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1.
Nat Med ; 25(11): 1733-1738, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700171

RESUMO

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Hiperfagia/genética , Obesidade/genética , Adolescente , Adulto , Criança , Metabolismo Energético/genética , Feminino , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperfagia/complicações , Hiperfagia/metabolismo , Hiperfagia/patologia , Hipertensão/complicações , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Fatores de Risco , Adulto Jovem
2.
Nat Med ; 25(11): 1739-1747, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700183

RESUMO

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.


Assuntos
Complemento C3a/genética , Fator D do Complemento/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fosfatases de Especificidade Dupla/genética , Células Secretoras de Insulina/efeitos dos fármacos , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Animais , Índice de Massa Corporal , Desdiferenciação Celular/efeitos dos fármacos , Fator D do Complemento/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/patologia , Insulina/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD
3.
BMC Complement Altern Med ; 19(1): 309, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718632

RESUMO

BACKGROUND: Sheng Mai San (SMS) has been proven to exhibit cardio-protective effects. This study aimed to explore the molecular mechanisms of SMS on hyperglycaemia (HG)-induced apoptosis in H9C2 cells. METHODS: HG-induced H9C2 cells were established as the experimental model, and then treated with SMS at 25, 50, and 100 µg/mL. H9C2 cell viability and apoptosis were quantified using MTT and Annexin V-FITC assays, respectively. Furthermore, Bcl-2/Bax signalling pathway protein expression and Fas and FasL gene expression levels were quantified using western blotting and RT-PCR, respectively. RESULTS: SMS treatments at 25, 50, 100 µg/mL significantly improved H9C2 cell viability and inhibited H9C2 cell apoptosis (p < 0.05). Compared to the HG group, SMS treatment at 25, 50, and 100 µg/mL significantly downregulated p53 and Bax expression and upregulated Bcl-2 expression (p < 0.05). Moreover, SMS treatment at 100 µg/mL significantly downregulated Fas and FasL expression level (p < 0.05) when compared to the HG group. CONCLUSION: SMS protects H9C2 cells from HG-induced apoptosis probably by downregulating p53 expression and upregulating the Bcl-2/Bax ratio. It may also be associated with the inhibition of the Fas/FasL signalling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Hiperglicemia/fisiopatologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
4.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(12): 158532, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31647995

RESUMO

Exosomes have been demonstrated to be one of the mechanisms mediating the release of intracellular signaling molecules to conduct cell-to-cell communication. However, it remains unknown whether and how exosomes mediate the release of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome products such as interleukin-1 beta (IL-1ß) from endothelial cells. The present study hypothesized that lysosomal acid ceramidase (AC) determines the fate of multivesicular bodies (MVBs) to control the exosome-mediated release of NLRP3 inflammasome products during hyperglycemia. Using a streptozotocin (STZ)-induced diabetes mouse model, we found that endothelium-specific AC gene knockout mice (Asah1fl/fl/ECcre) significantly enhanced the formation and activation of NLRP3 inflammasomes in coronary arterial ECs (CECs). These mice also had increased thickening of the coronary arterial wall and reduced expression of tight junction protein compared to wild-type (WT/WT) littermates. We also observed the expression of exosome markers such as CD63 and alkaline phosphatase (ALP) was augmented in STZ-treated Asah1fl/fl/ECcre mice compared to WT/WT mice, which was accompanied by an increased IL-1ß release of exosomes. In the primary cultures of CECs, we demonstrated that AC deficiency markedly enhanced the formation and activation of NLRP3 inflammasomes, but significantly down-regulated tight junction proteins when these cells were exposed to high levels of glucose. The CECs from Asah1fl/fl/ECcre mice had decreased MVB-lysosome interaction and increased IL-1ß-containing exosome release in response to high glucose stimulation. Together, these results suggest that AC importantly controls exosome-mediated release of NLRP3 inflammasome products in CECs, which is enhanced by AC deficiency leading to aggravated arterial inflammatory response during hyperglycemia.


Assuntos
Ceramidase Ácida/imunologia , Células Endoteliais/imunologia , Hiperglicemia/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ceramidase Ácida/genética , Animais , Vasos Coronários/imunologia , Vasos Coronários/patologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Células Endoteliais/patologia , Exossomos/imunologia , Exossomos/patologia , Feminino , Deleção de Genes , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Knockout
5.
Endocrinology ; 160(11): 2759-2772, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504428

RESUMO

Thyroid hormones (THs) are crucial regulators of glucose metabolism and insulin sensitivity. Moreover, inactivating mutations in type 2 deiodinase (DIO2), the major TH-activating enzyme, have been associated with type 2 diabetes mellitus in both humans and mice. We studied the link between Dio2 deficiency and glucose homeostasis in fasted males of two different Dio2 knockout (KO) zebrafish lines. Young adult Dio2KO zebrafish (6 to 9 months) were hyperglycemic. Both insulin and glucagon expression were increased, whereas ß and α cell numbers in the main pancreatic islet were similar to those in wild-types. Insulin receptor expression in skeletal muscle was decreased at 6 months, accompanied by a strong downregulation of hexokinase and pyruvate kinase expression. Blood glucose levels in Dio2KO zebrafish, however, normalized around 1 year of age. Older mutants (18 to 24 months) were normoglycemic, and increased insulin and glucagon expression was accompanied by a prominent increase in pancreatic islet size and ß and α cell numbers. Older Dio2KO zebrafish also showed strongly decreased expression of glucagon receptors in the gastrointestinal system as well as decreased expression of glucose transporters GLUT2 and GLUT12, glucose-6-phosphatase, and glycogen synthase 2. This study shows that Dio2KO zebrafish suffer from transient hyperglycemia, which is counteracted with increasing age by a prominent hyperplasia of the endocrine pancreas together with decreases in hepatic glucagon sensitivity and intestinal glucose uptake. Further research on the mechanisms allowing compensation in older Dio2KO zebrafish may help to identify new therapeutic targets for (TH deficiency-related) hyperglycemia.


Assuntos
Glucose/metabolismo , Iodeto Peroxidase/deficiência , Envelhecimento/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Homeostase , Hiperglicemia/genética , Iodeto Peroxidase/genética , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/fisiologia , Masculino , Proglucagon/metabolismo , Proinsulina/metabolismo , Receptor de Insulina/metabolismo , Receptores de Glucagon/metabolismo , Peixe-Zebra
6.
Mol Med Rep ; 20(4): 3728-3734, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485651

RESUMO

Hyperglycemia promotes podocyte apoptosis and contributes to the pathogenesis of diabetic nephropathy (DN). However, the mechanisms of hyperglycemia­induced podocyte apoptosis remain unknown. Recent studies have implicated Src­associated substrate during mitosis of 68 kDa (Sam68) in various cellular processes including RNA metabolism, apoptosis, signal transduction. This study sought to examine the effect of Sam68 on high glucose (HG)­induced podocytes apoptosis, and the mechanism underlying this effect. Immortalized mouse podocytes were exposed to medium containing normal glucose, or HG and Sam68 siRNA, respectively. The expression of Sam68 in podocytes was determined by fluorescence quantitative PCR (qPCR), immunofluorescence and immunoblotting. The role of Sam68 in HG­induced podocyte apoptosis was further evaluated by inhibiting Sam68 expression by Sam68 siRNA and performing flow cytometry. The mRNA and protein expression of pro­apoptosis gene Bax and anti­apoptotic gene Bcl­2 were assessed by qRCR and immunoblotting. In the present study, it was first demonstrated that Sam68 was upregulated in a time and dose­dependent manner in in vitro HG­treated podocytes. Pretreatment with Sam68 siRNA markedly decreased nuclear Sam68 expression. Moreover, the effects of HG­induced apoptosis were also abrogated by Sam68 knockdown in cultured podocytes. Furthermore, HG increased Bax and decreased Bcl­2 protein expression in cultured podocytes, and this effect was blocked by Sam68 knockdown. The results of the present study revealed that Sam68 mediated HG­induced podocyte apoptosis, probably through the Bax/Bcl­2 signaling pathway, and thus may be a potential therapeutic target for DN.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Nefropatias Diabéticas/genética , Hiperglicemia/genética , Podócitos/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas de Ligação a RNA/genética , Proteína X Associada a bcl-2/genética , Animais , Apoptose , Linhagem Celular , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Regulação para Baixo , Hiperglicemia/complicações , Hiperglicemia/patologia , Camundongos , Podócitos/metabolismo , Regulação para Cima
7.
Nutrients ; 11(8)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398873

RESUMO

Disturbances in adipose tissue significantly contribute to the development of metabolic disorders, which are connected with hyperglycemia (HG) and underlain by epigenetics-based mechanisms. Therefore, we aimed to evaluate the effect of hyperglycemia on proliferating, differentiating and maturating human visceral pre/adipocytes (HPA-v). Three stages of cell culture were conducted under constant or variable glycemic conditions. Adipogenesis progress was assessed using BODIPY 505/515 staining. Lipid content typical for normal and hyperglycemic conditions of adipocytes was analyzed using Raman spectroscopy and imaging. Expression of adipogenic markers, PPARγ and C/EBPα, was determined at the mRNA and protein levels. We also examined expression of miRNAs proven to target PPARγ (miR-34a-5p) and C/EBPα (miR-137-3p), employing TaqMan Low-Density Arrays (TLDA) cards. Hyperglycemia altered morphology of differentiating HPA-v in relation to normoglycemia by accelerating the formation of lipid droplets and making their numbers and volume increase. Raman results confirmed that the qualitative and quantitative lipid composition under normal and hyperglycemic conditions were different, and that the number of lipid droplets increased in (HG)-treated cells. Expression profiles of both examined genes markedly changed either during adipogenesis under physiological and hyperglycemic conditions, orat particular stages of adipogenesis upon chronic and/or variable glycemia. Expression levels of PPARγ seemed to correspond to some expression changes of miR-34a-5p. miR-137-3p, whose expression was rather stable throughout the culture, did not seem to affect C/EBPα. Our observations revealed that chronic and intermittent hyperglycemia change the morphology of visceral pre/adipocytes during adipogenesis. Moreover, hyperglycemia may utilize miR-34a-5p to induce some expression changes in PPARγ.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Hiperglicemia/genética , PPAR gama/metabolismo , Técnicas de Cultura de Células , Diferenciação Celular/genética , Proliferação de Células/genética , Humanos , MicroRNAs/metabolismo
8.
J Sci Food Agric ; 99(15): 6981-6988, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31414473

RESUMO

BACKGROUND: Diabetes mellitus is a serious chronic disease, characterized by hyperglycemia. This study administered either ß-mannanase-treated yeast cell autolysis supernatant (YCS) or yeast cell-wall residues after autolysis (YCR) to investigate their influence on the alleviation of diabetes in a diabetic mouse model. RESULTS: Application of either YCS or YCR led to body weight gain, blood glucose reduction, and an improvement in lipid composition in the diabetic mice. Administration of YCS was more effective in inhibiting oxidative stress than YCR. The expression of PPARα and CPT1α was enhanced, improving lipid biosynthesis, and Trx1 and HIF-1-α genes were downregulated due to the activation of thioredoxin following the interventions, indicating that the processes of lipid metabolism and oxidative stress were heavily involved in the reduction of diabetic characteristics following the interventions. The current study revealed that consumption of YCR also led to a reduction in hyperglycemia, this being associated with its richness in mineral elements, such as chromium and selenium. CONCLUSION: This study may highlight the potential of both YCS and YCR as functional ingredients in dietary formula for improving diabetic syndromes. © 2019 Society of Chemical Industry.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Saccharomyces cerevisiae/química , beta-Manosidase/química , Animais , Biocatálise , Glicemia/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Suplementos Nutricionais/análise , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Minerais/análise , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo
9.
Postgrad Med ; 131(8): 597-606, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31419922

RESUMO

The association between cancer and dysglycemia has been well documented. It is underappreciated, however, that sustained dysglycemia could potentially be a catalyst toward a pro-cancer physiologic milieu and/or increase the burden of cancer. Hyperglycemia, hyperinsulinemia and energy metabolism at large impact a cascade of growth pathways, epi/genetic modifications, and mitochondrial changes that could feasibly link to tumor processes. Oxidative stress is a recurring motif in cell dysfunction: in diabetes, oxidative stress and reactive oxygen species (ROS) feature prominently in the damage and demise of pancreatic beta cells, as well as cell damage contributing to diabetes-related complications. Oxidative stress may be one intersection at which metabolic and oncogenic processes cross paths with deleterious results in the development of precancer, cancer, and cancer progression. This would augur for tight glucose control. Regrettably, some medical societies have recently relaxed hemoglobin A1c targets. A framework for the hyperglycemic state is presented that helps account and translate the full scope of effects of dysglycemia to ultimately improve clinical best practices.


Assuntos
Hiperglicemia/epidemiologia , Hiperglicemia/fisiopatologia , Neoplasias/epidemiologia , Neoplasias/fisiopatologia , Proteínas de Ligação a DNA/biossíntese , Progressão da Doença , Metabolismo Energético/fisiologia , Hemoglobina A Glicada , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperinsulinismo/fisiopatologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Neoplasias/genética , Obesidade/epidemiologia , Estresse Oxidativo/fisiologia , Prognóstico , Proteínas Proto-Oncogênicas/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
10.
J Med Case Rep ; 13(1): 258, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31366392

RESUMO

BACKGROUND: Neonatal diabetes mellitus with hyperglycemia during the first 6 months of life is a rare disorder that can occur in all races and societies. CASE PRESENTATION: In this study, we introduced an Iranian (Persian) 65-day-old patient with neonatal diabetes mellitus with novel homozygous mutation in the pancreatic and duodenal homeobox 1, PDX1, gene, which is also known as IPF1 gene, located in exon 2. This case was a newborn boy born in Vali-Asr Hospital, Tehran; he was diagnosed as having hyperglycemia on 28th day. Genetic analysis detected a homozygous mutation on PDX1 gene on chromosome 13. It is a novel homozygous mutation in the PDX1 gene (NM_000209.3), p.Phe167Val. This mutation was confirmed by Sanger sequencing. There was no evidence of agenesis of the pancreas. CONCLUSIONS: We reported a case of neonatal diabetes mellitus due to novel homozygous mutation in the PDX1 gene without exocrine pancreas manifestations.


Assuntos
Diabetes Mellitus/genética , Proteínas de Homeodomínio , Hiperglicemia/genética , Transativadores , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Humanos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Lactente , Recém-Nascido , Doenças do Recém-Nascido , Insulina/administração & dosagem , Irã (Geográfico) , Masculino , Mutação
11.
DNA Cell Biol ; 38(10): 1134-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433203

RESUMO

Diabetes mellitus is a complicated metabolic disease characterized by hyperglycemia. Diabetic nephropathy (DN) is a progressive kidney disease, which results in mortality in diabetic patients. The present study was designed to investigate the effect of applying spironolactone (S), captopril (C), and their combination (S+C) on some renal performance indices and microRNAs' (miRNAs) expression. A total of 35 two-month-old male Wistar rats were provided for the study. Intraperitoneal injection of freshly dissolved streptozotocin (60 mg/kg) in cold citrate buffer was used to induce diabetes. Blood samples were examined through calorimetry to assess serum concentrations of glucose, blood urea nitrogen (BUN), and creatinine. To measure the microalbuminuria and transforming growth factor-ß (TGF-ß) levels and to evaluate the miRNAs expression levels of the kidney tissue, the ELISA method and the real-time PCR were used. The obtained results serve as in vivo evidence for the positive relationship between miR-192 and TGF-ß levels in the DN rats. A significant increase and decrease were found for miR-29a/b/c and the miR-192 expression of DN after treatment with S, C, and S+C. TGF-ß levels and microalbuminuria of diabetic rats also increased. The results obtained from this research study suggest that S, C, and S + C can improve DN by targeting miR-192 and miR-29 family and changing their expression. These findings suggest that miR-192 and miRs-29a/b/c can be potential targets for DN remediation.


Assuntos
Captopril/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Espironolactona/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Diuréticos/farmacologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
12.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269778

RESUMO

The high incidence and poor prognosis of heart failure (HF) patients affected with diabetes (DM) is in part related to a specific cardiac remodeling currently recognized as diabetic cardiomyopathy (DCM). This cardiac frame occurs regardless of the presence of coronary artery diseases (CAD) and it can account for 15-20% of the total diabetic population. The pathogenesis of DCM remains controversial, and several molecular and cellular alterations including myocardial hypertrophy, interstitial fibrosis, oxidative stress and vascular inflammation, have been postulated. The main cardio-vascular alterations associated with hyperglycemia comprise endothelial dysfunction, adverse effects of circulating free fatty acids (FFA) and increased systemic inflammation. High glucose concentrations lead to a loss of mitochondrial networks, increased reactive oxygen species (ROS), endothelial nitric oxide synthase (eNOS) activation and a reduction in cGMP production related to protein kinase G (PKG) activity. Current mechanisms enhance the collagen deposition with subsequent increased myocardial stiffness. Several concerns regarding the exact role of DCM in HF development such as having an appearance as either dilated or as a concentric phenotype and whether diabetes could be considered a causal factor or a comorbidity in HF, remain to be clarified. In this review, we sought to explain the different DCM subtypes and the underlying pathophysiological mechanisms. Therefore, the traditional and new molecular and signal alterations and their relationship with macroscopic structural abnormalities are described.


Assuntos
Cardiomiopatias Diabéticas/patologia , Miocárdio/patologia , Animais , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Regulação da Expressão Gênica , Produtos Finais de Glicação Avançada/genética , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Inflamação/complicações , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo
13.
Clin Lab ; 65(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31307169

RESUMO

BACKGROUND: The current study aims to explore the changes of serum miR-587 level in patients with metabolic syndrome (MS) and analyze its clinical diagnostic value. METHODS: The serum levels of miR-587 in 50 patients with hyperglycemia, 50 patients with hyperlipidemia, and 50 healthy controls were detected by RT-qPCR. The diagnostic value of serum miR-587 was detected by ROC analy-sis and correlation analysis in MS. Dual luciferase reporter assay was carried out to determine the possible target gene of miR-587. RESULTS: The results of RT-qPCR showed that the relative content of serum miR-587 in patients with hyperglyce-mia and hyperlipidemia was 0.45 ± 0.30, 0.41 ± 0.30, compared with 1 ± 0.87 in healthy people. The area under ROC curve (AUC) of serum miR-587 in hyperglycemic patients was 0.830 (95% CI = 0.716 - 0.863, p < 0.001), with the sensitivity of 68.6% and specificity of 89.3%. The AUC of serum miR-587 in hyperlipidemia patients was 0.790 (95% CI = 0.759 - 0.851, p < 0.001), with the sensitivity of 78% and specificity of 89.7%. Correlation analysis showed that serum miR-587 level was negatively correlated with fasting blood glucose (FBG) (r = -0.291, p < 0.05), and negatively correlated with total cholesterol (TC) (r = -0.243, p < 0.01). Furthermore, dual luciferase reporter assay showed that PTEN was the target gene of miR-587. CONCLUSIONS: In summary the decreased expression of miR-587 in serum is a potential diagnostic marker and in-dependent risk factor in patients with MS.


Assuntos
Biomarcadores/sangue , Regulação da Expressão Gênica , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , MicroRNAs/sangue , Glicemia/metabolismo , Colesterol/sangue , Jejum/sangue , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/genética , Hiperlipidemias/sangue , Hiperlipidemias/diagnóstico , Hiperlipidemias/genética , Masculino , Síndrome Metabólica/genética , MicroRNAs/genética , Pessoa de Meia-Idade , Curva ROC
14.
Biofactors ; 45(5): 703-711, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31343786

RESUMO

Metformin is the most widely prescribed treatment of hyperglycemia and type II diabetes since 1970s. During the last 15 years, its popularity increased due to epidemiological evidence, that metformin administration reduces incidence of cancer. However, despite the ongoing effort of many researchers, the molecular mechanisms underlying antihyperglycemic or antineoplastic action of metformin remain elusive. Most frequently, metformin is associated with modulation of mitochondrial metabolism leading to lowering of blood glucose or activation of antitumorigenic pathways. Here we review the reported effects of metformin on mitochondrial metabolism and their potential relevance as effective molecular targets with beneficial therapeutic outcome.


Assuntos
Antineoplásicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Neoplasias/prevenção & controle , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação Oxidativa , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
15.
Biomed Pharmacother ; 118: 109256, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31362245

RESUMO

α-Mangostin play crucial role in several cellular progress, including hyperglycemia-induced inhibition of cell growth and promotion of cell apoptosis. Increasing evidence displayed the important roles of lncRNAs and their potential as novel targets for drug development in human disease. However, there is rare study to comprehensively and systematically explore the role and underlying mechanism of lncRNAs in human umbilical vein endothelial cells (HUVECs) under hyperglycemia with or without α-Mangostin. In this study, we firstly found that α-Mangostin reduced the high glucose-induced inhibition of cell proliferation and migration potential of HUVECs. Then, we performed RNA-seq to dissect the expression profiles of lncRNAs in HUVECs treated with high glucose or high glucose supplemented with α-Mangostin. The results showed that the expression of H19 and HE4 was down-regulated by high glucose and further, α-Mangostin restored the high glucose-induced inhibition of H19 and HE4 expression. Further examination demonstrated that the modulation of the H19 and HE4 expression affected the function of α-Mangostin in hyperglycemia. In addition, H19 regulated HE4 expression via the modulation of the miR-140 expression. Finally, we showed that H19 exerted its function via the modulation of H19/miR-140/HE4 in hyperglycemia with α-Mangostin. In summary, this study is the first to comprehensively identify the lncRNAs/mRNAs network in hyperglycemia with or without α-Mangostin, highlighting a novel regulatory pathway in hyperglycemia with or without α-Mangostin and indicating the potential therapeutic role of α-Mangostin in diabetes mellitus.


Assuntos
Células Endoteliais da Veia Umbilical Humana/metabolismo , Hiperglicemia/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Xantonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , /metabolismo
16.
PLoS Pathog ; 15(6): e1007890, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31220189

RESUMO

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world's population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.


Assuntos
Tecido Adiposo , Linfócitos T CD8-Positivos , Infecções por Herpesviridae , Hiperglicemia , Muromegalovirus/imunologia , Paniculite , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Tecido Adiposo/virologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Hiperglicemia/genética , Hiperglicemia/imunologia , Hiperglicemia/patologia , Hiperglicemia/virologia , Memória Imunológica , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Inflamação/virologia , Camundongos , Camundongos Knockout , Paniculite/genética , Paniculite/imunologia , Paniculite/patologia , Paniculite/virologia
17.
J Diabetes Res ; 2019: 2936962, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214621

RESUMO

Objective: Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. Research Design and Method: 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. Results: We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. Conclusion: The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatologia , Retinopatia Diabética/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Nefropatias Diabéticas/genética , Feminino , Genótipo , Glucose/análise , Células HEK293 , Humanos , Hiperglicemia/genética , Hiperglicemia/fisiopatologia , Hipóxia , Masculino , Pessoa de Meia-Idade , Mutação , Prolina/genética , Fatores de Risco , Serina/genética , Ativação Transcricional , Adulto Jovem
18.
Int J Med Sci ; 16(5): 696-703, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31217737

RESUMO

Background: Bone fragility and related fractures are increasingly being recognized as an important diabetic complication. Mesenchymal progenitors often serve as an important source of bone formation and regeneration. In the present study, we have evaluated the effects of diabetes on osteoblastogenesis of mesenchymal progenitors. Methods: Primary bone marrow stromal cells (BMSCs) were isolated from control and streptozotocin-induced diabetic rats. These cells were evaluated for the effects of in vivo hyperglycemia on the survival and function of mesenchymal progenitors. We concomitantly investigated the effects of different concentrations of glucose, osmolality, and advanced glycation end product (AGE) on osteogenic differentiation and matrix mineralization of rat bone marrow mesenchymal stem cells (RMSC-bm). The relationship between the expression levels of Notch proteins and the corresponding ALP levels was also examined. Results: Our results revealed that in vivo hyperglycemia increased cell proliferation rate but decreased osteogenic differentiation and matrix mineralization of primary rat BMSCs. In vitro high glucose treatment, instead of high AGE treatment, induced a dose-dependent inhibition of osteoblastogenesis of RMSC-bm cells. Activation of the Notch2 signaling pathway, instead of the Notch1 or osmotic response pathways, was associated with these diabetic effects on osteoblastogenesis of mesenchymal progenitors. Conclusions: Hyperglycemia might inhibit osteoblastogenesis of mesenchymal progenitors via activation of the Notch2 signaling pathway.


Assuntos
Diabetes Mellitus Experimental/genética , Hiperglicemia/genética , Osteogênese/genética , Receptor Notch2/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Regulação da Expressão Gênica/genética , Humanos , Hiperglicemia/complicações , Hiperglicemia/patologia , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética
19.
Genet Epidemiol ; 43(7): 776-785, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31218750

RESUMO

Nontraditional glycemic biomarkers, including fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are potential alternatives or complement to traditional measures of hyperglycemia. Genetic variants are associated with these biomarkers, but the heritability, or extent to which genetics control their variation, is not known. We estimated pedigree-based, SNP-based, and bivariate heritabilities for traditional glycemic biomarkers (fasting glucose, HbA1c), and nontraditional biomarkers (fructosamine, glycated albumin, 1,5-AG) among white participants in the Atherosclerosis Risk in Communities (ARIC) Study (N = 400 first-degree relatives from sibships, N = 5,575 unrelated individuals). Pedigree-based heritabilities (representing heritability from the entire genome) for nontraditional biomarkers were substantial (0.44-0.55) and comparable to HbA1c (0.34); the fasting glucose estimate was nonsignificant. SNP-based heritabilities (representing heritability from common variants) were lower than pedigree-based heritabilities for all biomarkers. Bivariate heritabilities showed shared genetics between fructosamine and glycated albumin (0.46 pedigree-based, 1.00 SNP-based) and glycated albumin and 1,5-AG (0.50 pedigree-based, 0.47 SNP-based). Genetic factors contribute to a considerable proportion of the variance of fructosamine, glycated albumin, and 1,5-AG and a portion of this heritability likely comes from common variants.


Assuntos
Aterosclerose/genética , Biomarcadores/metabolismo , Hiperglicemia/genética , Padrões de Herança/genética , Glicemia/metabolismo , Feminino , Frutosamina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Albumina Sérica/metabolismo
20.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232032

RESUMO

BACKGROUND: The current study mainly evaluated whether peripheral blood miR-937 could be a biomarker to differentiate patients with metabolic disorders and healthy controls. METHODS: The peripheral blood was collected with patients with hyperglycemia, hyperlipidemia and healthy control. The relative peripheral blood miR-937 level in patients with metabolic disorders and healthy individuals were evaluated by real-time PCR. Receiver operating characteristic curve (ROC) analysis and Spearman's correlation coefficient were applied to evaluate whether miR-937 could be a potential biomarker for metabolic disorders. Dual luciferase reporter assay was performed to identify the possible target genes of miR-937. RESULTS: First, miR-937 was significantly increased (8.02 ± 8.27) in the peripheral blood of hyperglycemia patients. The level of miR-937 of patients with hyperlipidemia (13.7 ± 14.72) was also enhanced obviously compared with healthy controls (1 ± 1.35). ROC analysis showed that the peripheral blood levels of miR-937 could screen patients with hyperglycemia or hyperlipidemia from healthy controls. Furthermore, peripheral blood miR-937 level posi-tively correlated with serum glucose level (r = 0.556, p < 0.01) as well as total serum TG/TC levels (r = 0.455, p < 0.01). Dual luciferase reporter assay indicated that miR-937 suppressed the relative luciferase activity of pmir-GLO-AMPKα-3'UTR. CONCLUSIONS: The upregulation of circulating miR-937 level may cause a metabolism disorder by suppressing the expression of AMPKα. miR-937 could be a potential biomarker to differentiate patients with metabolism syndrome from healthy controls.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Biomarcadores/metabolismo , Doenças Metabólicas/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Biomarcadores/sangue , Feminino , Regulação da Expressão Gênica , Células HEK293 , Células Hep G2 , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/genética , Hiperlipidemias/sangue , Hiperlipidemias/diagnóstico , Hiperlipidemias/genética , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/diagnóstico , MicroRNAs/sangue , Pessoa de Meia-Idade , Curva ROC
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