Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.

Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.

Hyperosmolarity Deserves More Attention in Critically Ill COVID-19 Patients with Diabetes: A Cohort-Based Study.

PURPOSE: Recently, a cluster of pneumonia caused by SARS-CoV-2 were identified in Wuhan and spread throughout the world. More information about risk factors for mortality of critically ill patients infected with SARS-CoV-2 remain to be evaluated. METHODS: We included adult patients confirmed with SARS-CoV-2 infection who were critically ill and admitted to the intensive care unit (ICU) of Tongji Hospital in Wuhan from Feb 4, 2020 to Feb 20, 2020. Data were collected and compared between patients who died and improved. Logistic regression was used to explore the risk factors for death of SARS-CoV-2-infected critically ill patients. RESULTS: A total of 160 critically ill patients with SARS-CoV-2 infection were included, of which 146 patients with appeared outcomes were included into the final analysis. The random blood glucose, serum sodium and effective plasma osmolarity were higher in deceased patients, especially in patients with diabetes. There were 7 patients with diabetes with hyperosmolar status and all of them were deceased. Multivariable regression revealed that older age (odds ratio 4.28, 95% CI 1.01-18.20; p = 0.049), higher C-reactive protein (odds ratio 1.01, 1.00-1.03; p = 0.024), higher interleukin-6 (odds ratio 1.01, 1.00-1.03; p = 0.0323), and d-dimer greater than 1 µg/mL (odds ratio 1.10, 1.01-1.20; p = 0.032) at admission were associated with increased odds of death. CONCLUSION: In conclusion, hyperosmolarity needs more attention and may contribute to mortality in critically ill patients with COVID-19, especially in those with diabetes. Older age, inflammatory response, and thrombosis may be risk factors for death of critically ill patients with SARS-CoV-2 infection.

Effects of soluble fiber supplementation on glycemic control in adults with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND & AIMS: Soluble dietary fiber is prompted as an important part of reducing blood glucose, ameliorating insulin resistance and controlling body weight. Thus, we performed this systematic review and meta-analysis of randomized controlled trials (RCTs) to quantify and synthesize the effects of soluble fiber supplementation on glycemic control and BMI modification in adults with type 2 diabetes. METHODS: We searched MEDLINE, Embase, Web of Science, ClinicalTrials.gov, and Cochrane databases until February 13, 2020 to identify RCTs that detected the effects of soluble fiber supplementation on glycemic control in adults with type 2 diabetes. A random-effects model with the generic inverse variance method was used to analyze the pooled data. The meta-regression and subgroup analyses were conducted to identify the variables that influenced the pooled results. The robust error meta-regression model was used to conduct the dose-response test. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was undertaken to evaluate the overall quality of the evidence. RESULTS: A total of 29 RCTs (33 comparisons) involving 1517 participants were identified in this meta-analysis. Results showed that supplemental soluble dietary fiber significantly reduced glycosylated hemoglobin (HbA1c, MD -0.63%, 95% CI [-0.90, -0.37]; P < 0.00001), fasting plasma glucose (FPG, MD -0.89 mmol/L, 95% CI [-1.28, -0.51]; P < 0.00001), fasting insulin (SMD -0.48, 95% CI [-0.80, -0.17]; P = 0.003), homeostatic model assessment of insulin resistance (HOMA-IR, SMD -0.58, 95% CI [-0.86, -0.29], P < 0.0001), fructosamine (SMD -1.03, 95% CI [-1.51, -0.55]; P < 0.0001), 2-h postprandial plasma glucose (SMD -0.74, 95% CI [-1.00, -0.48]; P < 0.00001), and BMI (SMD -0.31, 95% CI [-0.61, -0.00], P = 0.05) compared with control diets in patients with type 2 diabetes. Specifically, dose-response meta-analyses presented that a daily dosage of 7.6-8.3 g was recommended. CONCLUSION: Intake of soluble fiber supplementation is effective in improving glycemic control and BMI level in type 2 diabetes and is also a convenient way to help individuals meet standard dietary fiber needs. But due to the evidence of substantial heterogeneity in most pooled estimates, further long-term and high-quality RCTs are needed.

Vascular endothelial growth factor B promotes transendothelial fatty acid transport into skeletal muscle via histone modifications during catch-up growth.

Caloric restriction (CR) followed by refeeding, a phenomenon known as catch-up growth (CUG), results in excessive lipid deposition and insulin resistance in skeletal muscle, but the underlying mechanisms remain elusive. Recent reports have suggested that vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation by regulating endothelial fatty acid transport. Here, we found continuous activation of VEGF-B signaling and increased lipid uptake in skeletal muscle from CR to refeeding, as well as increased lipid deposition and impaired insulin sensitivity after refeeding in the skeletal muscle of CUG rodents. Inhibiting VEGF-B signaling reduced fatty acid uptake in and transport across endothelial cells. Knockdown of Vegfb in the tibialis anterior (TA) muscle of CUG mice significantly attenuated muscle lipid accumulation and ameliorated muscle insulin sensitivity by decreasing lipid uptake. Furthermore, we showed that aberrant histone methylation (H3K9me1) and acetylation (H3K14ac and H3K18ac) at the Vegfb promoter might be the main cause of persistent VEGF-B upregulation in skeletal muscle during CUG. Modifying these aberrant loci using their related enzymes [PHD finger protein 2 (PHF2) or E1A binding protein p300 (p300)] could regulate VEGF-B expression in vitro. Collectively, our findings indicate that VEGF-B can promote transendothelial lipid transport and lead to lipid overaccumulation and insulin resistance in skeletal muscle during CUG, which might be mediated by histone methylation and acetylation.

High fat-induced inflammation in vascular endothelium can be improved by Abelmoschus esculentus and metformin via increasing the expressions of miR-146a and miR-155.

BACKGROUND: Obesity is associated with chronic inflammation, which contributes to cardiovascular diseases. MicroRNAs (miRNAs) are reported to be involved in vascular inflammation and atherosclerosis. Abelmoschus esculentus (AE) and metformin have been suggested to improve inflammation in vascular system. The aim of this study is to evaluate whether miRNAs are involved in high fat induced endothelial inflammation, and whether AE and metformin improve endothelial inflammation by regulating miRNAs. METHODS: We established high fat treated rats and human aortic endothelial cells (HAECs). AE and metformin were added to explore their effects on endothelial inflammation induced by high fat and the possible mechanism. RESULTS: The vascular inflammatory genes were increased in rats treated with high fat diet. The decreased miR-146a and miR-155 were involved in endothelial inflammation induced by high fat through targeting IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6) and nuclear factor-κB p65 (NF-κB p65), respectively. While AE and metformin could ameliorate the endothelial inflammation by increasing miR-146a and miR-155. CONCLUSIONS: These results indicate that miR-146a and miR-155 play roles in the high fat induced endothelial inflammation, which could be potential therapeutic targets. AE and metformin can attenuate endothelial inflammation through regulating miR-146a and miR-155.

Low-glycemic index diets as an intervention for diabetes: a systematic review and meta-analysis.

BACKGROUND: Low-glycemic index (GI) diets are thought to reduce postprandial glycemia, resulting in more stable blood glucose concentrations. OBJECTIVE: We hypothesized that low-GI diets would be superior to other diet types in lowering measures of blood glucose control in people with type 1 or type 2 diabetes, or impaired glucose tolerance. METHODS: We searched PubMed, the Cochrane Library, EMBASE, and clinical trials registries for published and unpublished studies up until 1 March, 2019. We included 54 randomized controlled trials in adults or children with impaired glucose tolerance, type 1 diabetes, or type 2 diabetes. Continuous data were synthesized using a random effects, inverse variance model, and presented as standardized mean differences with 95% CIs. RESULTS: Low-GI diets were effective at reducing glycated hemoglobin (HbA1c), fasting glucose, BMI, total cholesterol, and LDL, but had no effect on fasting insulin, HOMA-IR, HDL, triglycerides, or insulin requirements. The reduction in fasting glucose and HbA1c was inversely correlated with body weight. The greatest reduction in fasting blood glucose was seen in the studies of the longest duration. CONCLUSIONS: Low-GI diets may be useful for glycemic control and may reduce body weight in people with prediabetes or diabetes.

In Silico Integration Approach Reveals Key MicroRNAs and Their Target Genes in Follicular Thyroid Carcinoma.

To better understand the molecular mechanism for the pathogenesis of follicular thyroid carcinoma (FTC), this study aimed at identifying key miRNAs and their target genes associated with FTC, as well as analyzing their interactions. Based on the gene microarray data GSE82208 and microRNA dataset GSE62054, the differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained using R and SAM software. The common DEMs from R and SAM were fed to three different bioinformatic tools, TargetScan, miRDB, and miRTarBase, respectively, to predict their biological targets. With DEGs intersected with target genes of DEMs, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed through the DAVID database. Then a protein-protein interaction (PPI) network was constructed by STRING. Finally, the module analysis for PPI network was performed by MCODE and BiNGO. A total of nine DEMs were identified, and their function might work through regulating hub genes in the PPI network especially KIT and EGFR. KEGG analysis showed that intersection genes were enriched in the PI3K-Akt signaling pathway and microRNAs in cancer. In conclusion, the study of miRNA-mRNA network would offer molecular support for differential diagnosis between malignant FTC and benign FTA, providing new insights into the potential targets for follicular thyroid carcinoma diagnosis and treatment.

Evaluation of Serum microRNAs in Patients with Diabetic Kidney Disease: A Nested Case-Controlled Study and Bioinformatics Analysis.

BACKGROUND Diabetic kidney disease (DKD) can result in end-stage kidney disease and renal failure. This study aimed to examine the expression of serum microRNAs (miRNAs), miR-20a, miR-99b, miR-122-5p, and miR-486-5p, and to use bioinformatics data to investigate the pathways involved in DKD. MATERIAL AND METHODS Serum miRNAs were obtained from 25 healthy volunteers, 50 patients with non-complicated type 2 diabetes mellitus (T2DM), and 42 patients with T2DM and DKD. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of serum miRNAs. Specificity and sensitivity of the association between serum miRNAs in DKD were evaluated by analysis of the receiver operating characteristic (ROC) area under the curve (AUC). Serum miRNAs and clinical parameters of the patients were compared. Bioinformatics data analysis accessed the miRNA targets involved in the pathways related to the pathogenesis of DKD. RESULTS Serum levels of miR-99b and miR-122 significantly increased, and mir-20a and miR-486 decreased in the DKD group compared with healthy controls. Serum levels of miR-20a, miR-99b, miR-486-5p, and miR-122-5p were significantly correlated with albuminuria, estimated glomerular filtration rate (eGFR), blood glucose and lipid profiles. ROC curve analysis showed that diagnostic accuracy of serum levels of miR-99b for DKD was superior to miR-486-5p, miR-122-5p, and miR-20a, resulting in AUCs of 0.895, 0.853, 0.80, and 0.697, respectively. These four miRNAs regulate several genes affecting oxidative stress, inflammation, and apoptosis. CONCLUSIONS Serum miR-99b, miR-486-5p, miR-122-5p, and miR-20a were differentially expressed in patients with T2DM and DKD and should be evaluated further as potential biomarkers for DKD.

Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis.

BACKGROUND: Several studies have linked vascular endothelial growth factors (VEGFs) with metabolic syndrome or its components. However, there has been no systematic appraisal of the findings of these studies to date. The current systematic review and meta-analysis was conducted to explore this association. METHODS: PubMed, EMBASE, the Cochrane library, and clinical trials registries were used to retrieve peer-reviewed clinical studies that had evaluated the association of VEGFs with metabolic syndrome or its components without applying language and date restrictions. The final search was performed on 29 September 2017. RESULTS: We included 32 studies in this systematic review and meta-analysis, of which 16 studies (19 study arms) were included in the meta-analysis and remaining studies were qualitatively assessed. Overall, VEGF-A, VEGF-B and VEGF-C were strongly associated with metabolic syndrome or its components. The components of metabolic syndrome varied in their association. Obesity was not correlated with increased VEGF-A expression (p = 0.12), whereas VEGF-B and VEGF-C expression was significantly higher in those with obesity. In contrast, hyperglycemia in type 1 diabetes was strongly associated with increased VEGF-A levels (p < 0.00001), as was type 2 diabetes (p = 0.0006). The studies included in the qualitative analysis similarly showed an increase in VEGF family expression in people with metabolic syndrome, and with its components. CONCLUSION: The increased concentrations of vascular endothelial growth factors are variably associated with metabolic syndrome or its components. Each VEGF protein has a unique set of associations with the disease state.

NADPH oxidase 4 and endothelial nitric oxide synthase contribute to endothelial dysfunction mediated by histone methylations in metabolic memory.

"Metabolic memory" is identified as a phenomenon that transient hyperglycemia can be remembered by vasculature for quite a long term even after reestablishment of normoglycemia. NADPH oxidases (Noxs) and endothelial nitric oxide synthase (eNOS) are important enzymatic sources of reactive oxygen species (ROS) in diabetic vasculature. The aim of this study is to explore the roles of epigenetics and ROS derived from Noxs and eNOS in the metabolic memory. In this study, we demonstrated that vascular ROS was continuously activated in endothelium induced by transient high glucose, as well as sustained vascular endothelial dysfunction. The Nox4 and uncoupled eNOS are the major sources of ROS, while inhibition of Nox4 and eNOS significantly attenuated oxidative stress and almost recovered the endothelial function in metabolic memory. Furthermore, the aberrant histone methylation (H3K4me1, H3K9me2, and H3K9me3) at promoters of Nox4 and eNOS are the main causes for the persistent up-regulation of these two genes. Modifying the histone methylation could reduce the expression levels of Nox4 and eNOS, thus obviously attenuating endothelial dysfunction. These results indicate that histone methylation of Nox4 and eNOS play a key role in metabolic memory and may be the potential intervention targets for metabolic memory.

The role of vascular endothelial growth factor-B in metabolic homoeostasis: current evidence.

It has been shown that adipose tissue and skeletal muscles in lean individuals respond to meal-induced hyperinsulinemia by increase in perfusion, the effect not observed in patients with metabolic syndrome. In conditions of hyperglycaemia and hypertriglyceridemia, this insufficient vascularization leads to the liberation of reactive oxygen species (ROS), and disruption of nitric oxide (NO) synthesis and endothelial signalling responsible for the uptake of circulating fatty acids (FAs), whose accumulation in skeletal muscles and adipose tissue is widely associated with the impairment of insulin signalling. While the angiogenic role of VEGF-A and its increased circulating concentrations in obesity have been widely confirmed, the data related to the metabolic role of VEGF-B are diverse. However, recent discoveries indicate that this growth factor may be a promising therapeutic agent in patients with metabolic syndrome. Preclinical studies agree over two crucial metabolic effects of VEGF-B: (i) regulation of FAs uptake and (ii) regulation of tissue perfusion via activation of VEGF-A/vascular endothelial growth factor receptor (VEGFR) 2 (VEGFR2) pathway. While in some preclinical high-fat diet studies, VEGF-B overexpression reverted glucose intolerance and stimulated fat burning, in others it further promoted accumulation of lipids and lipotoxicity. Data from clinical studies point out the changes in circulating or tissue expression levels of VEGF-B in obese compared with lean patients. Potentially beneficial effects of VEGF-B, achieved through enhanced blood flow (increased availability of insulin and glucose uptake in target organs) and decreased FAs uptake (prevention of lipotoxicity and improved insulin signalling), and its safety for clinical use, remain to be clarified through future translational research.