to-renin ratio (ARR) are associated with kidney disease. The aim of this study was to retrospectively investigate the relationship between ARR, urinary albumin excretion (UAE), and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes from a single center. MATERIAL AND METHODS We included 70 patients with type 2 diabetes, UAE ≤100 mg/day, not taking renin-aldosterone system inhibitors, did not meet the diagnostic criteria for PA, and had an ARR <20. The patients were divided into 3 groups: the normal low (NL) group (33 patients) with a UAE <10 mg/day, the normal (N) group (22 patients) with a UAE of 10-29 mg/day, and the microalbuminuria (M) group (15 patients) with a UAE of 30-100 mg/day. The ARR, plasma renin activity (PRA), and plasma aldosterone (PAC) were compared among groups. RESULTS The ARR was highest in group M (10.1±4.6), 6.5±0.3 in group NL, and 7.0±2.7 in group N. The PRA and PAC were significantly lower in group M (P<0.001). The ARR showed a significant positive correlation with log UAE (r=0.37, P<0.001) and a significant negative correlation with eGFR (r=-0.33, P<0.01). CONCLUSIONS High levels of aldosterone relative to renin, which did not fulfill confirmatory criteria for PA, may be one of the risk factors for the development of diabetic nephropathy in patients with diabetes. The present results are supported by previous research showing that an increased ARR without PA was a risk factor for kidney disease.


Assuntos
Aldosterona/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Renina/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
Rev Cardiovasc Med ; 23(2): 73, 2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35229564

RESUMO

Endothelial activation and dysfunction is an important contributor to atherosclerosis, cardiovascular diseases and cardiorenal syndrome. Endothelial dysfunction is also linked with metabolic syndrome and type II diabetes. The search for specific and sensitive biomarkers of endothelial activation and dysfunction may have important clinical implications. This review pinpoints the differences in biomarkers between endothelial activation and endothelial dysfunction in cardiovascular diseases, and then briefly describes the most relevant biomarkers of endothelial activation. Biomarkers of endothelial activation include endothelial adhesion molecules, cytokines, C-reactive protein, CD62E+/E-selectin activated endothelial microparticles, oxidation of low density lipoproteins, asymmetric dimethylarginine and endocan. This review also presents an update on the novel biomarkers of endothelial dysfunction, such as matrix metalloproteinases (e.g., MMP-7, MMP-9), ANGPTL2, endogdlin, annexin V+ endothelial apoptotic microparticles, and serum homocysteine. Finally, this review emphasizes the limitations of biomarkers of endothelial activation and dysfunction in clinical setting.


Assuntos
Doenças Cardiovasculares , Endotélio Vascular , /sangue , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Micropartículas Derivadas de Células/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Humanos
5.
J Biol Chem ; 298(4): 101803, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35257744

RESUMO

Hepatocyte nuclear factor 1A (HNF-1A) is a transcription factor expressed in several embryonic and adult tissues, modulating the expression of numerous target genes. Pathogenic variants in the HNF1A gene are known to cause maturity-onset diabetes of the young 3 (MODY3 or HNF1A MODY), a disease characterized by dominant inheritance, age of onset before 25 to 35 years of age, and pancreatic ß-cell dysfunction. A precise diagnosis can alter management of this disease, as insulin can be exchanged with sulfonylurea tablets and genetic counseling differs from polygenic forms of diabetes. Therefore, more knowledge on the mechanisms of HNF-1A function and the level of pathogenicity of the numerous HNF1A variants is required for precise diagnostics. Here, we structurally and biophysically characterized an HNF-1A protein containing both the DNA-binding domain and the dimerization domain, and determined the folding and DNA-binding capacity of two established MODY3 HNF-1A variant proteins (P112L, R263C) and one variant of unknown significance (N266S). All three variants showed reduced functionality compared to the WT protein. Furthermore, while the R263C and N266S variants displayed reduced binding to an HNF-1A target promoter, we found the P112L variant was unstable in vitro and in cells. Our results support and mechanistically explain disease causality for these investigated variants and present a novel approach for the dissection of structurally unstable and DNA-binding defective variants. This study indicates that structural and biochemical investigation of HNF-1A is a valuable tool in reliable variant classification needed for precision diabetes diagnostics and management.


Assuntos
Diabetes Mellitus Tipo 2 , Fator 1-alfa Nuclear de Hepatócito , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Variação Genética , Fator 1-alfa Nuclear de Hepatócito/química , Fator 1-alfa Nuclear de Hepatócito/genética , Humanos , Ligação Proteica , Domínios Proteicos
6.
J Diabetes Res ; 2022: 5126968, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35237694

RESUMO

The prevalence of diabetes mellitus (DM) is increasing at a staggering rate around the world. In the United States, more than 30.3 million Americans have DM. Type 2 diabetes mellitus (T2DM) accounts for 91.2% of diabetic cases and disproportionately affects African Americans and Hispanics. T2DM is a major risk factor for cardiovascular disease (CVD) and is the leading cause of morbidity and mortality among diabetic patients. While significant advances in T2DM treatment have been made, intensive glucose control has failed to reduce the development of macro and microvascular related deaths in this group. This highlights the need to further elucidate the underlying molecular mechanisms contributing to CVD in the setting of T2DM. Endothelial dysfunction (ED) plays an important role in the development of diabetes-induced vascular complications, including CVD and diabetic nephropathy (DN). Thus, the endothelium provides a lucrative means to investigate the molecular events involved in the development of vascular complications associated with T2DM. microRNAs (miRNA) participate in numerous cellular responses, including mediating messages in vascular homeostasis. Exosomes are small extracellular vesicles (40-160 nanometers) that are abundant in circulation and can deliver various molecules, including miRNAs, from donor to recipient cells to facilitate cell-to-cell communication. Endothelial cells are in constant contact with exosomes (and exosomal content) that can induce a functional response. This review discusses the modulatory role of exosomal miRNAs and proteins in diabetes-induced endothelial dysfunction, highlighting the significance of miRNAs as markers, mediators, and potential therapeutic interventions to ameliorate ED in this patient group.


Assuntos
Diabetes Mellitus Tipo 2/genética , Células Endoteliais/efeitos dos fármacos , MicroRNAs/análise , MicroRNAs/farmacologia , Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Células Endoteliais/metabolismo , Exossomos/efeitos dos fármacos , Exossomos/transplante , Humanos , MicroRNAs/uso terapêutico
7.
J Diabetes Res ; 2022: 9982390, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35257014

RESUMO

Background: It remains controversial whether body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), or triglyceride glucose (TyG) index has a stronger association with diabetes. The aims of the study were to compare the magnitude of associations of four indicators with diabetes risk. Methods: Data collected from annual health examination dataset in the Xinzheng during 2011 and 2019. A total of 41,242 participants aged ≥ 45 years were included in this study. Cox proportional hazard regression models were used to examine associations between the four indicators and diabetes risk. Results: After 205,770 person-years of follow up, diabetes developed in 2,472 subjects. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of diabetes (highest vs reference group) were 1.92 (1.71-2.16) for BMI, 1.99 (1.78-2.23) for WC, 1.65 (1.47-1.86) for WHtR, and 1.66 (1.47-1.87) for TyG, respectively. In addition, the risk of diabetes increased with baseline BMI (HR: 1.30; 95% CI: 1.25, 1.35) and TyG (HR: 1.25; 95% CI: 1.20, 1.30), but the lowest HR was 0.78 (95% CI 0.65-0.92) when WC was approximately 72 cm, and 0.85 (95% CI 0.72-0.99) when WHtR was approximately 0.47 in women. In joint analyses, the highest risk was observed in participants with a high BMI combined with a high WC (HR: 2.26; 95% CI: 1.98, 2.58). Conclusions: In middle-aged and elderly Chinese population, BMI and WC were more strongly associated with diabetes than WHtR or TyG, especially the combined effect of BMI and WC.


Assuntos
Índice de Massa Corporal , Diabetes Mellitus Tipo 2/fisiopatologia , Índice de Gravidade de Doença , Circunferência da Cintura/fisiologia , Razão Cintura-Estatura , Adulto , Idoso , Glicemia/análise , China/epidemiologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Triglicerídeos/análise , Triglicerídeos/sangue
8.
Int J Mol Sci ; 23(5)2022 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35269594

RESUMO

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glutationa/análogos & derivados , Hesperidina/uso terapêutico , Lactoilglutationa Liase/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Quimioterapia Combinada , Indução Enzimática/efeitos dos fármacos , Glutationa/química , Glutationa/uso terapêutico , Glicosilação/efeitos dos fármacos , Hesperidina/química , Humanos , Resistência à Insulina/fisiologia , Lactoilglutationa Liase/antagonistas & inibidores , Camundongos , Estrutura Molecular , Neoplasias Experimentais/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/fisiopatologia , Aldeído Pirúvico/química , Aldeído Pirúvico/metabolismo , Resveratrol/química
9.
J Diabetes Res ; 2022: 2391188, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35242878

RESUMO

BACKGROUND: Impaired bile acid (BA) metabolism has been associated with the progression of type 2 diabetes (T2D). However, the contribution of BAs to the pathogenesis of latent autoimmune diabetes in adults (LADA) remains unclear. This study was aimed at investigating the association of serum BAs with different diabetes types and analyzing its correlation with main clinical and laboratory parameters. METHODS: Patients with LADA, patients with T2D, and healthy controls (HCs) were enrolled. Serum BA profiles and inflammatory cytokines were measured. The correlation of BA species with different indicators was assessed by Spearman's correlation method. RESULTS: Patients with diabetes (LADA and T2D) had significantly higher serum BAs, especially conjugated BAs, compared with those in HCs. Nevertheless, serum BA profiles had no special role in the progression of LADA, because no significant differences in BAs were observed between LADA and T2D patients. Interestingly, HbA1c levels and HOMA-ß were found to be correlated with a series of BA species. Proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and anti-inflammatory cytokine (IL-10) were all positively associated with several BA species, especially the conjugated secondary BAs. CONCLUSION: Serum BAs regulate glucose homeostasis, but have no special value in the pathogenesis of LADA patients. Our study adds further information about the potential value of serum BAs in different types of diabetes.


Assuntos
Ácidos e Sais Biliares/análise , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Autoimune Latente em Adultos/etiologia , Adulto , Idoso , Análise de Variância , Ácidos e Sais Biliares/sangue , Índice de Massa Corporal , China/epidemiologia , Citocinas/análise , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Diabetes Autoimune Latente em Adultos/fisiopatologia , Masculino , Pessoa de Meia-Idade
10.
J Diabetes Res ; 2022: 9537741, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35242882

RESUMO

BACKGROUND: Several experimental studies have suggested beneficial effects of Ceriporia lacerata on glucose metabolism. However, there has been no human study assessing the effects of C. lacerata on glucose metabolism. Therefore, we investigated whether C. lacerata improves glucose control and insulin resistance in type 2 diabetes patients. METHODS: Ninety patients diagnosed with type 2 diabetes (T2DM) for more than 6 months were enrolled. Subjects were randomly divided into placebo (n = 45) or C. lacerata (n = 45) groups and then assigned to take placebo or C. lacerata capsules (500 mg/capsule) for a 12-week intervention period. Biochemical markers, including fasting glucose, 2-hour postprandial plasma glucose, and lipid profile levels, as well as insulin, c-peptide, and Hba1c, were measured. Furthermore, insulin sensitivity indices, such as HOMA-IR, HOMA-beta, and QUICKI, were assessed before and after the 12-week administration. RESULTS: Eighty-four patients completed the study. There were no significant differences in fasting, postprandial glucose, HbA1c, or lipid parameters. HOMA-IR and QUICKI indices were improved at week 12 in the C. lacerata group, especially in subjects with HOMA-IR of 1.8 or more (p < 0.05). Fasting, postprandial c-peptide, and insulin levels decreased at week 12 in the C. lacerata group (p < 0.05). These significant differences were not observed in the placebo group. CONCLUSION: Twelve-week administration of C. lacerata in T2DM patients resulted in significant improvement in insulin resistance, especially in those with lower insulin sensitivity. A larger population study with a longer follow-up period and an effort to elucidate the mechanism is warranted to further assess the effects of C. lacerata on T2DM patients.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Resistência à Insulina/fisiologia , Extratos Vegetais/farmacologia , Polyporales/metabolismo , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico
11.
FASEB J ; 36(3): e22177, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35142393

RESUMO

Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) exhibit detrimental effects. Exercise improves endothelial function in part via the secretion of exosomes into circulation. Extracellular superoxide dismutase (SOD3) is a major secretory copper (Cu) antioxidant enzyme that catalyzes the dismutation of O2 •- to H2 O2 whose activity requires the Cu transporter ATP7A. However, the role of SOD3 in exercise-induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here, we show that both SOD3 and ATP7A proteins were present in plasma exosomes in mice, which was significantly increased after two weeks of volunteer wheel exercise. A single bout of exercise in humans also showed a significant increase in SOD3 and ATP7A protein expression in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human ECs or mouse skin wound healing models, which was associated with a decrease in ATP7A, but not SOD3 expression in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in ECs by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3-/- mice. Furthermore, exosomes overexpressing SOD3 significantly enhanced angiogenesis in ECs by increasing local H2 O2  levels in a heparin-binding domain-dependent manner as well as restored defective wound healing and angiogenesis in T2DM or SOD3-/- mice. In conclusion, exercise improves the angiogenic potential of circulating exosomes in T2DM in a SOD3-dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic disease.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Exossomos/metabolismo , Neovascularização Fisiológica , Corrida , Superóxido Dismutase/metabolismo , Animais , Células Cultivadas , ATPases Transportadoras de Cobre/sangue , ATPases Transportadoras de Cobre/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Exercício Físico , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Condicionamento Físico Animal/métodos , Ratos , Superóxido Dismutase/sangue
12.
Biomed Res Int ; 2022: 6450844, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35187168

RESUMO

AIMS: Type 2 diabetes (T2D) is associated with sarcopenia and decreased muscle strength. Explosive and isometric voluntary handgrip strengths (EHGS and HGS) are frequently utilized methods to ascertain health status and a marker of overall muscle strength. We have previously shown that a portable, motorized device, which produces effortless, rapid stepping in place (passive simulated jogging device (JD)), improves glucose homeostasis. This study quantitatively evaluated the effects of JD in modifying parameters of the modified EHGS curve in T2D and nondiabetic (ND) subjects. METHODS: Twenty-one adult participants (11 ND and 10 T2D) (mean age: 41.3 ± 13.5 yr) performed a modified explosive handgrip strength (EHGS) test on study day 1 followed by daily use of JD (90 min per day) for 7 days. The EHGS was repeated after 3 and 7 days' use of JD (JD3 and JD7) and 3 days after completion of JD (Carryover). EHGS curves were analyzed for the following: maximal peak force value (MAX); rate of force development at 25%,75%, and 90% of maximum force; and maximum force (RFD25%, RFD75%, RFD90%, and RFDmax); time to 90%, 75%, and 25% of maximal force (t 90, t 75, t 25) and time to maximal force (t max); and the integrated area under the curve for force vs. time until task failure (iAUCTF); and fatigue resistance times at 50% and 25% of maximal force (FR50 and FR25) and fatigue resistance time to task failure (FRTF). RESULTS: At baseline, T2D had lower MAX compared to ND. There were no differences at baseline for force development time or fatigue resistance time between T2D and ND. In both T2D and ND, 7 days of JD increased FR25 and FRTF and iAUCTF compared to baseline. CONCLUSION: JD for at least 7 days prior to EHGS increased time to task failure (fatigue resistance) and iAUCTF of the force-time curve. JD is a reasonable intervention to decrease sedentary behavior and improve muscle fatigue resistance under various clinical and nonclinical scenarios. This trial is registered with NCT03550105 (08-06-2018).


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Força da Mão/fisiologia , Corrida Moderada , Fadiga Muscular/fisiologia , Adulto , Feminino , Humanos , Masculino
13.
J Diabetes Res ; 2022: 4950528, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35187177

RESUMO

AIMS: We aimed to explore whether visceral adiposity indices were significantly associated with obstructive sleep apnea (OSA) in type 2 diabetes (T2DM) patients. METHODS: 100 patients with T2DM who underwent overnight polysomnography were analyzed in this study. Anthropometric data, lipid profiles, and glycemic parameters were recorded. Body fat percentage (BFP) and visceral adipose tissue area (VAT area) were collected from a whole body scan using dual-energy X-ray absorptiometry (DXA). Multivariate logistic regression analysis was performed to explore the associations of AHI with BFP, VAT area, and CVAI. RESULTS: The prevalence rate of OSA was 80%, and the mean (±SD) of age was 47.0 ± 13.6 years. Apnea-hypopnea index (AHI) was significantly and positively associated with either VAT area (r = 0.433, p ≤ 0.001) or Chinese visceral adiposity index (CVAI) (r = 0.355, p ≤ 0.001) but not for BFP (r = 0.107, p = 0.294). Multivariate logistic regression analyses showed that VAT area and CVAI were significantly associated with increased risk of OSA, and the adjusted ORs were (95% CI) 1.025 (1.003-1.047, p = 0.023) and 1.018 (1.002-1.034, p = 0.030), respectively. However, there was no significant association between BFP and increased risk of OSA. CONCLUSIONS: VAT area and CVAI were independent risk factors of OSA in the patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Gordura Intra-Abdominal , Apneia Obstrutiva do Sono/etiologia , Absorciometria de Fóton/métodos , Absorciometria de Fóton/estatística & dados numéricos , Adulto , Análise de Variância , China/epidemiologia , Correlação de Dados , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia/métodos , Polissonografia/estatística & dados numéricos , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/fisiopatologia , Estatísticas não Paramétricas
14.
J Diabetes Res ; 2022: 7153238, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35103244

RESUMO

INTRODUCTION: Adipose tissue (AT) expandability may be facilitated by adiponectin and suppressed by orosomucoid, and reduced AT expandability may be associated with first-degree relatives of type 2 diabetes. We tested the hypothesis that orosomucoid may be associated not only with adiponectin and adipose tissue insulin resistance but also with a family history of type 2 diabetes (FHD). Research Design and Methods. Anthropometric and metabolic variables, adipokines, and measures of inflammatory and insulin resistance were cross-sectionally investigated in 153 young normal weight Japanese women. Stepwise multivariate linear regression analyses were used to identify the most important determinants of orosomucoid. RESULTS: Orosomucoid was higher in women with positive (n = 57) compared to women with negative FHD and was associated positively with FHD (both p = 0.01). Orosomucoid also showed positive associations with fasting glucose (p < 0.001), free fatty acids (p = 0.001), and HbA1c (p = 0.007), whereas there was no association with fasting insulin and serum lipids. In addition, orosomucoid was associated inversely with adiponectin (p = 0.02) and positively with adipose tissue-insulin resistance index (AT-IR, the product of fasting insulin and free fatty acids; p = 0.001) but not with homeostasis model assessment-insulin resistance, leptin, and high-sensitivity C-reactive protein. In multivariate analyses, AT-IR (standardized ß, 0.22; p = 0.003), serum adiponectin (standardized ß, -0.163; p = 0.032), FHD+ (standardized ß, 0.178; p = 0.029), and HbA1c (standardized ß, 0.213; p = 0.005) emerged as independent determinants of orosomucoid and explained 15.2% of its variability. CONCLUSIONS: These results are the first to demonstrate that orosomucoid is associated not only with adipose tissue-insulin resistance and adiponectin but also with FHD.


Assuntos
Adiponectina/análise , Diabetes Mellitus Tipo 2/diagnóstico , Resistência à Insulina/fisiologia , Orosomucoide/análise , Adiponectina/sangue , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Adulto , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Insulina/análise , Insulina/biossíntese , Insulina/sangue , Japão/epidemiologia , Masculino , Anamnese/métodos , Anamnese/estatística & dados numéricos , Pessoa de Meia-Idade , Orosomucoide/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-35219959

RESUMO

The gut microbiota (GM) and metabolites are important factors in mediating the development of type-2 diabetes mellitus (T2DM). An imbalance in the gut microbiota and metabolites can disrupt the function of the intestinal barrier, cause changes in the permeability of the intestinal mucosa and promote the immune inflammatory response, thereby aggravating the fluctuation of blood glucose level and promoting the occurrence and development of the chronic complications of DM. Manipulating the GM and metabolites is a promising therapeutic intervention and is being studied extensively. Shenqi compound (SQC) is a traditional Chinese medicine formulation, which has been widely used to improve T2DM. Studies have demonstrated that SQC can reduce glycemic variability, alleviate the inflammatory response, etc. However, its underlying mechanism remains unknown. Therefore, in this experiment, We administered SQC to Goto-Kakizaki (GK) rats and evaluated its effect on blood glucose homeostasis and the intestinal mucosal barrier. We identified the profiles of the GM and metabolites with the aid of 16S rDNA gene sequencing and non-target metabolomics analysis. It showed that SQC intervention could reduce glycemic variability, regulate serum levels of glucagon and insulin, and improve injury to the intestinal mucosal barrier of GK rats. In the gut, the ratio of bacteria of the phyla Bacteroidetes/Firmicutes could be improved after SQC intervention. SQC also regulated the relative abundance of Prevotellaceae, Butyricimonas, Bacteroides, Blautia, Roseburia, Lactobacillus, and Rothia. We found out that expression of 40 metabolites was significantly improved after SQC intervention. Further analyses of metabolic pathways indicated that the therapeutic effect of SQC might be related predominantly to its ability to improve gluconeogenesis/glycolysis, amino acid metabolism, lipid metabolism, citrate cycle, and butanoate metabolism. These results suggest that SQC may exert a beneficial role in T2DM by modulating the GM and metabolites in different pathways.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/microbiologia , Medicamentos de Ervas Chinesas/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Gluconeogênese/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Insulina/sangue , Masculino , Ratos , Ratos Wistar
16.
Diabetes ; 71(3): 367-375, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35196393

RESUMO

Secretion of insulin from pancreatic ß-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of ß-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.


Assuntos
Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Canais KATP/fisiologia , Animais , Glicemia , Cálcio/farmacologia , Humanos , Resistência à Insulina , Secreção de Insulina/genética , Secreção de Insulina/fisiologia , Canais KATP/genética , Camundongos , Camundongos Knockout , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Receptores de Sulfonilureias/genética , Receptores de Sulfonilureias/fisiologia
17.
Int J Mol Sci ; 23(4)2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35216423

RESUMO

The prevalence of obesity has reached pandemic levels and is becoming a serious health problem in developed and developing countries. Obesity is associated with an increased prevalence of comorbidities that include type II diabetes, cardiovascular diseases and some cancers. The recognition of adipose tissue as an endocrine organ capable of secreting adipokines that influence whole-body energy homeostasis was a breakthrough leading to a better molecular understanding of obesity. Of the adipokines known to be involved in the regulation of energy metabolism, very few are considered central regulators of insulin sensitivity, metabolism and energy homeostasis, and the discovery and characterization of new adipocyte-derived factors are still ongoing. Proteomics techniques, such as liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry, have proven to be useful tools for analyzing the secretory function of adipose tissue (the secretome), providing insights into molecular events that influence body weight. Apart from the identification of novel proteins, the considerable advantage of this approach is the ability to detect post-translational modifications that cannot be predicted in genomic studies. In this review, we summarize recent efforts to identify novel bioactive secretory factors through proteomics.


Assuntos
Tecido Adiposo/fisiologia , Células Endócrinas/fisiologia , /fisiologia , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Metabolismo Energético/fisiologia , Humanos , Obesidade/fisiopatologia
18.
Life Sci ; 295: 120382, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35143826

RESUMO

Dysfunctional adipocytes/ß-cells advance type 2 diabetes (T2D). Calorie restriction (CR) improves insulin sensitivity and fasting blood glucose (FBG) levels, while γ-aminobutyric acid (GABA) exerts regenerative effects. The impact of therapies was assessed by a high-fat diet (HFD) + streptozotocin (STZ) induced T2D mouse model. The mice were fed a CR diet (30% reduction of HFD) and treated with GABA (2.5 mg/kg i.p) for 5 weeks. Standard protocols were used to assess metabolic parameters. The mRNA expression was monitored by SYBR Green-qPCR in the targeted tissues. Oxygen consumption rate in the mitochondrial complexes was evaluated by oxytherm clark-type oxygen electrode. Pancreatic ß-cell regeneration and apoptosis were analysed by immunohistochemistry. CR + GABA combination therapy showed improved metabolic parameters compared to the monotherapies. We have observed improved transcript levels of G6Pase, PEPCK, Glycogen Phosphorylase, GLUT2 and GCK in liver; ACC and ATGL in adipose tissue. Also increased SIRT-1, PGC-1α and TFAM expression; up-regulated mitochondrial complexes I-III activities were observed. We have seen increased BrdU/Insulin and PDX1/Ngn3/Insulin co-positive cells in CR + GABA treated group with a reduction in apoptotic marker (TUNEL/Insulin co-positive cells). Our results indicate that CR in combination with GABA ameliorates T2D in HFD + STZ treated mice by GABA induced ß-cell regeneration, and CR mediated insulin sensitivity.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/metabolismo , Ácido gama-Aminobutírico/farmacologia , Animais , Glicemia/metabolismo , Restrição Calórica , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Insulina/metabolismo , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina/farmacologia , Ácido gama-Aminobutírico/metabolismo
19.
Sci Rep ; 12(1): 2434, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35165331

RESUMO

Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the "circadian syndrome" and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms.


Assuntos
Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/terapia , Transtornos Cronobiológicos/complicações , Transtornos Cronobiológicos/terapia , Ritmo Circadiano , Depressão/complicações , Depressão/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Terapia por Exercício/métodos , Condicionamento Físico Animal/métodos , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Ansiedade/terapia , Glicemia/análise , Doenças Cardiovasculares/fisiopatologia , Transtornos Cronobiológicos/fisiopatologia , Depressão/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Gerbillinae , Teste de Tolerância a Glucose , Insulina/sangue , Locomoção , Masculino , Ratos , Núcleo Supraquiasmático/fisiopatologia , Resultado do Tratamento
20.
J Diabetes Res ; 2022: 8115173, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35224109

RESUMO

OBJECTIVE: In patients with type 2 diabetes mellitus (T2DM), it is unknown whether acylcarnitine changes in the patient's plasma as diabetic peripheral neuropathy (DPN) occurs. The purpose of the present study was to investigate the correlation between acylcarnitines and DPN in Chinese patients with T2DM. METHODS: A total of 508 patients admitted to the First Affiliated Hospital of Jinzhou Medical University were included in this study, and all of whom were hospitalized for T2DM from January 2018 to December 2020. The diagnostic criteria for DPN were based on the 2017 Chinese Guidelines for the Prevention of Type 2 Diabetes. The contents of 25 acylcarnitine metabolites in fasting blood were determined by mass spectrometry. The measured acylcarnitines were classified by factor analysis, and the factors were extracted. To determine the correlation between acylcarnitines and DPN, binary logistic regression analysis was applied. RESULTS: Among the 508 T2DM patients, 270 had DPN. Six factors were extracted from 25 acylcarnitines, and the cumulative contribution rate of variance was 61.02%. After the adjustment for other potential confounding factors, such as other carnitines and conventional risk factors, Factor 2 was positively associated with an increased risk of DPN (OR: 1.38, 95% CI: 1.13-1.69). Factor 2 contained acetylcarnitine (C2), propionylcarnitine (C3), butylcarnitine (C4), and isovalerylcarnitine (C5). CONCLUSIONS: Plasma levels of short-chain acylcarnitines (C2, C3, C4, and C5) were positively associated with DPN risk.


Assuntos
Carnitina/análogos & derivados , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Adulto , Idoso , Índice de Massa Corporal , Carnitina/metabolismo , Carnitina/farmacologia , Carnitina/uso terapêutico , China , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/etiologia , Fatores de Risco
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