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Abstract Background The genetic factors associated with insulin resistance (IR) are not well understood. Clinical studies on first-degree relatives of type 2 diabetic (T2D) patients, which have the highest genetic predisposition to T2D, have given insights into the role of IR in T2D pathogenesis. Induced pluripotent stem cells (iPSCs) are excellent tools for disease modeling as they can retain the genetic imprint of the disease. Therefore, in this study, we aimed to investigate the genetic perturbations associated with insulin resistance (IR) in the offspring of T2D parents using patient-specific iPSCs. Methods We generated iPSCs from IR individuals (IR-iPSCs) that were offspring of T2D parents as well as from insulin-sensitive (IS-iPSCs) individuals. We then performed transcriptomics to identify key dysregulated gene networks in the IR-iPSCs in comparison to IS-iPSCs and functionally validated them. Results Transcriptomics on IR-iPSCs revealed dysregulated gene networks and biological processes indicating that they carry the genetic defects associated with IR that may lead to T2D. The IR-iPSCs had increased lactate secretion and a higher phosphorylation of AKT upon stimulation with insulin. IR-iPSCs have increased cellular oxidative stress indicated by a high production of reactive oxygen species and higher susceptibility to H2O2 -induced apoptosis. Conclusions IR-iPSCs generated from offspring of diabetic patients confirm that oxidative stress and increased lactate secretion, associated with IR, are inherited in this population, and may place them at a high risk of T2D. Overall, our IR-iPSC model can be employed for T2D modeling and drug screening studies that target genetic perturbations associated with IR in individuals with a high risk for T2D.

Abstract Background Mobile health (mHealth) is increasingly advocated for diabetes management. It is unclear if mobile applications are effective in improving glycaemic control, clinical outcomes, quality of life and overall patient satisfaction in patients with type 2 diabetes (T2DM). A new mobile application was specifically built for people with T2DM with the help of the local expertise. The objective of the study was to evaluate the effectiveness of the mobile app. Methods The planned study is an ongoing open-label randomised controlled trial in which adults living with T2DM treated with insulin will be randomised 1:1 to the use of this diabetes application versus current standard care. The primary outcome will be the difference in mean HbA1c from baseline to 6 months. Other outcome measures include anthropometric measures, hypoglycaemic events, medication adjustments, number of clinical interactions and missed appointments and patient perceptions of their disease and diabetes self-management. The study will randomise 180 subjects for assessment of the primary outcome. Discussion We hypothesise that the diabetes-specific mobile application will improve glycaemic control, increase patient empowerment for self-management of diabetes and improve interaction between patients and healthcare providers. If the Qatar Diabetes Mobile Application Trial (QDMAT) demonstrates this, it will inform clinical services for the future self-management of T2DM. Trial registration ClinicalTrials.gov Identifier: NCT03998267 . Registered on 26 June 2019

Abstract Background There is controversy regarding the role of in-person attendance in schools and transmission of the SARS-CoV-2 pandemic. Several studies have demonstrated no increase in transmission, while some have reported large outbreaks with in-person attendance. We determined the incidence and risk factors for SARS-CoV-2 infection among school staff after one school term. Methods Nasopharyngeal swabs (NPS) for SARS-CoV-2 RT-PCR and blood for SARS-CoV-2 antibody testing were obtained from staff at a large international school in Qatar at the beginning of the 2020–2021 school year and repeated at the end of the first term. Results A total of 376 staff provided samples for testing. At the beginning of the 2020–2021 school year, the PCR positivity for SARS-CoV-2 was 13%, while seropositivity was 30.1%. A majority of those who tested positive either by PCR or serologically, were non-teaching staff. At the end of the first school term four months later, only 3.5% of the initially antibody-negative staff had seroconverted. In multivariable logistic regression analysis, male gender (OR 11.48, 95%CI 4.77–27.64), non-teaching job category (OR 3.09, 95%CI 1.10–8.64), contact with a confirmed case (OR 20.81, 95%CI 2.90–149.18), and presence of symptoms in the preceding 2 weeks [1–2 symptoms OR 4.82, 95%CI 1.79–12.94); ≥3 symptoms OR 42.30, 95%CI 3.76–476.43) independently predicted SARS-CoV-2 infection in school staff before school starting. Conclusion Male gender, non-teaching job, presence of symptoms, and exposure to a confirmed case were associated with higher risk of infection. These data can help policymakers in determining the optimal strategy for school reopening.

Abstract Background Polycystic ovary syndrome (PCOS) is associated with obesity, diabetes, and insulin resistance. The circulating C1Q/TNF-related proteins (CTRP-2, CTRP-9) and growth differentiation factors (GDF-8, GDF-15) contribute to glucose and lipid homeostasis. The effects of intralipids and insulin infusion on CTRP-2, CTRP-9, GDF-8 and GDF-15 in PCOS and control subjects before and after chronic exercise training were examined. Methods Ten PCOS and nine healthy subjects were studied at baseline status and after moderate-intensity chronic exercise training (1 h exercise, 3 times per week, 8 weeks). All participants were infused with 1.5 mL/min of saline or intralipids (20%) for 5 h, and during the last 2 h of saline or intralipids infusion hyperinsulinemic-euglycemic clamp (HIEC) was performed. CTRP-2, CTRP-9, GDF-8 and GDF-15 levels were measured at 0, 3 and 5 h. Results Intralipids dramatically increased CTRP-2 levels in PCOS (P = 0.02) and control (P = 0.004) subjects, which was not affected by insulin infusion or by exercise. Intralipids alone had no effects on CTRP-9, GDF-8, or GDF-15. Insulin increased the levels of GDF-15 in control subjects (P = 0.05) during the saline study and in PCOS subjects (P = 0.04) during the intralipid infusion. Insulin suppressed CTRP9 levels during the intralipid study in both PCOS (P = 0.04) and control (P = 0.01) subjects. Exercise significantly reduced fasting GDF-8 levels in PCOS (P = 0.03) and control (P = 0.04) subjects; however, intralipids infusion after chronic exercise training increased GDF-8 levels in both PCOS (P = 0.003) and control (P = 0.05) subjects and insulin infusion during intralipid infusion reduced the rise of GDF-8 levels. Conclusion This study showed that exogenous lipids modulate CTRP-2, which might have a physiological role in lipid metabolism. Since chronic exercise training reduced fasting GDF-8 levels; GDF-8 might have a role in humoral adaptation to exercise. GDF-15 and CTRP-9 levels are responsive to insulin, and thus they may play a role in insulin responses.

Abstract Obesity and insulin resistance are key elements of the metabolic syndrome, which includes type 2 diabetes (T2D), dyslipidemia, systemic inflammation, hypertension, elevated risk for cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS). C1Q Tumor necrosis factor-related proteins (CTRPs) have recently emerged as important regulators of metabolism as a core component in the interrelationship between insulin resistance, adiposity and inflammation. To date 15 CTRP members have been identified and most of the CTRPs are dysregulated in obesity, T2D, coronary artery disease and NAFLD. Pharmacological intervention and lifestyle modification alter expression of CTRPs in circulation and in metabolically active tissues. CTRPs enhance metabolism mainly through activation of AMPK/AKT dependent pathways and possess insulin sensitizing properties. Thus dysregulated expression of CTRPs in metabolic disorders could contribute to the pathogenesis of the disease. For these reasons CTRPs appear to be promising targets for early detection, prevention and treatment of metabolic disorders. This review article aims at exploring the role of CTRPs in metabolic syndrome.

Abstract Objectives A decrease in Emergency Department (ED) visits for cardiac conditions has recently been reported from the US and Western Europe due to the COVID-19 pandemic. The data are still scant, and the correlation between cardiac symptoms and confirmed diagnoses are not available. There are no reports on changes in ED volumes at a national level, or from countries in the Asia-Middle Eastern region. We report data from national referral centers for tertiary care and cardiac care centers in Qatar, which see > 80% of cardiac emergencies in the country. Results We analyzed 102,033 ED visits in the COVID-19-era (March–April 2020 and 2019) and determined the proportion presenting for cardiac symptoms and their confirmed diagnoses. We observed a 16–37% decline in ED volumes overall, with a 25–50% decline in patients presenting with cardiac symptoms in March and April 2020 compared with March and April 2019. Among those presenting with cardiac symptoms, we observed a 24–43% decline in cardiac diagnoses in March and April 2020 compared with March and April 2019.

Abstract Background Pregnant women with gestational diabetes mellitus (GDM) or type 2 diabetes mellitus (T2DM) are at increased risks of pre-term labor, hypertension and preeclampsia. In this study, metabolic profiling of blood samples collected from GDM, T2DM and control pregnant women was undertaken to identify potential diagnostic biomarkers in GDM/T2DM and compared to pregnancy outcome. Methods Sixty-seven pregnant women (21 controls, 32 GDM, 14 T2DM) in their second trimester underwent targeted metabolomics of plasma samples using tandem mass spectrometry with the Biocrates MxP® Quant 500 Kit. Linear regression models were used to identify the metabolic signature of GDM and T2DM, followed by generalized linear model (GLMNET) and Receiver Operating Characteristic (ROC) analysis to determine best predictors of GDM, T2DM and pre-term labor. Results The gestational age at delivery was 2 weeks earlier in T2DM compared to GDM and controls and correlated negatively with maternal HbA1C and systolic blood pressure and positively with serum albumin. Linear regression models revealed elevated glutamate and branched chain amino acids in GDM + T2DM group compared to controls. Regression models also revealed association of lower levels of triacylglycerols and diacylglycerols containing oleic and linoleic fatty acids with pre-term delivery. A generalized linear model ROC analyses revealed that that glutamate is the best predictors of GDM compared to controls (area under curve; AUC = 0.81). The model also revealed that phosphatidylcholine diacyl C40:2, arachidonic acid, glycochenodeoxycholic acid, and phosphatidylcholine acyl-alkyl C34:3 are the best predictors of GDM + T2DM compared to controls (AUC = 0.90). The model also revealed that the triacylglycerols C17:2/36:4 and C18:1/34:1 are the best predictors of pre-term delivery (≤ 37 weeks) (AUC = 0.84). Conclusions This study highlights the metabolite alterations in women in their second trimester with diabetes mellitus and identifies predictive indicators of pre-term delivery. Future studies to confirm these associations in other cohorts and investigate their functional relevance and potential utilization for targeted therapies are warranted.

Abstract Background There are conflicting data regarding the risk of hepatocellular carcinoma (HCC) after direct-acting antiviral agent (DAA) treatment. Risk of HCC in HCV genotype-3 infected persons after DAA therapy is not well known. Methods We prospectively studied HCV infected persons initiated on a DAA regimen between October 2014 and March 2017 at two centers in Pakistan. All persons were free of HCC at study initiation. HCC was confirmed based on characteristic CT scan findings. Patients were followed for 12 months after the completion of therapy. Results A total of 662 persons initiated treatment. Median age (IQR) was 50 (41, 57) years and 48.8% were male. At baseline, 49.4% were cirrhotic, 91% were genotype 3 and 91.9% attained SVR. Treatment regimens used were: Sofosbuvir (SOF)/ribavirin (RBV)/pegylated interferon (PEG-IFN), 25.2%; SOF/RBV, 62.4%; SOF/RBV/daclatasavir (DCV), 10.6%; SOF/DCV, 2.0%. Incident HCC was detected in 42 patients (12.8%) in the 12-month period after treatment completion and was exclusively observed in those with cirrhosis. In multivariable Cox regression analysis, SVR was associated with a reduction in HCC risk (HR, 95% CI: 0.35, 0.14,0.85). In Kaplan-Meier plots by treatment regimen, those treated with SOF/RBV, SOF/RBV/DCV, or SOF/DCV regimens had a shorter HCC-free survival compared with those treated with a SOF/RBV/PEG-IFN regimen. Conclusion In a predominantly genotype 3 cohort, incident HCC occurred frequently and early after treatment completion, and exclusively in those with pre-treatment cirrhosis. SVR reduced the risk of HCC. Treating HCV infected persons before development of cirrhosis may reduce risk of HCC.

Abstract Background Cystic fibrosis (CF) lung disease is associated with chronic inflammation leading to progress in lung function. Adiponectin is a predominantly anti-inflammatory adipokine that may have a role in CF lung. This study aims to determine total sputum and total plasma adiponectin levels in clinically stable adults CF patients with CFTR I1234V mutation, compared to plasma adiponectin levels in healthy controls and to investigate their correlations with body mass index (BMI) and spirometry in patients with CF. Methods A cross-sectional study comprises 17 CF patients and 18 healthy controls. Adiponectin levels were measured by magnetic bead-based multiplex assay. Results The mean age of adult CF patients was 22.9 years±3.8 (18–30) and 76.5% CF patients had pancreatic sufficiency. The mean BMI in healthy controls was slightly higher than CF patients. The mean sputum adiponectin level was significantly lower than plasma adiponectin levels in CF patients and healthy controls (p

Abstract Background Type 2 diabetes mellitus (T2DM) and obesity are syndemic and will have a significant impact on affected individuals and healthcare services worldwide. Evidence shows that T2DM remission can be achieved with significant weight loss in those who are younger with early diabetes and requiring fewer medications for glycaemic control. DIADEM-I aims to examine the impact of an intensive lifestyle intervention (ILI) using a low-energy diet (LED) meal replacement approach combined with physical activity in younger individuals with early T2DM. Methods The planned study is an ongoing, non-blinded, pragmatic, randomised controlled, parallel-group trial examining the impact of an LED-based ILI on body weight and diabetes remission in younger (18–50 years) T2DM individuals with early diabetes (≤ 3-year duration). The ILI will be compared to usual medical care (UMC). The primary outcome will be weight loss at 12 months. Other key outcomes of interest include diabetes remission, glycaemic control, diabetes complications, cardiovascular health, physical activity, mental health, and quality of life. It is planned for the study to include 138 subjects for assessment of the primary outcome. Safety will be assessed throughout. Discussion If DIADEM-I demonstrates a clinically significant effect for younger individuals with early T2DM, it will inform clinical guidelines and services of the future for management of T2DM. Trial registration ISRCTN: ISRCTN20754766 (date assigned: 7 June 2017); ClinicalTrials.gov, ID: NCT03225339 Registered on 26 June 2017.

Abstract Background The genetic basis of type 2 diabetes (T2D) is under-investigated in the Middle East, despite the rapidly growing disease prevalence. We aimed to define the genetic determinants of T2D in Qatar. Methods Using whole genome sequencing of 11,436 participants (2765 T2D cases and 8671 controls) from the population-based Qatar Biobank (QBB), we conducted a genome-wide association study (GWAS) of T2D with and without body mass index (BMI) adjustment. Results We replicated 93 known T2D-associated loci in a BMI-unadjusted model, while 96 known loci were replicated in a BMI-adjusted model. The effect sizes and allele frequencies of replicated SNPs in the Qatari population generally concurred with those from European populations. We identified a locus specific to our cohort located between the APOBEC3H and CBX7 genes in the BMI-unadjusted model. Also, we performed a transethnic meta-analysis of our cohort with a previous GWAS on T2D in multi-ancestry individuals (180,834 T2D cases and 1,159,055 controls). One locus in DYNC2H1 gene reached genome-wide significance in the meta-analysis. Assessing polygenic risk scores derived from European- and multi-ancestries in the Qatari population showed higher predictive performance of the multi-ancestry panel compared to the European panel. Conclusion Our study provides new insights into the genetic architecture of T2D in a Middle Eastern population and identifies genes that may be explored further for their involvement in T2D pathogenesis.

Abstract Objectives To examine the hypothesis that obesity complicated by the metabolic syndrome, compared to uncomplicated obesity, has distinct molecular signatures and metabolic pathways. Methods We analyzed a cohort of 39 participants with obesity that included 21 with metabolic syndrome, age-matched to 18 without metabolic complications. We measured in whole blood samples 754 human microRNAs (miRNAs), 704 metabolites using unbiased mass spectrometry metabolomics, and 25,682 transcripts, which include both protein coding genes (PCGs) as well as non-coding transcripts. We then identified differentially expressed miRNAs, PCGs, and metabolites and integrated them using databases such as mirDIP (mapping between miRNA-PCG network), Human Metabolome Database (mapping between metabolite-PCG network) and tools like MetaboAnalyst (mapping between metabolite-metabolic pathway network) to determine dysregulated metabolic pathways in obesity with metabolic complications. Results We identified 8 significantly enriched metabolic pathways comprising 8 metabolites, 25 protein coding genes and 9 microRNAs which are each differentially expressed between the subjects with obesity and those with obesity and metabolic syndrome. By performing unsupervised hierarchical clustering on the enrichment matrix of the 8 metabolic pathways, we could approximately segregate the uncomplicated obesity strata from that of obesity with metabolic syndrome. Conclusions The data suggest that at least 8 metabolic pathways, along with their various dysregulated elements, identified via our integrative bioinformatics pipeline, can potentially differentiate those with obesity from those with obesity and metabolic complications.