Investigating the Role of FABP4 in Diabetes and Obesity and the Influence of Age and Ethnicity: A Comprehensive Analysis of a Cohort from the KEDP-Study.

Adipocyte P2 (aP2), also known as FABP4, is an adipokine that adipose tissue produces and expresses in macrophages. Its primary role is to facilitate the transportation of fatty acids across cell membranes. Numerous studies have reported associations between FABP4 and the development of metabolic disorders. However, there is limited knowledge regarding FABP4 expression in diabetes and obesity, especially about different age groups, genders, and ethnicities. This study aims to investigate the association between FABP4 levels, diabetes mellitus, and obesity within various ethnic groups. We measured plasma FABP4 concentrations in a cohort of 2083 patients from the KDEP study and gathered anthropometric data. Additionally, we collected and analyzed clinical, biochemical, and glycemic markers using multivariate regression analysis. The average FABP4 concentration was significantly higher in female participants than in males (18.8 ng/mL vs. 14.4 ng/mL, p < 0.001, respectively), and in those over 50 years old compared to those under 50 years of age (19.3 ng/mL vs. 16.2 ng/mL, p < 0.001, respectively). In this study, significant positive associations were found between the plasma level of FABP4 and obesity markers: BMI (r = 0.496, p < 0.001), hip circumference (r = 0.463, p < 0.001), and waist circumference (WC) (r = 0.436, p < 0.001). Similar observations were also seen with glycemic markers, which included HbA1c (r = 0.126, p < 0.001), fasting blood glucose (FBG) (r = 0.184, p < 0.001), fasting insulin (r = 0.326, p < 0.001), and HOMA-IR (r = 0.333, p < 0.001). Importantly, these associations remained significant even after adjusting for age, gender, and ethnicity. Furthermore, FABP4 levels were negatively associated with male gender (ß: -3.85, 95% CI: -4.92, -2.77, p < 0.001), and positively associated with age (ß: 0.14, 95% CI: 0.096, 0.183, p < 0.001), BMI (ß: 0.74, 95% CI: 0.644, 0.836, p < 0.001), and fasting insulin (ß: 0.115, 95% CI: 0.091, 0.138, p < 0.001). In this study, plasma FABP4 levels were significantly higher in diabetic and obese participants, and they were strongly influenced by age, gender, and ethnicity. These findings suggest that FABP4 may serve as a valuable prognostic and diagnostic marker for obesity and diabetes, particularly among female patients, individuals over 50 years old, and specific ethnic groups.

Evaluating the correlation of sclerostin levels with obesity and type 2 diabetes in a multiethnic population living in Kuwait.

Obesity and Type 2 Diabetes Mellitus (T2DM) are intricate metabolic disorders with a multifactorial etiology, often leading to a spectrum of complications. Recent research has highlighted the impact of these conditions on bone health, with a particular focus on the role of sclerostin (SOST), a protein molecule integral to bone metabolism. Elevated circulating levels of SOST have been observed in patients with T2DM compared to healthy individuals. This study aims to examine the circulating levels of SOST in a multiethnic population living in Kuwait and to elucidate the relationship between SOST levels, obesity, T2DM, and ethnic background. The study is a cross-sectional analysis of a large cohort of 2083 individuals living in Kuwait. The plasma level of SOST was measured using a bone panel multiplex assay. The study found a significant increase in SOST levels in individuals with T2DM (1008.3 pg/mL, IQR-648) compared to non-diabetic individuals (710.6 pg/mL, IQR-479). There was a significant gender difference in median SOST levels, with males exhibiting higher levels than females across various covariates (diabetes, IR, age, weight, and ethnicity). Notably, SOST levels varied significantly with ethnicity: Arabs (677.4 pg/mL, IQR-481.7), South Asians (914.6 pg/mL, IQR-515), and Southeast Asians (695.2 pg/mL, IQR-436.8). Furthermore, SOST levels showed a significant positive correlation with gender, age, waist circumference, systolic and diastolic blood pressure, fasting blood glucose, HbA1c, insulin, total cholesterol, triglycerides, HDL, LDL, ALT, and AST (p-Value ≥0.05). South Asian participants, who exhibited the highest SOST levels, demonstrated the most pronounced associations, even after adjusting for age, gender, BMI, and diabetes status (p-Value ≥0.05). The observed correlations of SOST with various clinical parameters suggest its significant role in the diabetic milieu, particularly pronounced in the South Asian population compared to other ethnic groups.

Global analysis of urinary extracellular vesicle small RNAs in autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal disease progressing to end-stage renal disease. There is a pressing need for the identification of early ADPKD biomarkers to enable timely intervention and the development of effective therapeutic approaches. Here, we profiled human urinary extracellular vesicles small RNAs by small RNA sequencing in patients with ADPKD and compared their differential expression considering healthy control individuals to identify dysregulated small RNAs and analyze downstream interaction to gain insight about molecular pathophysiology. METHODS: This is a cross-sectional study where urine samples were collected from a total of 23 PKD1-ADPKD patients and 28 healthy individuals. Urinary extracellular vesicles were purified, and small RNA was isolated and sequenced. Differentially expressed Small RNA were identified and functional enrichment analysis of the critical miRNAs was performed to identify driver genes and affected pathways. RESULTS: miR-320b, miR-320c, miR-146a-5p, miR-199b-3p, miR-671-5p, miR-1246, miR-8485, miR-3656, has_piR_020497, has_piR_020496 and has_piR_016271 were significantly upregulated in ADPKD patient urine extracellular vesicles and miRNA-29c was significantly downregulated. Five 'driver' target genes (FBRS, EDC3, FMNL3, CTNNBIP1 and KMT2A) were identified. CONCLUSIONS: The findings of the present study make significant contributions to the understanding of ADPKD pathogenesis and to the identification of novel biomarkers and potential drug targets aimed at slowing disease progression in ADPKD.

Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a complicated condition related to type 2 diabetes mellitus (T2D). ANGPTL8 is a hepatic protein highlighted as a risk factor for DN in patients with T2D; additionally, recent evidence from DN studies supports the involvement of growth hormone/IGF/IGF-binding protein axis constituents. The potential link between ANGPTL8 and IGFBPs in DN has not been explored before. Here, we assessed changes in the circulating ANGPTL8 levels in patients with DN and its association with IGFBP-1, -3, and -4. Our data revealed a significant rise in circulating ANGPTL8 in people with DN, 4443.35 ± 396 ng/mL compared to 2059.73 ± 216 ng/mL in people with T2D (p < 0.001). Similarly, levels of IGFBP-3 and -4 were significantly higher in people with DN compared to the T2D group. Interestingly, the rise in ANGPTL8 levels correlated positively with IGFBP-4 levels in T2DM patients with DN (p < 0.001) and this significant correlation disappeared in T2DM patients without DN. It also correlated positively with serum creatinine and negatively with the estimated glomerular filtration rate (eGFR, All < 0.05). The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8 and IGFBP4 was 0.76 (0.69-0.84), p < 0.001, and the specificity was 85.9%. In conclusion, our results showed a significant increase in ANGPTL8 in patients with DN that correlated exclusively with IGFBP-4, implicating a potential role of both proteins in the pathophysiology of DN. Our findings highlight the significance of these biomarkers, suggesting them as promising diagnostic molecules for the detection of diabetic nephropathy.

Increased Glucagon Immunoreactivity in a Rat Model of Diet-induced Obesity following Sleeve Gastrectomy.

OBJECTIVE: Bariatric surgery is currently the most effective treatment for obesity, and procedures such as Roux-en Y gastric bypass and sleeve gastrectomy (SG) also result in rapid improvements in insulin sensitivity and glucose tolerance. In addition, these procedures cause changes in the secretion of various gut-derived hormones. The role these hormones play in the mechanism of the beneficial effects of bariatric surgery is still debated, but nonetheless, their importance provides inspiration for novel obesity-targeted pharmacotherapies. METHODS: Male Sprague Dawley rats were fed either regular chow or a cafeteria diet to induce obesity. A sub-group of the obese animals then underwent either sham surgery or SG. RESULTS: Following a 4-week recovery period, SG rats weighed significantly less than obese or sham-operated rats. Improvements in glucose tolerance and insulin sensitivity also occurred in the SG group, but these were not always statistically significant. We measured the intracellular lipid content of liver samples and found that obese rats showed signs of non-alcoholic fatty liver disease, which were significantly ameliorated by SG. There were significantly higher glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to a standard mixed meal in the SG group, as well as paradoxically higher glucagon secretion. CONCLUSION: These data highlight the need for more specific anti-glucagon antibodies to characterize the changes in proglucagon-derived peptide concentrations that occur following SG. Further studies are required to determine whether these peptides contribute to the therapeutic effects of SG.

Plasma insulin is required for the increase in plasma angiopoietin-like protein 8 in response to nutrient ingestion.

BACKGROUND: Plasma levels of angiopoietin-like protein 8 (ANGPTL8) are regulated by feeding and they increase following glucose ingestion. Because both plasma glucose and insulin increase following food ingestion, we aimed to determine whether the increase in plasma insulin and glucose or both are responsible for the increase in ANGPTL8 levels. METHODS: ANGPTL8 levels were measured in 30 subjects, 14 with impaired fasting glucose (IFG), and 16 with normal fasting glucose (NFG); the subjects received 75g glucose oral Glucose tolerance test (OGTT), multistep euglycaemic hyperinsulinemic clamp and hyperglycaemic clamp with pancreatic clamp. RESULTS: Subjects with IFG had significantly higher ANGPTL8 than NGT subjects during the fasting state (p < 0.05). During the OGTT, plasma ANGPTL8 concentration increased by 62% above the fasting level (p < 0.0001), and the increase above fasting in ANGPTL8 levels was similar in NFG and IFG individuals. During the multistep insulin clamp, there was a dose-dependent increase in plasma ANGPTL8 concentration. During the 2-step hyperglycaemic clamp, the rise in plasma glucose concentration failed to cause any change in the plasma ANGPTL8 concentration from baseline. CONCLUSIONS: In response to nutrient ingestion, ANGPTL8 level increased due to increased plasma insulin concentration, not to the rise in plasma glucose. The incremental increase above baseline in plasma ANGLPTL8 during OGTT was comparable between people with normal glucose tolerance and IFG.

The association between biomarker angiopoietin-like protein five and obstructive sleep apnea in patients undergoing bariatric surgery.

PURPOSE: Obstructive sleep apnea (OSA) is prevalent in the bariatric population. OSA should be recognized in patients undergoing bariatric surgery preoperatively to prevent peri- and post-operative complications. Lipid metabolism-related biomarkers are associated with OSA. Triglyceride metabolism is, among others, regulated by angiopoietin-like protein five (ANGPTL5). We aimed to evaluate the level of ANGPTL5 in patients with OSA of different severity levels before and after bariatric surgery. METHODS: We performed a single-center prospective cohort study including a consecutive series of patients who underwent bariatric surgery. We collected the clinical data, polysomnography (PSG) or polygraphy (PG) parameters, and plasma derived via venipuncture before and 6 to 12 months after surgery. Lipid profile, glucose levels, and ANGPTL5 levels were assessed. ANGPTL5 levels were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The study included 88 patients for analysis. The patients were divided into two subgroups: no or mild OSA (apnea-hypopnea index (AHI) < 15 events/hour, n = 57) and moderate-to-severe OSA (AHI ≥ 15 events/hour, n = 31). The ANGPTL5 level was higher in the moderate-to-severe OSA group (20.5 [15.6, 26.5] ng/mL) compared to the no or mild OSA group (16.3 [12.5, 19.4] ng/mL) (p = 0.008). A significant positive correlation was observed between ANGPTL5 and AHI (ρ = 0.256, p = 0.017), apnea index (AI) (ρ = 0.318, p = 0.003), and triglyceride levels (ρ = 0.240, p = 0.025). ANGPTL5 levels were reduced significantly after bariatric surgery in both moderate-to-severe OSA (15.6 [10.3, 18.7] ng/mL) and no or mild OSA (13.4 [9.2, 15.8] ng/mL) groups, though to a lower level in the group without or mild OSA. Post-surgery, the significant positive correlation between ANGPTL5 and AHI (ρ = 0.210, p = 0.047), AI (ρ = 0.230, p = 0.034), and triglyceride (ρ = 0.397, p < 0.001) remained. CONCLUSION: The data showed increased levels of ANGPTL5 in patients with moderate-to-severe OSA. Both AHI and ANGPTL5 levels decreased significantly after bariatric surgery. We also report an association between ANGPTL5 levels and OSA severity.

Adolescent obesity and ANGPTL8: correlations with high sensitivity C-reactive protein, leptin, and chemerin.

Angiopoietin-like proteins (ANGPTLs) mediate many metabolic functions. We had recently reported increased plasma levels of ANGPTL8 in obese adults of Arab ethnicity. However, data on ANGPTL8 levels in adolescent obesity is lacking. Arab population is characterized by a rapid transition, due to sudden wealth seen in the post-oil era, in lifestyle, food habits and extent of physical activity. We adopted a cross-sectional study on Arab adolescents from Kuwait to examine the role of ANGPTL8 in adolescent obesity. The study cohort included 452 adolescents, aged 11-14 years, recruited from Middle Schools across Kuwait. BMI-for-age growth charts were used to categorize adolescents as normal-weight, overweight, and obese. ELISA and bead-based multiplexing assays were used to measure plasma levels of ANGPTL8 and other inflammation and obesity-related biomarkers. Data analysis showed significant differences in the plasma levels of ANGPTL8 among the three subgroups, with a significant increase in overweight and obese children compared to normal-weight children. This observation persisted even when the analysis was stratified by sex. Multinomial logistic regression analysis illustrated that adolescents with higher levels of ANGPTL8 were 7 times more likely to become obese and twice as likely to be overweight. ANGPTL8 levels were correlated with those of hsCRP, leptin and chemerin. ANGPTL8 level had a reasonable prognostic power for obesity with an AUC of 0.703 (95%-CI=0.648-0.759). These observations relating to increased ANGPTL8 levels corresponding to increased BMI-for-age z-scores indicate that ANGPTL8, along with hsCRP, leptin and chemerin, could play a role in the early stages of obesity development in children. ANGPTL8 is a potential early marker for adolescent obesity and is associated with well-known obesity and inflammatory markers.

Association of COVID-19 Vaccines ChAdOx1-S and BNT162b2 with Circulating Levels of Coagulation Factors and Antithrombin.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is associated with increased risk of thrombosis and thromboembolism. Exposure to COVID-19 vaccines is also associated with immune thrombotic thrombocytopenia, ischemic stroke, intracerebral haemorrhage, and cerebral venous thrombosis, and it is linked with systemic activation of coagulation. METHODS: We assess the circulating levels of coagulation factors (factors XI, XII, XIII, and prothrombin) and antithrombin in individuals who completed two doses of either ChAdOx1-S or BNT162b2 COVID-19 vaccine, within the timeframe of two months, who had no previous history of COVID-19. RESULTS: Elevated levels of factors XI, XII, XIII, prothrombin, and antithrombin were seen compared to unvaccinated controls. Levels of coagulation factors, antithrombin, and prothrombin to antithrombin ratio were higher with BNT162b2 compared to ChAdOx1-S vaccine. CONCLUSIONS: The clinical significance of such coagulation homeostasis disruption remains to be elucidated but it is worthy of global scientific follow-up effort.

Increased plasma ANGPTL7 levels with increased obstructive sleep apnea severity.

Background: Weight-loss surgery is one of the recommended methods for treating obstructive sleep apnea (OSA) in obese patients. While weight reduction is critical to relieve symptoms of OSA, the biochemical factors involved in post-surgery improvement are still unknown. We aimed to explore the link between ANGPTL7 and OSA in patients with different OSA severity. Furthermore, we examined the effect of treating OSA with bariatric surgery on ANGPTL7 level. Methods: We quantified levels of circulating ANGPTL7 in fasting plasma and adipose tissue samples of 88 participants before and after bariatric surgery. Confocal microscopy analyses were also performed to assess the ANGPTL7 expression in subcutaneous white adipose tissue biopsies obtained from people with moderate-to-severe OSA compared to those with none or mild OSA. The study involved 57 individuals with none or mild OSA and 31 patients with moderate-to-severe OSA. Results: Levels of circulating ANGPTL7 were significantly higher in people with moderate-to-severe OSA (1440 ± 1310 pg/ml) compared to the none or mild OSA group (734 ± 904 pg/ml, p = 0.01). The increase in ANGPTL7 correlated significantly and positively with the apnea-hypopnea index (AHI, r = .226, p = .037), and AHI-supine (r = .266, p = .019) in participants with moderate-to-severe OSA. Multivariate logistic regression analysis demonstrated an association between ANGPTL7 and OSA severity (log2 ANGPTL7; OR =1.24, p = 0.024). ANGPTL7 levels exhibited significant positive correlations with the levels of TG and oxLDL (p-value = 0.002 and 0.01 respectively). Bariatric surgery reduced the levels of both ANGPTL7 and AHI significantly. Conclusion: Here we report significantly increased levels of ANGPTL7 both in the circulation and in adipose tissue of patients with OSA, which concurred with increased inflammation and OSA severity. Levels of ANGPTL7 decreased significantly as OSA showed a significant improvement post-surgery supporting a potential role for ANGPTL7 in either OSA progression or a role in an OSA-related mechanism.

GALNT2 rs4846914 SNP Is Associated with Obesity, Atherogenic Lipid Traits, and ANGPTL3 Plasma Level.

N-Acetylgalactosaminyltransferase 2 (GALNT2) is associated with serum lipid levels, insulin resistance, and adipogenesis. Additionally, angiopoietin-like (ANGPTL) proteins have emerged as regulators of lipoprotein lipase and lipid metabolism. In this study, we evaluated the association between GALNT2 rs4846914 variant, known for its association with lipid levels in European cohorts, with plasma levels of ANGPTL proteins, apolipoproteins, lipids, and obesity traits in individuals of Arab ethnicity. GALNT2 rs4846914 was genotyped in a cohort of 278 Arab individuals from Kuwait. Plasma levels of ANGPTL3 and ANGPTL8 were measured by ELISA and apolipoproteins by Luminex multiplexing assay. Allele-based association tests were performed with Bonferroni-corrected p-value thresholds. The GALNT2 rs4846914_G allele was associated with increased ANGPTL3 (p-values ≤ 0.05) but not with ANGPTL8 plasma levels. The allele was associated significantly with higher BMI and weight (p-values < 0.003), increased ApoC1 levels (p-values ≤ 0.006), and reduced HDL levels (p-values ≤ 0.05). Individuals carrying the GG genotype showed significantly decreased HDL and increased BMI, WC, ApoC1, and TG. Interactions exist between (AG+GG) genotypes and measures of percentage body fat, ApoA1A, ApoC1, and ApoB48-mediated HDL levels. GALNT2 is confirmed further as a potential link connecting lipid metabolism and obesity and has the potential to be a drug target for treating obesity and dyslipidemia.

Changes in the expression of meteorin-like (METRNL), irisin (FNDC5), and uncoupling proteins (UCPs) after bariatric surgery.

OBJECTIVE: Bariatric surgery is currently the most effective treatment for severe obesity. This study aims to investigate the changes in expression levels of meteorin-like protein (METRNL), irisin (FNDC5), and uncoupling proteins (UCP) 1/2/3 following bariatric surgery to understand their involvement in enhancing metabolism after surgery. METHOD: A total of 40 participants were enrolled in this interventional study, 20 with obesity BMI ≥ 35 kg/m2 and 20 with BMI ≤ 25 kg/m2 . Bariatric surgery (laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) was performed. The levels of various molecules of interest were analyzed before and after surgery. RESULTS: Gene expression analysis revealed significantly higher levels of METRNL, UCP1, and UCP3 in individuals with obesity when compared with healthy individuals before surgery (p < 0.05). Gene expression levels of METRNL and UCP2 showed a significant increase after bariatric surgery (p < 0.05). METRNL plasma level was significantly higher in individuals with obesity before surgery (mean [SEM], 55,222.6 [1,421.1] pg/mL, p = 0.0319), as well as at 6 and 12 months (57,537.3 [1,303.9] pg/mL, p = 0.0005; 59,334.9 [1,214.3] pg/mL, p < 0.0001) after surgery. CONCLUSION: The changes in the levels of various molecules of interest support their possible involvement in the inflammatory and thermogenic responses following bariatric surgery.

Immunogenicity of BNT162b2 Vaccine Booster Dose in Patients With Inflammatory Bowel Disease Receiving Infliximab Combination Therapy: A Prospective Observational Study.

Introduction: Few data exist regarding the immunogenicity of the third dose of BNT162b2 relative to the second dose in patients with inflammatory bowel disease (IBD) on different immunosuppressive therapies. We investigated the immunogenicity of BNT162b2 vaccine booster dose in patients with IBD on infliximab combination therapy. Method: This is a prospective single-center observational study conducted from January 1, 2022 to February 28, 2022. Patients were recruited at the time of attendance at the infusion center. Eligibility criteria included patients with a confirmed diagnosis of IBD who are receiving infliximab with azathioprine or 6-mercaptopurine. Patients who received two doses of BNT162b2 vaccine (second dose group) were compared to patients who had received three doses of BNT162b2 vaccine [third dose (booster) group]. Patients were excluded if they were infected or had symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) previously since the start of the pandemic or received other vaccines than the BNT162b2. Our primary outcome was the concentrations of SARS-CoV-2 antibodies Immunoglobulin G (IgG) and neutralizing antibodies 40-45 weeks from the first dose of BNT162b2 vaccine in patients with IBD receiving infliximab combination therapy. Medians with interquartile range (IQR) were calculated. Results: In total, 162 patients with IBD and receiving infliximab combination therapy were recruited, and the number of patients in both the second dose group and third dose (booster) group was 81. Mean age was 35 years old in both groups. Median (IQR) SARS-CoV-2 IgG levels were significantly lower after the second dose [125 BAU/ml (43, 192)] compared to patients who received the third booster dose [207 BAU/ml (181, 234)] (P = 0.003). Neutralizing antibody levels were also lower after the second dose [80% (21, 95)] compared to patients who received the third booster dose [96% (93, 99)] (P ≤ 0.001). The percentage of patients who achieved positive SARS-CoV-2 IgG levels in the third (booster) dose group was 96.3%, whereas it was 86.4% in the second dose group. The percentage of participants who received the third (booster) dose and achieved a positive SARS-CoV-2-neutralizing antibody level was 100%, whereas it was 88.9% in the participants who received the second dose only. Conclusion: Most patients with IBD on infliximab combination therapy had positive SARS-CoV-2 IgG and neutralizing antibody concentrations 40-45 weeks post BNT162b2 vaccination. However, SARS-CoV-2 IgG and neutralizing antibody concentrations were lower in patients who received two doses only compared to patients who received a third dose. A longer follow-up study is needed to evaluate decay in antibodies over time.

Potential Role of N-Cadherin in Diagnosis and Prognosis of Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious complication of diabetes affecting about half the people with diabetes and the leading cause of end stage renal disease (ESRD). Albuminuria and creatinine levels are currently the classic markers for the diagnosis of DN. However, many shortcomings are arising from the use of these markers mainly because they are not specific to DN and their levels are altered by multiple non-pathological factors. Therefore, the aim of this study is to identify better markers for the accurate and early diagnosis of DN. The study was performed on 159 subjects including 42 control subjects, 50 T2D without DN and 67 T2D subjects with DN. Our data show that circulating N-cadherin levels are significantly higher in the diabetic patients who are diagnosed with DN (842.6 ± 98.6 mg/l) compared to the diabetic patients who do not have DN (470.8 ± 111.5 mg/l) and the non-diabetic control group (412.6 ± 41.8 mg/l). We also report that this increase occurs early during the developmental stages of the disease since N-cadherin levels are significantly elevated in the microalbuminuric patients when compared to the healthy control group. In addition, we show a significant correlation between N-cadherin levels and renal markers including creatinine (in serum and urine), urea and eGFR in all the diabetic patients. In conclusion, our study presents N-cadherin as a novel marker for diabetic nephropathy that can be used as a valuable prognostic and diagnostic tool to slow down or even inhibit ESRD.

Association of significantly elevated plasma levels of NGAL and IGFBP4 in patients with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a type of progressive kidney disease affecting approximately 40% of patients with diabetes. Current DN diagnostic criteria predominantly rely on albuminuria and serum creatinine (sCr) levels. However, the specificity and reliability of both markers are limited. Hence, reliable biomarkers are required for early diagnosis to effectively manage DN progression. METHODS: In this study, a cohort of 159 individuals were clinically evaluated and the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 were determined using Multiplexing Assays. Additionally, the association between the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 in patients with DN were compared to those in patients with T2D without kidney disease and control participants. RESULTS: Circulating level of NGAL were significantly higher in people with DN compared to people with T2D and non-diabetic groups (92.76 ± 7.5, 57.22 ± 8.7, and 52.47 ± 2.9 mg/L, respectively; p <  0.0001). IGFBP-4 showed a similar pattern, where it was highest in people with DN (795.61 ng/ml ±130.7) compared to T2D and non-diabetic people (374.56 ng/ml ±86.8, 273.06 ng/ml ±27.8 respectively, ANOVA p <  0.01). The data from this study shows a significant positive correlation between NGAL and IGFBP-4 in people with DN (ρ = .620, p <  0.005). IGFBP-4 also correlated positively with creatinine level and negatively with eGFR, in people with DN supporting its involvement in DN. CONCLUSION: The data from this study shows a parallel increase in the plasma levels of NGAL and IGFBP-4 in DN. This highlights the potential to use these markers for early diagnosis of DN.

Robust Antibody Levels in Both Diabetic and Non-Diabetic Individuals After BNT162b2 mRNA COVID-19 Vaccination.

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.

Previous COVID-19 Infection and Antibody Levels After Vaccination.

Background: The emergence of new COVID-19 variants of concern coupled with a global inequity in vaccine access and distribution has prompted many public health authorities to circumvent the vaccine shortages by altering vaccination protocols and prioritizing persons at high risk. Individuals with previous COVID-19 infection may not have been prioritized due to existing humoral immunity. Objective: We aimed to study the association between previous COVID-19 infection and antibody levels after COVID-19 vaccination. Methods: A serological analysis to measure SARS-CoV-2 immunoglobulin (Ig)G, IgA, and neutralizing antibodies was performed on individuals who received one or two doses of either BNT162b2 or ChAdOx1 vaccines in Kuwait. A Student t-test was performed and followed by generalized linear regression models adjusted for individual characteristics and comorbidities were fitted to compare the average levels of IgG and neutralizing antibodies between vaccinated individuals with and without previous COVID-19 infection. Results: A total of 1,025 individuals were recruited. The mean levels of IgG, IgA, and neutralizing antibodies were higher in vaccinated subjects with previous COVID-19 infections than in those without previous infection. Regression analysis showed a steeper slope of decline for IgG and neutralizing antibodies in vaccinated individuals without previous COVID-19 infection compared to those with previous COVID-19 infection. Conclusion: Previous COVID-19 infection appeared to elicit robust and sustained levels of SARS-CoV-2 antibodies in vaccinated individuals. Given the inconsistent supply of COVID-19 vaccines in many countries due to inequities in global distribution, our results suggest that even greater efforts should be made to vaccinate more people, especially individuals without previous COVID-19 infection.

Serological Response to BNT162b2 and ChAdOx1 nCoV-19 Vaccines in Patients with Inflammatory Bowel Disease on Biologic Therapies.

Introduction: The immunogenicity of SARS-CoV-2 vaccines in patients with inflammatory bowel disease (IBD) on biologic therapies is not well studied. The goal of this study was to measure the serological response to BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with IBD receiving different biologic therapies. Methods: We performed a multi-center prospective study between 1 August 2021 and 15 September 2021. We measured the seropositivity of SARS-CoV-2 antibodies (SARS-CoV-2 IgG) and neutralizing antibody concentrations in patients with IBD receiving biologic therapies 4-10 weeks after their second dose or 3-6 weeks after their first dose of BNT162b2 or ChAdOx1 nCoV-19 vaccines. Results: A total of 126 patients were enrolled (mean age, 31 years; 60% male; 71% Crohn's disease, 29% ulcerative colitis). Of these, 92 patients were vaccinated with the BNT162b2 vaccine (73%) and 34 patients with the ChAdOx1 nCoV-19 vaccine (27%). In patients being treated with infliximab and adalimumab, the proportion of patients who achieved positive anti-SARS-CoV-2 IgG antibody levels after receiving two doses of the vaccine were 44 out of 59 patients (74.5%) and 13 out of 16 patients (81.2%), respectively. In contrast, of those receiving ustekinumab and vedolizumab, the proportion of patients who achieved positive anti-SARS-CoV-2 IgG antibody levels after receiving two doses of the vaccine were 100% and 92.8%, respectively. In patients receiving infliximab and adalimumab, the proportion of patients who had positive anti-SARS-CoV-2 neutralizing antibody levels after two-dose vaccination was 40 out of 59 patients (67.7%) and 14 out 16 patients (87.5%), respectively. On the other hand, the proportion of patients who had positive anti-SARS-CoV-2 neutralizing antibody levels were 12 out of 13 patients (92.3%) and 13 out of 14 patients (92.8%) in patients receiving ustekinumab and vedolizumab, respectively. Conclusions: The majority of patients with IBD who were on infliximab, adalimumab, and vedolizumab seroconverted after two doses of SARS-CoV-2 vaccination. All patients on ustekinumab seroconverted after two doses of SARS-CoV-2 vaccine. The BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines are both likely to be effective after two doses in patients with IBD on biologics. Larger follow-up studies are needed to evaluate if decay of antibodies occurs over time.

Association Between Factors Involved in Bone Remodeling (Osteoactivin and OPG) With Plasma Levels of Irisin and Meteorin-Like Protein in People With T2D and Obesity.

The musculoskeletal system consisting of bones and muscles have been recognized as endocrine organs secreting hormones that are involved in regulating metabolic and inflammatory pathways. Obesity and type 2 diabetes (T2D) are associated with several musculoskeletal system complications. We hypothesized that an interaction exists between adipomyokines namely, irisin and METRNL, and various molecules involved in bone remodeling in individuals with obesity and T2D. A total of 228 individuals were enrolled in this study, including 124 non-diabetic (ND) and 104 T2D. A Multiplex assay was used to assess the level of various osteogenic molecules namely osteoactivin, Syndecan, osteoprotegerin (OPG) and osteonectin/SPARC. Our data shows elevated levels of Osteoactivin, Syndecan, OPG and SPARC in T2D as compared to ND individuals (p ≤ 0.05). Using Spearman's correlation, a positive correlation was observed between irisin and Osteoactivin as well as OPG (p < 0.05). Similarly, a positive association was observed between METRNL and Osteoactivin (p < 0.05). The strong positive association shown in this study between irisin, METRNL and various molecules with osteogenic properties emphasize a possible interaction between these organs. This report suggests that having a dysregulation in the level of the aforementioned molecules could potentially affect the development of bone and muscle related complications that are associated with obesity and T2D.

The Rise of IGFBP4 in People with Obstructive Sleep Apnea and Multilevel Sleep Surgery Recovers Its Basal Levels.

IGFBP4 is the smallest member of the insulin-like growth factor binding protein family (IGFBP). It is a hepatic protein that plays a role in modulating the activity and bioavailability of IGF-I. The expression of IGFBP4 was found to increase under conditions of hypoxia. Obstructive sleep apnea (OSA) is a common disorder, characterized by cyclic episodes of intermittent hypoxia and fragmented sleep. Our aim was to quantify levels of circulating IGFBP1, IGFBP2, IGFBP3, IGFBP4, and IGFBP7 in fasting plasma samples of 69 Kuwaiti participants and explore its correlation with indices of OSA. The quantification was performed using multiplexing assay. The study involved 28 controls and 41 patients with OSA. Levels of circulating IGFBP4 were significantly higher in people with OSA (289.74 ± 23.30 ng/ml) compared to the control group (217.60 ± 21.74 ng/ml, p = 0.028). The increase in IGFBP4 correlated significantly and positively with AHI (r = .574, p = .01) and AI (r = .794, p = .001) in people with moderate and severe OSA. There was a significant decline in circulating IGFBP4 after 3 months of surgery (225.89 ± 18.16 ng/ml, p = 0.012). This was accompanied by a prominent improvement in OSA (AHI 8.97 ± 2.37 events/h, p = 0.001). In this study, our data showed a significant increase in circulating IGFBP4 in people with OSA. We also report a significant positive correlation between IGFBP4 and indices of OSA at baseline, which suggests IGFBP4 as a potential diagnostic biomarker for OSA. There was a significant improvement in OSA after 3 months of surgical intervention, which concurred with a significant decline in IGFBP4 levels. Altogether, the detected change suggests a potential link between IGFBP4 and OSA or an OSA-related factor, whereby OSA might play a role in triggering the induction of IGFBP4 expression.