Salivary α-amylase activity is associated with cardiometabolic and inflammatory biomarkers in overweight/obese, non-diabetic Qatari women.

Introduction: Obesity, prevalent in approximately 80% of Qatar's adult population, increases the risk of complications like type 2 diabetes and cardiovascular diseases. Predictive biomarkers are crucial for preventive strategies. Salivary α-amylase activity (sAAa) inversely correlates with obesity and insulin resistance in adults and children. However, the connection between sAAa and cardiometabolic risk factors or chronic low-grade inflammation markers remains unclear. This study explores the association between serum sAAa and adiposity markers related to cardiovascular diseases, as well as markers indicative of chronic low-grade inflammation. Methods: Serum samples and clinical data of 1500 adult, non-diabetic, Overweight/Obese participants were obtained from Qatar Biobank (QBB). We quantified sAAa and C reactive protein (CRP) levels with an autoanalyzer. Cytokines, adipokines, and adiponectin of a subset of 228 samples were quantified using a bead-based multiplex assay. The associations between the sAAa and the adiposity indices and low-grade inflammatory protein CRP and multiple cytokines were assessed using Pearson's correlation and adjusted linear regression. Results: The mean age of the participants was 36 ± 10 years for both sexes of which 76.6% are women. Our analysis revealed a significant linear association between sAAa and adiposity-associated biomarkers, including body mass index ß -0.032 [95% CI -0.049 to -0.05], waist circumference ß -0.05 [95% CI -0.09 to -0.02], hip circumference ß -0.052 [95% CI -0.087 to -0.017], and HDL ß 0.002 [95% CI 0.001 to 0.004], albeit only in women. Additionally, sAAa demonstrated a significant positive association with adiponectin ß 0.007 [95% CI 0.001 to 0.01]while concurrently displaying significant negative associations with CRP ß -0.02 [95% CI -0.044 to -0.0001], TNF-α ß -0.105 [95% CI -0.207 to -0.004], IL-6 ß [95% CI -0.39 -0.75 to -0.04], and ghrelin ß -5.95 [95% CI -11.71 to -0.20], specifically within the female population. Conclusion: Our findings delineate significant associations between sAAa and markers indicative of cardiovascular disease risk and inflammation among overweight/obese adult Qatari females. Subsequent investigations are warranted to elucidate the nuances of these gender-specific associations comprehensively.

Untargeted Metabolomic Profiling Reveals Differentially Expressed Serum Metabolites and Pathways in Type 2 Diabetes Patients with and without Cognitive Decline: A Cross-Sectional Study.

Diabetes is recognized as a risk factor for cognitive decline, but the underlying mechanisms remain elusive. We aimed to identify the metabolic pathways altered in diabetes-associated cognitive decline (DACD) using untargeted metabolomics. We conducted liquid chromatography-mass spectrometry-based untargeted metabolomics to profile serum metabolite levels in 100 patients with type 2 diabetes (T2D) (54 without and 46 with DACD). Multivariate statistical tools were used to identify the differentially expressed metabolites (DEMs), and enrichment and pathways analyses were used to identify the signaling pathways associated with the DEMs. The receiver operating characteristic (ROC) analysis was employed to assess the diagnostic accuracy of a set of metabolites. We identified twenty DEMs, seven up- and thirteen downregulated in the DACD vs. DM group. Chemometric analysis revealed distinct clustering between the two groups. Metabolite set enrichment analysis found significant enrichment in various metabolite sets, including galactose metabolism, arginine and unsaturated fatty acid biosynthesis, citrate cycle, fructose and mannose, alanine, aspartate, and glutamate metabolism. Pathway analysis identified six significantly altered pathways, including arginine and unsaturated fatty acid biosynthesis, and the metabolism of the citrate cycle, alanine, aspartate, glutamate, a-linolenic acid, and glycerophospholipids. Classifier models with AUC-ROC > 90% were developed using individual metabolites or a combination of individual metabolites and metabolite ratios. Our study provides evidence of perturbations in multiple metabolic pathways in patients with DACD. The distinct DEMs identified in this study hold promise as diagnostic biomarkers for DACD patients.

The triglyceride glucose-waist-to-height ratio outperforms obesity and other triglyceride-related parameters in detecting prediabetes in normal-weight Qatari adults: A cross-sectional study.

Introduction: The triglyceride-glucose (TyG)-driven indices, incorporating obesity indices, have been proposed as reliable markers of insulin resistance and related comorbidities such as diabetes. This study evaluated the effectiveness of these indices in detecting prediabetes in normal-weight individuals from a Middle Eastern population. Methods: Using the data of 5,996 adult Qatari participants from the Qatar Biobank cohort, we employed adjusted logistic regression to assess the ability of various obesity and triglyceride-related indices to detect prediabetes in normal-weight (18.5 ≤ BMI <25 kg/m2) adults (≥18 years). Results: Of the normal-weight adults, 13.62% had prediabetes. TyG-waist-to-height ratio (TyG-WHTR) was significantly associated with prediabetes among normal-weight men [OR per 1-SD 2.68; 95% CI (1.67-4.32)] and women [OR per 1-SD 2.82; 95% CI (1.61-4.94)]. Compared with other indices, TyG-WHTR had the highest area under the curve (AUC) value for prediabetes in men [AUC: 0.76, 95% CI (0.70-0.81)] and women [AUC: 0.73, 95% CI (0.66-0.80)], and performed significantly higher than other indices (p < 0.05) in detecting prediabetes in men. Tyg-WHTR shared similar diagnostic values as fasting plasma glucose (FPG). Discussion: Our findings suggest that the TyG-WHTR index could be a better indicator of prediabetes for general clinical usage in normal weight Qatari adult men than other obesity and TyG-related indices. TyG-WHTR can help identify a person's risk for developing prediabetes in both men and women when combined with FPG results.

Comparative Transcriptome Analysis Reveals That Exendin-4 Improves Steatosis in HepG2 Cells by Modulating Signaling Pathways Related to Lipid Metabolism.

No therapy exists for non-alcoholic fatty liver disease (NAFLD). However, glucagon-like peptide receptor agonists (GLP-1RAs) showed a beneficial effect on NAFLD, although the underpinning mechanisms remain unclear due to their pleiotropic effects. We examined the implicated signaling pathways using comparative transcriptomics in a cell model of steatosis to overcome pleiotropy. We treated steatotic HepG2 cells with the GLP-1RA Exendin-4 (Ex-4). We compared the transcriptome profiles of untreated steatotic, and Ex-4-treated steatotic cells, and used Ingenuity Pathway Analysis (IPA) to identify the signaling pathways and associated genes involved in the protective effect of Ex-4. Ex-4 treatment significantly reduces steatosis. RNA-seq analysis revealed 209 differentially expressed genes (DEGs) between steatotic and untreated cells, with farnesoid X receptor/retinoid X receptor (FXR/RXR) (p = 8.9 × 10-7) activation being the top regulated canonical pathway identified by IPA. Furthermore, 1644 DEGs were identified between steatotic cells and Ex-4-treated cells, with liver X receptor/retinoid X receptor (LXR/RXR) (p = 2.02 × 10-7) and FXR/RXR (p = 3.28 × 10-7) activation being the two top canonical pathways. The top molecular and cellular functions between untreated and steatotic cells were lipid metabolism, molecular transport, and small molecular biochemistry, while organismal injury and abnormalities, endocrine system disorders, and gastrointestinal disease were the top three molecular and cellular functions between Ex-4-treated and steatotic cells. Genes overlapping steatotic cells and Ex-4-treated cells were associated with several lipid metabolism processes. Unique transcriptomic differences exist between steatotic cells and Ex-4-treated steatotic cells, providing an important resource for understanding the mechanisms that underpin the protective effect of GLP-1RAs on NAFLD and for the identification of novel therapeutic targets for NAFLD.

Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating the cells with 400 µM oleic acid (OA) overnight. Further treatment with 200 nM Ex-4 for 3 h significantly reduced the OA-induced lipid accumulation (p < 0.05). Concomitantly, Ex-4 substantially reduced the expression levels of Fatty Acid-Binding Protein 1 (FABP1) and its primary activator, Forkhead box protein A1 (FOXA1). Interestingly, the silencing of ß-catenin with siRNA abolished the effect of Ex-4 on these genes, suggesting dependency on the Wnt/ß-catenin pathway. Additionally, after ß-catenin silencing, OA treatment significantly increased the expression of nuclear transcription factors SREBP-1 and TCF4, whereas Ex-4 significantly decreased this upregulation. Our findings suggest that direct activation of GLP-1R by Ex-4 reduces OA-induced steatosis in HepG2 cells by reducing fatty acid uptake and transport via FABP1 downregulation.

Association of dyslipidemia, diabetes and metabolic syndrome with serum ferritin levels: a middle eastern population-based cross-sectional study.

Elevated serum ferritin (SFer) levels are implicated in many energy metabolism abnormalities. The association between SFer levels and metabolic disorders has not been studied in Middle Eastern populations. We aimed at exploring the association between SFer levels and serum lipids, diabetes determinants, and metabolic syndrome in a sample of Qatari adults. This study used biochemical parameters obtained from 1928 participants from the Qatar Biobank cohort. We utilized adjusted multivariable logistic regression analysis to estimate the odds ratios (ORs) for dyslipidemia, type 2 diabetes, the homeostasis model assessment of insulin resistance (HOMA-IR), and metabolic syndrome (MetS) according to sex-specific SFer quartiles (Q1 to Q4). Results revealed that the ORs for dyslipidemia increased progressively and significantly across the SFer quartiles, up to two folds in Q4 for women (OR 2.47 (1.68-3.62)) and men (OR 2.24 (1.41-3.55)) versus Q1 (OR:1). Exclusively in women, the ORs for IR (HOMA-IR > 3.58) increased significantly in Q4 (OR 1.79 (1.19-2.70)) versus OR 1 in Q1 as did the ORs for diabetes (OR: 2.03 (1.15-3.57) in Q4 versus OR 1 in Q1). We observed the same result when we pooled the participants with prediabetes and diabetes in one group. The OR for MetS also increased significantly across the Sfer Quartiles from OR: 1 in Q1 to 1.92 (1.06-3.02) in Q4 for women and to 2.07 (1.08-3.98) in Q4 in men. Our results suggest the elevated Sfer levels as a potential risk biomarker for dyslipidemia and MetS in adult Qatari men and women, and diabetes and IR in women only.

Comprehensive analysis of LncRNAs expression profiles in an in vitro model of steatosis treated with Exendin-4.

BACKGROUND AND AIMS: The hallmark of non-alcoholic fatty liver disease (NAFLD) is the excessive hepatic lipid accumulation. Currently, no pharmacotherapy exists for NAFLD. However, the glucagon-like peptide-1 receptor agonists have recently emerged as potential therapeutics. Here, we sought to identify the long non-coding RNAs (LncRNAs) associated with the steatosis improvement induced by the GLP-1R agonist Exendin-4 (Ex-4) in vitro. METHODS: Steatosis was induced in HepG2 cells with oleic acid. The transcriptomic profiling was performed using total RNA extracted from untreated, steatotic, and Ex-4-treated steatotic cells. We validated a subset of differentially expressed LncRNAs with qRT-PCR and identified the most significantly enriched cellular functions associated with the relevant LncRNAs. RESULTS: We confirm that Ex-4 improves steatosis in HepG2 cells. We found 379 and 180 differentially expressed LncRNAs between untreated and steatotic cells and between steatotic and Ex-4-treated steatotic cells, respectively. Interestingly, 22 upregulated LncRNAs in steatotic cells became downregulated with Ex-4 exposure, while 50 downregulated LncRNAs in steatotic cells became upregulated in the presence of Ex-4. Although some LncRNAs, such as MALAT1, H19, and NEAT1, were previously associated with NAFLD, the association of others with steatosis and the positive effect of Ex-4 is being reported for the first time. Functional enrichment analysis identified many critical pathways, including fatty acid and pyruvate metabolism, and insulin, PPAR, Wnt, TGF-ß, mTOR, VEGF, NOD-like, and Toll-like receptors signaling pathways. CONCLUSION: Our results suggest that LncRNAs may play essential roles in the mechanisms underlying steatosis improvement in response to GLP-1R agonists and warrant further functional studies.

Reduced odds of diabetes associated with high plasma salivary α-amylase activity in Qatari women: a cross-sectional study.

The association of salivary α-amylase activity (SAA) activity or low copy number of its coding gene AMY1 with diabetes remains controversial. We aimed to reinvestigate the association of these factors with diabetes in Qatar, where diabetes prevalence is about 16%. We obtained cross-sectional data of 929 Qataris (age > 18 years) from the Qatar Biobank. We estimated AMY1 copy number variants (CNV) from whole-genome data, and quantified the SAA activity in plasma (pSAA). We used adjusted logistic regression to examine the association between pSAA activity or AMY1 CNV and diabetes odds. We found a significant association between high pSAA activity, but not AMY1 CNV, and reduced odds of diabetes in Qatari women. The OR per pSAA activity unit was 0.95 [95% CI 0.92, 0.98] (p = 0.002) (pSAA activity range: 4.7 U/L to 65 U/L) in women. The association is driven largely by the highest levels of pSAA activity. The probability of having diabetes was significantly lower in the fifth pSAA activity quintile relative to the first (0.21 ± 0.03 (Q1) versus 0.82 ± 0.02 (Q5)), resulting in significantly reduced diabetes prevalence in Q5 in women. Our study indicates a beneficial effect of high pSAA activity, but not AMY1 CN, on diabetes odds in Qatari women, and suggests pSAA activity levels as a potential marker to predict future diabetes in Qatari women.