Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.

BACKGROUND & AIMS: Microvascular invasion (MVI), a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma (HCC), is only detectable by microscopic examination of the surgical specimen. We aimed to define a transcriptomic signature associated with MVI in HCC than can be applied to formalin-fixed paraffin-embedded (FFPE) biopsies for use in clinical practice. METHODS: To identify a gene expression signature related to MVI by using NanoString technology, we selected a set of 200 genes according to the literature and RNA-sequencing data obtained from a cohort of 150 frozen HCC samples previously published. We used 178 FFPE-archived HCC samples, including 109 surgical samples for the training set and 69 paired pre-operative biopsies for the validation set. In 14 cases of the training set, a paired biopsy was available and was also analyzed. RESULTS: We identified a 6-gene signature (ROS1, UGT2B7, FAS, ANGPTL7, GMNN, MKI67) strongly associated with MVI in the training set of FFPE surgical HCC samples, with 82% accuracy (sensitivity 82%, specificity 81%, AUC 0.82). The NanoString gene expression was highly correlated in 14 paired surgical/biopsy HCC samples (mean R: 0.97). In the validation set of 69 FFPE HCC biopsies, the 6-gene NanoString signature predicted MVI with 74% accuracy (sensitivity 73%, specificity 76%, AUC 0.74). Moreover, on multivariate analysis, the MVI signature was associated with overall survival in both sets (hazard ratio 2.29; 95% CI 1.03-5.07; p = 0.041). CONCLUSION: We defined a 6-gene signature that can accurately predict MVI in FFPE HCC biopsy samples, which is also associated with overall survival, although its survival impact must be confirmed by extensive study with further clinical data. LAY SUMMARY: Microvascular invasion, a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma, is only detectable by microscopic examination of a surgical specimen. In this study, we defined a relevant surrogate signature of microvascular invasion in hepatocellular carcinoma that may be applied in clinical practice with routine tumor biopsy and integrated into the therapeutic strategy.

Serum Angiopoietin-Like Protein 2 and NT-Pro BNP Levels and Their Associated Factors in Patients with Chronic Heart Failure Participating in a Phase III Cardiac Rehabilitation Program.

Angiopoietin-like protein 2 (ANGPTL2) promotes chronic inflammation and plays a key role in the pathogenesis of heart failure. Cardiac rehabilitation (CR) is an integral component of heart failure management and has been shown to have anti-inflammatory effects. However, ANGPTL2 concentration in chronic heart failure patients undergoing CR has not been evaluated. This study aimed to investigate serum ANGPTL2 levels and their associated factors and compare the results with those of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with chronic heart failure undergoing phase III CR.A total of 56 patients were enrolled. Clinical characteristics including body composition, grip strength, exercise tolerance, duration of CR, blood counts and biochemistry, and echocardiographic parameters were evaluated for their association with serum ANGPTL2 and NT-proBNP levels.The median (first and third quartiles) value of ANGPTL2 was 4.05 (2.70-5.57) ng/mL. Clinical parameters that correlated with serum ANGPTL2 levels were body weight, body mass index, body fat mass, body fat percentage, anaerobic threshold (AT), C-reactive protein, and total protein (TP), which were mostly distinct from those that correlated with serum NT-proBNP levels. A multivariate analysis revealed that AT and TP were independent factors related to ANGPTL2 levels, whereas age, left ventricular ejection fraction, and left atrial dimension were independently related to NT-proBNP levels.These observations suggest that CR increases the exercise tolerance and exhibits anti-inflammatory effects simultaneously, and this situation is reflected by decreased serum ANGPLT2 and TP levels. ANGPTL2 may be a useful marker of inflammation and impaired exercise tolerance in patients with chronic heart failure.

Acute consumption of pecans decreases angiopoietin-like protein-3 in healthy males: a secondary analysis of randomized controlled trials.

Angiopoietin-like proteins (ANGPTL)-3 and -4 regulate lipid metabolism, but the effect of tree nuts of varying fatty acid composition on post-meal responses is unknown. The purpose of the study was to conduct a secondary analysis of two studies on ANGPTL3 and -4 responses to meals containing different tree nuts. We hypothesized that the pecan-containing meal would mitigate postprandial rises in ANGPTL3 compared to the traditional meal without nuts in males, but not females. In addition, we hypothesized that there would be no other differences between any other treatments in ANGPTL3 or -4 responses. The two studies were double-blind, randomized crossover trials. Twenty-two adults (10=male, 12=female) completed study 1, which compared meals containing pecans vs. no nuts (control), and thirty adults (14=male, 16=female) completed study 2, which compared meals containing black walnuts, English walnuts (EW), or no nuts (control). Blood was collected at fasting, 30, 60, 120, and 180min postprandially. In study 1, ANGPTL3 was suppressed more in pecan vs. control in males (iAUC: -579.4±219.4 vs. -128.4±87.1pg/mL/3h, P<.05). In study 2, there was no difference in ANGPTL3 between black walnuts vs. EW, but ANGPTL3 was suppressed more in control vs. black walnuts in females only (iAUC: -196.4±138.4 vs. 102.1±90.1pg/mL/3h, P<.05). There were no differences in ANGPTL4 between treatments. In conclusion, adding pecans to a meal decreased ANGPTL3 in males, but not females. These data highlight the importance of investigating the impact of nutrients and sex on postprandial ANGPTL3 ad -4 responses to better understand their ability to reduce cardiovascular disease risk.

Association of betatrophin amounts with 25-(OH)D levels in patients with gestational diabetes mellitus.

ABSTRACT: To determine the association of betatrophin amounts with 25-(OH)D levels in gestational diabetes mellitus (GDM) patients, and to provide new targets for the prevention and treatment of GDM.This study included 40 GDM patients (GDM group) and 37 healthy pregnant women (control group). Betatrophin, 25-(OH)D, fasting blood glucose (FBG), HbA1c, hsCRP, and FINS levels in peripheral blood, as well as betatrophin and 25-(OH)D amounts in cord blood, were measured. Then, associations of betatrophin levels with 25-(OH)D amounts and other indexes were determined.Maternal (P = .011) and cord (P = .022) blood betatrophin levels were significantly lower in the GDM group compared with control group. Cord blood betatrophin levels were higher compared with maternal blood amounts in both the GDM and control groups (both P = .000). Serum betatrophin levels were positively associated with 25-(OH)D levels (r = 0.677, P = .000), but negatively associated with hsCRP (r = -0.335, P = .037) and HOMA-IR (r = -0.346, P = .031) levels in the GDM group. Fetal weight was higher in the GDM group compared with control group (P = .023), and negatively associated with cord blood betatrophin amounts in the GDM group (r = -0.342, P = .031). However, cord blood betatrophin levels were not significantly associated with body length, Apgar score, and cord blood 25-(OH)D levels in the GDM group (all P > .05).Serum betatrophin and 25-(OH) D levels were positively associated in women with GDM, and both significantly lower compared with control values. Fetal weight was higher in the GDM group and associated with cord blood betatrophin. These findings provide insights into developing new predictive biomarkers or therapeutic targets for GDM.

Genetic and Metabolic Determinants of Plasma Levels of ANGPTL8.

CONTEXT: ANGPTL8 (A8) plays a key role in determining the tissue fate of circulating triglycerides (TGs). Plasma A8 levels are associated with several parameters of glucose and TG metabolism, but the causality of these relationships and the contribution of genetic variants to differences in A8 levels have not been explored. OBJECTIVE: To characterize the frequency distribution of plasma A8 levels in a diverse population using a newly-developed enzyme-linked immunosorbent assay (ELISA) and to identify genetic factors contributing to differences in plasma A8 levels. METHODS: We studied a population-based sample of Dallas County, comprising individuals in the Dallas Heart Study (DHS-1, n = 3538; DHS-2, n = 3283), including 2131 individuals with repeated measurements 7 to 9 years apart (age 18-85 years; >55% female; 52% Black; 29% White; 17% Hispanic; and 2% other). The main outcome measures were associations of A8 levels with body mass index (BMI), plasma levels of glucose, insulin, lipids, and hepatic TGs, as well as DNA variants identified by exome-wide sequencing. RESULTS: A8 levels varied over a 150-fold range (2.1-318 ng/mL; median, 13.3 ng/mL) and differed between racial/ethnic groups (Blacks > Hispanics > Whites). A8 levels correlated with BMI, fasting glucose, insulin, and TG levels. A variant in A8, R59W, accounted for 17% of the interindividual variation in A8 levels but was not associated with the metabolic parameters correlated with plasma A8 concentrations. CONCLUSIONS: A8 levels were strongly associated with indices of glucose and TG metabolism, but the lack of association of genetic variants at the A8 locus that impact A8 levels with these parameters indicates that differences in A8 levels are not causally related to the associated metabolic phenotypes.

Higher levels of circulating ANGPTL2 are associated with macular edema in patients with type 2 diabetes.

ABSTRACT: Macular edema (ME) is an inflammatory disease characterized by increased microvascular permeability. Here, we proposed that plasma angiopoietin-like protein 2 (ANGPTL2) level may be related to the severity of ME patients with type 2 diabetes mellitus (T2DM). In this cross-sectional study, 172 T2DM patients were recruited and divided into clinically significant macular edema (CSME), non-CSME (nCSME), and control groups. Serum ANGPTL2 level was quantified by ELISA and best corrected vision acuity (BCVA) was detected. After adjust age, sex, body mass index (BMI), and duration of diabetes variables, ANGPTL2 performed statistics difference among CSME-, nCSME-groups, and control group (4.46 [3.97, 4.96, 95%CI] ng/mL in CSME group, 3.80 [3.42, 4.18, 95%CI] ng/mL in nCSME-group, 3.33 [3.03, 3.63, 95%CI] ng/mL in control, P < .01). After adjustment of confounding factors, high levels of circulating ANGPTL2 were related with the diagnosis of ME, BCVA, and C reactive protein (CRP) through univariate regression analysis (P < .05). Meanwhile, in the multiple regression model, ANGPTL2 took the mainly effect proportion for the diagnosis of diabetic macular edema (DME), with a LogWorth value 3.559 (P < .001). Our study suggested that elevated circulating ANGPTL2 may be associated with the development of DME and the severity of visual impairment in patients with type 2 diabetes.

Elevated Plasma Angiopoietinlike Protein 5 (ANGPTL5) Is More Positively Associated with Glucose Metabolism Disorders in Patients with Metabolic Syndrome.

BACKGROUND Angiopoietinlike protein 5 (ANGPTL5) is an adipocytokine and has an important role in metabolic processes including lipid metabolism, obesity, and type 2 diabetes mellitus. On the basis of these roles, the present study aimed to investigate the level and role of plasma ANGPTL5 in metabolic syndrome (MS) patients. MATERIAL AND METHODS A total of 139 participants was enrolled in this study; 69 of them were diagnosed with MS. Plasma ANGPTL5 levels were measured by enzyme-linked immunosorbent assay. Sex, age, and other laboratory tests were compared statistically. Correlations between ANGPTL5 and biochemical parameters such as lipid levels and insulin resistance were all evaluated statistically. RESULTS In patients with MS, plasma ANGPTL5 levels were higher than in those without MS (P<0.05). Moreover, after adjusting for the glucose profiles, positive correlations were found between plasma ANGPTL5 levels and body mass index (BMI), waist circumference, and waist-hip ratio (WHR); a weak negative correlation was found between ANGPTL5 concentration and high-density lipoprotein cholesterol. After controlling the lipid profiles, positive correlations were found between ANGPTL5 concentration and BMI, WHR, fasting plasma glucose, fasting insulin, glycated hemoglobin, and homeostatic model assessment (HOMA) of insulin resistance; a negative correlation was found between plasma ANGPTL5 concentration and HOMA of ß-cell function. The area under the curve was approximately 0.912 in receiver operating characteristic curve analysis. CONCLUSIONS The findings in the present study showed that plasma ANGPTL5 was more positively correlated with glucose metabolism disorders than with lipid metabolism disorders in patients with MS, which suggested that ANGPTL5 might serve as a potential and useful clinical predictor of MS.

Decreased serum betatrophin may correlate with the improvement of obstructive sleep apnea after Roux-en-Y Gastric Bypass surgery.

Obesity is strongly correlated with obstructive sleep apnea (OSA), and bariatric surgery can effectively treat obesity and alleviate OSA. However, the contributing factors are still unclear. We aimed to explore the relationship between betatrophin and OSA in patients undergoing Roux-en-Y gastric bypass (RYGB) surgery. Our study consisted of thirty-seven individuals with OSA and type 2 diabetes (16 males, 21 females) undergoing RYGB surgery. The polysomnography test, anthropometric results, serum betatrophin, and abdominal magnetic resonance images were evaluated both before and 1 year after RYGB surgery. Factors that may correlate with the alleviation of OSA were investigated. In our study, RYGB surgery significantly decreased apnea hypopnea index (AHI) and serum betatrophin concentration (p < 0.001). The abdominal visceral fat area, subcutaneous fat area and HOMA-IR were also significantly decreased (p < 0.001). The preoperative AHI, postoperative AHI and the change in AHI were significantly correlated with the preoperative betatrophin, postoperative betatrophin and the change in betatrophin, respectively (p < 0.05). These correlations were still significant after adjustment for other risk factors. The change in betatrophin was also independently associated with the change in minimum oxygen saturation (p < 0.001). Our data might indicate that serum betatrophin was significantly independently correlated with the improvement of OSA after bariatric surgery.

Circulating micro RNA-223 and angiopoietin-like protein 8 as biomarkers of gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is a serious health problem associated with both foetal and maternal complications. New biomarkers that can predict or help in the early diagnosis of GDM are needed to minimize the hazards of hyperglycaemia in pregnant women and their offspring. We hypothesised a link between levels of microRNA-223 (miRNA-223) and Angiopoietin-Like Protein 8 (ANGPTL8) and GDM. MATERIALS AND METHODS: The study included 109 patients with confirmed early diagnosed GDM and 103 healthy control pregnant women in their second or third trimester. miRNA-223 and ANGPTL8 blood levels were assessed by real-time RT-PCR and sandwich ELISA, respectively, laboratory markers by standard methods. RESULTS: There was a significant increase in mean [SD] miRNA-223 and ANGPTL8 in GDM (0.31 [0.06] relative units) and (692 [199] pg/ml), respectively, in the GDM women compared to healthy pregnant women (0.17[0.05] relative units) and (261 [127] pg/ml), respectively, P  < 0.001. miRNA-223 and ANGPTL8 correlated significantly with each other (r = 0.38, P  < 0.001) and with fasting, 1-h and 2-h postprandial blood glucose levels (all P ≤ 0.002) HbA1 c (P  < 0.025), total cholesterol (P < 0.01), LDL-C and triglycerides (both P ≤ 0.005). The ROC area under curve (AUC) (95%CI) was 0.94 (0.91-0.97) for ANGPTL8, 0.92 (0.88-0.96) for miRNA-223 and 0.97 (0.95 - 0.99) for their combination. CONCLUSIONS: These findings support the hypothesis of involvement of both miRNA-223 and ANGPTL8 in the pathogenesis of GDM. The difference between levels in GDM patients and in control pregnant women indicates potential use for early diagnosis or prediction of GDM.

Effects of a One-week Vacation with Various Activity Programs on Metabolism and Adipokines.

This study was conducted as part of a larger study of East Tyrolean health tourism, and investigates the effects of an active seven-day vacation on metabolic parameters and adipokines. Fifty-two healthy vacationers participated in two types of vacation activities (golf vs. Nordic walking or e-biking [nw&eb]). In the former group, 30 subjects played golf for a mean duration of 33.5 h per week; in the NW&EB group, 22 persons performed Nordic walking or e-biking for a mean duration of 14.2 h per week. Metabolic parameters and adipokines, such as leptin, adiponectin, GF-21, irisin, omentin-1, betatrophin, and resistin, were measured one day before and one day after the stay. After one week, only the NW&EB group experienced a significant decrease of 1.0 kg in body weight. Significant changes in HDL-C, FGF-21, irisin, and omentin-1 were seen in the golf group; and in triglycerides, HbA1c, leptin and adiponectin in the NW&EB group. No significant changes in betatrophin or resistin were registered in either group. A seven-day vacation with an activity program for several hours per week causes favorable changes in metabolic parameters and adipokines known to be involved in the pathophysiology of the metabolic syndrome. The changes differed in their magnitude and significance, depending on the type of activity.

Cord Blood Levels of Angiopoietin-Like 7 (ANGPTL7) in Preterm Infants.

OBJECTIVE: ANGPTL7 is a member of the angiogenin-like protein family. Compared to other members, ANGPTL7 is the least known. Recent studies have explored the relationship between ANGPTL7 and multiple pathological processes and diseases. However, there is no research about ANGPTL7 in neonates. This study was designed to investigate the concentration of ANGPTL7 in cord blood of preterm infants. METHOD: Singleton infants born in November 2017 to June 2019 in the study hospital were enrolled in the study. Maternal and neonatal clinical data were collected. ANGPTL7 levels in cord blood and serum on the third day after birth were measured by an enzyme-linked immunosorbent assay. RESULT: A total of 182 infants were enrolled in this study. Patients were categorized into two groups by gestational age (102 preterm, 80 full-term). ANGPTL7 levels in preterm infants were significantly higher than that in full-term babies (t = 15.4, P < 0.001). In multiple line regression analysis, ANGPTL7 levels independently correlated with gestational age (ß = -0.556, P < 0.001). There is also no correlation between preterm outcomes and ANGPTL7 levels. Cord blood levels of ANGPTL7 were significantly higher than those in serum on the third day after birth (t = 13.88, P < 0.001). CONCLUSION: Cord blood ANGPTL7 levels are higher in preterm infants than full-term babies. The levels are independently influenced by gestational ages and attenuated significantly after birth. The underlying mechanism needs to be further studied.

Serum angiopoietin-like 3 levels are elevated in obese non diabetic men but are unaffected during an oral glucose tolerance test.

This study aimed to determine ANGPTL3 serum levels in healthy young lean and obese non-diabetic men during an oral glucose tolerance test (OGTT) and correlate them with anthropometric, biochemical and hormonal parameters. A case-control study was carried out and 30 young obese non-diabetic (23.90 ± 3.84 years and BMI 37.92 ± 4.85 kg/m2) and 28 age-matched healthy lean (24.56 ± 3.50 years and BMI of 22.10 ± 1.72 kg/m2) men were included in this study. The primary outcome measures were serum basal ANGPTL3 and ANGPTL3-area under the curve (AUC) levels. The percentage of body fat was measured by dual-energy X-ray absorptiometry and biochemical, hormonal and insulin resistance indices were determined. Basal ANGPTL3 and ANGPTL3-AUC levels were significantly elevated (p < 0.05) in young obese subjects compared with lean subjects and were positively and significantly associated with different anthropometric measurements. Fasting ANGPTL3 serum levels were positively correlated with fasting insulin, leptin, Leptin/Adiponectin index and triglyceride-glucose index. Moreover, ANGPTL3-AUC was negatively correlated with Matsuda index. In this regard, chronically high ANGPTL3 levels in young obese subjects might favor triglyceride-rich lipoprotein clearance to replenish triglyceride stores by white adipose tissue rather than oxidative tissues.

Angiopoietin-like 2 is a potential biomarker for diabetic foot patients.

BACKGROUND: Circulating angiopoietin-like 2 (ANGPTL2) protein levels are known to be significantly increased in numerous chronic inflammatory diseases and are associated with the diagnosis and/or prognosis of cardiovascular diseases, diabetes, chronic kidney disease, and various types of cancers. However, no data regarding the relationship between ANGPTL2 and diabetic foot ulcers (DFUs) are available. Here, we explored the potential link between ANGPTL2 and DFUs. METHODS: A total of 68 participants with type 2 diabetes mellitus (T2DM) were recruited, including 28 patients with DFU and 40 diabetic patients without DFUs. The clinical characteristics of T2DM patients with and without DFUs were compared. Serum concentrations of ANGPTL2 and VEGF were measured using enzyme-linked immunosorbent assay (ELISA) kits. The correlations between ANGPTL2 and clinical variables were analyzed. Multiple linear regression and logistic regression models were constructed to test the associations between ANGPTL2 and the severity and presence of DFUs. RESULTS: Serum levels of ANGPTL2 were higher in patients with DFUs than those in diabetic controls. Serum ANGPTL2 levels were higher in the advanced stages of DFUs. Spearman correlation analysis revealed strong positive associations of ANGPTL2 with CRP, VEGF and ESR in all subjects. In addition, serum ANGPTL2 was still positively correlated with DFUs stage after adjusting the risk factors. After adjusting for age, sex, HbA1C and duration of diabetes, ANGPTL2 was found to be independently associated with the presence of DFUs. CONCLUSIONS: Circulating ANGPTL2 levels are an independent risk factor for DFUs. This suggests that ANGPTL2 may play important roles in the development of DFUs, a possibility that needs to investigated in prospective studies.

The multi-faces of Angptl8 in health and disease: Novel functions beyond lipoprotein lipase modulation.

Angiopoietin-like protein (ANGPTL) family members, mainly ANGPTL3, ANGPTL4 and ANGPTL8, are physiological inhibitors of lipoprotein lipase (LPL), and play a critical role in lipoprotein and triglyceride metabolism in response to nutritional cues. ANGPTL8 has been described by different names in various studies and has been ascribed various functions at the systemic and cellular levels. Circulating ANGPTL8 originates mainly from the liver and to a smaller extent from adipose tissues. In the blood, ANGPTL8 forms a complex with ANGPTL3 or ANGPTL4 to inhibit LPL in fed or fasted conditions, respectively. Evidence is emerging for additional intracellular and receptor-mediated functions of ANGPTL8, with implications in NFκB mediated inflammation, autophagy, adipogenesis, intra-cellular lipolysis and regulation of circadian clock. Elevated levels of plasma ANGPTL8 are associated with metabolic syndrome, type 2 diabetes, atherosclerosis, hypertension and NAFLD/NASH, even though the precise relationship is not known. Whether ANGPTL8 has direct pathogenic role in these diseases, remains to be explored. In this review, we develop a balanced view on the proposed association of this protein in the regulation of several pathophysiological processes. We also discuss the well-established functions of ANGPTL8 in lipoprotein metabolism in conjunction with the emerging novel extracellular and intracellular roles of ANGPTL8 and the implicated metabolic and signalling pathways. Understanding the diverse functions of ANGPTL8 in various tissues and metabolic states should unveil new opportunities of therapeutic intervention for cardiometabolic disorders.

Evaluation of angiopoietin-like protein 3 (ANGPTL3) levels in polycystic ovary syndrome.

AIM: Angiopoietin-like protein 3 (ANGPTL3) is recognized as a regulator of lipid metabolism. However, little is known about its association with insulin resistance in polycystic ovary syndrome (PCOS) setting. The present study aimed to investigate the serum levels of ANGPTL3 and adiponectin in PCOS women compared to healthy controls. MAIN METHOD: In this study, a total of 175 premenopausal women (117 PCOS and 58 non-PCOS) were enrolled. Serum concentrations of ANGPTL3, adiponectin, fasting insulin, and other hormonal variables were measured using ELISA technique. KEY FINDINGS: Results showed that adiponectin levels were significantly lower in PCOS group than those of non-PCOS group. However, serum levels of ANGPTL3, high-sensitivity C-reactive protein (hs-CRP), and homocysteine (Hcy) were found to be higher in PCOS patients, when compared to non-PCOS ones. Moreover, serum ANGPTL3 positively correlated with BMI and serum triglyceride, while it inversely correlated with serum HDL-C in PCOS patients. SIGNIFICANCE: Our results demonstrated that increased levels of ANGPTL3 correlated with insulin resistance and dyslipidemia in PCOS patients, highlighting the need for future studies targeting its role in the pathogenesis of this disease.

Association between circulating microRNAs 486, 146b and 15b and serum betatrophin levels in obese; type 2 diabetic and non-diabetic children.

BACKGROUND: This study tested the association between serum levels of microRNA-486, -146b and -15b and betatrophin in normal and obese children with/without type 2 diabetes mellitus (T2DM). METHODS: the study included 120 children; divided into three groups: G1 (50 healthy), G2 (35 obese) and G3 (35 obese with T2DM). The levels of microRNA-486, 146b and 15b and serum betatrophin were measured by their corresponding methods. RESULTS: serum microRNA-486, -146b, -15b and betatrophin levels were significantly high in G3 followed by G2 then G1 (p = 0.002, > 0.001, > 0.001, and > 0.001, respectively). Especially in G3, these levels correlated positively with the BMI percentile (r = 0.44, 0.58, 0.38, and 0.46, p = 0.007, > 0.001, 0.021, and 0.005, respectively), serum glucose (r = 0.56, 0.49, 0.82, 0.60, and 0.42, p > 0.001, 0.003, > 0.001, and > 0.001, respectively) and HbA1c% (r = 0.56, 0.39, 0.66, and 0.42, p > 0.001, 0.019, > 0.001, and 0.032, respectively) while, showed negative correlations with correlated with serum insulin levels (r = - 0.37, - 0.42, - 0.58, and - 0.41, p = 0.021, 0.012, > 0.001 and 0.013, respectively) and with serum C-peptide levels (r = - 0.76, - 0.50, - 0.35 and - 0.42, p > 0.001, 0.002, 0.036 and 0.011, respectively). Serum betatrophin levels correlated positively with microRNA-486, -146b and -15b levels in G2 (r = 0.35, 0.80, and 0.67, p = 0.036, > 0.001, and,> 0.001, respectively), and in G3 (r = 0.57, 0.36, and 0.38, p > 0.001, 0.029 and, 0.023, respectively). CONCLUSIONS: Circulating microRNA-486, 146b and 15b increase significantly in obese children with T2DM and these levels correlate positively with serum betatrophin levels. Further studies are required to test the role of targeting of these microRNAs and betatrophin in the timely management of obesity and/or T2DM in children.

Betatrophin is downregulated in pregnant women with a history of RYGB operation and a high risk of postprandial hypoglycaemia.

Betatrophin is a liver and adipose tissue-derived protein which has recently been linked to glucose metabolism. So far, no data exist about the role of betatrophin in pregnant women with a history of Roux-En-Y gastric bypass (RYGB) operation with a high risk of postprandial hypoglycaemia. In this prospective clinical study, an oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed between the 24th and 28th week of pregnancy and 3-6 months post-partum in a cohort of obese and normal-weight pregnant women, as well as in women with a history of RYGB operation. In the cohort of pregnant women with RYGB and exaggerated risk of postprandial hypoglycaemic events, basal and dynamic betatrophin levels during the OGTT were lower than in the obese or normal-weight pregnant women (basal levels: 13.66 ± 5.88 vs. 19.03 ± 4.15 vs. 15.68 ± 6.48, p = 0.016; OGTT 60': 13.33 ± 5.40 vs. 17.37 ± 3.16 vs. 15.84 ± 4.99, p = 0.030). During the OGTT, basal and dynamic betatrophin levels at 60' were positively associated with glucose levels at 60 min (r = 0.55, p = 0.01 and r = 0.45, p = 0.039). This positive association was followed by significant hypoglycaemic events in the RYGB group. It was only in the RYGB group that betatrophin was negatively related to the disposition index (rho = -0.53, p = 0.014). After pregnancy there was a decrease in basal and stimulated betatrophin levels during the OGTT in all three patient groups. In comparison to normal-weight and obese pregnant women, women with a history of RYGB operation and a high risk of postprandial hypoglycaemic events have lower levels of betatrophin. This indicate a mechanistic role in order to decrease the risk of postprandial hypoglycaemia in this specific cohort.

Predictive values of ANGPTL8 on risk of all-cause mortality in diabetic patients: results from the REACTION Study.

BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8), an important regulator of lipid metabolism, is increased in diabetes and is associated with insulin resistance. However, the role of ANGPTL8 in the outcomes of diabetic patients remains unclear. This study aimed to investigate circulating levels of ANGPTL8 in participants with and without diabetes and its potential associations with clinical outcomes in a 5 year cohort study. METHODS: Propensity-matched cohorts of subjects with and without diabetes from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A longitudinal (REACTION) study were generated on the basis of age, sex and body mass index at baseline. The primary outcome was all-cause mortality. The secondary outcomes were a composite of new-onset major adverse cardiovascular events, hospitalization for heart failure, and renal dysfunction (eGFR < 60/min/1.73 m2). RESULTS: We identified 769 matched pairs of diabetic patients and control subjects. Serum ANGPTL8 levels were elevated in patients with diabetes compared to control subjects (618.82 [Formula: see text] 318.08 vs 581.20 [Formula: see text] 299.54 pg/mL, p = 0.03). Binary logistic regression analysis showed that elevated ANGPTL8 levels were associated with greater risk ratios (RRs) of death (RR in quartile 4 vs. quartile 1, 3.54; 95% CI 1.32-9.50) and renal dysfunction (RR in quartile 4 vs. quartile 1, 12.43; 95% CI 1.48-104.81) only in diabetic patients. Multivariable-adjusted restricted cubic spline analyses revealed a significant, linear relationship between ANGPTL8 and all-cause mortality in diabetic patients (p for nonlinear trend = 0.99, p for linear trend = 0.01) but not in control subjects (p for nonlinear trend = 0.26, p for linear trend = 0.80). According to ROC curve analysis, the inclusion of ANGPTL8 in QFrailty score significantly improved its predictive performance for mortality in patients with diabetes. CONCLUSION: Serum ANGPTL8 levels were associated with an increased risk of all-cause mortality and could be used as a potential biomarker for the prediction of death in patients with diabetes.

Angiopoietin-like protein 3, an emerging cardiometabolic therapy target with systemic and cell-autonomous functions.

Angiopoietin like protein 3 (ANGPTL3) is best known for its function as an inhibitor of lipoprotein and endothelial lipases. Due to the capacity of genetic or pharmacologic ANGPTL3 suppression to markedly reduce circulating lipoproteins, and the documented cardioprotection upon such suppression, ANGPTL3 has become an emerging therapy target for which both antibody and antisense oligonucleotide (ASO) therapeutics are being clinically tested. While the antibody is relatively selective for circulating ANGPTL3, the ASO also depletes the intra-hepatocellular protein, and there is emerging evidence for cell-autonomous functions of ANGPTL3 in the liver. These include regulation of hepatocyte glucose and fatty acid uptake, insulin sensitivity, LDL/VLDL remnant uptake, VLDL assembly/secretion, polyunsaturated fatty acid (PUFA) and PUFA-derived lipid mediator content, and gene expression. In this review we elaborate on (i) why ANGPTL3 is considered one of the most promising new cardiometabolic therapy targets, and (ii) the present evidences for its intra-hepatocellular or cell-autonomous functions.

The circulating ANGPTL8 levels show differences among novel subgroups of adult patients with diabetes and are associated with mortality in the subsequent 5 years.

ANGPTL8, an important regulator of glucose and lipid metabolism, is associated with diabetes, but the role of ANGPTL8 in the outcomes of novel subgroups of diabetes remains unclear. To assess the circulating ANGPTL8 levels in novel subgroups of diabetes and their association with health outcomes, we performed a data-driven cluster analysis (k-means) of patients with newly diagnosed diabetes (741 patients enrolled from 2011 through 2016) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: a longitudinal (REACTION) study. The primary outcomes were mortality from all causes and cardiovascular diseases (CVD), and the secondary outcome was any cardiovascular event. Comparisons among groups were performed using the Kruskal-Wallis test, and the correlations between variables were assessed using the Pearson correlation test. Logistic regression was used to detect associations between the risk of outcomes and the ANGPTL8 levels. We identified four replicable clusters of patients with diabetes that exhibited significantly different patient characteristics and risks of all-cause mortality. The serum ANGPTL8 levels in the cluster of mild age-related diabetes (MARD), severe insulin-resistant diabetes (SIRD), and severe insulin-deficient diabetes (SIDD) were significantly higher than those in the mild obesity-related diabetes (MOD) cluster (685.01 ± 24.50 vs. 533.5 ± 18.39, p < 0.001; 649.69 ± 55.83 vs. 533.5 ± 18.39, = 0.040; 643.29 ± 30.89 vs. 533.5 ± 18.39, p = 0.001). High circulating ANGPTL8 levels were more highly associated with a greater hazard of all-cause mortality (quartile 4 vs 1: risk ratio [RR] 3.23, 95% CI 1.13-9.22; per unit increase in the Z score: RR 1.53, 95% CI 1.17-2.01) than low circulating ANGPTL8 levels. In conclusion, this 5-year follow-up REACTION study revealed that the circulating ANGPTL8 levels show differences among novel subgroups of adult patients with diabetes and are associated with all-cause mortality in the subsequent 5 years.