OBJECTIVE: This study examines whether Angiopoietin Like 8 (ANGPTL8) is linked to cardiometabolic risk factors (CMRFs) in Saudi women with type 2 diabetes (T2DM).
METHODS: Case-control investigation compared 150 women aged 30-60 with T2DM to 140 healthy women of the same age and gender.
RESULTS: ANGPTL8 levels differed significantly between T2DM and non-diabetics. Fasting blood glucose (FBG), insulin resistance (IR), triglycerides (TG), high-sensitivity C-reactive protein (hs-CRP), body mass index (BMI), and atherogenic index (AIP) of plasma all correlated positively with ANGPTL8 concentrations. Insulin levels correlated negatively with ANGPTL8. Multiple linear regression models showed that elevated ANGPTL8 independently predicted higher FBG, hs-CRP, IR, TG, and AIP in T2DM patients.
CONCLUSIONS: The study found a significant association between ANGPTL8 levels and IR, hs-CRP, TG, AIP, and BMI in women with T2DM. These components are classified as CMRFs and have the potential to contribute to the development of cardiovascular disease (CVD).

Our study aimed to investigate the role of lipids in melanoma risk and the effect of lipid-lowering drug targets on melanoma. Using Mendelian Randomization analysis, we examined the genetic agents of nine lipid-lowering drugs and their association with melanoma risk. We found that genetically proxied inhibition of HMGCR, ABCG5/ABCG8, and ANGPTL3 was associated with a reduced risk of melanoma. On the other hand, inhibition of LPL and Apo-B100 was significantly associated with an increased risk of melanoma. Sensitivity analyses did not reveal any statistical evidence of bias from pleiotropy or genetic confounding. We did not find a robust association between lipid traits NPC1L1, PCSK9, APOC3 inhibition, and melanoma risk. These findings were validated using two independent lipid datasets. Our analysis also revealed that HMGCR, ANGPTL3, and ABCG5/ABCG8 inhibitors reduced melanoma risk independent of their effects on lipids. This suggests that these targets may have potential for melanoma prevention or treatment. In conclusion, our study provides evidence for a causal role of lipids in melanoma risk and highlights specific lipid-lowering drug targets that may be effective in reducing the risk of melanoma. These findings contribute to the understanding of the underlying mechanisms of melanoma development and provide potential avenues for further research and therapeutic interventions.

The primary goals of this study were to clarify 1) the effect of weight loss by lifestyle intervention on circulating total angiopoietin-like protein 8 (ANGPTL8), and 2) the role of physical activity on serum total ANGPTL8 in northern Americans with obesity but without diabetes.
A total of 130 subjects with body mass index (BMI) ≧ 35 kg/m2 but without diabetes were recruited, and 121 subjects completed a weight loss program for data analysis. Abdominal adipose tissue was determined by non-contrast computed tomography (CT). Serum total ANGPTL8 was higher in the group with obesity than in the lean control group. Serum total ANGPTL8 was positively correlated with waist circumference (WC), BMI, fasting insulin, HOMA-IR, HOMA-B, QUICKI, hs-CRP, IL-6, and leptin. Serum total ANGPTL8 did not significantly differ between the two intervention groups at baseline, and it was significantly lower after weight loss, with comparable changes with diet only and diet plus physical activity.
Among northern Americans with obesity but without diabetes, a lifestyle modification resulted in significant reduction of circulating total ANGPTL8 concentrations in a 6-month weight-loss period. Although addition of physical activity resulted in greater total and liver fat loss, it did not promote further significant decline of serum total ANGPTL8 beyond diet alone.

Aging is an important medical and social problem. Excessive angiopoietin-like protein (ANGPTL)-2 signaling causes chronic tissue inflammation, promoting development and progression of aging-related diseases. Moreover, circulating ANGPTL2 levels reportedly predict the risk of some aging-related diseases and subsequent death. However, there are, as yet, no reports of whether circulating ANGPTL2 levels predict vital prognosis in younger-old, community-dwelling populations. This study investigated associations between plasma ANGPTL2 levels and all-cause and specific-cause mortality in this population. The case-cohort study was abstracted from an ongoing, age-specific prospective cohort study: the New Integrated Suburban Seniority Investigation Project. This project enrolled 3 073 participants aged 64 years at the beginning of the investigation from 1996 through 2005. A subcohort of 714 randomly sampled participants plus 387 cases representing deceased participants followed through 2015 underwent survival analysis. Plasma ANGPTL2 concentrations were positively associated with >80% and 100% higher risk of all-cause mortality and cancer mortality, respectively, after adjustment for gender, smoking, alcohol consumption, walking time, sleep duration, caloric intake, medical status, disease history, BMI, and triglyceride, creatinine, uric acid, and high sensitivity C-reactive protein levels. A more robust association between ANGPTL2 levels and all-cause and cancer mortality was seen in participants with either frailties or with lifestyles of heavier drinking or current smoking. Elevated plasma ANGPTL2 levels are associated with high all-cause and cancer mortality in a community-dwelling sample of younger-old adults. These findings expand our knowledge of human aging and associated diseases.

Androgen abuse is associated with unfavourable changes in blood pressure, lipid metabolism and erythrocytosis. Most knowledge is based on cross-sectional studies sensitive to bias. We assessed the magnitude of these effects and their recovery in a prospective cohort study which included 100 men (≥18 years) performing an androgen cycle. Clinic visits took place before the cycle, at the end, 3 months after and 1 year after start of the cycle and included measurement of blood pressure, lipid parameters and haematocrit. During androgen use, systolic and diastolic blood pressure increased 6.87 (95% CI 4.34-9.40) and 3.17 mmHg (1.29-5.04) compared to baseline respectively. LDL cholesterol and ApoB increased 0.45 mmol/L (0.29-0.61) and 18.2 mg/dl (13.5-22.8) respectively, whereas HDL cholesterol, ApoA and Lp(a) decreased with 0.40 mmol/L (-0.45 to 0.35), 36.6 mg/dl (30.2-42.9) and 37.6% (13.9-61.3). ANGPTL3 increased 20.3% (7.38-33.2). Mean haematocrit increased 0.03 L/L (0.02-0.03). Three months after the cycle, and 1 year after the start, these parameters returned to baseline. In conclusion, androgen abuse induces small but clinically relevant adverse changes in blood pressure, lipid metabolism and erythrocytosis which are rapidly reversible after cessation. As follow-up was limited to 1 year, the impact of androgen abuse on cardiovascular disease remains uncertain.

Background: Chronic kidney disease (CKD) is recognized as a major public health problem with high morbidity and mortality worldwide. Recently, angiopoietin-like protein 8 (ANGPTL8) was found to regulate lipid metabolism. Previous studies suggested that serum ANGPTL8 levels increased in patients with diabetes, especially in diabetic patients with albuminuria. This study aimed to investigate the association between circulating levels of ANGPTL8 and kidney function in the general population. Methods: The subjects were patients with renal dysfunction [estimated glomerular filtration rate (eGFR) <60/min/1.73 m2] from Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal study (the REACTION study). Each case was matched by age, sex, and body mass index (BMI) with one control whose eGFR was ≥ 90 ml/min/1.73 m2. The case and control groups were compared using a paired t-test. Binary logistic regression analysis was used to calculate the odds ratio (OR) of renal dysfunction (RD). Results: Among 135 case-control pairs, circulating ANGPTL8 levels were elevated in patients with RD compared to control subjects [799.96 (410.12-1086.44) vs. 609.58 (365.13-740.06) pg/ml, p < 0.05]. Partial correlations showed that ANGPTL8 levels were negatively correlated with eGFR (r = -0.26, p < 0.05). Multivariable-adjusted binary logistic regression analysis showed that elevated ANGPTL8 levels were associated with an increased risk of RD (OR in quartile 4 vs. 1, 3.80; 95% CI, 1.71-8.41). Interestingly, the association between ANGPTL8 levels and RD was consistent with the overall findings in both nondiabetic individuals (OR, 1.44; 95% CI, 1.09 to 1.91) and diabetic patients (OR, 2.71; 95% CI, 1.13-6.49) in the subgroup analyses. Furthermore, the estimates for this association were also significant in females (OR, 2.12; 95% CI, 1.33-3.37), individuals aged > 60 years (OR, 1.55; 95% CI, 1.16-2.07), individuals with a BMI <24 (OR, 1.66; 95% CI, 1.16-2.39), and individuals without hyperlipidaemia (OR, 1.61; 95% CI, 1.16-2.23) (all p-values <0.05). Conclusion: Elevated circulating ANGPTL8 levels were associated with increased risk of RD in the general population, especially among females, individuals aged > 60 years, individuals with a BMI < 24, individuals without diabetes mellitus, individuals with diabetes mellitus (DM), and individuals without hyperlipidaemia. This finding implies that ANGPTL8 may play a role in the pathological process of RD.

Metabolic syndrome (MetS) pathogenesis involves oxidative stress associated with mitochondrial dysfunction, which triggers integrated stress responses via various compensatory metabolic modulators like mitokines and hepatokines. However, the regulatory mechanisms underlying the exercise-derived benefits with respect to mitokines and hepatokines (potential MetS biomarkers) are unknown. Thus, we investigated the effects of exercise training on MetS biomarkers and their associations with clinical parameters. In this single-center trial, 30 women with MetS were randomly assigned to 12-week supervised exercise or control groups (1:1) and compared with 12 age-matched healthy volunteers. All participants completed the study except one subject in the control group. Expectedly, serum levels of the mitokines, fibroblast growth factor-21 (FGF21), growth differentiation factor-15 (GDF15), and the hepatokine, angiopoietin-like 6 (ANGPTL6), were higher in MetS patients than in healthy volunteers. Moreover, their levels were markedly attenuated in the exercise group. Further, exercise-mediated changes in serum FGF21 and GDF15 correlated with changes in the homeostasis model of assessment of insulin resistance (HOMA-IR) and appendicular lean mass (ALM), respectively. Additionally, changes in serum triglycerides and ANGPTL6 were correlated with changes in leptin. Aberrant mitokine and hepatokine levels can be rectified by relieving metabolic stress burden. Therefore, exercise training may reduce the need for the compensatory upregulation of MetS metabolic modulators by improving gluco-lipid metabolism.

Despite statin and antihypertensive therapies, older Americans have high atherosclerotic cardiovascular disease (ASCVD) risk. Novel measures of triglyceride-rich lipoproteins, low-density lipoprotein triglycerides (LDL-TG), and remnant-like particle cholesterol (RLP-C), are associated with ASCVD in middle-aged adults. Polymorphisms in genes encoding angiopoietin-related protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III), two proteins involved in triglyceride catabolism, are associated with increased risk for hypertriglyceridaemia and ASCVD and are potential therapeutic targets. We examined associations of LDL-TG, RLP-C, apoC-III, and ANGPTL3 levels with ASCVD events in older adults in the Atherosclerosis Risk in Communities (ARIC) study.
In 6359 participants (mean age 75.8 ± 5.3 years) followed for ASCVD events [coronary heart disease (CHD) or ischaemic stroke] up to 6 years, associations between LDL-TG, RLP-C, apoC-III, and ANGPTL3 and ASCVD events were assessed using Cox regression. With adjustment for age, sex, and race, RLP-C, LDL-TG, apoC-III, and ANGPTL3 (as continuous variables) were significantly associated with CHD. However, after adjustment for traditional risk factors and lipid-lowering medications, only LDL-TG and ANGPTL3 were significantly associated with ASCVD events [hazard ratio (HR) 1.72, 95% confidence interval (CI) 1.25-2.37 per log unit increase in LDL-TG; HR 1.63, 95% CI 1.17-2.28 per log unit increase in ANGPTL3].
In older adults, LDL-TG, RLP-C, apoC-III, and ANGPTL3 were associated with CHD events in minimally adjusted models; LDL-TG and ANGPTL3 remained independent predictors of ASCVD events with further adjustment. Future studies should assess potential benefit of lowering hepatic apoC-III or ANGPTL3 expression in patients with elevated triglyceride-rich lipoproteins.

Chronic low-grade inflammation is receiving much attention as a critical pathology that induces various aging phenotypes, a concept known as \"inflammaging\". Uremic patients undergoing hemodialysis therapy show vascular aging phenotypes characterized by greater arterial stiffness and calcification compared to healthy controls of the same generation. In the current study, we investigated whether levels of inflammaging markers in the circulation were associated with vascular aging phenotypes in hemodialysis patients, as estimated by the cardio-ankle vascular index (CAVI).
We conducted a multicenter cross-sectional study of 412 patients receiving hemodialysis and evaluated the relationship between circulating hs-CRP or ANGPTL2 levels, as markers of inflammaging, and CAVI.
Of 412 patients, 376 were analyzed statistically. While circulating hs-CRP levels had no significant association with CAVI, generalized linear models revealed that high circulating ANGPTL2 levels were significantly associated with increasing CAVI after adjustment for classical metabolic factors and hemodialysis-related parameters [β 0.63 (95%CI 0.07-1.18)]. Exploratory analysis revealed that high circulating ANGPTL2 levels were also strongly associated with increased CAVI, particularly in patients with conditions of increased vascular mechanical stress, such elevated blood pressure [β 1.00 (95%CI 0.23-1.76)], elevated pulse pressure [β 0.75 (95%CI 0.52-0.98)], or excess body fluid [β 1.25 (95%CI 0.65-1.84)].
We conclude that circulating levels of ANGPTL2 rather than hs-CRP are positively associated with CAVI in the uremic population and that ANGPTL2 could be a unique marker of progression of vascular aging in patients receiving hemodialysis.

Evinacumab, an angiopoietin-like protein 3 monoclonal antibody, reduced low-density lipoprotein cholesterol (LDL-C) significantly in a Phase 2 study of patients with homozygous familial hypercholesterolemia. In this double-blind, placebo-controlled Phase 1 study, we compared safety, tolerability, pharmacokinetics, and pharmacodynamics of evinacumab between healthy Japanese and Caucasian adults.
Subjects with LDL-C ≥2.6 and <4.1 mmol/L were enrolled to one of four dose cohorts: evinacumab subcutaneous (SC) 300 mg single dose, SC 300 mg once weekly for eight doses, intravenous (IV) 5 mg/kg, or IV 15 mg/kg once every 4 weeks for two doses. Each cohort comprised 24 subjects (12 Japanese; 12 Caucasian), randomized (3:1) to receive evinacumab or placebo within each ethnic group with a 24-week follow-up.
The safety profile of evinacumab (IV and SC) in both ethnicities was comparable with placebo, with no serious or severe treatment-emergent adverse events. Pharmacokinetic profiles were comparable between Japanese and Caucasian subjects across IV and SC groups. Mean calculated LDL-C decreased from baseline with both IV doses, beginning on day 3 up to week 8. Triglyceride changes observed with evinacumab IV were rapid (seen by day 2) and sustained up to week 8. Evinacumab SC doses also reduced LDL-C and triglyceride levels, although lower doses induced smaller changes. Evinacumab (IV and SC) reduced other lipids, including apolipoprotein B, versus placebo.
In both ethnicities, evinacumab (IV and SC) was generally well tolerated, exhibiting comparable pharmacokinetic profiles. Dose-related reductions in LDL-C and triglycerides were observed with evinacumab in both ethnic groups.