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Myeloperoxidase (MPO) is positively associated with obesity and diet-induced insulin resistance. Angiopoietin-like protein 6 (ANGPTL6) regulates metabolic processes and counteract obesity through increased energy expenditure. This study aims to evaluate the plasma MPO and ANGPTL6 levels in obese and diabetic individuals as well as MPO association with biochemical markers of obesity. A total of 238 participants were enrolled, including 137 control and 101 type 2 diabetes (T2D) patients. ANGPTL6 and MPO levels and other biomarkers were measured via ELISA. ANGPTL6 levels were significantly higher in the diabetic population and obese individuals. When the group was stratified based on T2D, ANGPTL6 levels were significantly higher in obese-diabetic participants compared with non-obese-diabetics, but obese-non-diabetic individuals had similar ANGPTL6 levels to their controls. MPO levels were higher in obese compared with non-obese participants but did not differ between T2D and control participants. MPO levels were upregulated in obese compared with non-obese in both diabetics and non-diabetics. MPO was positively associated with ANGPTL6, triglyceride, BMI, TNF-alpha, high-sensitivity C-reactive protein, interleukin-6, and plasminogen activator inhibitor-1. Taken together, our findings suggest that both MPO and ANGPTL6 may regulate obesity, although MPO exerts this effect independent of diabetes while ANGPTL6 may have a modulatory role in diabetes.

ANGPTL8 is a liver and adipose tissue produced protein that regulates the level of triglyceride in plasma as well as glucose homeostasis. This study was designed to evaluate the level of ANGPTL8 in obese and non-obese subjects before and after exercise training. A total of 82 non-obese and 62 adult obese were enrolled in this study. Subjects underwent a three months of exercise training. Both full length and C-terminal 139-198 form of ANGPTL8 were measured by ELISA. Our data show that the full length ANGPTL8 level was increased in obese subjects (1150.04 ± 108.10 pg/mL) compared to non-obese (775.54 ± 46.12) pg/mL (p-Value = 0.002). C-terminal 139-198 form of ANGPTL8 was also increased in obese subjects 0.28 ± 0.04 ng/mL vs 0.20 ± 0.02 ng/mL in non-obese (p-value = 0.058). In obese subjects, the levels of both forms were reduced after three months of exercise training; full length was reduced from 1150.04 ± 108.10 pg/mL to 852.04 ± 51.95 pg/mL (p-Values 0.015) and c-terminal form was reduced from 0.28 ± 0.04 ng/mL to 0.19 ± 0.03 ng/mL (p-Value = 0.058). Interestingly, full length ANGPTL8 was positively associated with fasting blood glucose (FBG) in non-obese (r = 0.317, p-Value = 0.006) and obese subjects (r = 0.346, p-Value = 0.006) C-terminal 139-198 form of ANGPTL8 on the other hand, did not show any correlation in both groups. In conclusion, our data demonstrate that ANGPTL8 was increased in obesity and reduced after exercise training supporting the potential therapeutic benefit of reducing ANGPTL8. The various forms of ANGPTL8 associated differently with FBG suggesting that they have different roles in glucose homeostasis.

The emergence of effective vaccines for COVID-19 has been welcomed by the world with great optimism. Given their increased susceptibility to COVID-19, the question arises whether individuals with type-2 diabetes mellitus (T2DM) and other metabolic conditions can respond effectively to the mRNA-based vaccine. We aimed to evaluate the levels of anti-SARS-CoV-2 IgG and neutralizing antibodies in people with T2DM and/or other metabolic risk factors (hypertension and obesity) compared to those without. This study included 262 people (81 diabetic and 181 non-diabetic persons) that took two doses of BNT162b2 (Pfizer–BioNTech) mRNA vaccine. Both T2DM and non-diabetic individuals had a robust response to vaccination as demonstrated by their high antibody titers. However, both SARS-CoV-2 IgG and neutralizing antibodies titers were lower in people with T2DM. The mean ( ± 1 standard deviation) levels were 154 ± 49.1 vs. 138 ± 59.4 BAU/ml for IgG and 87.1 ± 11.6 vs. 79.7 ± 19.5% for neutralizing antibodies in individuals without diabetes compared to those with T2DM, respectively. In a multiple linear regression adjusted for individual characteristics, comorbidities, previous COVID-19 infection, and duration since second vaccine dose, diabetics had 13.86 BAU/ml (95% CI: 27.08 to 0.64 BAU/ml, p=0.041) less IgG antibodies and 4.42% (95% CI: 8.53 to 0.32%, p=0.036) fewer neutralizing antibodies than non-diabetics. Hypertension and obesity did not show significant changes in antibody titers. Taken together, both type-2 diabetic and non-diabetic individuals elicited strong immune responses to SARS-CoV-2 BNT162b2 mRNA vaccine; nonetheless, lower levels were seen in people with diabetes. Continuous monitoring of the antibody levels might be a good indicator to guide personalized needs for further booster shots to maintain adaptive immunity. Nonetheless, it is important that people get their COVID-19 vaccination especially people with diabetes.

Metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM) share overlapping pathophysiological mechanisms, including insulin resistance and chronic inflammation. Recent evidence suggests that Orosomucoid-2 (ORM2), an acute-phase immunomodulatory protein, may play a role in metabolic regulation; however, its specific involvement in MAFLD remains unclear. This study examined the association between circulating ORM2 levels and the severity of hepatic steatosis, insulin resistance, and T2DM in a cohort of 449 adults. MAFLD was assessed using FibroScan® with hepatic steatosis categorized by Controlled Attenuation Parameter (CAP) scores, while plasma ORM2 levels were measured via ELISA. Statistical analyses using Spearman correlation and multiple logistic regression revealed that elevated ORM2 levels were significantly correlated with greater hepatic steatosis, insulin resistance, triglycerides, ALT, and hip circumference (p < 0.001). Individuals with severe steatosis (CAP > 290 dB/m) had markedly higher ORM2 levels (312.3 ng/mL) compared to those with normal CAP scores (210.4 ng/mL; p < 0.001). ORM2 was identified as an independent predictor of steatosis severity and after adjusting for several metabolic variables (AOR = 1.005; 95% CI: 1.002–1.007). ROC analysis incorporating ORM2 and metabolic variables demonstrated strong predictive capability for MAFLD (AUC = 0.864, 95% CI: 0.825–0.902). These findings support ORM2 as a promising non-invasive diagnosis for MAFLD, involving only blood sampling without direct invasion of the liver and associated metabolic dysfunction.

Background Hypertension is a risk factor for both cardiovascular diseases (CVDs) and type 2 diabetes (T2D). Angiopoietin-like proteins (ANGPTLs), mainly ANGPTL3, ANGPTL4 and ANGPTL8, are associated with increased plasma lipid content due to their role in regulating the activity of lipoprotein lipase, a key enzyme in metabolism of the lipoprotein in circulation. Dyslipidaemia is a risk factor for hypertension development; however, the roles of ANGPTL3, ANGPTL4 and ANGPTL8 in subjects with hypertension have not yet been established. This study compared the plasma and adipose tissue levels of ANGPTL3, ANGPTL4 and ANGPTL8 in age- and body mass index-matched subjects with and without hypertension. Methods A total of 119 subjects, including 69 hypertensive and 50 non-hypertensive subjects, were enrolled. ANGPTL3, ANGPTL4 and ANGPTL8 plasma levels were measured by ELISA, whereas their levels in adipose tissue were assessed via real-time PCR. Results We found that ANGPTL4 (202.49 ± 17.44 ng/mL vs. 160.64 ± 10.36 ng/mL, p  = 0.04) and ANGPTL8 levels (2310.96 ± 194.88 pg/mL vs. 1583.35 ± 138.27 pg/mL, p  = 0.001) were higher in hypertensive subjects than non-hypertensive subjects. However, ANGPTL3 levels were not significantly different between the two populations. Similarly, ANGPTL4 and ANGPTL8 levels were also elevated in subjects with T2D and hypertension than in those with T2D but not hypertension. Additionally, people with highest tertiles of ANGPTL8 had higher odds of having hypertension (odd ratio [OR] = 3.8, 95% confidence interval [CI] = (1.5-9.8), p -Value = 0.005. Similar to its plasma levels, ANGPTL4 and ANGPTL8 were higher in adipose tissue. Conclusions In conclusion, our data illustrate that ANGPTL4 and ANGPTL8 levels in both plasma and adipose tissues are increased in subjects with hypertension. The elevated levels of ANGPTL4 and ANGPTL8 in hypertensive subjects highlight their potential involvement, their potential role as biomarkers for hypertension and their therapeutic value in hypertension given their roles in regulating lipid metabolism.

Background Hypertriglyceridemia is associated with increased risk for cardiovascular diseases and type 2 diabetes (T2D). Angiopoietin like proteins particularly 3, 4 and recently 8 are well established regulators of plasma triglyceride level through regulating the activity of lipoprotein lipase. Plasma level and association between ANGPTL3, 4 and 8 is not well established in human subjects. This study was designed to establish the level of these proteins in plasma and adipose tissues and investigate the association between ANGPTL8 with ANGPTL3 and 4 in T2D and non-diabetics subjects. Methods A total of 235 subjects were enrolled in this study, 144 non-diabetics and 91 T2D. ANGPTL 3, 4 and 8 levels were measured in plasma by ELISA and using real time RT-PCR in adipose tissues. Results In this study, we showed that ANGPTL3, 4 and 8 were higher in T2D subjects. Dividing the non-diabetic subjects according to their BMI showed higher level of ANGPTL3, 4 and 8 in obese subjects compared to non-obese subjects. No significant difference was observed between the T2D subjects. ANGPTL8 was showed positive correlation with ANGPTL3 in the non-diabetic subjects in the non-obese ( r  = 0.2437, p -Value = 0.0543) and obese subjects ( r  = 0.418, p -Value = 0.0125). No association was observed in the T2D subjects. On the other hand, ANGPTL4 was positively associated with the obese subjects in both the non-diabetics ( r  = 0.3322, p -Value = 0.0316) and the obese T2D subjects ( r  = 0.3161, p -Value = 0.0211). Conclusion In conclusion, our data shows that ANGPTL3, 4 and 8 are increased in obesity and T2D. ANGPTL8 associates with ANGPTL3 in the non-diabetic subjects while it associated more with ANGPTL4 in the obese and T2D subjects. Taken together, this data highlight the role of these proteins in metabolic diseases and how they interact with each other’s under different physiological and pathophysiological conditions.

Type 2 diabetes (T2D) is a growing pandemic associated with metabolic dysregulation and chronic inflammation. Meteorin-like hormone (METRNL) is an adipomyokine that is linked to T2D. Our objective was to evaluate the changes in METRNL levels in T2D and obesity and assess the association of METRNL levels with irisin. Overall, 228 Arab individuals were enrolled. Plasma levels of METRNL and irisin were assessed using immunoassay. Plasma levels of METRNL and irisin were significantly higher in T2D patients than in non-diabetic patients (p < 0.05). When the population was stratified based on obesity, METRNL and irisin levels were significantly higher in obese than in non-obese individuals (p < 0.05). We found a significant positive correlation between METRNL and irisin (r = 0.233 and p = 0.001). Additionally, METRNL and irisin showed significant correlation with various metabolic biomarkers associated with T2D and Obesity. Our data shows elevated METRNL plasma levels in individuals with T2D, further exacerbated with obesity. Additionally, a strong positive association was observed between METRNL and irisin. Further studies are necessary to examine the role of these proteins in T2D and obesity, against their ethnic background and to understand the mechanistic significance of their possible interplay.

Background: Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-β (TGF-β) superfamily, is upregulated under cellular stress conditions and has emerged as a potential biomarker for metabolic disorders. However, its expression in relation to diabetes and obesity across different demographic groups remains understudied. This study investigated the association between plasma GDF-15 levels, diabetes mellitus, and obesity in individuals of varying ages, ethnicities, and genders. Methods: In a cross-sectional study, plasma GDF-15 concentrations were measured in 2083 participants enrolled in the Kuwait Diabetes Epidemiology Program (KDEP). The dataset included anthropometric, clinical, biochemical, and glycemic markers. Multivariate regression analysis was used to examine associations between GDF-15 levels and metabolic phenotypes. Results: Mean plasma GDF-15 levels were significantly higher in males than females (580.6 vs. 519.3 ng/L, p < 0.001), and in participants >50 years compared to those <50 years (781.4 vs. 563.4 ng/L, p < 0.001). Arab participants had higher GDF-15 levels than South and Southeast Asians (597.0 vs. 514.9 and 509.9 ng/L, respectively; p < 0.001). Positive correlations were found with BMI, waist and hip circumferences, blood pressure, insulin, and triglycerides; negative correlations were observed with HDL cholesterol. Median regression indicated that elevated GDF-15 levels were independently and significantly associated with male gender, older age, obesity, diabetes, and insulin resistance. Adjusted median regression indicated that male gender (β = 30.1, 95%CI: 11.7, 48.5), older age (β = 9.4, 95%CI: 8.0, 10.7), and insulin resistance (β = 7.73, 95%CI: 1.47, 14.0) indicated a significant positive association with GDF-15. South Asian participants (β= −41.7, 95%CI: −67.2, −16.2) had significantly but Southeast Asian participants (β= −23.3, 95%CI: −49.2, 2.56) had marginally significantly lower GDF-15 levels compared to participants of Arab ethnicity. Conclusions: Higher GDF-15 levels are associated with age, male gender, Arab ethnicity, obesity, and diabetic traits. These findings support the potential role of GDF-15 as a biomarker for metabolic disorders, particularly in high-risk demographic subgroups.

Cardiovascular disease (CVD) risks persist in patients despite treatment. CVD susceptibility also varies with sex and ethnicity and is not entirely explained by conventional CVD risk factors. The aim of the present study was to identify novel CVD candidate markers in circulating Peripheral blood mononuclear cells (PBMCs) and plasma from Arab obese subjects with and without CVD using proteomic approaches. Human adults with confirmed CVD (n = 208) and matched non-CVD controls (n = 152) living in Kuwait were examined in the present cross-sectional study. Anthropometric and classical biochemical parameters were determined. We employed a shotgun proteomic profiling approach on PBMCs isolated from a subset of the groups (n = 4, each), and differentially expressed proteins selected between the two groups were validated at the mRNA level using RT-PCR (n = 6, each). Plasma levels of selected proteins from the proteomics profiling: Proteinase-3 (PR3), Annexin-A3 (ANX3), Defensin (DEFA1), and Matrix Metalloproteinase-9 (MMP9), were measured in the entire cohort using human enzyme-linked immunosorbent assay kits and were subsequently correlated with various clinical parameters. Out of the 1407 we identified and quantified from the proteomics profiling, 47 proteins were dysregulated with at least twofold change between the two subject groups. Among the differentially expressed proteins, 11 were confirmed at the mRNA levels. CVD influenced the levels of the shortlisted proteins (MMP9, PR3, ANX3, and DEFA1) in the PBMCs and plasma differentially. Despite the decreased levels of both protein and mRNA in PBMCs, PR3 circulating levels increased significantly in patients with CVD and were influenced by neither diabetes nor statin treatment. No significant changes were; however, observed in the DEFA1, MMP9, and ANX3 levels in plasma. Multivariate logistic regression analysis revealed that only PR3 was independently associated with CVD. Our results suggest that the dysregulation of PR3 levels in plasma and PBMCs reflects underlying residual CVD risks even in the treated population. More prospective and larger studies are required to establish the role of PR3 in CVD progression.

Sedentary lifestyle and excessive energy intake are prominent contributors to obesity; a major risk factors for the development of insulin resistance, type 2 diabetes and cardiovascular diseases. Elucidating the molecular mechanisms underlying these chronic conditions is of relevant importance as it might lead to the identification of novel anti-obesity targets. The purpose of the current study is to investigate differentially expressed proteins between lean and obese subjects through a shot-gun quantitative proteomics approach using peripheral blood mononuclear cells (PBMCs) extracts as well as potential modulation of those proteins by physical exercise. Using this approach, a total of 47 proteins showed at least 1.5 fold change between lean and obese subjects. In obese, the proteomic profiling before and after 3 months of physical exercise showed differential expression of 38 proteins. Thrombospondin 1 (TSP1) was among the proteins that were upregulated in obese subjects and then decreased by physical exercise. Conversely, the histone deacetylase 4 (HDAC4) was downregulated in obese subjects and then induced by physical exercise. The proteomic data was further validated by qRT-PCR, Western blot and immunohistochemistry in both PBMCs and adipose tissue. We also showed that HDAC4 levels correlated positively with maximum oxygen consumption (VO2 Max) but negatively with body mass index, percent body fat, and the inflammatory chemokine RANTES. In functional assays, our data indicated that ectopic expression of HDAC4 significantly impaired TNF-α-dependent activation of NF-κB, establishing thus a link between HDAC4 and regulation of the immune system. Together, the expression pattern of HDAC4 in obese subjects before and after physical exercise, its correlation with various physical, clinical and metabolic parameters along with its inhibitory effect on NF-κB are suggestive of a protective role of HDAC4 against obesity. HDAC4 could therefore represent a potential therapeutic target for the control and management of obesity and presumably insulin resistance.