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1.
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
2.
Nat Commun ; 11(1): 4718, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948777

RESUMO

Disturbances in glucose homeostasis and low-grade chronic inflammation culminate into metabolic syndrome that increase the risk for the development of type 2 diabetes mellitus (T2DM). The recently discovered group 2 innate lymphoid cells (ILC2s) are capable of secreting copious amounts of type 2 cytokines to modulate metabolic homeostasis in adipose tissue. In this study, we have established that expression of Death Receptor 3 (DR3), a member of the TNF superfamily, on visceral adipose tissue (VAT)-derived murine and peripheral blood human ILC2s is inducible by IL-33. We demonstrate that DR3 engages the canonical and/or non-canonical NF-κB pathways, and thus stimulates naïve and co-stimulates IL-33-activated ILC2s. Importantly, DR3 engagement on ILC2s significantly ameliorates glucose tolerance, protects against insulin-resistance onset and remarkably reverses already established insulin-resistance. Taken together, these results convey the potent role of DR3 as an ILC2 regulator and introduce DR3 agonistic treatment as a novel therapeutic avenue for treating T2DM.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Linfócitos/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Adipócitos/metabolismo , Adolescente , Adulto , Idoso , Animais , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Glucose/metabolismo , Homeostase , Humanos , Imunidade Inata , Resistência à Insulina , Interleucina-33/metabolismo , Gordura Intra-Abdominal/metabolismo , Masculino , Síndrome Metabólica/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Membro 25 de Receptores de Fatores de Necrose Tumoral/uso terapêutico , Adulto Jovem
3.
Lancet Diabetes Endocrinol ; 8(10): 834-844, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32946820

RESUMO

BACKGROUND: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. METHODS: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1-4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391. FINDINGS: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [-10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference -0·2 [-0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference -0·4 [95% CI -0·5 to -0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference -1·8 [-2·7 to -0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference -218 [-353 to -82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference -1·41 [-2·6 to -0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group). INTERPRETATION: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. FUNDING: Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Adolescente , Adulto , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Método Duplo-Cego , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Agências Internacionais , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Adulto Jovem
4.
Diab Vasc Dis Res ; 17(7): 1479164120942119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32744067

RESUMO

Type 2 diabetes mellitus is a type of metabolic disorder characterized by hyperglycaemia with multiple serious complications, such as diabetic neuropathies, diabetic nephropathy, diabetic retinopathy, and diabetic foot. Platelet-derived growth factors are growth factors that regulate cell growth and division, playing a critical role in diabetes and its harmful complications. This review focused on the cellular mechanism of platelet-derived growth factors and their receptors on diabetes development. Furthermore, we raise some proper therapeutic molecular targets for the treatment of diabetes and its complications.


Assuntos
Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/uso terapêutico , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Transdução de Sinais
5.
N Engl J Med ; 383(8): 721-732, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32813948

RESUMO

BACKGROUND: Some studies have suggested that in people with type 2 diabetes, Roux-en-Y gastric bypass has therapeutic effects on metabolic function that are independent of weight loss. METHODS: We evaluated metabolic regulators of glucose homeostasis before and after matched (approximately 18%) weight loss induced by gastric bypass (surgery group) or diet alone (diet group) in 22 patients with obesity and diabetes. The primary outcome was the change in hepatic insulin sensitivity, assessed by infusion of insulin at low rates (stages 1 and 2 of a 3-stage hyperinsulinemic euglycemic pancreatic clamp). Secondary outcomes were changes in muscle insulin sensitivity, beta-cell function, and 24-hour plasma glucose and insulin profiles. RESULTS: Weight loss was associated with increases in mean suppression of glucose production from baseline, by 7.04 µmol per kilogram of fat-free mass per minute (95% confidence interval [CI], 4.74 to 9.33) in the diet group and by 7.02 µmol per kilogram of fat-free mass per minute (95% CI, 3.21 to 10.84) in the surgery group during clamp stage 1, and by 5.39 (95% CI, 2.44 to 8.34) and 5.37 (95% CI, 2.41 to 8.33) µmol per kilogram of fat-free mass per minute in the two groups, respectively, during clamp stage 2; there were no significant differences between the groups. Weight loss was associated with increased insulin-stimulated glucose disposal, from 30.5±15.9 to 61.6±13.0 µmol per kilogram of fat-free mass per minute in the diet group and from 29.4±12.6 to 54.5±10.4 µmol per kilogram of fat-free mass per minute in the surgery group; there was no significant difference between the groups. Weight loss increased beta-cell function (insulin secretion relative to insulin sensitivity) by 1.83 units (95% CI, 1.22 to 2.44) in the diet group and by 1.11 units (95% CI, 0.08 to 2.15) in the surgery group, with no significant difference between the groups, and it decreased the areas under the curve for 24-hour plasma glucose and insulin levels in both groups, with no significant difference between the groups. No major complications occurred in either group. CONCLUSIONS: In this study involving patients with obesity and type 2 diabetes, the metabolic benefits of gastric bypass surgery and diet were similar and were apparently related to weight loss itself, with no evident clinically important effects independent of weight loss. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02207777.).


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Derivação Gástrica , Obesidade/dietoterapia , Obesidade/cirurgia , Perda de Peso/fisiologia , Adulto , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/cirurgia , Feminino , Técnica Clamp de Glucose , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Estudos Prospectivos , Indução de Remissão
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 ; 258: 118243, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791154

RESUMO

AIMS: Although autophagy impairment is a well-established cause of muscle atrophy and P300 has recently been identified as an important regulator of autophagy, the effects of P300 on autophagy and muscle atrophy in type 2 diabetes (T2D) remain unexplored. We aimed at characterizing the role of P300 in diabetic muscle and its underlying mechanism. MAIN METHODS: Protein levels of phosphorylated P300, total P300, acetylated histone H3, LC3, p62 and myosin heavy chain, and mRNA levels of Atrogin-1 and MuRF1 were analyzed in palmitic acid (PA)-treated myotubes and db/db mice. Autophagic flux was assessed using transmission electron microscopy, immunofluorescence and mRFP-GFP-LC3 lentivirus transfection in cells. Muscle weight, blood glucose and grip strength were measured in mice. Hematoxylin and eosin (H&E) staining was performed to determine changes in muscle fiber size. To investigate the effects of P300 on autophagy and myofiber remodeling, a P300 specific inhibitor, c646, was utilized. 3-Methyladenine (3-MA) was utilized to inhibit autophagosomes formation, and chloroquine (CQ) was used to block autophagic flux. KEY FINDINGS: Phosphorylation of P300 in response to PA enhanced its activity and subsequently suppressed autophagic flux, leading to atrophy-related morphological and molecular changes in myotubes. Inhibition of P300 reestablished autophagic flux and ameliorated PA-induced myotubes atrophy. However, this effect was largely abolished by co-treatment with the autophagy inhibitor CQ. In vivo results demonstrated that inhibition of P300 partially rescued muscle wasting in db/db mice, accompanied with autophagy reactivation. SIGNIFICANCE: The findings revealed that T2D-induced overactivation of P300 contributes to muscle atrophy by blocking autophagic flux.


Assuntos
Autofagia/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Proteína p300 Associada a E1A/metabolismo , Atrofia Muscular/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Proteína p300 Associada a E1A/genética , Força da Mão/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Atrofia Muscular/genética , Atrofia Muscular/patologia , Mioblastos/metabolismo , Mioblastos/patologia
8.
Gene ; 761: 145036, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32777525

RESUMO

Lupinus albus γ-conglutin is proposed to positively affect glucose metabolism through inhibition of hepatic glucose production and insulin-mimetic activity; however, the action mechanism is not entirely known. Besides, most studies had focused on its effect on molecular targets directly related to glucose metabolism, and few studies have investigated how γ-conglutin may affect the liver gene expression or if it plays a role in other metabolic processes. Therefore, we investigated the influence of γ-conglutin on the liver transcriptome of streptozotocin-induced diabetic rats using DNA microarrays, ontological analyses, and quantitative PCR. Of the 22,000 genes evaluated, 803 and 173 were downregulated and upregulated, respectively. The ontological analyses of the differentially expressed genes revealed that among others, the mitochondria, microtubules, cytoskeleton, and oxidoreductase activity terms were enriched, implying a possible role of γ-conglutin on autophagy. To corroborate the microarray results, we selected and quantified, by PCR, the expression of two genes associated with autophagy (Atg7 and Snx18) and found their expression augmented two and threefold, respectively; indicating a higher autophagy activity in animals treated with γ-conglutin. Although complementary studies are required, our findings indicate for the first time that the hypoglycaemic effects of γ-conglutin may involve an autophagy induction mechanism, a pivotal process for the preservation of cell physiology and glucose homeostasis.


Assuntos
Colectinas/farmacologia , Lupinus/metabolismo , Soroglobulinas/farmacologia , Transcriptoma/genética , Animais , Glicemia/metabolismo , Colectinas/metabolismo , Colectinas/fisiologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Fígado/patologia , Lupinus/genética , Masculino , Proteínas de Plantas/genética , Ratos , Ratos Wistar , Sementes/metabolismo , Soroglobulinas/metabolismo , Soroglobulinas/fisiologia
9.
Diabetes Res Clin Pract ; 167: 108351, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32711001

RESUMO

AIMS: Coronavirus disease (COVID-19), also referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is instigated by a novel coronavirus. The disease was initially reported in Wuhan, China, in December 2019. Diabetes is a risk factor associated with adverse outcomes. Herein, our objective was to investigate the characteristics of laboratory findings of type 2 diabetes mellitus (T2DM) patients infected with SARS-CoV-2. METHODS: This was a retrospective study and included 80 T2DM patients of Jinling Hospital from 2010 to 2020, as well as 76 COVID-19 patients without T2DM and 55 COVID-19 patients with T2DM who were treated at Huoshen hill Hospital from February 11 to March 18, 2020. We then compared the differences in laboratory test results between the three groups. RESULTS: The levels of lymphocytes, uric acid (UA), and globulin in the T2DM group were significantly higher. In contrast, C-reactive protein (CRP), creatinine, and lactic dehydrogenase (LDH)levels were lower than those in the COVID-19 (p < 0.05) and COVID-19 + T2DM groups (p < 0.05). No considerable difference was observed regarding the levels of alanine aminotransferase (ALT), white blood cell (WBC), aspartate aminotransferase (AST), globulin, and blood urea nitrogen (BUN) in the three groups (p > 0.05). CONCLUSION: T2DM patients infected with SARS-CoV-2 showed decreased levels of body mass index (BMI), lymphocytes, UA, and albumin, and increased CRP levels. The decreased BMI, UA, and albumin levels may be associated with oxidative stress response and nutritional consumption. The decreased lymphocyte counts and increased CRP levels may be related to the infection.


Assuntos
Infecções por Coronavirus/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Pneumonia Viral/metabolismo , Idoso , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Betacoronavirus , Nitrogênio da Ureia Sanguínea , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Comorbidade , Infecções por Coronavirus/complicações , Creatinina/metabolismo , Diabetes Mellitus Tipo 2/complicações , Feminino , Globulinas/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Contagem de Linfócitos , Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/metabolismo , Ácido Úrico/metabolismo
10.
Diab Vasc Dis Res ; 17(4): 1479164120945675, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722929

RESUMO

Activation of the prostaglandin E2 receptor EP4 alters polarization of adipose tissue macrophages towards the anti-inflammatory M2 phenotype to suppress chronic inflammation. However, the role of EP4 signalling in pancreatic macrophages that affect insulin secretion is unclear. We examined the role of EP4 signalling in islet inflammation in vitro and in vivo. Obese diabetic db/db mice were treated with an EP4-selective agonist or vehicle for 4 weeks. Islet morphology did not significantly differ and glucose-stimulated insulin secretion was increased, whereas the pancreatic M1/M2 ratio was decreased in the EP4 agonist-treated group compared to the vehicle group. Because EP4 activation in MIN6 cells did not affect insulin secretion, we used a MIN6/macrophage co-culture system to evaluate the role of EP4 signalling in islet inflammation and subsequent inhibition of insulin release. Co-culture with M1-polarized macrophages markedly suppressed insulin expression in MIN6 cells; however, modulation of M1 polarization by the EP4 agonist significantly reversed the negative impact of co-cultivation on insulin production. The enhanced expression levels of pro-inflammatory cytokines in co-cultured MIN6 cells were markedly inhibited by EP4 agonist treatment of M1 macrophages. Thus, EP4 activation may suppress islet inflammation and protect ß-cell function by altering inflammatory macrophages in the diabetic pancreas.


Assuntos
Plasticidade Celular , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/metabolismo , Células Secretoras de Insulina/metabolismo , Macrófagos Peritoneais/metabolismo , Obesidade/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ativação de Macrófagos , Macrófagos Peritoneais/patologia , Camundongos , Obesidade/patologia , Fenótipo , Via Secretória , Transdução de Sinais
11.
Gene ; 761: 144971, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32707301

RESUMO

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes across the world. Recently, many circular RNAs (circRNAs) can exert a crucial role in DN progression. Our investigation was designed to study whether circ_0123996 was associated with DN and aimed to find out the underlying mechanisms. We observed that circ_0123996 expression was significantly increased in Type 2 diabetes (T2D) with DN in comparison to those patients without DN. Consistently, circ_0123996 was also obviously elevated in DN mice models and high glucose (HG)-incubated MMCs. Then, it was proved transfection of circ_0123996 siRNA in mice mesangial cells (MMCs) restrained MMCs proliferation greatly. In addition, it was demonstrated that decrease of circ_0123996 alleviated fibrosis-related protein expression including FN and Col-4 in MMCs. Next, it was confirmed by our study that circ_0123996 can serve as a sponge for miR-149-5p. miR-149-5p has been identified in several diseases including diabetes. At present, we observed that miR-149-5p was decreased in DN. Overexpression of miR-149-5p greatly repressed the effect of circ_0123996 on MMCs. BTB and CNC homology 1 (Bach1) is reported in various disease including some vascular diseases.Here, Bach1 was confirmed as a target of miR-149-5p. Circ_0123996 upregulated Bach1 expression and restrained MMCs proliferation and fibrosis through sponging miR-149-5p. Thus, it was revealed that circ_0123996 was involved in DN via sponging miR-149-5p and modulating Bach1 expression.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/biossíntese , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Nefropatias Diabéticas/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Adulto , Animais , Apoptose/fisiologia , Fatores de Transcrição de Zíper de Leucina Básica/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Circular/genética
12.
Life Sci ; 258: 118160, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730837

RESUMO

AIMS: Diabetic kidney disease (DKD) is a major prevalent chronic microvascular complication of type 2 diabetes (T2D). However, the present diagnostic indicators have limitations in the early diagnosis of DKD. This study concentrated on the sensitive and specific biomarkers in early diagnosis of DKD by metabolomics. MATERIALS AND METHODS: In this cross-sectional study, we performed a UPLC-MS based nontargeted metabolomics assay to profile the urinary metabolites in patients with DKD. Principal Component Analysis (PCA) and orthogonal partial least square discriminant analysis (OPLS-DA) were used for screening out the metabolomic variables. KEY FINDINGS: A total of 147 urinary metabolites were identified and 5 metabolic pathways were correlated with DKD pathophysiology. Pantothenate and coenzyme A biosynthesis pathway alteration was found the most prominent in DKD subjects. 4 metabolites, including dihydrouracil, ureidopropionic acid, pantothenic acid (PA), and adenosine 3',5'-diphosphate involved in pantothenate and CoA biosynthesis were significantly down-regulated. SIGNIFICANCE: Our finding indicates that PA would be served as a novel predictive biomarker associated with DKD development and progression. Furthermore, our results provide a promising prospect that PA and CoA biosynthesis pathway can be potential therapeutic targets for DKD treatment.


Assuntos
Vias Biossintéticas , Coenzima A/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Ácido Pantotênico/metabolismo , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/urina , Feminino , Humanos , Masculino , Espectrometria de Massas , Metaboloma , Pessoa de Meia-Idade
13.
Rev Med Suisse ; 16(697): 1186-1190, 2020 Jun 10.
Artigo em Francês | MEDLINE | ID: mdl-32520456

RESUMO

DPP-4 inhibitors are a well-established treatment for type 2 diabetes. They act by improving glycemic control through the incretin system. This class of molecules are well-tolerated and are associated with a low risk of hypoglycemia. Yet, their efficacy in glycemic control is rather moderate and they don't offer a benefit in terms of cardiovascular or renal protection. Even if they have a good safety profile, it is important to pay attention to the risk of cardiac failure and pancreatitis. This article provides an overview of the use of DPP-4 inhibitors in 2020.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/metabolismo
14.
Eur J Endocrinol ; 183(3): 285-295, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32567559

RESUMO

Objective: Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease. Design: To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort). Methods: A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed. Results: People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D. Conclusions: The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.


Assuntos
Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Genômica/métodos , Proteômica/métodos , Adulto , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Masculino , Estado Pré-Diabético/sangue , Estado Pré-Diabético/genética , Estado Pré-Diabético/metabolismo , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
15.
PLoS One ; 15(6): e0233364, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530969

RESUMO

Type 2 diabetes mellitus (T2DM) is among the most prevalent diseases in the world, affecting over 420 million people. The disease is marked by a poor metabolic effect of insulin leading to chronic hyperglycaemia, which can result in microvascular complications. It is widely known that postprandial glycaemia is reliant on the total carbohydrate content of a meal. However, the importance of the amount and the source of these carbohydrates remains controversial due to mechanisms other than insulin secretion. Oxidative stress, inflammation, pyruvate production and the quality of the intestinal microbiota, resulting in plasma lipopolysaccharides and short-chain fatty acids production, play an important role in blood sugar control and consequently in type 2 diabetes. Thus, we systematically reviewed the preclinical evidences on the impact of the amount and type of carbohydrate found in different diets and its influence on blood glucose levels in diabetic animals. We used a comprehensive and structured search in biomedical databases Medline (PubMed), Scopus and Web of Science, recovering and analyzing 27 original studies. Results showed that sucrose-rich diets deteriorated diabetic condition in animal models regardless of the total dietary carbohydrate content. On the other hand, fiber, particularly resistant starch, improved blood glucose parameters through direct and indirect mechanisms, such as delayed gastric emptying and improved gut microbiota. All studies used rodents as animal models and male animals were preferred over females. Improvements in T2DM parameters in animal models were more closely related to the type of dietary carbohydrate than to its content on a diet, i. e., resistant starch seems to be the most beneficial source for maintaining normoglycemia. Results show that current literature is at high risk of bias due to neglecting experimental methods.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Carboidratos da Dieta/análise , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Dieta/métodos , Carboidratos da Dieta/metabolismo , Fibras na Dieta/metabolismo , Sacarose na Dieta/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Masculino , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue
16.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 12-16, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476367

RESUMO

OBJECTIVE: To study the effects of acute and chronic exercise on phosphatidylinositol 3-hydroxy kinase(PI3K)/protein kinase B(AKT)/glucose transporter 4(GLUT4)signaling pathway in adipose tissue of rats with type 2 diabetes mellitus (T2DM) induced by high-fat diet and low-dose streptozotocin (STZ). METHODS: A total of 52 SD male rats aged 15 months were randomly divided into normal control group (13) and high-fat group (39), and fed normal and high fat diets. After 8 weeks, the body weight of the high-fat group was higher 20% than that of the normal control group. After a small dose of STZ, the blood glucose level was >16.7 mmol/l, and the model was successfully established. The diabetic model group was randomly divided into a diabetic control group (DC, n=13), a diabetic chronic exercise group (DCE, n=13), and a diabetic acute exercise group (DAE, n=13). The DCE group underwent an 8-week swimming exercise and the DAE group performed a one-time swimming exercise. Blood lipids, blood glucose and serum insulin levels were measured, and the contents of fat PI3K, AKT and GLUT4 proteins were determined by Western blot method. RESULTS: The levels of body weight, blood lipids, blood glucose and insulin in the diabetic group were significantly higher than those in the normal control group (P<0.01); high density liptein cholesterol(HDL-C) levels were decreased (P<0.05), and the expressions of PI3K, AKT and GLUT4 protein in adipose tissue were decreased (P<0.01). After 8 weeks of swimming training, the levels of body weight, blood lipids, blood glucose and insulin all were decreased significantly (P<0.01); while the level of HDL-C was increased (P<0.05), and the expressions of PI3K, AKT and GLUT4 protein were increased (P<0.01). After acute exercise, the levels of blood lipids, blood glucose and insulin were decreased (P<0.05); the level of HDL-C was increased (P<0.05), and the expression levels of fat PI3K, AKT and GLUT4 were increased significantly (P<0.05). CONCLUSION: ①High fat diet combined with low-dose STZ induced damage to the PI3K/AKT pathway in adipose tissue of T2DM rats reduced insulin sensitivity. ②Acute and chronic aerobic exercise can improve the disorder of glucose and lipid metabolism through PI3K/AKT pathway, and the chronic exercise is better than acute exercise.


Assuntos
Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/terapia , Resistência à Insulina , Condicionamento Físico Animal , Transdução de Sinais , Animais , Glicemia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Lipídeos/sangue , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Rev Assoc Med Bras (1992) ; 66(3): 334-337, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32520154

RESUMO

OBJECTIVE: To present the results of metabolic control in patients with type 2 Diabetes Mellitus from a private clinic in Northern Mexico. METHODS: This cross-sectional study used retrospective data obtained from electronic records from a private outpatient clinic at the end of 2018. Inclusion criteria were a diagnosis of T2DM and age ≥ 18 years. Baseline characteristics (age, gender, drug use) were reported. The achievement of glycated hemoglobin goals was established as <7%. RESULTS: A total of 3820 patients were evaluated. Their mean age was 59.86 years (+/-15.01). Of the population, 46.72% were men, and 53.28% were women. Glycated hemoglobin goals were adequate in 1872 (54%) patients. There were 3247 patients (85%) treated with oral medications, of which 1948 (60%) reported glycated hemoglobin less than 7%. Insulin use was reported in 573 (15%) patients, with 115 (20%) reporting glycated hemoglobin less than 7%. The most frequently used basal insulin was glargine in 401 (70%) patients. CONCLUSIONS: Our findings are clearly higher than the control rate reported by our national health surveys of 25% with glycated hemoglobin < 7%, but similar to that reported in other countries. The most commonly used therapeutic scheme was the combination of oral hypoglycemic agents. The percentage of cases that include insulin in their treatment was lower. Clinical inertia to insulin initiation and intensification has been defined as an important cause of this problem.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina Glargina/administração & dosagem , Insulina/administração & dosagem , Adulto , Idoso , Estudos Transversais , Quimioterapia Combinada , Feminino , Hemoglobina A Glicada , Humanos , Masculino , México , Pessoa de Meia-Idade , Estudos Retrospectivos
18.
PLoS Med ; 17(6): e1003102, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32530938

RESUMO

BACKGROUND: De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). METHODS AND FINDINGS: Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. CONCLUSIONS: Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos/metabolismo , Lipogênese , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Ácidos Graxos/sangue , Feminino , Humanos , Incidência , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Estudos Prospectivos
19.
Rev Col Bras Cir ; 47: e20202394, 2020.
Artigo em Português, Inglês | MEDLINE | ID: mdl-32555961

RESUMO

OBJETIVO: To evaluate the differences in the metabonomic profile of patients who achieved remisison of Type 2 diabetes mellitus (T2DM) after bariatric surgery in relation to those who presented maintenance or recurrence of this condition after surgery. METHODS: Thirthy-three patients with obesity and T2D were submitted to bariatric/metabolic surgery, among which, 22 experienced complete remission of T2D, and 11 did not experience remission in the postoperative period. Blood samples were taken in order to assess the serum profiles through a 1H NMR-based metabonomic study. RESULTS: The metabonomic model for the assessment of T2D recurrence presented an accuracy of 93.9%, sensibility of 81.8%, specificity of 100%, positive predictive value of 100% and a negative predictive value of 91.7%. CONCLUSION: bariatric surgery provide specific effects on the distribution of metabolites in those patients who achieved remission of T2DM, and this new distribution can be assessed through a metabonomic model.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Obesidade Mórbida/cirurgia , Biomarcadores/metabolismo , Glicemia/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/metabolismo , Valor Preditivo dos Testes , Indução de Remissão , Sensibilidade e Especificidade , Fatores de Tempo , Resultado do Tratamento , Perda de Peso
20.
Nat Commun ; 11(1): 2695, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483258

RESUMO

Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors that are characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority are located in non-coding DNA regions. This suggests that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Elementos Facilitadores Genéticos , Resistência à Insulina/genética , Músculo Esquelético/metabolismo , Obesidade/genética , Obesidade/metabolismo , Animais , Linhagem Celular , Cromatina/genética , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Obesidade/patologia , Ácido Palmítico/farmacologia , Fatores de Iniciação de Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/farmacologia
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