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1.
Food Chem ; 335: 127505, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32739823

RESUMO

Dysregulation of glucose homeostasis result in hyperglycemia and pigmented rice, unique combination of high quality starch and phenolics has the potential in regulating it. In this study, pigmented rice was characterized in terms of nutraceutical starch (NS) and phenolic content. Further the effect of rice phenolics on carbolytic enzyme inhibition, glucose uptake, hepatic glucose homeostasis and anti-glycation ability was analyzed in vitro. The most relevant effect on enzyme inhibition (α-amylase: IC50-42.34 µg/mL; α-glucosidase: IC50:63.89 µg/mL), basal uptake of glucose (>39.5%) and anti-glycation ability (92%) was found in red rice (RR), than black rice (BR). The role of RR phenolics in regulating glucose homeostasis was deciphered using hepatic cell line system, which found up-regulation of glucose transporter 2 (GLUT2) and glycogen synthase 2 (GYS2); while expression of gluconeogenic genes were found down regulated. To our knowledge this study is the first report validating the role of starch-phenolic quality towards anti-hyperglycemic effect of RR.


Assuntos
Glucose/metabolismo , Homeostase , Hiperglicemia/metabolismo , Fígado/metabolismo , Oryza/química , Proantocianidinas/análise , Amido/análise , Transporte Biológico/efeitos dos fármacos , Suplementos Nutricionais/análise , Inibidores de Glicosídeo Hidrolases/farmacologia , Homeostase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fenol/análise , Fenol/farmacologia , alfa-Amilases/antagonistas & inibidores
2.
Front Endocrinol (Lausanne) ; 11: 574541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123093

RESUMO

Background: Diabetes mellitus is considered a common comorbidity of COVID-19, which has a wide spectrum of clinical manifestations ranging from asymptomatic infection to severe respiratory symptoms and even death. However, the impact of COVID-19 on blood glucose has not been fully understood. This meta-analysis aimed to summarize available data on the association between glycemic parameters and severity of COVID-19. Methods: PubMed, EMBASE, and Cochrane Library were searched from December 1, 2019 to May 15, 2020. Observational studies investigating blood glucose or glycated hemoglobin A1c (HbA1c) according to the severity of COVID-19 were considered for inclusion. Two independent researchers extracted data from eligible studies using a standardized data extraction sheet and then proceeded to cross check the results. Data were pooled using a fixed- or random-effects model to calculate the weighted mean differences (WMDs) and 95% confidence intervals (CIs). Results: Three studies reported blood glucose and HbA1c according to the severity of COVID-19 and were included in this meta-analysis. The combined results showed that severe COVID-19 was associated with higher blood glucose (WMD 2.21, 95% CI: 1.30-3.13, P < 0.001). In addition, HbA1c was slightly higher in patients with severe COVID-19 than those with mild COVID-19, yet this difference did not reach significance (WMD 0.29, 95% CI: -0.59 to 1.16, P = 0.52). Conclusions: This meta-analysis provides evidence that severe COVID-19 is associated with increased blood glucose. This highlights the need to effectively monitor blood glucose to improve prognosis in patients infected with COVID-19.


Assuntos
Betacoronavirus/isolamento & purificação , Glicemia/análise , Infecções por Coronavirus/complicações , Hemoglobina A Glicada/análise , Hiperglicemia/epidemiologia , Pneumonia Viral/complicações , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/virologia , Pandemias
3.
J Pharmacol Sci ; 144(4): 197-203, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070838

RESUMO

The role of cytoskeleton dynamics in the oxidative stress toward human vasculature has been unclear. The current study examined whether the cytoskeleton-disrupting agent cytochalasin B reduces oxidative stress caused by high glucose in the human arterial smooth muscle. All experiments in the human omental arteries without endothelium or the cultured human coronary artery smooth muscle cells were performed in d-glucose (5.5 mmol/L). The exposure toward d-glucose (20 mmol/L) for 60 min reduced the relaxation or hyperpolarization to an ATP sensitive K+ channel (KATP) opener levcromakalim (10-8 to 3 × 10-6 mol/L and 3 × 10-6 mol/L, respectively). Cytochalasin B and a superoxide inhibitor Tiron, restored them similarly. Cytochalasin B reduced the NADPH oxidase activity, leading to a decrease in superoxide levels of the arteries treated with high d-glucose. Also, cytochalasin B impaired the F-actin constitution and the membrane translocation of an NADPH oxidase subunit p47phox in artery smooth muscle cells treated with high d-glucose. A clinical concentration of cytochalasin B prevented human vascular smooth muscle malfunction via the oxidative stress caused by high glucose. Regulation of the cytoskeleton may be essential to keep the normal vascular function in patients with hyperglycemia.


Assuntos
Citocalasina B/farmacologia , Citoesqueleto/metabolismo , Glucose/efeitos adversos , Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adulto , Idoso , Células Cultivadas , Cromakalim/farmacologia , Feminino , Humanos , Hiperglicemia/fisiopatologia , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , NADPH Oxidases/metabolismo , Superóxidos/metabolismo
4.
Yonsei Med J ; 61(9): 780-788, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882762

RESUMO

PURPOSE: This research was designed to investigate how miR-542-5p regulates the progression of hyperglycemia and hyperlipoidemia. MATERIALS AND METHODS: An in vivo model with diabetic db/db mice and an in vitro model with forskolin/dexamethasone (FSK/DEX)-induced primary hepatocytes and HepG2 cells were employed in the study. Bioinformatics analysis was conducted to identify the expression of candidate miRNAs in the liver tissues of diabetic and control mice. H&E staining revealed liver morphology in diabetic and control mice. Pyruvate tolerance tests, insulin tolerance tests, and intraperitoneal glucose tolerance test were utilized to assess insulin resistance. ELISA was conducted to evaluate blood glucose and insulin levels. Red oil O staining showed lipid deposition in liver tissues. Luciferase reporter assay was used to depict binding between miR-542-5p and forkhead box O1 (FOXO1). RESULTS: MiR-542-5p expression was under-expressed in the livers of db/db mice. Further in vitro experiments revealed that FSK/DEX, which mimics the effects of glucagon and glucocorticoids, induced cellular glucose production in HepG2 cells and in primary hepatocytes cells. Notably, these changes were reversed by miR-542-5p. We found that transcription factor FOXO1 is a target of miR-542-5p. Further in vivo study indicated that miR-542-5p overexpression decreases FOXO1 expression, thereby reversing increases in blood glucose, blood lipids, and glucose-related enzymes in diabetic db/db mice. In contrast, anti-miR-542-5p exerted an adverse influence on blood glucose and blood lipid metabolism, and its stimulatory effects were significantly inhibited by sh-FOXO1 in normal control mice. CONCLUSION: Collectively, our results indicated that miR-542-5p inhibits hyperglycemia and hyperlipoidemia by targeting FOXO1.


Assuntos
Diabetes Mellitus Tipo 2/genética , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , MicroRNAs/genética , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Teste de Tolerância a Glucose , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hiperglicemia/metabolismo , Hiperlipidemias/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , MicroRNAs/metabolismo , MicroRNAs/farmacologia
5.
Diabetes Res Clin Pract ; 167: 108382, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32853686

RESUMO

Hyperglycemia with or without blood glucose in diabetes range is an emerging finding not uncommonly encountered in patients with COVID-19. Increasingly, all evidence currently available hints that both new-onset hyperglycemia without diabetes and new-onset diabetes in COVID-19 is associated with a poorer outcome compared with normoglycemic individuals and people with pre-existing diabetes.


Assuntos
Infecções por Coronavirus/mortalidade , Diabetes Mellitus/epidemiologia , Hiperglicemia/epidemiologia , Pneumonia Viral/mortalidade , Betacoronavirus , Glicemia/metabolismo , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/metabolismo , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Prognóstico
6.
PLoS One ; 15(8): e0237660, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841254

RESUMO

This study evaluated the influence of type 2 diabetes mellitus on bone loss, bone repair and cytokine production in hyperglycemic rats, treated or not with metformin. The animals were distributed as follow: Non-Hyperglycemic (NH), Non Hyperglycemic with Ligature (NH-L), Treated Non Hyperglycemic (TNH), Treated Non Hyperglycemic with Ligature Treated (TNH-L), Hyperglycemic (H), Treated Hyperglycemic (TH), Hyperglycemic with Ligature (H-L), Treated Hyperglycemic with Ligature (TH-L). At 40th day after induction of hyperglycemia, the groups NH-L, TNH-L, H-L, TH-L received a ligature to induce periodontitis. On the 69th, the TNH, TNH-L, TH, TH-L groups received metformin until the end of the study. Bone repair was evaluated at histometric and the expression levels of Sox9, RunX2 and Osterix. Analysis of the ex-vivo expression of TNF-α, IFN-γ, IL-12, IL-4, TGF-ß, IL-10, IL-6 and IL-17 were also evaluated. Metformin partially reverse induced bone loss in NH and H animals. Lower OPG/RANKL, increased OCN and TRAP expression were observed in hyperglycemic animals, and treatment with metformin partially reversed hyperglycemia on the OPG/RANKL, OPN and TRAP expression in the periodontitis. The expression of SOX9 and RunX2 were also decreased by hyperglycemia and metformin treatment. Increased ex vivo levels of TNF-α, IL-6, IL-4, IL-10 and IL-17 was observed. Hyperglycemia promoted increased IL-10 levels compared to non-hyperglycemic ones. Treatment of NH with metformin was able to mediate increased levels of TNF-α, IL-10 and IL-17, whereas for H an increase of TNF-α and IL-17 was detected in the 24- or 48-hour after stimulation with LPS. Ligature was able to induce increased levels of TNF-α and IL-17 in both NH and H. This study revealed the negative impact of hyperglycemia and/or treatment with metformin in the bone repair via inhibition of transcription factors associated with osteoblastic differentiation.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Hiperglicemia/complicações , Metformina/administração & dosagem , Periodontite/prevenção & controle , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/metabolismo , Processo Alveolar/citologia , Processo Alveolar/efeitos dos fármacos , Processo Alveolar/metabolismo , Processo Alveolar/patologia , Animais , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/genética , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Osteoblastos/fisiologia , Periodontite/etiologia , Periodontite/metabolismo , Ratos , Estreptozocina/toxicidade , Fatores de Transcrição/metabolismo
7.
Life Sci ; 260: 118339, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841660

RESUMO

AIMS: To design and screen a potent GLP-1/GIP/Gcg receptors triagonist with therapeutic potential in rodent animals with diabetes and obesity. MAIN METHODS: First, we obtained a 12-mer dual GIP/Gcg receptor agonist from a large combinatorial peptide library via high-throughput screening technique and then fused to the Exendin (9-39) to generate a potent GLP-1/GIP/Gcg triagonist. Further site fatty chain modification was performed to improve the druggability via enhancing in vivo stability and cyclic half-life. In vitro signaling and functional assays in cell lines expressing each receptor and in vivo efficacy evaluation in rodent model animals with hyperglycemia and obesity were all carefully performed. KEY FINDINGS: We screened and obtained a potent GLP-1/GIP/Gcg triagonist, termed XFL0, which promotes in vitro GLP-1, GIP, Gcg receptor activation comparable to native GLP-1, GIP and glucagon, respectively. Site-specific fatty acid modification significantly enhanced plasma stability of XFL0 and exhibited no obvious impact on receptor activation. The selected XFL0 conjugates termed XFL6, showed glucose-dependent insulin secretion and improved glucose tolerance by acting on all GLP-1, GIP and Gcg receptors in gene-deficient mice of which the effects were all significantly greater than any single receptor agonist. After chronic treatment in rodent animals with diabetes and obesity, XFL6 potently decreased body weight and food intake, ameliorated the hyperglycemia and hemoglobin A1c levels as well as the lipid metabolism and diabetic nephropathy related disorders. SIGNIFICANCE: XFL6, as a novel GLP-1/GIP/Gcg receptor triagonist, held potential to deliver outstanding improvement in correcting hyperglycemia, obesity and diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Desenho de Fármacos , Polipeptídeo Inibidor Gástrico/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/agonistas , Hiperglicemia/prevenção & controle , Obesidade/prevenção & controle , Animais , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Polipeptídeo Inibidor Gástrico/fisiologia , Glucagon/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia
8.
Diabetes Res Clin Pract ; 167: 108338, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32712122

RESUMO

AIMS: The objective of this study is to explore the association between documented diabetes, fasting plasma glucose (FPG), and the clinical outcomes of Coronavirus disease 2019 (COVID-19). METHODS: This retrospective study included 255 patients with COVID-19. Of these, 214 were admitted to isolation wards and 41were admitted to intensive care units (ICUs). Demographic, clinical, treatment, and laboratory data were collected and compared between ICU and non-ICU patients. Multivariable logistic regression models were used to explore the risk factors associated with poor clinical outcomes (ICU admission or death). RESULTS: There were significant changes in several clinical parameters in ICU patients (leukopenia, lymphopenia, elevated D-dimer, as well as higher levels of FPG, cardiac troponin, serum ferritin, IL-6, and high-sensitivity C-reactive protein)compared with non-ICU patients. The prevalence of known diabetes was substantially higher in ICU than non-ICU patients (31.7% vs. 17.8%, P = 0.0408). Multivariable regression analysis showed that a history of diabetes [odds ratio (OR), 0.099; 95% confidence interval (CI), 0.016-0.627; P = 0.014], high FPG at admission (OR, 1.587; 95% CI, 1.299-1.939, P < 0.001), high IL-6 (OR, 1.01; 95% CI, 1.002-1.018, P = 0.013), and D-dimer higher than 1 mg/L at admission (OR, 4.341; 95% CI, 1.139-16.547, P = 0.032) were independent predictors of poor outcomes. Cox proportional hazards analysis showed that compared with FPG < 7 mmol/L, FPG levels of 7.0-11.1 mmol/L and ≥ 11.1 mmol/L were associated with an increased hazard ratio (HR) for poor outcome (HR, 5.538 [95% CI, 2.269-13.51] and HR, 11.55 [95% CI, 4.45-29.99], respectively). CONCLUSION: Hyperglycemia and a history of diabetes on admission predicted poor clinical outcomes in COVID-19.


Assuntos
Glicemia/metabolismo , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Hiperglicemia/metabolismo , Unidades de Terapia Intensiva , Pneumonia Viral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Diabetes Mellitus/epidemiologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hospitalização , Humanos , Hiperglicemia/epidemiologia , Interleucina-6/metabolismo , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mortalidade , Análise Multivariada , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
10.
Life Sci ; 256: 117914, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512010

RESUMO

Hyperglycemia and oxidative stress are the primary stressors that elicit mitochondria specific cell stress in diabetes. Here we hypothesized that elevated level of ROS in high glucose (HG) environment, trigger mitochondrial stress by damaging mitochondrial DNA (mtDNA), altering inflammatory mediators, and neurodegenerative markers via stress signalling pathway in retinal ganglion cells (RGC-5). Mechanistically, our findings illustrated that the HG environment increases the ROS production in retinal cells leading to the disruption of antioxidant defence mechanism, and altering mitochondrial machinery such as an increase in loss of mitochondrial membrane potential (ΔΨm), increase in mitochondrial mass, and increase in mtDNA fragmentation. Furthermore, fragmented mtDNA escape from mitochondria into the cytosol, where it engaged with cyclic GMP-AMP synthase (cGAS) and stimulator of IFN gene (STING) phosphorylation and activate interferon regulatory factor 3 (IRF3) via ERK1/2-Akt-tuberin-mTOR dependent pathways. Our results further indicate that siRNA-mediated gene silencing of tuberin suppresses the strong downregulation of tuberin-mTOR-IRF3 activation. HG environment resulted in activation of IRF3, coinciding with the increased expression of inflammatory mediators and neurodegenerative markers. Pre-treatment of N-acetyl-l-cysteine (NAC) or ERK1/2 or phosphoinositide3-kinase (PI3-K)/Akt inhibitors in RGC-5 cells significantly reduced the HG-induced IRF3 expression and declined the expression of neurodegenerative markers. Collectively, our results demonstrates that HG-induced over production of ROS, disrupts the antioxidant defence mechanism and mitochondrial dysfunction, leading to alterations of inflammatory mediators and neurodegenerative markers through the ERK1/2-Akt-tuberin-mTOR dependent signalling pathway in RGC-5 cells.


Assuntos
Inibidores Enzimáticos/metabolismo , Glucose/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Ganglionares da Retina/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Acetilcisteína/metabolismo , Animais , DNA Mitocondrial , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperglicemia/metabolismo , Inflamação/metabolismo , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Potencial da Membrana Mitocondrial , Camundongos , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
11.
J Vis Exp ; (159)2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32510516

RESUMO

The insulin tolerance test is commonly used in metabolic studies to assess whole body insulin sensitivity in rodents. It is a relatively simple test that involves measurement of blood glucose levels over time following a single intraperitoneal injection of insulin. Given that it is performed in the conscious state and blood is often collected via a tail snip, it has the potential to elicit a stress response from animals due to anxiety associated with handling and blood collection. As such, a stress-induced rise in blood glucose can occur, making it difficult to detect and interpret the primary endpoint measure, namely an insulin-mediated reduction in blood glucose. This has been seen in many mouse strains, and is quite common in diabetic db/db mice, where glucose levels can increase, rather than decrease, after insulin administration. Here, we describe a method of acclimating mice to handling, injections and blood sampling prior to performing the insulin tolerance test. We find that this lowers stress-induced hyperglycemia and results in data that more accurately reflects whole body insulin sensitivity.


Assuntos
Aclimatação , Artefatos , Hiperglicemia/metabolismo , Hiperglicemia/psicologia , Resistência à Insulina , Estresse Psicológico/complicações , Estresse Psicológico/fisiopatologia , Animais , Glicemia/metabolismo , Hiperglicemia/sangue , Hiperglicemia/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos
12.
Diabetes Metab Syndr ; 14(4): 519-520, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32388332

RESUMO

BACKGROUND AND AIMS: Administration of corticosteroids is common in obstetric practice. In this concise review we queried on the effects of corticosteroids in pregnancies complicated by SARS-CoV-2. METHODS: We performed a literature search on PubMed, regarding the use of corticosteroids in patients with SARS-CoV-2 infection, in pregnancies complicated by SARS-CoV-2, as well as their impact on glycemia in pregnant women with or without diabetes. Furthermore, we searched for effects of SARS-CoV-2 and of other coronaviridae on insulin secretion and glycemia. RESULTS: SARS-CoV-2 infection appears to be a risk factor for complications in pregnancy. Corticosteroids may not be recommended for treating SARS-CoV-2 pneumonia but they may be needed for at-risk pregnancies. Corticosteroids in pregnancy have a diabetogenic potential. SARS-CoV-2 and other coronaviridae may have effects on glycemia. CONCLUSIONS: Caution should be exercised while using corticosteroids in pregnant women with COVID-19 requiring preterm delivery.


Assuntos
Corticosteroides/farmacologia , Infecções por Coronavirus/complicações , Diabetes Mellitus/fisiopatologia , Hiperglicemia/patologia , Hipoglicemia/patologia , Pneumonia Viral/complicações , Complicações Infecciosas na Gravidez/patologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Feminino , Homeostase , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hipoglicemia/etiologia , Hipoglicemia/metabolismo , Secreção de Insulina/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/etiologia , Complicações Infecciosas na Gravidez/metabolismo
13.
Eur J Clin Invest ; 50(7): e13262, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32383239

RESUMO

The Covid-19 pandemic confronted us with unknown clinical pictures, also in diabetology and endocrinology. Sharing clinical experiences is therefore of enormous importance. Actually, information about the care given in the Covid-19 ward (in contrast to that provided in the Emergency Room/ICU) is still sparse. The last weeks we built experience and gathered knowledge while giving hospital care to patients who had a pre-existent endocrine disease (and diabetes; most patients suffered from a type two diabetes). In our contribution we presented our insights obtained from this intensive period obtained in the Covid-19 ward.


Assuntos
Infecções por Coronavirus/terapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Pneumonia Viral/terapia , Insuficiência Adrenal/complicações , Insuficiência Adrenal/tratamento farmacológico , Bélgica , Betacoronavirus , Glicemia/metabolismo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Complicações do Diabetes , Diabetes Insípido/complicações , Diabetes Insípido/terapia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Gerenciamento Clínico , Hemoglobina A Glicada/metabolismo , Unidades Hospitalares , Hospitalização , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo
14.
Mol Cell ; 79(1): 43-53.e4, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32464093

RESUMO

The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Hiperglicemia/patologia , Insulina/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/análise , Gluconeogênese/genética , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Interleucina-10/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Período Pós-Prandial , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Proteína 2 do Complexo Esclerose Tuberosa/fisiologia
15.
J Med Virol ; 92(7): 770-775, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-145051

RESUMO

Coronavirus disease-2019 (COVID-19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Hidroxicloroquina/uso terapêutico , Hiperglicemia/tratamento farmacológico , Hiperglicemia/epidemiologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Anticorpos Neutralizantes/biossíntese , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Glucose/imunologia , Glucose/metabolismo , Glicosilação/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Incidência , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/virologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
16.
J Med Virol ; 92(7): 770-775, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-60510

RESUMO

Coronavirus disease-2019 (COVID-19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Hidroxicloroquina/uso terapêutico , Hiperglicemia/tratamento farmacológico , Hiperglicemia/epidemiologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Anticorpos Neutralizantes/biossíntese , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Glucose/imunologia , Glucose/metabolismo , Glicosilação/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Incidência , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/virologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
17.
Nat Commun ; 11(1): 1896, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312960

RESUMO

Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cells of T2D donors, without changes in voltage-dependent ion currents or granule trafficking. Dispersed α-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits α-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect α-cell insensitivity to paracrine inhibition at hyperglycemia.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Exocitose/fisiologia , Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Insulina/metabolismo , Imagem Óptica , Receptores de Somatostatina/metabolismo , Somatostatina/metabolismo
18.
Biochim Biophys Acta Mol Cell Res ; 1867(8): 118723, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32302668

RESUMO

A growing body of evidence suggests a role of proteolytic enzymes in the development of diabetic nephropathy. Cathepsin C (CatC) is a well-known regulator of inflammatory responses, but its involvement in podocyte and renal injury remains obscure. We used Zucker rats, a genetic model of metabolic syndrome and insulin resistance, to determine the presence, quantity, and activity of CatC in the urine. In addition to the animal study, we used two cellular models, immortalized human podocytes and primary rat podocytes, to determine mRNA and protein expression levels via RT-PCR, Western blot, and confocal microscopy, and to evaluate CatC activity. The role of CatC was analyzed in CatC-depleted podocytes using siRNA and glycolytic flux parameters were obtained from extracellular acidification rate (ECAR) measurements. In functional analyses, podocyte and glomerular permeability to albumin was determined. We found that podocytes express and secrete CatC, and a hyperglycemic environment increases CatC levels and activity. Both high glucose and non-specific activator of CatC phorbol 12-myristate 13-acetate (PMA) diminished nephrin, cofilin, and GLUT4 levels and induced cytoskeletal rearrangements, increasing albumin permeability in podocytes. These negative effects were completely reversed in CatC-depleted podocytes. Moreover, PMA, but not high glucose, increased glycolytic flux in podocytes. Finally, we demonstrated that CatC expression and activity are increased in the urine of diabetic Zucker rats. We propose a novel mechanism of podocyte injury in diabetes, providing deeper insight into the role of CatC in podocyte biology.


Assuntos
Catepsina C/metabolismo , Hiperglicemia/metabolismo , Rim/lesões , Rim/metabolismo , Podócitos/metabolismo , Animais , Catepsina C/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Humanos , Resistência à Insulina , Rim/patologia , Proteínas de Membrana , Síndrome Metabólica , Obesidade , Permeabilidade , RNA Mensageiro , Ratos , Ratos Zucker , Albumina Sérica/metabolismo , Transcriptoma
19.
Am J Physiol Endocrinol Metab ; 318(6): E856-E865, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315211

RESUMO

Obesity is associated with several chronic comorbidities, one of which is type 2 diabetes mellitus (T2DM). The pathogenesis of obesity and T2DM is influenced by alterations in diet macronutrient composition, which regulate energy expenditure, metabolic function, glucose homeostasis, and pancreatic islet cell biology. Recent studies suggest that increased intake of dietary carbohydrates plays a previously underappreciated role in the promotion of obesity and consequent metabolic dysfunction. Thus, in this study, we utilized mouse models to test the hypothesis that dietary carbohydrates modulate energetic, metabolic, and islet adaptions to high-fat diets. To address this, we exposed C57BL/6J mice to 12 wk of 3 eucaloric high-fat diets (>60% calories from fat) with varying total carbohydrate (1-20%) and sucrose (0-20%) content. Our results show that severe restriction of dietary carbohydrates characteristic of ketogenic diets reduces body fat accumulation, enhances energy expenditure, and reduces prevailing glycemia and insulin resistance compared with carbohydrate-rich, high-fat diets. Moreover, severe restriction of dietary carbohydrates also results in functional, morphological, and molecular changes in pancreatic islets highlighted by restricted capacity for ß-cell mass expansion and alterations in insulin secretory response. These studies support the hypothesis that low-carbohydrate/high-fat diets provide antiobesogenic benefits and suggest further evaluation of the effects of these diets on ß-cell biology in humans.


Assuntos
Dieta Hiperlipídica , Dieta Cetogênica , Carboidratos da Dieta , Metabolismo Energético , Hiperglicemia/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Obesidade/metabolismo , Adaptação Fisiológica , Tecido Adiposo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Dieta com Restrição de Gorduras , Sacarose na Dieta , Teste de Tolerância a Glucose , Secreção de Insulina , Camundongos
20.
Diabet Med ; 37(7): 1094-1102, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333691

RESUMO

The month of Ramadan forms one of the five pillars of the Muslim faith. Adult Muslims are obligated to keep daily fasts from dawn to sunset, with exceptions. This year Ramadan is due to begin on 23 April 2020 and the longest fast in the UK will be approximately 18 hours in length. In addition, due to the often high-calorie meals eaten to break the fast, Ramadan should be seen as a cycle of fasting and feasting. Ramadan fasting can impact those with diabetes, increasing the risk of hypoglycaemia, hyperglycaemia and dehydration. This year, Ramadan will occur during the global COVID-19 pandemic. Reports show that diabetes appears to be a risk factor for more severe disease with COVID-19. In addition, the UK experience has shown diabetes and COVID-19 is associated with dehydration, starvation ketosis, diabetic ketoacidosis and hyperosmolar hyperglycaemic state. This makes fasting in Ramadan particularly challenging for those Muslims with diabetes. Here, we discuss the implications of fasting in Ramadan during the COVID-19 pandemic and make recommendations for those with diabetes who wish to fast.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Jejum/metabolismo , Férias e Feriados , Islamismo , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Desidratação/epidemiologia , Desidratação/metabolismo , Desidratação/prevenção & controle , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Cetoacidose Diabética/epidemiologia , Dietoterapia , Gerenciamento Clínico , Jejum/efeitos adversos , Hidratação , Humanos , Hiperglicemia/epidemiologia , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Coma Hiperglicêmico Hiperosmolar não Cetótico/epidemiologia , Coma Hiperglicêmico Hiperosmolar não Cetótico/metabolismo , Hipoglicemia/epidemiologia , Hipoglicemia/metabolismo , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Cetose/epidemiologia , Cetose/metabolismo , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Medição de Risco , Reino Unido
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