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Type 1 diabetes (T1D) is a chronic disease characterized by self‐destruction of insulin‐producing pancreatic β cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue‐resident memory T (TRM) cells have been shown to contribute to cytotoxic T cell recruitment. TRM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of TRM cells in the development of T1D is investigated. The presence of TRM cells in pancreatic islets is observed in non‐obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid‐binding protein 4 (FABP4) potentiates the survival and alarming function of TRM cells by promoting fatty acid utilization and C‐X‐C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of TRM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction‐associated steatohepatitis (MASH) is the severe form of non‐alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin‐derived peptide ALY688 (ALY688‐SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell‐derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High‐fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688‐SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688‐SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin‐like signaling, including the AMP‐activated protein kinase and p38 mitogen‐activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688‐SR in mice did not influence body weight but significantly ameliorated CDAHF‐induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688‐SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro‐inflammatory and pro‐fibrotic genes as demonstrated by transcriptomic analysis. ALY688‐SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin‐mediated signaling. [ABSTRACT FROM AUTHOR]

Background and Purpose: Adipocyte fatty acid‐binding protein (A‐FABP) exacerbates cerebral ischaemia injury by disrupting the blood–brain barrier (BBB) through inducing expression of MMP‐9. Circulating A‐FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A‐FABP by a neutralizing antibody would alleviate ischaemic stroke outcome. Experimental Approach: Monoclonal antibodies (mAbs) against A‐FABP were generated using mouse hybridoma techniques. Binding affinities of a generated mAb named 6H2 towards various FABPs were determined using Biacore. Molecular docking studies were performed to characterize the 6H2‐A‐FABP complex structure and epitope. The therapeutic potential and safety of 6H2 were evaluated in mice with transient middle cerebral artery occlusion (MCAO) and healthy mice, respectively. Key Results: Replenishment of recombinant A‐FABP exaggerated the stroke outcome in A‐FABP‐deficient mice. 6H2 exhibited nanomolar to picomolar affinities to human and mouse A‐FABP, respectively, with minimal cross‐reactivities with heart and epidermal FABPs. 6H2 effectively neutralized JNK/c‐Jun activation elicited by A‐FABP and reduced MMP‐9 production in macrophages. Molecular docking suggested that 6H2 interacts with the "lid" of the fatty acid binding pocket of A‐FABP, thus likely hindering the binding of its substrates. In mice with transient MCAO, 6H2 significantly attenuated BBB disruption, cerebral oedema, infarction, neurological deficits, and decreased mortality associated with reduced cytokine and MMP‐9 production. Chronic 6H2 treatment showed no obvious adverse effects in healthy mice. Conclusion and Implications: These results establish circulating A‐FABP as a viable therapeutic target for ischaemic stroke, and provide a highly promising antibody drug candidate with high affinity and specificity. [ABSTRACT FROM AUTHOR]

Objective: Baseline circulating thrombospondin‐2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. Design: Serum TSP2 levels were measured in participants from a randomized, open‐label intervention study, at baseline and after 24‐weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration‐controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. Patients and Measurements: Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p =.012), CAP (p =.015) and LS (p =.011) after 24 weeks. Results: Serum TSP2 level decreased significantly from baseline in dapagliflozin‐treated participants (p =.035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r =.487, p =.006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. Conclusions: Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes. [ABSTRACT FROM AUTHOR]

In the process of electric power transmission, the defects in the copper wire interact with the electrons which results in a thermal effect, accordingly, causing the changes of microstructure and properties of the copper wire. Herein, the evolution of microstructure, strength, and electrical conductivity of the oxygen‐free copper wires annealed at different temperatures is investigated. In addition, the effects of various microstructures on strength and electrical conductivity are quantitatively revealed. In the low‐temperature region (80–150 °C), dislocation recovery is the main reason for the decrease in strength; while, the increase in electrical conductivity is mainly due to the decrease in dislocation density and the transformation of grain boundary from nonequilibrium state to equilibrium state. In the high‐temperature region (above 210 °C), the strength loss is mainly related to the increasing recrystallized grain size and the disappearance of dislocations in the recrystallized region. The increase in electrical conductivity is mainly attributed to the significant decrease in grain boundary density and the further recovery of dislocations. [ABSTRACT FROM AUTHOR]

Dysfunctional triglyceride‐very low‐density lipoprotein (TG‐VLDL) metabolism is linked to metabolic‐associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG‐VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte‐specific deletion of MDM2 protects against high‐fat high‐cholesterol diet‐induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG‐VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein–protein interaction, which leads to reduced TG‐VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2‐ApoB interaction alleviates dietary‐induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG‐VLDL secretion. The effect of MDM2 on VLDL metabolism is p53‐independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG‐VLDL secretion in MAFLD. Inhibition of the MDM2‐ApoB interaction may represent a potential therapeutic approach for MAFLD treatment. [ABSTRACT FROM AUTHOR]

Although obesity occurs in most of the patients with type 2 diabetes (T2D), a fraction of patients with T2D are underweight or have normal weight. Several studies have linked the gut microbiome to obesity and T2D, but the role of gut microbiota in lean individuals with T2D having unique clinical characteristics remains unclear. A metagenomic and targeted metabolomic analysis is conducted in 182 lean and abdominally obese individuals with and without newly diagnosed T2D. The abundance of Akkermansia muciniphila (A. muciniphila) significantly decreases in lean individuals with T2D than without T2D, but not in the comparison of obese individuals with and without T2D. Its abundance correlates inversely with serum 3β‐chenodeoxycholic acid (βCDCA) levels and positively with insulin secretion and fibroblast growth factor 15/19 (FGF15/19) concentrations. The supplementation with A. muciniphila is sufficient to protect mice against high sucrose‐induced impairment of glucose intolerance by decreasing βCDCA and increasing insulin secretion and FGF15/19. Furthermore, βCDCA inhibits insulin secretion and FGF15/19 expression. These findings suggest that decreased abundance of A. muciniphila is linked to the impairment of insulin secretion and glucose homeostasis in lean T2D, paving the way for new therapeutic options for the prevention or treatment of diabetes. [ABSTRACT FROM AUTHOR]

Development of liver fibrosis results in drastic changes in the liver microenvironment, which in turn accelerates disease progression. Although the pathological function of various hepatic cells in fibrogenesis is identified, the crosstalk between them remains obscure. The present study demonstrates that hepatic expression of adipocyte fatty acid binding protein (A‐FABP) is induced especially in the liver sinusoidal endothelial cells (LSECs) in mice after bile duct ligation (BDL). Genetic ablation and pharmacological inhibition of A‐FABP attenuate BDL‐ or carbon tetrachloride‐induced liver fibrosis in mice associating with reduced collagen accumulation, LSEC capillarization, and hepatic stellate cell (HSC) activation. Mechanistically, elevated A‐FABP promotes LSEC capillarization by activating Hedgehog signaling, thus impairs the gatekeeper function of LSEC on HSC activation. LSEC‐derived A‐FABP also acts on HSCs in paracrine manner to potentiate the transactivation of transforming growth factor β1 (TGFβ1) by activating c‐Jun N‐terminal kinase (JNK)/c‐Jun signaling. Elevated TGFβ1 subsequently exaggerates liver fibrosis. These findings uncover a novel pathological mechanism of liver fibrosis in which LSEC‐derived A‐FABP is a key regulator modulating the onset and progression of the disease. Targeting A‐FABP may represent a potential approach against liver fibrosis. [ABSTRACT FROM AUTHOR]

Aim: To investigate the frequency, clinical phenotype, inflammatory cytokine levels and genetics of glutamic acid decarboxylase autoantibody (GADA)‐positive phenotypic youth‐onset type 2 diabetes. Materials and Methods: This nationwide, multicentre, cross‐sectional study included 5324 newly diagnosed subjects with phenotypic type 2 diabetes aged 15 years or older enrolled in the LADA China study. GADA was screened in 248 subjects with youth‐onset type 2 diabetes aged 15–29 years. Subjects who presented as GADA‐positive were defined as having latent autoimmune diabetes in youth (LADY). We added subjects with LADY, type 1 diabetes, type 2 diabetes and controls from the Diabetes Center of Central South University, and measured serum concentrations of interleukin‐6, lipocalin 2, high‐sensitivity C‐reactive protein, adiponectin and human leukocyte antigen (HLA) genotyping in subjects with LADY, age‐ and sex‐matched GADA‐negative type 2 diabetes, type 1 diabetes and controls. Results: Twenty‐nine of the 248 subjects (11.7%) were GADA positive. Compared with subjects with type 2 diabetes, subjects with LADY were less probable to have metabolic syndrome (27.6% vs. 59.4%; p =.001). The fasting C‐peptide levels tended to be lower in subjects with LADY than in subjects with type 2 diabetes, but the difference was not statistically significant (LADY vs. type 2 diabetes: 0.21 [0.17–0.64] vs. 0.47 [0.29–0.77] nmol/L; p =.11). The cytokine levels of subjects with LADY were indistinguishable from subjects with type 1 diabetes, but subjects with LADY presented increased adiponectin levels compared with subjects with type 2 diabetes after adjusting for age, sex and body mass index (7.19 [4.05–11.66] vs. 3.42 [2.35–5.74] μg/mL; p <.05). The frequency of total susceptible HLA genotypes (DR3/3, −3/9 and −9/9) in subjects with LADY and type 1 diabetes were similarly higher than controls (LADY and type 1 diabetes vs. controls: 21.4% and 30.8% vs. 2.6%, respectively; p <.001). Conclusions: A high GADA positivity was observed in youth‐onset type 2 diabetes subjects in China. As subjects with LADY had an increased susceptible HLA genetic load and different cytokine levels compared with subjects with type 2 diabetes, differentiating LADY from phenotypic type 2 diabetes subjects is important. [ABSTRACT FROM AUTHOR]

Vascular complications from diabetes often result in poor outcomes for patients, even after optimized interventions. Forkhead box protein O1 (FoxO1) is a key regulator of cellular metabolism and plays an important role in vessel formation and maturation. Alterations of FoxO1 occur in the cardiovascular system in diabetes, yet the role of FoxO1 in diabetic vascular complications is poorly understood. In Streptozotocin (STZ)‐induced type 1 diabetic rats, FoxO1 expression was up‐regulated in carotid arteries at 8 weeks of diabetes that was accompanied with adverse vascular remodelling characterized as increased wall thickness, carotid medial cross‐sectional area, media‐to‐lumen ratio and decreased carotid artery lumen area. This adverse vascular remodelling induced by hyperglycaemia in diabetic rats required FoxO1 activation as pharmacological inhibition of FoxO1 with 50mg/kg AS1842856 (AS) reversed vascular remodelling in type 1 diabetic rats. The adverse vascular remodelling in type 1 diabetes mellitus (T1DM) occurred concomitantly with increases in pro‐inflammatory factors, adhesion factors, apoptosis, NOD‐like receptor family protein‐3 inflammasome activation and the phenotypic switch of arterial smooth muscle cells, which were all reversed by AS. In addition, FoxO1 inhibition counteracted the down‐regulation of its upstream mediator PDK1 in T1DM. PDK1 activator reduced FoxO1 nuclear translocation, which serves as the basis for subsequent transcriptional regulation during hyperglycaemia. Taken together, our data suggest that FoxO1 is a critical trigger for type 1 diabetes‐induced vascular remodelling in rats, and inhibition of FoxO1 thus offers a potential therapeutic option for diabetes‐associated cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Lipocalin‐2 is a functional biomarker for acute and chronic kidney diseases, heart failure and obesity‐related medical complications. It is rapidly induced in epithelial cells under stress conditions, but constitutively produced from pre‐adipocytes and mature adipocytes. Measuring the lipocalin‐2 levels represents an effective approach for risk prediction, patient stratification and disease management. Nevertheless, due to ligand‐binding, post‐translational modification and protein‐protein interaction, lipocalin‐2 exists as multiple variants that elicit different pathophysiological functions. To characterize the specific structure‐functional relationships of lipocalin‐2 variants is critical for the development of biomarker assays with sufficient precision and reliability. Moreover, identifying the pathological forms of lipocalin‐2 will provide new therapeutic targets and treatment approaches for obesity‐related complications. [ABSTRACT FROM AUTHOR]

Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non‐obese insulin‐deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over‐activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1‐selective inhibitor AS1842856 was administered to streptozotocin‐induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non‐diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P <.05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Background & Aims: It is unknown how concomitant hepatic steatosis affects disease progression in chronic hepatitis B (CHB). Adipokines such as fibroblast growth factor 21 (FGF21) and adipocyte fatty acid‐binding protein (AFABP) have been associated with non‐alcoholic fatty liver disease. We determined the significance of these metabolic markers in CHB‐related liver injury. Methods: We recruited CHB patients on antiviral treatment for transient elastography assessment to determine liver stiffness (advanced fibrosis/cirrhosis, F3/F4, defined by EASL‐ALEH criteria) and controlled attenuation parameter (hepatic steatosis, defined as ≥ 248 dB/m). Plasma FGF‐21, AFABP and adiponectin levels were measured. Results: A total of 415 patients [mean age 59.6 years, 71.6% male, median treatment duration 6.2 years] were recruited. Patients with F3/F4 (N = 151) had lower FGF‐21 (11.7 vs 13.6 pg/mL, P = 0.055), higher AFABP (126.8 vs 84.1 pg/mL, P < 0.001) and HOMA‐IR (7.1 vs 5.1, P = 0.004) levels compared to those without F3/F4 (N = 264). Multivariate analysis showed that FGF‐21 level was associated with hepatic steatosis (OR 1.005, 95% CI 1.001‐1.009) and F3/F4 (OR 0.993, 95% CI 0.989‐0.998), while AFABP level (OR 1.001, 95% CI 1‐1.002), body mass index (BMI) (OR 1.107, 95% CI 1.037‐1.182) and presence of diabetes mellitus (OR 2.059, 95% CI 1.206‐3.516) were associated with F3/F4. With the combined presence of BMI ≥ 25 kg/m2, diabetes and AFABP > 105.9 pg/mL, the odds ratio for F3/F4 was 3.712 (95% CI 1.364‐10.105, P = 0.010). Conclusions: Low FGF‐21 and high AFABP levels were associated with advanced fibrosis/cirrhosis in CHB patients on antiviral treatment. Plasma AFABP, together with other metabolic risk factors, may aid identification of patients lacking fibrosis improvement during antiviral treatment. [ABSTRACT FROM AUTHOR]

Abstract: Organic field‐effect transistors (OFETs)‐based sensors have a great potential to be integrated with the next generation smart surgical tools for monitoring different real‐time signals during surgery. However, allowing ultraflexible OFETs to have compatibility with standard medical sterilization procedures remains challenging. A novel capsule‐like OFET structure is demonstrated by utilizing the fluoropolymer CYTOP to serve both encapsulation and peeling‐off enhancement purposes. By adapting a thermally stable organic semiconductor, 2,10‐diphenylbis[1]benzothieno[2,3‐d;2′,3′‐d′]naphtho[2,3‐b;6,7‐b′]dithiophene (DPh‐BBTNDT), these devices show excellent stability in their electrical performance after sterilizing under boiling water and 100 °C‐saturated steam for 30 min. The ultrathin thickness (630 nm) enables the device to have superb mechanical flexibility with smallest bending radius down to 1.5 µm, which is essential for application on the highly tortuous medical catheter inside the human body. By immobilizing anti‐human C‐reactive protein (CRP) (an inflammation biomarker) monoclonal antibody on an extended gate of the OFET, a sensitivity for detecting CRP antigen down to 1 µg mL−1 can be achieved. An ecofriendly water floatation method realized by employing the wettability difference between CYTOP and polyacrylonitrile (PAN) can be used to transfer the device on a ventricular catheter, which successfully distinguishes an inflammatory patient from a healthy one. [ABSTRACT FROM AUTHOR]

Background and Purpose: Increasing energy expenditure through adipocyte thermogenesis is generally accepted as a promising strategy to mitigate obesity and its related diseases. However, few clinically effective and safe agents are known to promote adipocyte thermogenesis. In this study, 20 traditional Chinese herbal medicines were screened to examine whether they induced adipocyte thermogenesis.Experimental Approach: The effects of Chinese herbal medicines or components isolated from extracts of A. membranaceus, on adipocyte thermogenesis were analysed by assessing expression of uncoupling protein 1 (UCP1) by qPCR. Eight-week-old C57BL6/J male mice were fed a high-fat diet for 8 weeks and then randomized to two groups treated with vehicle or formononetin for another 8 weeks. Glucose tolerance tests and staining of adipose tissue with haematoxylin and eosin were carried out. Whole-body oxygen consumption was measured with an open-circuit indirect calorimetry system.Key Results: Extracts of A. membranaceus increased expression of Ucp1 in primary cultures of mouse adipocytes. Formononetin was the only known component of A. membranaceus extracts to increase adipocyte Ucp1 expression. Diet-induced obese mice treated with formononetin gained less weight and showed higher energy expenditure than untreated mice. In addition, formononetin binds directly with PPARγ.Conclusions and Implication: Taken together, our study demonstrates that the Chinese herbal medicine from A. membranaceus and its constituent formononetin have the potential to reduce obesity and associated metabolic disorders. Our results suggest that formononetin regulates adipocyte thermogenesis as a non-classical PPARγ agonist. [ABSTRACT FROM AUTHOR]

Abstract: Activation of brown adipose tissue (BAT) and beige fat by cold increases energy expenditure. Although their activation is known to be differentially regulated in part by hypothalamus, the underlying neural pathways and populations remain poorly characterized. Here, we show that activation of rat‐insulin‐promoter‐Cre (RIP‐Cre) neurons in ventromedial hypothalamus (VMH) preferentially promotes recruitment of beige fat via a selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue (sWAT), but has no effect on BAT. Genetic ablation of APPL2 in RIP‐Cre neurons diminishes beiging in sWAT without affecting BAT, leading to cold intolerance and obesity in mice. Such defects are reversed by activation of RIP‐Cre neurons, inactivation of VMH AMPK, or treatment with a β3‐adrenergic receptor agonist. Hypothalamic APPL2 enhances neuronal activation in VMH RIP‐Cre neurons and raphe pallidus, thereby eliciting SNS outflow to sWAT and subsequent beiging. These data suggest that beige fat can be selectively activated by VMH RIP‐Cre neurons, in which the APPL2–AMPK signaling axis is crucial for this defending mechanism to cold and obesity. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Lipocalin‐2 is a pro‐inflammatory molecule characterized by a highly diversified pattern of expression and structure–functional relationships. In vivo, this molecule exists as multiple variants due to post‐translational modifications and/or protein–protein interactions. Lipocalin‐2 is modified by polyamination, which enhances the clearance of this protein from the circulation and prevents its excessive accumulation in tissues. On the other hand, animal studies suggest that non‐polyaminated lipocalin‐2 (npLcn2) plays a causal role in the pathogenesis of obesity‐associated medical complications. The present study examined the presence of npLcn2 in samples from healthy volunteers or patients with cardiac abnormalities and evaluated npLcn2 as a biomarker for cardiometabolic risk assessment. Methods and results: Immunoassays were developed to quantify npLcn2 in blood and urine samples collected from 100 volunteers (59 men and 41 women), or venous plasma and pericardial fluid samples obtained from 37 cardiothoracic surgery patients. In healthy volunteers, npLcn2 levels in serum are significantly higher in obese and overweight than in lean subjects. After adjustment for age, gender, smoking, and body mass index (BMI), serum npLcn2 levels are positively correlated with heart rate, circulating triglycerides, high‐sensitivity C‐reactive protein (hsCRP), and creatinine in plasma. The npLcn2 levels in urine are significantly increased in subjects with metabolic syndrome and positively correlated with BMI, heart rate, circulating triglycerides, and urinary aldosterone. In cardiothoracic surgery patients, the circulating concentrations of npLcn2 are higher (more than two‐fold) than those of healthy volunteers and positively correlated with the accumulation of this protein in the pericardial fluid. Heart failure patients exhibit excessive expression and distribution of npLcn2 in mesothelial cells and adipocytes of the parietal pericardium, which are significantly correlated with the elevated plasma levels of npLcn2, total cholesterol, and creatinine. Conclusions: Quantitative and qualitative evaluation of npLcn2 in human biofluid samples and tissue samples can be applied for risk assessment of healthy individuals and disease management of patients with obesity‐related cardiometabolic and renal complications. [ABSTRACT FROM AUTHOR]

Adipose tissue inflammation, characterized by augmented infiltration and altered polarization of macrophages, contributes to insulin resistance and its associated metabolic diseases. The NAD+-dependent deacetylase SIRT1 serves as a guardian against metabolic disorders in multiple tissues. To dissect the roles of SIRT1 in adipose tissues, metabolic phenotypes of mice with selective ablation of SIRT1 in adipocytes and myeloid cells were monitored. Compared to myeloid-specific SIRT1 depletion, mice with adipocyte-selective deletion of SIRT1 are more susceptible to diet-induced insulin resistance. The phenotypic changes in adipocyte-selective SIRT1 knockout mice are associated with an increased number of adipose-resident macrophages and their polarization toward the pro-inflammatory M1 subtype. Mechanistically, SIRT1 in adipocytes modulates expression and secretion of several adipokines, including adiponectin, MCP-1, and interleukin 4, which in turn alters recruitment and polarization of the macrophages in adipose tissues. In adipocytes, SIRT1 deacetylates the transcription factor NFATc1 and thereby enhances the binding of NFATc1 to the Il4 gene promoter. These findings suggest that adipocyte SIRT1 controls systemic glucose homeostasis and insulin sensitivity via the cross talk with adipose-resident macrophages. [ABSTRACT FROM AUTHOR]

Objective Fibroblast growth factor 21 ( FGF21) improves glucose and lipid metabolism, but high circulating levels are found in type 2 diabetes, suggesting FGF21 resistance. Serum FGF21 predicts incident diabetes, but its performance compared to established and emerging predictors is not known. We aimed to study the performance of FGF21 in diabetes prediction, relative to other adipokines and established risk factors including 2-h plasma glucose (2hG) during the oral glucose tolerance test ( OGTT). Design/Participants/Measurements We studied 1380 nondiabetic subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study using the second visit (2000-2004) as baseline when serum levels of FGF21 and other adipokines were measured. Glycaemic status was assessed by OGTT. Incident diabetes was defined as fasting glucose level ( FG) ≥ 7 mmol/l or 2hG ≥ 11·1 mmol/l or use of antidiabetic agents, at subsequent visits. Results A total of 123 participants developed diabetes over 9·0 years (median). On multivariable logistic regression analysis, FGF21 ( P = 0·003), adipocyte fatty acid-binding protein ( P = 0·003) and adiponectin ( P = 0·035) were independent predictors of incident diabetes. FGF21 had the best change in log likelihood when added to a diabetes prediction model ( DP) based on age, family history, smoking, hypertension, BMI, dyslipidaemia and FG. It also improved the area under ROC curve ( AUROC) of diabetes prediction ( DP) from 0·797 to 0·819 ( P = 0·0072), rendering its performance comparable to the ' DP + 2hG' model ( AUROC=0·838, P = 0·19). Conclusions As a biomarker for diabetes prediction, serum FGF21 appeared to be superior to other adipokines and, on its own, could be considered as an alternative to the OGTT. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is an autoimmune disease that afflicts millions of people worldwide. It occurs as the consequence of destruction of insulin-producing pancreatic β-cells triggered by genetic and environmental factors. The initiation and progression of the disease involves a complicated interaction between β-cells and immune cells of both innate and adaptive systems. Immune cells, such as T cells, macrophages and dendritic cells, have been well documented to play crucial roles in type 1 diabetes pathogenesis. However, the particular actions of neutrophils, which are the most plentiful immune cell type and the first immune cells responding to inflammation, in the etiology of this disease might indeed be unfairly ignored. Progress over the past decades shows that neutrophils might have essential effects on the onset and perpetuation of type 1 diabetes. Neutrophil-derived cytotoxic substances, including degranulation products, cytokines, reactive oxygen species and extracellular traps that are released during the process of neutrophil maturation or activation, could cause destruction to islet cells. In addition, these cells can initiate diabetogenic T cell response and promote type 1 diabetes development through cell-cell interactions with other immune and non-immune cells. Furthermore, relevant antineutrophil therapies have been shown to delay and dampen the progression of insulitis and autoimmune diabetes. Here, we discuss the relationship between neutrophils and autoimmune type 1 diabetes from the aforementioned aspects to better understand the roles of these cells in the initiation and development of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Alterations in lipids in muscle and plasma have been documented in insulin-resistant people with obesity. Whether these lipid alterations are a reflection of insulin resistance or obesity remains unclear.Methods: Nondiabetic sedentary individuals not treated with lipid-lowering medications were studied (n = 51). Subjects with body mass index (BMI) > 25 kg/m(2) (n = 28) were stratified based on median glucose infusion rate during a hyperinsulinemic-euglycemic clamp into insulin-sensitive and insulin-resistant groups (above and below median, obesity/insulin-sensitive and obesity/insulin-resistant, respectively). Lean individuals (n = 23) served as a reference group. Lipidomics was performed in muscle and plasma by liquid chromatography electrospray ionization-tandem mass spectrometry. Pathway analysis of gene array in muscle was performed in a subset (n = 35).Results: In muscle, insulin resistance was characterized by higher levels of C18:0 sphingolipids, while in plasma, higher levels of diacylglycerol and cholesterol ester, and lower levels of lysophosphatidylcholine and lysoalkylphosphatidylcholine, indicated insulin resistance, irrespective of overweight/obesity. The sphingolipid metabolism gene pathway was upregulated in muscle in insulin resistance independent of obesity. An overweight/obesity lipidomic signature was only apparent in plasma, predominated by higher triacylglycerol and lower plasmalogen species.Conclusions: Muscle C18:0 sphingolipids may play a role in insulin resistance independent of excess adiposity. [ABSTRACT FROM AUTHOR]

The plasticity of macrophages with selective functional phenotypes partially arises in respective to their microenvironment. Tumor-associated macrophages (TAMs) may promote disease progression with tumor specific manner. Here we report that in pediatric malignant soft-tissue tumors, the presence of TAMs and expression of adiponectin (APN) are heterogeneous. Both APN and TAMs had high expression in rhabdomyosarcoma, especially in the malignant subtype, alveolar rhabdomyosarcoma. To investigate the mode of action of APN on TAM activation, a murine MN/MCA1 sarcoma model was used. The Results revealed that exogenous APN had no effect on MN/MCA1 proliferation but tumor size was markedly reduced in apn−/− mice versus WT controls. The accumulation of TAMs in apn−/− mice was also reduced which correlated to downregulated serum levels of MCP-1. Likewise, TAMs in apn−/− mice exhibited a M1-like phenotype, characterized by increase in MHC IIhigh population and M1 phenotypic markers, such as iNOS gene and serum TNF-α accompanied by a decrease in M2 markers, namely YM1 gene and serum IL-10. In addition, APN deficiency increased the number of CD4+ T cells, CD8+ T cells and NK cells in tumors and reduced tumor metastasis. The altered phenotype of TAMs in apn−/− mice was associated with a marked decrease in phospho-p38 and treatment with a p38 MAPK inhibitor significantly reduced tumor size and increased MHC II expression on TAMs in WT mice, implying p38 MAPK signaling pathway may contribute to APN-mediated TAM polarization. Collectively, our findings suggest that APN may have a potential role in regulating soft tissue sarcoma growth. [ABSTRACT FROM AUTHOR]

Obesity is considered to be a chronic inflammatory state in which the dysfunction of adipose tissue plays a central role. The adipokines, which are cytokines secreted by adipose tissue, are key links between obesity and related diseases such as metabolic syndrome and atherosclerosis. LCN2 and A-FABP, both of which are major adipokines predominantly produced in adipose tissue, have recently been shown to be pivotal modulators of vascular function. However, different adipokines modulate the development of atherosclerosis in distinctive manners, which are partly attributable to their unique regulatory mechanisms and functions. This review highlights recent advances in the understanding of the role of two adipokines in mediating chronic inflammation and the pathogenesis of atherosclerosis. [ABSTRACT FROM AUTHOR]

While molecular regulation of insulin granule exocytosis is relatively well understood, insulin granule biogenesis and maturation and its influence on glucose homeostasis are relatively unclear. Here, we identify a novel protein highly expressed in insulin-secreting cells and name it BIG3 due to its similarity to BIG/ GBF of the Arf- GTP exchange factor (GEF) family. BIG3 is predominantly localized to insulin- and clathrin-positive trans-Golgi network ( TGN) compartments. BIG3-deficient insulin-secreting cells display increased insulin content and granule number and elevated insulin secretion upon stimulation. Moreover, BIG3 deficiency results in faster processing of proinsulin to insulin and chromogranin A to β-granin in β-cells. BIG3-knockout mice exhibit postprandial hyperinsulinemia, hyperglycemia, impaired glucose tolerance, and insulin resistance. Collectively, these results demonstrate that BIG3 negatively modulates insulin granule biogenesis and insulin secretion and participates in the regulation of systemic glucose homeostasis. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease ( NAFLD) describes a spectrum of liver conditions from simple steatosis, steatohepatitis to end-stage liver disease. The prevalence of NAFLD has been on the rise in many parts of the world, including Asia, and NAFLD is now the liver disease associated with the highest mortality, consequent to the increased risk of cardiovascular diseases and hepatocellular carcinoma. Whereas NAFLD is an independent risk factor for type 2 diabetes, increased hepatic and peripheral insulin resistance contribute to the pathogenesis of both NAFLD and diabetes, which are associated with enhanced cardiovascular risk. Studies in humans and animal models have suggested obesity as the common link of these two diseases, likely mediated by adipose tissue inflammation and dysregulated adipokine production in obesity. In the present review, we discuss recent advances in our understanding of the role of several novel adipokines (adiponectin, adipocyte fatty acid binding protein and fibroblast growth factor-21) in the pathophysiology of NAFLD and diabetes, as well as their use as potential biomarkers and therapeutic targets for dysglycemia in NAFLD patients. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 ( FGF21), a metabolic hormone predominantly produced by the liver, is also expressed in adipocytes and the pancreas. It regulates glucose and lipid metabolism through pleiotropic actions in these tissues and the brain. In mice, fasting leads to increased PPAR-α mediated expression of FGF21 in the liver where it stimulates gluconeogenesis, fatty acid oxidation, and ketogenesis, as an adaptive response to fasting and starvation. In the fed state, FGF21 acts as an autocrine factor in adipocytes, regulating the activity of PPAR-γ through a feed-forward loop mechanism. Administration of recombinant FGF21 has been shown to confer multiple metabolic benefits on insulin sensitivity, blood glucose, lipid profile and body weight in obese mice and diabetic monkeys, without mitogenic or other side effects. Such findings highlight the potential role of FGF21 as a therapeutic agent for obesity-related medical conditions. However, in human studies, high circulating FGF21 levels are found in obesity and its related cardiometabolic disorders including the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease and coronary artery disease. These findings may indicate the presence of FGF21 resistance or compensatory responses to the underlying metabolic stress, and imply the need for supraphysiological doses of FGF21 to achieve therapeutic efficacy. On the other hand, serum FGF21 has been implicated as a potential biomarker for the early detection of these cardiometabolic disorders. This review summarizes recent developments in the understanding of FGF21, from physiological and clinical perspectives. [ABSTRACT FROM AUTHOR]

Abstract: G protein-coupled receptor 116 (GPR116) is a novel member of the G protein-coupled receptors and its function is largely unknown. To investigate the physiological function of GPR116 in vivo, we generated adipose tissue specific conditional Gpr116 knockout mice (CKO) and fed them on standard chow or high fat diets. Selective deletion of Gpr116 in adipose tissue caused a pronounced glucose intolerance and insulin resistance in mice, especially when challenged with a high fat diet. Biochemical analysis revealed a more severe hepatosteatosis in CKO mice. Additionally, we found that CKO mice showed a lowered concentration of circulating adiponectin and an increased level of serum resistin. Our study suggests that GPR116 may play a critical role in controlling adipocyte biology and systemic energy homeostasis. [Copyright &y& Elsevier]

Summary Objectives Pigment epithelium-derived factor (PEDF) is secreted from the adipose tissue. It circulates at high concentrations, and was reported to play a causal role in obesity-induced insulin resistance and metabolic dysfunctions in mice. Previous cross-sectional studies also demonstrated plasma PEDF concentration correlated positively with systolic blood pressure (BP) and pulse pressure, and inversely with small artery elasticity. Here we investigated the relationship of plasma PEDF concentration with BP and incident hypertension in a 10-year prospective study. Methods Baseline plasma PEDF concentrations were measured by ELISA in 520 Chinese subjects, aged 51 ± 12 years, followed up long-term from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study. The association between plasma PEDF concentration and BP was investigated in both cross-sectional and prospective studies, using multiple linear regression and path analyses. Cox proportional hazards analysis was used to determine whether baseline PEDF concentration was independently related to the subsequent development of hypertension over 10 years. Results Baseline plasma concentrations of PEDF were higher in men ( P < 0·001), and were directly related to systolic BP at 2 and 5 years, and to diastolic BP at 2 years, after adjustment for covariates. Of the 386 normotensive subjects at baseline, high baseline PEDF concentration was predictive of incident hypertension, independent of the effects of age, sex, baseline BP and obesity parameters (hazard ratio: 1·135; 95% CI: 1·039-1·241; P = 0·005). Conclusion Our data suggest that plasma PEDF concentration is significantly associated with BP, and incident hypertension. PEDF may be involved in the pathogenesis of hypertension in humans. [ABSTRACT FROM AUTHOR]

Unlabelled: The global epidemic of obesity is accompanied by an increased prevalence of cardiovascular disease (CVD), in particular stroke and heart attack. Dysfunctional adipose tissue links obesity to CVD by secreting a multitude of bioactive lipids and pro-inflammatory factors (adipokines) with detrimental effects on the cardiovascular system. Adiponectin is one of the few adipokines that possesses multiple salutary effects on insulin sensitivity and cardiovascular health. Clinical investigations have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for CVD. In animals, elevation of plasma adiponectin by either pharmacological or genetic approaches alleviates obesity-induced endothelial dysfunction and hypertension, and also prevents atherosclerosis, myocardial infarction and diabetic cardiomyopathy. Furthermore, many therapeutic benefits of the peroxisome-proliferator activated receptor gamma agonists, the thiazolidinediones, are mediated by induction of adiponectin. Adiponectin protects cardiovascular health through its vasodilator, anti-apoptotic, anti-inflammatory and anti-oxidative activities in both cardiac and vascular cells. This review summarizes recent findings in the understanding of the physiological role and clinical relevance of adiponectin in cardiovascular health, and in the identification of the receptor and postreceptor signalling events that mediate the cardiovascular actions of adiponectin. It also discusses adiponectin-targeted drug discovery strategies for treating obesity, diabetes and CVD.Linked Articles: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Lipocalin-2 is a pro-inflammatory adipokine up-regulated in obese human subjects and animal models. Its circulating levels are positively correlated with the unfavourable lipid profiles, elevated blood pressure and insulin resistance index. Augmented lipocalin-2 has been found in patients with cardiovascular abnormalities.The present study was designed to investigate the role of lipocalin-2 in regulating endothelial function and vascular reactivity. EXPERIMENTAL APPROACH Wild-type and lipocalin-2 knockout (Lcn2-KO) mice were fed with either a standard chow or a high-fat diet. Blood pressures and endothelium-dependent relaxations/contractions were monitored at 2 week intervals. RESULTS Systolic blood pressure was elevated by high-fat diet in wild-type mice but not in Lcn2-KO mice. Endothelial dysfunction, reflected by the impaired endothelium-dependent relaxations to insulin and augmented endothelium-dependent contractions to ACh, was induced by high-fat diet in wild-type mice. In contrast, Lcn2-KO mice were largely protected from the deterioration of endothelial function caused by dietary challenges. The eNOS dimer/monomer ratio, NO bioavailability, basal and insulin-stimulated PKB/eNOS phosphorylation responses were higher in aortae of Lcn2-KO mice. Administration of lipocalin-2 attenuated endothelium-dependent relaxations to insulin and promoted endothelium-dependent contractions to ACh. It induced eNOS uncoupling and elevated COX expression in the arteries. Treatment with sulphaphenazole, a selective inhibitor of cytochrome P450 2C9, improved endothelial function in wild-type mice and blocked the effects of lipocalin-2 on both endothelium-dependent relaxations to insulin and endothelium-dependent contractions to ACh, as well as eNOS uncoupling. CONCLUSIONS Lipocalin-2, by modulating cytochrome P450 2C9 activity, is critically involved in diet-induced endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Background and Purpose: Adipocyte fatty acid-binding protein (A-FABP) is up-regulated in regenerated endothelial cells and modulates inflammatory responses in macrophages. Endothelial dysfunction accompanying regeneration is accelerated by hyperlipidaemia. Here, we investigate the contribution of A-FABP to the pathogenesis of endothelial dysfunction in the aorta of apolipoprotein E-deficient (ApoE(-/-) ) mice and in cultured human endothelial cells.Experimental Approach: A-FABP was measured in aortae of ApoE(-/-) mice and human endothelial cells by RT-PCR, immunostaining and immunoblotting. Total and phosphorylated forms of endothelial nitric oxide synthase (eNOS) were measured by immunoblotting. Changes in isometric tension were measured in rings of mice aortaeKey Results: A-FABP was expressed in aortic endothelium of ApoE(-/-) mice aged 12 weeks and older, but not at 8 weeks or in C57 wild-type mice. Reduced endothelium-dependent relaxations to acetylcholine, UK14304 (selective α(2) -adrenoceptor agonist) and A23187 (calcium ionophore) and decreased protein presence of phosphorylated and total eNOS were observed in aortae of 18 week-old ApoE(-/-) mice compared with age-matched controls. A 6 week treatment with the A-FABP inhibitor, BMS309403, started in 12 week-old mice, improved endothelial function, phosphorylated and total eNOS and reduced plasma triglyceride levels but did not affect endothelium-independent relaxations. The beneficial effect of BMS309403 on UK14304-induced relaxations was attenuated by Pertussis toxin. In cultured human microvascular endothelial cells, lipid-induced A-FABP expression was associated with reduced phosphorylated eNOS and NO production and was reversed by BMS309403.Conclusions and Implications: Elevated expression of A-FABP in endothelial cells contributes to their dysfunction both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

An understanding of the molecular mechanisms governing the survival of organ progenitor cells in vivo is crucial for in vitro tissue regeneration. Here, we have found that Xenopus appl1 and akt2 share a similar embryonic expression pattern, showing characteristic expression in the central nervous system as well as in the pancreas and part of the stomach/duodenum (SD) at tadpole stages of development. Specific knockdown of appl1 in endoderm or inhibition of akt activity did not affect the formation of endodermal organ primordia at tail bud stages of development, but led to a gut-coiling defect, strong apoptosis in endodermal organs, and pancreas and SD hypoplasia or even aplasia at tadpole stages of development. Furthermore, appl1 is required for akt phosphorylation and akt2 in turn can rescue appl1 knockdown phenotypes. Together, our data suggest that appl1-akt signaling is specifically required for the survival of pancreas and SD progenitor cells in Xenopus laevis embryos. Developmental Dynamics 239:2198-2207, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Objective Human resistin gene ( RETN) polymorphisms have been found to be associated with type 2 diabetes (T2DM), insulin resistance and/or obesity. We evaluated, in a 5-year prospective study, whether RETN polymorphisms could predict the progression of glycaemia in southern Chinese. Design and patients We conducted a systematic search for variants in RETN in 70 southern Chinese subjects. This was followed by the genotyping in 624 unrelated nondiabetic subjects of two polymorphisms, −420C→G and +62G→A, previously reported in cross-sectional studies to be associated with T2DM in Asians, to examine their relationship with the progression of glycaemia in this cohort. Results We identified 15 polymorphisms, including 2 novel but rare polymorphisms (−319G→A and +63G→C). Compared to subjects with the CC genotype, −420GG subjects had higher 2-h glucose (7·7 ± 1·8 vs. 7·2 ± 2·0 mmol/l, P = 0·011) and insulin (101·6 ± 69·5 vs. 79·8 ± 59·5 mU/l, P = 0·021) during an oral glucose tolerance test. Carriers of the +62A allele had higher body mass indices (25·3 ± 4·0 vs. 24·5 ± 3·6 kg/m2 in GG, P = 0·02) . The presence of the allele −420G (OR 2·15, 95% CI 1·28–3·60, P = 0·004) or +62A (OR1·86, 95% CI 1·08–3·21, P = 0·025) predicted the progression of glycaemia at Year 5, after adjustment for sex, age or body mass index. The haplotype G-A also conferred a higher risk of progression in glycaemia ( P = 0·002). Conclusion Our study would support the role of the resistin gene in obesity, insulin resistance and progression of glycaemia in southern Chinese. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) is an important regulator of adiposity and systemic energy metabolism. Here, we have investigated the effects of GH on production of adiponectin, an anti-diabetic and anti-atherogenic hormone secreted exclusively from adipocytes. Analysis using real time quantitative PCR revealed that GH significantly increased adiponectin gene expression in a dose-dependent manner. Time course study showed that the expression of adiponectin gene started to increase only after 30 h of GH treatment (10-8 M), suggesting it to be a chronic effect. GH-mediated induction of adiponectin gene expression was completely blocked by treatment with the Janus kinase2 (JAK2) inhibitor AG490 and the P38 mitogen activated protein (MAP) kinase inhibitor SB203580, while the specific inhibitors of phosphatidylinositol-3-kinase (LY294002) and p70S6 kinase (rapamycin) moderately enhanced GHs effect. Co-incubation of adipocytes with GH and the PPARγ agonist rosiglitazone produced additive effects on induction of adiponectin gene expression. These results collectively suggest that GH increases adiponectin gene expression through the JAK2-P38 MAP kinase pathway, and that elevation of adiponectin production might represent a novel mechanism by which GH regulates systemic energy metabolism and insulin sensitivity. [Copyright &y& Elsevier]

The SH3 domain of human AHI1 was cloned and expressed in Escherichia coli. The protein was purified by affinity and size-exclusion chromatography and was crystallized using the sitting-drop vapour-diffusion method at 293 K. A complete data set was collected to 2.5 Å resolution at 110 K. The crystal belonged to space group P41212, with unit-cell parameters a = 67.377, b = 67.377, c = 98.549 Å. [ABSTRACT FROM AUTHOR]

Background: Recent discoveries from animal models demonstrated that neutrophils can induce type 1 diabetes (T1D) through infiltrating into the islets. However, the evidence of their actions in T1D patients is relatively rare, and the change trend of neutrophil numbers and functions in different subtypes of diabetes has not been investigated.Methods: Patients with newly diagnosed T1D (n = 189), latent autoimmune diabetes in adults (LADA) (n = 86), T2D (n = 235), and healthy controls (n = 709) were enrolled. Circulating neutrophil counts were measured, and their correlations with clinical parameters were analysed. Neutrophils were isolated by density gradient centrifugation and magnetic bead cell sorting method. Neutrophil migration rate and chemokine levels in the blood were explored by trans-well and ELISA, respectively. Neutrophil phagocytosis rate, adhesion molecules and chemokine receptors expression were investigated by flow cytometry.Results: Compared with controls, neutrophil counts decreased in T1D patients but increased in T2D patients, with no change in LADA patients. The numbers showed a gradual increase trend from T1D, LADA to T2D. In autoimmune diabetes, neutrophil counts were associated with the number and titre of positive autoantibodies against β-cell antigens. No difference was found in neutrophil phagocytosis rate, but neutrophil migration in T1D patients was impaired and associated with CD62L expression, which was related closely to the titre of autoantibody.Conclusions: Neutrophil numbers and migration abilities displayed distinct levels in different types of diabetes. In T1D, CD62L seems to play an important role in the migration of neutrophils and β-cell autoimmunity. [ABSTRACT FROM AUTHOR]

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Regular exercise has both immediate and long-lasting benefits on cardiometabolic health, and has been recommended as a cornerstone of treatment in the management of diabetes and cardiovascular conditions. Exerkines, which are defined as humoral factors responsive to acute or chronic exercise, have emerged as important players conferring some of the multiple cardiometabolic benefits of exercise. Over the past decades, hundreds of exerkines released from skeletal muscle, heart, liver, adipose tissue, brain, and gut have been identified, and several exerkines (such as FGF21, IL-6, and adiponectin) have been exploited therapeutically as exercise mimetics for the treatment of various metabolic and cardiovascular diseases. Recent advances in metagenomics have led to the identification of gut microbiota, a so-called "hidden" metabolic organ, as an additional class of exerkines determining the efficacy of exercise in diabetes prevention, cardiac protection, and exercise performance. Furthermore, multiomics-based studies have shown the feasibility of using baseline exerkine signatures to predict individual responses to exercise with respect to metabolic and cardiorespiratory health. This review aims to explore the molecular pathways whereby exerkine networks mediate the cardiometabolic adaptations to exercise by fine-tuning inter-organ crosstalk, and discuss the roadmaps for translating exerkine-based discovery into the therapeutic application and personalized medicine in the management of the cardiometabolic disease., (© 2024. The Author(s).)

Background: Fibroblast growth factor 21 (FGF21) has demonstrated beneficial effects on lipid and carbohydrate metabolism. In cross-sectional studies, an association of raised circulating FGF21 levels with coronary heart disease (CHD) was found in some but not all studies. Here we investigated prospectively whether baseline serum FGF21 levels could predict incident CHD in subjects with type 2 diabetes mellitus and no known cardiovascular diseases., Methods and Results: Baseline serum FGF21 levels were measured in 3528 Chinese subjects with type 2 diabetes mellitus recruited from the Hong Kong West Diabetes Registry. The role of baseline serum FGF21 levels in predicting incident CHD over a median follow-up of 3.8 years was analyzed using Cox regression analysis. Among 3528 recruited subjects without known cardiovascular diseases, 147 (4.2%) developed CHD over a mean follow-up of 4 years. Baseline serum log-transformed FGF21 levels were significantly higher in those who had incident CHD than those who did not (222.7 pg/mL [92.8-438.4] versus 151.1 pg/mL [75.6-274.6]; P <0.001). On multivariable Cox regression analysis, baseline serum FGF21 levels, using an optimal cutoff of 206.22 pg/mL derived from our study, independently predicted incident CHD (hazard ratio, 1.55; 95% CI, 1.10-2.19; P =0.013) and significantly improved net reclassification index and integrated discrimination improvement after adjustment for conventional cardiovascular risk factors., Conclusions: We have demonstrated, for the first time, that serum FGF21 level is an independent predictor of incident CHD and might be usefully utilized as a biomarker for identifying type 2 diabetes mellitus subjects with raised CHD risk, for primary prevention., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Obesity is closely associated with various cardiovascular diseases (CVDs). Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of CVD. This study aimed to evaluate whether the 2 most abundant adipokines, adipocyte-fatty acid binding protein (A-FABP) and adiponectin, are independent risk factors predisposing to CVD., Method and Results: We investigated prospectively the 12-year development of CVD in relation to the baseline levels of A-FABP and adiponectin in a population-based community cohort comprising 1847 Chinese subjects recruited from the Hong Kong Cardiovascular Risk Factors Prevalence Study 2 (CRISPS 2) cohort without previous CVD. Baseline serum levels of A-FABP, adiponectin, and C-reactive protein (CRP), an established biomarker predictive of CVD, were measured. In all, 182 (9.9%) of the 1847 Chinese subjects developed CVD during a median follow-up of 9.4 years. The CVD group had more traditional risk factors, higher baseline levels of A-FABP and CRP (both P<0.001), but similar adiponectin levels (P=0.881) compared with the non-CVD group. In Cox regression analysis including both biomarkers, the adjusted HR for A-FABP and CRP for subjects above the optimal cutoff values were 1.57 (95% CI, 1.14 to 2.16; P=0.006) and 1.60 (95% CI, 1.12 to 2.27; P=0.01), respectively, after adjustment for traditional risk factors. The category-free net reclassification index, but not the c-statistic, showed improvement in predictive performance by the addition of A-FABP to the traditional risk factor model (P=0.017)., Conclusions: Circulating A-FABP level predicts the development of CVD after adjustment for traditional risk factors in a community-based cohort. Its clinical use for CVD prediction warrants further validation.

Background: Type 2 diabetes mellitus (DM) is associated with a decreased level of circulating endothelial progenitor cells (EPCs) and adiponectin. Experimental studies suggest a potential link between hypoadiponectinaemia and the depletion of the EPC level. This study investigated the relationships between adiponectin level and EPC in patients with type 2 DM., Methods: A total of 95 type 2 DM patients (58.5 ± 8.8 years, 42 men) and 95 age- and sex-matched healthy controls were recruited. Circulating EPC levels were determined by flow cytometry using CD133(+), CD34(+), CD133(+) /KDR(+) and CD34(+) /KDR(+) as surface markers. Plasma adiponectin levels were measured by enzyme-linked immunosorbent assay. EPC function was studied by in vitro tube formation and migration assay., Results: The levels of CD133(+) (p < 0.001) and CD133(+) /KDR(+) (p < 0.001) EPCs were independently associated with the presence of type 2 DM. The levels of CD34(+) (p = 0.004) and CD34(+) /KDR(+) (p = 0.013) EPCs were independently associated with haemoglobin A(1c). Nevertheless, there was no relationship between the number of EPCs and adiponectin level. Tube formation assay showed impaired pro-angiogenic function of EPC in DM patients compared with controls (p = 0.007). Interestingly, adiponectin supplementation (5 µg/mL) increased tube formation by 17.6% in EPCs from DM patients (p = 0.002). It also significantly enhanced cell migration by 35.9% in EPCs from DM patients (p = 0.01)., Conclusions: We detected no relationship between the reduction in the level of EPC and in the level of total adiponectin in blood from patients with type 2 diabetes. EPC from patients with diabetes were stimulated when exposed to adiponectin in the test tube, findings that warrant further study., (Copyright © 2011 John Wiley & Sons, Ltd.)