Search

Background Adverse events (AE) are responsible for annual deaths that exceed deaths due to motor vehicle accidents, breast cancer, and AIDS. Many AE are considered preventable. Thus, AE needs to be detected and analyzed. Incident reporting systems (IRS) are crucial in identifying AE. Nevertheless, the incident report (IR) process is flawed with underreporting, especially from the physicians' side. This limits its efficiency in detecting AE. Therefore, we aimed to assess the practice and identify the barriers associated with incident reporting among internal medicine physicians in a large tertiary hospital through a survey. Methods A cross-sectional descriptive study. We distributed an online survey to physicians working in the Internal Medicine Department of Qatar's largest tertiary academic institute. The questionnaire was validated and piloted ahead of the start of the trial. The response rate was 53%. Results A total of 115 physicians completed the survey; 59% acknowledged the availability of an institutional IRS. However, only 29% knew how to submit an online IR, and 20% have ever submitted an IR. The survey revealed that participants were less likely to submit an IR when they or a colleague is involved in the incident; 46% and 63%, respectively. The main barriers of reporting incidents were unawareness about the IRS (36%) and the perception that IR will not bring a system change (13%); moreover, there exists the fear of retaliation (13%). When asked about solutions, 57% recommended training and awareness, and 22% recommended sharing learnings and actions from previous IR. Conclusions IRS is underutilized by internal medicine physicians. The main barrier at the time of the survey is the lack of training and awareness. Promoting awareness and sharing previous learning and actions may improve the utilization of the IRS.

Metabolic pathways that are corrupted at early stages of insulin resistance (IR) remain elusive. This study investigates changes in body metabolism in clinically healthy and otherwise asymptomatic subjects that may become apparent already under compromised insulin sensitivity (IS) and prior to IR. 47 clinically healthy Arab male subjects with a broad range of IS, determined by hyperinsulinemic-euglycemic clamp (HIEC), were investigated. Untargeted metabolomics and complex lipidomics were conducted on serum samples collected under fasting and HIEC conditions. Linear models were used to identify associations between metabolites concentrations and IS levels. Among 1896 identified metabolites, 551 showed significant differences between fasting and HIEC, reflecting the metabolic switch in energy utilization. At fasting, 336 metabolites, predominantly di- and tri-acylglycerols, showed significant differences between subjects with low and high levels of IS. Changes in amino acid, carbohydrate and fatty acid metabolism in response to insulin were impaired in subjects with low IS. Association of altered mannose and amino acids with IS was also replicated in an independent cohort of T2D patients. We identified metabolic phenotypes that characterize clinically healthy Arab subjects with low levels of IS at their fasting state. Our study is providing further insights into the metabolic pathways that precede IR.

Treating HCV infection reduces overall mortality and reduces the risk of multiple extrahepatic complications. Whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications is unknown.We identified HCV-positive individuals treated for HCV, and propensity score-matched them to HCV-positive/untreated and HCV-uninfected individuals in ERCHIVES between 2002-2016. We extracted cause of death data from the National Center for Health Statistics' National Death Index. Viral hepatitis-associated liver-related mortality rates among treated and untreated HCV-infected persons were calculated by treatment and attainment of sustained virologic response (SVR).Among 50,674 HCV-positive/treated (Group A), 31,749 HCV-positive/untreated (Group B) and 73,526 HCV-uninfected persons (Group C), 8.6% in Group A, 35.0% in Group B, and 14.3% in Group C died. Among those who died, viral hepatitis-associated liver-related mortality rates per 100 patient-years (95% CI) were: 0.28 (0.27-0.30) for Group A; 1.44 (1.38-1.49) for Group B; and 0.06 (0.05-0.06) for Group C; (p0.0001 for both comparisons). Among HCV-positive/treated persons, rates were 0.06 (0.05-0.06) for those with SVR vs. 0.78 (0.74-0.83) for those without SVR. In competing risks Cox proportional hazards analysis, treatment with all-oral DAA regimens (adjusted hazard ratio 0.11; 95% CI 0.09-0.14) and SVR (adjusted hazard ratio 0.10; 95% CI 0.08-0.11) were associated with reduced hazards of liver-related mortality.Treatment for HCV is associated with a significant reduction in viral hepatitis-associated liver-related mortality, which is particularly pronounced in those treated with DAA regimens and those who attain SVR. This may account for a significant proportion of the reduction in all-cause mortality reported in previous studies.Treating hepatitis C virus (HCV) infection is known to reduce overall mortality. However, whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications was previously unknown. Herein, we show that while treating HCV with direct-acting antiviral regimens has numerous extrahepatic benefits, a significant benefit can be attributed specifically to the reduction in liver-related mortality.

Summary Background Type 2 diabetes is affecting people at an increasingly younger age, particularly in the Middle East and in north Africa. We aimed to assess whether an intensive lifestyle intervention would lead to significant weight loss and improved glycaemia in young individuals with early diabetes. Methods This open-label, parallel-group, randomised controlled trial (DIADEM-I), done in primary care and community settings in Qatar, compared the effects of an intensive lifestyle intervention with usual medical care on weight loss and glycaemic outcomes in individuals with type 2 diabetes, aged 18–50 years, with a short diabetes duration (≤3 years), had a BMI of 27·0 kg/m2 or more, and who were from the Middle East and north Africa region. Participants were randomly allocated (1:1) either to the intensive lifestyle intervention group or the usual medical care control group by a computer-generated sequence and an online randomisation service. The intensive lifestyle intervention comprised a total diet replacement phase, in which participants were given formula low-energy diet meal replacement products followed by gradual food reintroduction combined with physical activity support, and a weight-loss maintenance phase, involving structured lifestyle support. Participants in the control group received usual diabetes care, which was based on clinical guidelines. The primary outcome was weight loss at 12 months after receiving the assigned intervention. Our analysis was based on the intention-to-treat principle. Key secondary outcomes included diabetes control and remission. The trial was registered with the ISRCTN registry, ISRCTN20754766, and ClinicalTrials.gov , NCT03225339 . Findings Between July 16, 2017, and Sept 30, 2018, we enrolled and randomly assigned 158 participants (n=79 in each group) to the study. 147 participants (70 in the intervention group and 77 in the control group) were included in the final intention-to-treat analysis population. Between baseline and 12 months, the mean bodyweight of participants in the intervention group reduced by 11·98 kg (95% CI 9·72 to 14·23) compared with 3·98 kg (2·78 to 5·18) in the control group (adjusted mean difference −6·08 kg [95% CI −8·37 to −3·79], p Interpretation Our findings show that the intensive lifestyle intervention led to significant weight loss at 12 months, and was associated with diabetes remission in over 60% of participants and normoglycaemia in over 30% of participants. The provision of this lifestyle intervention could allow a large proportion of young individuals with early diabetes to achieve improvements in key cardiometabolic outcomes, with potential long-term benefits for health and wellbeing. Funding Qatar National Research Fund.

Objectives: Diabetes self-management educational (DSME) interventions can vary considerably, and it is unclear what is the operational conceptualization of the ideal delivery to individuals with type 2 diabetes (T2D). Design: From a search conducted concurrently we extracted and evaluated the 50 most recently published DSME intervention studies. Based on an analysis of these studies, we undertook a concept analysis using the Walker and Avant framework. Results: Five attributes describing the concept were recognized and organized into two groups. Group (a): skills related attributes that included (1) decision making, (2) problem solving and (3) taking action. Group (b): information related attributes that included (4) patient-provider interaction and (5) resource utilization. Conclusions: The outcomes of this study make the operational conceptualization of the ideal DSME intervention measurable through its attributes and hence clarifies its delivery. This will improve the implementation of the key attributes in diabetes self-management intervention programs for T2D. The authors thank the Division of Endocrinology, Hamad General Hospital, for support provided during the conduct of this work. Scopus

BACKGROUND: SARS-CoV-2 infection in pregnancy is associated with a higher risk of pregnancy-related complications and neonatal respiratory distress and hospitalization. Effectiveness of SARS-CoV-2 vaccines in pregnant women is not known. METHODS: All women with confirmed pregnancy who presented to the national referral hospital in Qatar between December 20, 2020, and May 30, 2021, with at least 1 SARS-CoV-2 test and not testing prior to pregnancy were included. We determined the vaccine effectiveness of mRNA vaccines in preventing confirmed SARS-CoV-2 infection during pregnancy using both cohort and test-negative case-control designs. Analyses were adjusted for age group, nationality, and gestational age. RESULTS: Among 4534 pregnant women, there were 407 vaccinated and 407 unvaccinated women in the matched cohort analysis. Vaccine effectiveness was 87.6% (95%CI 44.1%–97.2%) at least 14 days after the second dose. There were 386 test-positive and 834 matched women in the test-negative case control analysis. Vaccine effectiveness was 86.8% (95%CI 47.5%–98.5%) at least 14 days after the second dose. Adjustment for age, nationality, and gestational age yielded similar results for both designs. In the test-negative analysis, vaccine effectiveness at least 14 days after the first dose but before the second dose was 40.8% (95% CI 0.0%–80.4%). Of the 386 test-positive pregnant women, 74 cases were Alpha variant, 163 cases were Beta variant, and 156 cases were variants of unknown status. There were 9 severe or critical disease cases and no deaths in the test-positive pregnant women, all of whom were unvaccinated. CONCLUSION: The mRNA vaccines provide a high level of protection against documented SARS-CoV-2 infection, which supports the inclusion of pregnant women in vaccination campaigns. FUNDING: Hamad Medical Corporation, Weill Cornell Medicine Qatar, and the Ministry of Public Health Qatar.

IntroductionGestational Diabetes Mellitus (GDM) development is related to underlying metabolic syndrome that is associated with elevated complement C3 and C4. Elevated C3 levels have been associated with preeclampsia and the development of macrosomia.MethodsThis case-control study included 34 pregnant women with GDM and 16 non-diabetic (ND) women in their second trimester. Complement-related proteins were measured and correlated with demographic, biochemical, and pregnancy outcome data.ResultsGDM women were older with a higher BMI (pnd term diastolic blood pressure (pConclusionThe increased C3, C4 and Factor-H during the second trimester of pregnancy in GDM are not independently associated with GDM; inflammation and high BMI may be responsible for their elevation. The elevation of second trimester C3 in GDM is associated with earlier delivery and further work is needed to determine if this is predictive.

Aims: Disagreement about the appropriate criteria for the diagnosis of gestational diabetes mellitus (GDM) persists. This study examines an alternative approach which combines information from all time-points on the glucose tolerance test (GTT) into a single index and expands the GDM spectrum into four categories using data from three geographically and ethnically distinct populations. Methods: A retrospective observational study design was used. Data from Wisconsin, USA (723 women) was used in derivation of the criterion and data from Doha, Qatar (1284 women) and Cape Town, South Africa (220 women) for confirmation. Pregnant women without pre-existing diabetes with a GTT done between 23 and 30 weeks gestation were included. A novel index was derived from the GTT termed the weighted average glucose (wAG). This was categorized into four pre-defined groups (henceforth National Priorities Research Program (NPRP) criterion); i) normal gestational glycemia (NGG), ii) impaired gestational glycemia (IGG), iii) GDM and iv) high risk GDM (hGDM). Results: In the Doha cohort, compared to the NGG group, the odds of large for gestational age babies increased 1.33 fold (P = 0.432), 2.86 fold (P < 0.001) and 3.35 fold (P < 0.001) in the IGG, GDM and hGDM groups respectively. The odds of pregnancy induced hypertension increased 2.10 fold (P = 0.024) in GDM & hGDM groups compared to the IGG and NGG groups. In the Cape Town cohort, a third of women in the GDM group and two-thirds in the hGDM group progressed to T2DM at 5 years. Conclusions: The NPRP categorization identifies four distinct risk clusters of glycemia in pregnancy which may aid better decision making in routine management, avoid potential over-diagnosis of women at lower risk of complications and assist with diabetes prevention in women at high-risk after an index pregnancy with GDM.

AIMSDisagreement about the appropriate criteria for the diagnosis of gestational diabetes mellitus (GDM) persists. This study examines an alternative approach which combines information from all time-points on the glucose tolerance test (GTT) into a single index and expands the GDM spectrum into four categories using data from three geographically and ethnically distinct populations.METHODSA retrospective observational study design was used. Data from Wisconsin, USA (723 women) was used in derivation of the criterion and data from Doha, Qatar (1284 women) and Cape Town, South Africa (220 women) for confirmation. Pregnant women without pre-existing diabetes with a GTT done between 23 and 30 weeks gestation were included. A novel index was derived from the GTT termed the weighted average glucose (wAG). This was categorized into four pre-defined groups (henceforth National Priorities Research Program (NPRP) criterion); i) normal gestational glycemia (NGG), ii) impaired gestational glycemia (IGG), iii) GDM and iv) high risk GDM (hGDM).RESULTSIn the Doha cohort, compared to the NGG group, the odds of large for gestational age babies increased 1.33 fold (P=0.432), 2.86 fold (PCONCLUSIONSThe NPRP categorization identifies four distinct risk clusters of glycemia in pregnancy which may aid better decision making in routine management, avoid potential over-diagnosis of women at lower risk of complications and assist with diabetes prevention in women at high-risk after an index pregnancy with GDM.

Objective: Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder associated with mitochondrial dysfunction and insulin resistance (IR). MOTS-c, a mitochondrial peptide, promotes insulin sensitivity (IS) through activating AKT and AMPK-dependent pathways. The current study was designed to examine the response of MOTS-c to lipids (intralipid) followed by insulin in PCOS and healthy subjects. Methods: All subjects underwent 5-hour intralipid/saline infusion with a hyperinsulinemic-euglycaemic clamp in the final 2 hours. Plasma samples were collected to measure circulating MOTS-c using a commercial ELISA kit. Subsequently, this was repeated following an eight-week exercise intervention. Results: Intralipid significantly increased plasma MOTS-c both in controls and PCOS subjects, whilst the insulin infusion blunted the intralipid-induced response seen for both lipids and MOT-c. Intralipid elevated plasma MOTS-c to 232±124% of basal in control (P < 0.01) and to 349 ± 206% of basal in PCOS (P < 0.001) subjects. Administration of insulin suppressed intralipid-induced MOTS-c from 232 ± 124% to 165 ± 97% (NS) in control and from 349 ± 206% to 183 ± 177% (P < 0.05) in PCOS subjects, respectively. Following exercise, intralipid elevated plasma MOTS-c to 305 ± 153% of basal in control (P < 0.01) and to 215 ± 103% of basal in PCOS (P < 0.01) subjects; insulin suppressed intralipid-induced MOTS-c only in controls. Conclusions In conclusion, this is the first study to show increased lipid enhanced circulating MOTS-c whilst insulin attenuated the MOTS-c response in human. Further, eight weeks of moderate exercise training did not show any changes in circulating MOTS-c levels in healthy controls and in women with PCOS.

Background and purpose Neutrophil elastase (NE) has been implicated in the pathogenesis of airway inflammation in cystic fibrosis (CF) patients and it impairs defenses against Pseudomonas aeruginosa (PA) infection or colonization. Sputum NE may act as a biomarker of neutrophilic inflammation in CF patients. This study aimed to determine sputum and plasma total NE levels in clinically stable adult CF patients and control subjects, and their correlation to PA colonization and lung functions. Methods This is a cross-sectional study. Total NE was measured on spontaneously expectorated sputum and plasma obtained from 21 CF patients, aged 18-40 years, during routine visits to the adult CF clinic. This was compared to plasma obtained from 22 matching healthy controls. The levels of NE were measured by the magnetic bead-based multiplex assay. Results Sputum and plasma NE levels had a significant positive correlation (Pearson r=0.533, P=0.013) with PA colonization. Sixteen CF patients (76.2%) were chronically colonized with PA. Both median sputum and plasma NE were found to be higher in CF patients with PA as compared with non-PA patients, even though this difference was statistically insignificant. Sputum and plasma NE levels did not correlate with the percentage predicted forced expiratory volume in one second (FEV1), the forced vital capacity (FVC), and FEV1/FVC and no association with PA. Conclusion The findings suggest that clinically stable adult CF patients colonized with PA may have higher NE levels in both plasma and sputum as compared to non-PA CF patients and probably total NE does not influence lung functions.

Pregnancy may increase the risk of adverse maternal and neonatal outcomes in SARS-CoV-2 infection. Effectiveness of SARS-CoV-2 vaccines in pregnant women is not known. Using a test-negative case-control study, we determined the vaccine effectiveness of mRNA vaccines in preventing confirmed SARS-CoV-2 infection in pregnant women at a national referral hospital, which handles > 75% of the deliveries in Qatar. Among 2,020 pregnant women who met the study criteria, 397 had a positive SARS-CoV-2 RT-PCR and 1,623 had a negative test. Vaccine effectiveness ≥ 14 days after the second dose was 67.7% (95%CI 30.5–86.9), while vaccine effectiveness ≥ 14 days after the first dose but before the second dose was 40.3% (95%CI 0.0-80.4). There were nine severe/critical disease cases, and no deaths in the PCR-positive pregnant women, all among unvaccinated. The mRNA vaccines provide high level of protection against documented SARS-CoV-2 infection, which supports including pregnant women in vaccination campaigns.

BackgroundPolycystic ovary syndrome (PCOS) is a complex syndrome with clinical features of an endocrine/metabolic disorder. Various metabolites show significant association with PCOS; however, studies comparing the metabolic profile of pregnant women with and without PCOS are lacking. In this study, metabolomics analysis of blood samples collected from PCOS women and age and BMI matched controls in the second trimester of pregnancy was performed to identify metabolic differences between the two groups and determine their association with pregnancy outcome.MethodsSixteen PCOS and fifty-two healthy women 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 alterations associated with PCOS, followed by enrichment and Receiver Operating Characteristic (ROC) analyses to determine the best indicators of pregnancy outcomes.ResultsPCOS women had lower birth weight babies compared to healthy controls. As a group, systolic blood pressure (SBP) at both second trimester and at delivery negatively correlated with birth weight. Regression models indicated significant increases in the triglycerides C20:4_C34:3 and C18:2_C38:6 in the PCOS group [false discovery rate (FDR) ConclusionsPCOS pregnancies resulted in babies with a lower birth weight, marked by a unique metabolic signature that was enriched with specific triglycerides and unsaturated fatty acids. The functional significance of these associations needs further investigation.

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

Aims: Attributes that operationally conceptualize diabetes self-management education (DSME) interventions have never been studied previously to assess their impact on relevant outcomes of interest in people with type 2 diabetes (T2D). The aim of this study was to determine the impact of existing interventions classified by their delivery of skills or information related attributes on immediate (knowledge), intermediate (physical activity), post-intermediate (HbA1c), and long-term (quality of life) outcomes in people with T2D. Methods: PubMed, Embase, PsycINFO, and Cochrane Library/Cochrane CENTRAL as well as the grey literature were searched to identify interventional studies that examined the impact of DSME interventions on the four different outcomes. Eligible studies were selected and appraised independently by two reviewers. A meta-regression analysis was performed to determine the impact of delivery of the skills- and information-related attributes on the chosen outcomes. Results: 142 studies (n = 25,511 participants) provided data, of which 39 studies (n = 5278) reported on knowledge, 39 studies (n = 8323) on physical activity, 99 studies (n = 17,178) on HbA1c and 24 studies (n = 5147) on quality of life outcomes. Meta-regression analyses demonstrated that skills-related attributes had an estimated effect suggesting improvement in knowledge (SMD [standardized mean difference] increase of 0.80; P = 0.025) and that information-related attributes had an estimated effect suggesting improvement in quality of life (SMD increase of 0.96; P = 0.405). Skill- and information-related attributes did not have an estimated effect suggesting improvement in physical activity or in HbA1c. Conclusions: The study findings demonstrate that the skills and information related attributes contribute to different outcomes for people with T2D. This study provides, for the first time, preliminary evidence for differential association of the individual DSME attributes with different levels of outcome. LFK was supported by Australian National Health and Medical Research Council Early Career Fellowships ( APP1158469 ). Scopus

There are currently several diagnostic criteria for gestational diabetes (GDM). Both the WHO -2013 and NICE diagnose GDM based on a single step 75 g OGT; however; each uses different glucose thresholds. Previous studies have shown that the prevalence of GDM using the NICE criteria (GDM-N) is lower than that using the WHO-2013 criteria (GDM-W). Qatar has national diabetes in pregnancy program in which all pregnant women undergo OGTT screening using the WHO-2013 criteria. This study aims to define the prevalence of GDM using both criteria in a high-risk population. This retrospective study included 2000 women who underwent a 75 g (OGTT) between Jan 2016 and Apr 2016 and excluded patients with known pre-conception diabetes, multiple pregnancy, and those who did not complete the OGTT. We then classified the women into GDM-W positive, GDM-N positive but GDM-W negative, and normal glucose tolerance (NGT) population. A total of 1481 women (74%) had NGT using the NICE or the WHO-2013 criteria. The number of patients who met both criteria was 279 subjects (14%) with a good agreement (Kappa coefficient 0.67, p

Prescription opioid use (POU) is often a precursor to opioid use disorder (OUD) and subsequent consequences. Persons with chronic hepatitis C virus infection (CHC) may be at a higher risk of POU due to a higher comorbidity burden and social vulnerability factors. We sought to determine the burden of POU and associated risk factors among persons with CHC in the context of social vulnerability. We identified CHC persons and propensity-score matched HCV− controls in the electronically retrieved Cohort of HCV-Infected Veterans and determined the frequency of acute, episodic long-term and chronic long-term POU and the prevalence of social vulnerability factors among persons with POU. We used logistic regression analysis to determine factors associated with POU. Among 160,856 CHC and 160,856 propensity-score matched HCV-controls, acute POU was recorded in 38.4% and 38.0% (P = 0.01) respectively. Episodic long-term POU was recorded in 3.9% in each group (P = 0.5), while chronic long-term POU was recorded in 28.4% and 19.2% (P

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.

Context The comparative efficacy of gestational diabetes (GDM) treatments lack conclusive evidence for choice of first-line treatment. Objectives The aim of this study was to compare the efficacy of metformin and glibenclamide to insulin using a core outcome set (COS) to unify outcomes across trials investigating the treatment of gestational diabetes mellitus. Study design A network meta-analysis (NMA) was conducted. Data-source PubMed, Embase, and Cochrane Controlled Register of Trials were searched from inception to January 2020. Study selection RCTs that enrolled pregnant women who were diagnosed with GDM and that compared the efficacy of different pharmacological interventions for the treatment of GDM were included. Meta-analysis A generalized pairwise modelling framework was employed. Results A total of 38 RCTs with 6046 participants were included in the network meta-analysis. Compared to insulin, the estimated effect of metformin indicated improvements for weight gain (WMD −2·39 kg; 95% CI −3·31 to −1·46), maternal hypoglycemia (OR 0.34; 95% CI 0.12 to 0·97) and LGA (OR 0.61; 95% CI 0.38 to 0·98). There were also improvements in estimated effects for neonatal hypoglycemia (OR 0.48; 95% CI 0.19 to 1·25), pregnancy induced hypertension (OR 0.63; 95% CI 0.37 to 1·06), and preeclampsia (OR 0.74; 95% CI 0.538 to 1·04), though with limited evidence against our model hypothesis of equivalence with insulin for these outcomes. Conclusion Metformin is, at least, comparable to insulin for the treatment of GDM. Glibenclamide appears less favorable, in comparison to insulin, than metformin.

Highlights • Among 16,912 HCW tested, 10.6% tested positive for COVID-19 • 5% acquired infection at a COVID-19 facility and 95% at a non-COVID-19 facility • Exposure to a colleague (45%) or a patient (29%) were reported at non-COVID sites • Full PPE adherence was 82% at COVID-19 but only 68% at non-COVID-19 facilities, Background Our aim was to determine the prevalence of COVID-19 infection in healthcare workers (HCW) in a national healthcare system and to understand the risk factors for infection. Methods The study was conducted at Hamad Medical Corporation in Qatar, a national healthcare system with 14 hospitals and >28,000 employees, between March 10-June 24, 2020. Data on COVID-19+ HCW were retrieved from the electronic health records and employment records, followed by an email survey and a focused telephone interview. Results Among 16,912 HCW tested, 10.6% tested positive. Hospitalization rate was 11.6%, 1.3% required supplemental oxygen, 0.6% needed intensive care unit admission and 0.3% required mechanical ventilation. There were no deaths. In a follow-up survey of 393 HCW, 5% reported acquiring infection at a COVID-19-designated facility and 95% at a non-COVID-19 facility having acquired the infection through accidental exposure to a colleague (45%) or a patient (29%). Full PPE adherence was 82% at COVID-19-designated but only 68% at non-COVID-19 facilities. Conclusions COVID-19 infection among HCW often occurs among those not directly working with COVID-19 patients. PPE use is less stringent in such settings. Risk of exposure and need for strict PPE must be stressed upon all HCW in all settings.

Background: The fibroblast growth factors (FGF) 19 subfamily, also referred to as endocrine FGFs, includes FGF19, FGF21, and FGF23 are metabolic hormones involved in the regulation of glucose and lipid metabolism. Fetuin-A is a hepatokine involved in the regulation of beta-cell function and insulin resistance. Endocrine FGFs and fetuin-A are dysregulated in metabolic disorders including obesity, type 2 diabetes, non-alcoholic fatty liver disease and polycystic ovary syndrome (PCOS). Our study was designed to examine the response of endocrine FGFs and fetuin-A to an acute intralipid, insulin infusion and exercise in PCOS and healthy women. Subjects and Measurements: Ten healthy and 11 PCOS subjects underwent 5-h saline infusions with a hyperinsulinemic-euglycemic clamp (HIEC) performed during the final 2 h. One week later, intralipid infusions were undertaken with a HIEC performed during the final 2 h. After an 8 week of exercise intervention the saline, intralipid, and HIEC were repeated. Plasma levels of endocrine FGFs and fetuin-A were measured. Results: Baseline fetuin-A was higher in PCOS women but FGF19, FGF21, and FGF23 did not differ and were unaffected by exercise. Insulin administration elevated FGF21 in control and PCOS, suppressed FGF19 in controls, and had no effects on FGF23 and fetuin-A. Intralipid infusion suppressed FGF19 and increased FGF21. Insulin with intralipid synergistically increased FGF21 and did not have effects on lipid-mediated suppression of FGF19 in both groups. Conclusion: Our study provides evidence for insulin and lipid regulation of endocrine FGFs in healthy and PCOS women, suggesting that FGF family members play a role in lipid and glucose metabolism. Clinical Trial Registration: www.isrctn.org, Identifier: ISRCTN42448814.

BackgroundPregnant 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.MethodsSixty-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.ResultsThe 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).ConclusionsThis 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.

Background Impact of COVID-19 upon acute care admission rates and patterns are unknown. We sought to determine the change in rates and types of admissions to tertiary and specialty care hospitals in the COVID-19 era compared with pre-COVID-19 era. Methods Acute care admissions to the largest tertiary care referral hospital, designated national referral centers for cardiac, cancer and maternity hospital in the State of Qatar during March 2020 (COVID-19 era) and January 2020 and March 2019 (pre-COVID-19 era) were compared. We calculated total admissions, and admissions for eight specific acute care conditions, in-hospital mortality rate and length of stay at each hospital. Results A total of 18,889 hospital admissions were recorded. A sharp decline ranging from 9%-75% was observed in overall admissions. A decline in both elective and non-elective surgeries was observed. A decline of 9%-58% was observed in admissions for acute appendicitis, acute coronary syndrome, stroke, bone fractures, cancer and live births, while an increase in admissions due to respiratory tract infections was observed. Overall length of stay was shorter in the COVID-19 period possibly suggesting lesser overall disease severity, with no significant change in in-hospital mortality. Unadjusted mortality rate for Qatar showed marginal increase in the COVID-19 period. Conclusions We observed a sharp decline in acute care hospital admissions, with a significant decline in admissions due to seven out of eight acute care conditions. This decline was associated with a shorter length of stay, but not associated with a change in in-hospital mortality rate., Highlights • The change in rate and types of admissions to acute care hospitals during the COVID-19 era compared with pre-COVID-19 era is unknown. • We observed a sharp decline in overall admission volumes and in seven of eight common diagnostic categories, while observing an increase in respiratory infections when comparing COVID-19 vs. pre-COVID-19 timeframe. • A statistically non-significant decrease in in-hospital mortality was observed, while the national statistics demonstrated a slight increase in mortality rate in the country. • It is critical to determine whether there is an association between declining acute care admissions and overall mortality rate in the community, and whether a surge of patients with more advanced disease may be anticipated after COVID-19 related restrictions are removed.

Objective To define the epidemiologic curve of COVID-19 in Qatar, determine factors associated with severe or critical illness, and study the temporal relation between public health measures and case finding Design Epidemiologic investigation Setting and Participants All confirmed COVID-19 cases in the State of Qatar between February 28 and April 18, 2020 Main Outcome Measures Number of total and daily new COVID-19 infections; demographic characteristics and comorbidity burden and severity of infection; factors associated with severe or critical illness Results Between February 28 and April 18, 2020 (11:00AM local time), 5,685 cases of COVID-19 were identified. Mean age (SD) was 35.8(12.0) years, 88.9% were male and 8.7% were Qatari nationals. Overall, 83.6% had no concomitant comorbidity, and 3.0% had 3 or more comorbidities. The overwhelming majority (90.9%) were asymptomatic or with minimal symptoms, with 2.0% having severe or critical illness. Presence of hypertension or diabetes were associated with a higher risk of severe or critical illness. Seven deaths were observed during the time interval studied. The epidemiologic curve indicated two distinct patterns of infection, a larger cluster among expatriate craft and manual workers, and a smaller one among Qatari nationals returning from abroad during the epidemic. Conclusion COVID-19 infections in Qatar started in two distinct clusters, but then became more widespread in the population through community transmission. Infections were mostly asymptomatic or with minimal symptoms and associated with very low mortality. Severe/critical illness was associated with presence of hypertension or diabetes. Article Summary Strengths and limitations of this study: National study with unified contact tracing and testing All testing done at a single lab, and all tests performed in the State of Qatar during the study period were included, providing a robust national estimate of the number of infected persons among those tested Comorbidities were retrieved from the electronic medical records using ICD-10 AM codes Exact geographic location and contact tracing data were not included in the current report It is possible that some persons still under care on the study end date may have progressed to more severe disease after that date What is already known on this topic As of May 3, 2020, over 3.4 million persons have been infected with SARS-CoV-2 and over 244,000 deaths have been reported in persons with COVID-19 infection. Those at higher risk of complications include persons over age 60 years and those with chronic comorbid conditions. Mortality rate varies widely among different countries, and this can be associated both to the capacity of the health system to provide effective intensive care including ventilators as well as other factors, including demographic differences. Public health measures seem effective, but there is debate on the extent to which the measures need to be aggressive or the duration for which they should be implemented. What this study adds This study reports on the epidemic curve in a population with a unique demographic structure, comprising an overwhelming majority of expatriates and young male craft and manual workers. This is also the first study that reports on the epidemic curve of an Arab country in the Eastern Mediterranean Region (EMR). The study also overlays major public health measures on the epidemic curve, to provide an understanding of the context in which the epidemic is progressing. Patients with confirmed COVID-19 in Qatar were young with few comorbidities. Case fatality rate was very low (only 7 deaths among 5,685 infected persons). Severe and critical illness were associated with presence of hypertension or diabetes.

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.

Patient: Male, 44-year-old Final Diagnosis: Subacute thyroiditis Symptoms: Fever Medication: — Clinical Procedure: None Specialty: General and Internal Medicine Objective: Rare disease Background: Fever of unknown origin (FUO) is a diagnosis that requires a demanding workup from physicians before confirming a diagnosis. Thyroid diseases are a rare cause of FUO. Subacute thyroiditis is an inflammatory disease that can lead to a wide spectrum of presentations. Case Report: We report a case of a previously healthy male who presented with persistent fever of 4 weeks following an upper respiratory tract infection associated with constitutional symptoms. His laboratory workup included complete blood counts (CBC), complete metabolic panel (blood urea and creatinine, liver function tests, and serum electrolytes), blood cultures, abdominal and pelvic ultrasound, and computed tomography abdomen and pelvis that were inconclusive. His thyroid function tests showed a hyperthyroid state and a thyroid scan confirmed a picture of thyroiditis. The patient was treated with Ibuprofen and then with prednisolone; he showed significant improvement over a few days and was discharged with treatment of tapering doses of prednisolone over 6 weeks. Two weeks after discharge the patient had a follow-up at an outpatient clinic and was found to be in good health with resolution of his symptoms. Conclusions: Thyroid disorders are not a common cause of FUO, and even if the clinical assessment of the patient is not suggestive of thyroid disease, we should consider it a possible cause. and thyroid function test should be performed to exclude thyroid problems.

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 r = 0.47, p = 0.06). Sputum and plasma adiponectin levels in CF patients were correlated negatively with BMI and percentage predicted forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Conclusions Sputum adiponectin may provide a minimally invasive tool in the assessment of inflammatory status in CF patients. A further larger study to address any difference in sputum and plasma adiponectin levels among CF patients with pancreatic sufficiency versus pancreatic insufficiency.

Background Newer direct acting antiviral agents against HCV (DAAs) are safe and efficacious in persons with chronic kidney disease (CKD). Whether approval of newer DAAs has resulted in more persons with CKD initiating HCV treatment remains unknown. Methods We identified HCV+ persons in ERCHIVES between October 1999 and July 2016. We excluded HIV+ and HBsAg+ and those with missing baseline HCV RNA and baseline eGFR data. We identified persons initiated on any approved DAA-regimen through July 2016, by CKD stage. Logistic regression analyses were used to determine factors associated with treatment initiation. Results Among 83 706 evaluable persons, 21.1% initiated treatment. Rates differed significantly by CKD stage: 22.1% for eGFR>90 mL/min/1.73 m2 and CKD stage-2; 14.9% for CKD stage 3; and 8.0% for CKD stage-4/5. Those with CKD stage-3 were 33% less likely and those with CKD stage-4/5 were 60% less likely to initiate treatment with a DAA compared with those with baseline eGFR>90 mL/min/1.73 m2 . Treatment initiation was less likely in HCV genotype 2 (OR 0.59; 95%CI 0.53,0.66) or 3 (OR 0.53; 95%CI 0.47,0.61) and those with diabetes (OR 0.87, 95% CI 0.81,0.94), cardiovascular disease (OR 0.77, 95% CI 0.70,0.84), alcohol abuse or dependence (OR 0.74, 95% CI 0.70,0.79) or cirrhosis (OR 0.86, 95% CI 0.80,0.92) at baseline. Conclusions Persons with more advanced CKD are less likely to receive treatment for HCV despite recent data on safety and efficacy. Strategies are needed to improve treatment rates in the HCV/CKD population.

IntroductionDecreased insulin sensitivity occurs early in type 2 diabetes (T2D). T2D is highly prevalent in the Middle East and North Africa regions. This study assessed the variations in insulin sensitivity in normal apparently healthy subjects and the levels of adiponectin, adipsin and inflammatory markers.Research design and methodsA total of 60 participants (aged 18–45, body mass index 2/min) and body composition test by dual-energy X-ray absorptiometry scan. Blood samples were assayed for glucose, insulin, C peptide, inflammatory markers, oxidative stress markers, adiponectin and adipsin.ResultsThe subjects showed wide variations in the whole-body glucose disposal rate (M value) from 2 to 20 mg/kg/min and were divided into three groups: most responsive (M>12 mg/kg/min, n=17), least responsive (M≤6 mg/kg/min, n=14) and intermediate responsive (M=6.1–12 mg/kg/min, n=29). Insulin and C peptide responses to OGTT were highest among the least insulin sensitive group. Triglycerides, cholesterol, alanine transaminase (ALT) and albumin levels were higher in the least responsive group compared with the other groups. Among the inflammatory markers, C reactive protein (CRP) was highest in the least sensitivity group compared with the other groups; however, there were no differences in the level of soluble receptor for advanced glycation end products and Tumor Necrosis Factor Receptor Superfamily 1B (TNFRS1B). Plasma levels of insulin sensitivity markers, adiponectin and adipsin, and oxidative stress markers, oxidized low-density lipoprotein, total antioxidant capacity and glutathione peroxidase 1, were similar between the groups.ConclusionsA wide range in insulin sensitivity and significant differences in triglycerides, cholesterol, ALT and CRP concentrations were observed despite the fact that the study subjects were homogenous in terms of age, gender and ethnic background, and all had normal screening comprehensive chemistry and normal glucose response to OGTT. The striking differences in insulin sensitivity reflect differences in genetic predisposition and/or environmental exposure. The low insulin sensitivity status associated with increased insulin level may represent an early stage of metabolic abnormality.

Post-transplantation diabetes mellitus (PTDM) is a major complication in kidney transplant recipients leading to reduced allograft and patient survival. Given the high prevalence of diabetes in Qatar, which is twice the global average, we were interested in determining the incidence of PTDM, identifying risk factors, and comparing clinical outcomes in kidney transplant recipients with and without diabetes. We retrospectively followed up 191 adult kidney allograft recipients transplanted between January 1, 2012, and December 31, 2016, for a median of 41 months. A total of 76 patients (40%) had pre-existing diabetes. A total of 39 patients developed PTDM during follow-up; they represent 34% of patients who did not have diabetes prior to transplantation. Two thirds of PTDM occurred within 3-6 months post-transplantation. Prediabetes before transplant [OR = 6.07 (1.24-29.74), P = .026] older recipient's age at the time of transplantation [OR = 1.10 (1.00-1.20), P = .039] and average fasting blood sugar during 3-6 months post-transplant [OR = 1.06 (1.01-1.11), P = .010] were independently associated with PTDM. Patient and kidney allograft survival rates exceeded 97% in all groups. The incidence of PTDM in kidney transplant recipients living in Qatar is high. Older age and prediabetes are independent risk factors for developing PTDM.

For persons with baseline Fibrosis-4 1.46–3.25, cirrhosis incidence/1000 patient-years was 49.3 among hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfected and 18.2 among HCV monoinfected (P = .03). Cirrhosis risk was numerically higher but statistically nonsignificant among HBV/HCV coinfected (hazards ratio [HR] 1.51; 95% confidence intervals [CI], .37–6.05) but lower among those who attained sustained virologic response (HR, .52; 95% CI, .42–.63).

Prediabetes is a condition leading to increased risk of diabetes and its complications and cardiovascular disease. Annually, ∼10% prediabetic subjects progress to T2D. We, and other investigators, reported that grape skin extract (GSE) impacts postprandial glycemia through alpha glucosidase inhibition. This study aims to examine the effect of GSE on glycemic response to a starch challenge in healthy prediabetic subjects. The study was approved by the IRB of Hamad Medical Corporation. Subjects were screened from a high-risk population based on family history and/or fasting glucose (5.7-7.3 mmol) and IGT confirmed with 75 gram OGTT. Subjects were randomized to GSE capsule 600 (N=4), 1200 (N=8), 1800 (N=15) or 2400 mg (N=14). Each received a meal of 35 gram (uncooked weight) rice with or without the assigned dose of GSE and blood glucose was measured at time 0, 15, 30, 60 and 120 minutes. Area under the curve (AUC) was calculated using the trapezoidal method and the subjects were classified into “responders” or “non-responders” if AUC after GSE was reduced by at least 1 SD. A total of 41 eligible subjects (83% male; age 29±8 years; BMI 23.2%±5.9, 34% Arab, 24% African, 17% Asian, 24% Indian) with prediabetes were enrolled. A total of 4 (9.7%)subjects decreased AUC by 2SD; 24% decreased by 1 SD and the remainder had no positive response to a single dose of GSE. There were no responders to 600 mg; 2 in 1200 mg; 4 in 1800 mg; and 3 in 2400 mg dose. There were no differences between the responders and non-responders in clinical or biochemical characteristics. In conclusion, 24% of prediabetic subjects had a positive response to GSE in a starch challenge test. The value of the test in characterizing prediabetic subjects who may benefit from GSE to reverse their prediabetic condition is currently under further investigation. In Qatar, the prevalence of diabetes is 17% and expected to increase. Studies to develop natural products to prevent diabetes are of great public health interest. Disclosure M. Alkasem: None. I. Abdalhakam: None. N.N. Suleiman: None. A.N. Iskandarani: None. T.A. Samra: None. F.A. Mir: None. R.M. Mohammad: None. A. Abou-Samra: None. K. Zhou: None. M.C. Skarulis: None. Funding Qatar National Research Fund

Background: Mitochondrial dysfunction is implicated in the pathogenesis of Type 2 diabetes (T2D) and the development of diabetes related complications such as cardiovascular disease and stroke. Mitochondria produce several small polypeptides that may influence mitochondrial function and may impact on insulin sensitivity, such as humanin (HN) and the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) that are mitochondrial derived proteins (MDP). The aim of this study was to determine MDP in normal, prediabetes and diabetes subjects.Subjects and Measurements: In this cross-sectional study, we analyzed the serum concentrations of MDP and adiponectin (ADP) in 225 subjects: normal (n = 68), pre-diabetes (n = 33), T2D less than (good control; n = 31), and greater than HbA1c 7% (poor control; n = 93) subjects. The relationship of serum MDP and ADP concentrations with biochemical and anthropometric measurements were performed and assessed by multilinear regression.Results: Serum HN concentrations were lower in T2D (p < 0.0001) and negatively correlated with age (p < 0.0001), HbA1c (p < 0.0001), glucose (p < 0.0001), triglycerides (p < 0.003), ALT (p < 0.004), and TG/HDL ratio (p < 0.001). Circulating HN levels were positively correlated to cholesterol (p < 0.017), LDL (p < 0.001), and HDL (p < 0.001). Linear regression analysis showed that HbA1c and ALT were two independent predictors of circulating HN. Similarly, serum MOTS-c was significantly lower in T2D subjects compared to controls (p < 0.007). Circulating MOTS-c positively correlated with BMI (p < 0.035), total cholesterol (p < 0.0001), and LDL (p < 0.001) and negatively correlated with age (p < 0.002), HbA1c (p < 0.001), and glucose (p < 0.002). Serum ADP concentrations were lower in T2D (p < 0.002) and negatively correlated with HbA1c (p < 0.001), weight (p < 0.032) TG (p < 0.0001), and ALT (p < 0.0001); and positively correlated with HDL (p < 0.0001) and HN (p < 0.003). Linear regression analysis showed that HbA1c and weight were two independent predictors of circulating ADP. Multilinear regression showed that HN and MOT-c correlated with each other, and only HN correlated with HbA1c.Conclusion: The MDPs HN and MOT-c, similar to ADP, are decreased in T2D and correlate with HbA1c. The data provide an additional evidence that mitochondrial dysfunction contributes to glycemic dysregulation and metabolic defects in T2D.

Background The effects of interferon-based therapies for hepatitis C virus (HCV) upon the risk of diabetes are controversial. The effects of newer, directly acting antiviral agents (DAA) upon this risk are unknown. We sought to determine the effects of HCV treatment upon the risk and incidence of diabetes. Methods Using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database for persons with chronic HCV infection (n = 242 680), we identified those treated with a pegylated interferon and ribavirin regimen (PEG/RBV, n = 4764) or a DAA-containing regimen (n = 21 279), after excluding those with diabetes at baseline, those with a human immunodeficiency virus or hepatitis B virus coinfection, and those treated with both PEG/RBV and DAA regimens. Age-, race-, sex-, and propensity score–matched controls (1:1) were also identified. Results Diabetes incidence rates per 1000 person-years were 20.6 (95% confidence interval [CI] 19.6–21.6) among untreated persons, 19.8 (95% CI 18.3–21.4) among those treated with PEG/RBV, and 9.89 (95% CI 8.7–11.1) among DAA-treated persons (P < .001). Among the treated, rates were 13.3 (95% CI 12.2–14.5) for those with a sustained virologic response (SVR) and 19.2 (95% CI 17.4–21.1) for those without an SVR (P < .0001). A larger reduction was observed in persons with more advanced fibrosis/cirrhosis (absolute difference 2.9 for fibrosis severity score [FIB-4] < 1.25; 5.7 for FIB-4 1.26–3.25; 9.8 for FIB-4 >3.25). DAA treatment (hazard ratio [HR] 0.53, 95% CI .46–.63) and SVR (HR 0.81, 95% CI .70–.93) were associated with a significantly reduced risk of diabetes. DAA-treated persons had longer diabetes-free survival rates, compared to untreated and PEG/RBV-treated persons. There was no significant difference in diabetes-free survival rates between untreated and PEG/RBV-treated persons. The results were similar in inverse probability of treatment and censoring weight models. Conclusions DAA therapy significantly reduces the incidence and risk of subsequent diabetes. Treatment benefits are more pronounced in persons with more advanced liver fibrosis.

Introduction: Diabetes is a major public health concern in Qatar. This study examined diabetes knowledge and perception of available services for diabetes control among diabetic patients in Qatar.Methods: Data from 300 diabetic patients were collected through face-to-face interviews using a semi-structured questionnaire between February and May 2015 at Hamad Medical Corporation healthcare facilities in Qatar. Survey responses were represented as frequencies, and Chi-square tests were used to compare proportions across gender. A p-value of 0.05 was considered statistically significant.Results: 31% of patients had Type 1 Diabetes (T1D) (females 36.6%, males 26.5%) and 54% had Type 2 Diabetes (T2D) (males 56.6%, females 50%). Knowledge about diabetes types did not differ by sex (P=0.16). 32.3% of patients were treated for diabetes-related complications including: high cholesterol (39.2%), vision problems (33.1%), hypertension (30.0%), and foot problems (25.1 %). Most patients were diagnosed at primary care clinics (41.7%). During visits, 78.3% of patients reported that they were fully advised about different diabetes tests. 57.0% of patients had ≥4 visits for diabetes checkups in the past 12 months. 66.7% of patients reported that they were confident or very confident in managing their diabetes as a result of their healthcare visits in the past year. The majority of patients reported receiving diabetes-related guidance from physicians (89.7%).Conclusions: Study participants had variable knowledge of diabetes, its complications and risk factors, and services available to diabetics. More comprehensive education and awareness about diabetes is recommended for both patients and family members. At the provider level, further improvement in patient counseling and promotion of available services can be beneficial.

// Jiankun Gao 1,2 , Asfar S. Azmi 3 , Amro Aboukameel 2 , Michael Kauffman 4 , Sharon Shacham 4 , Abdul-Badi Abou-Samra 5 , and Ramzi M. Mohammad 2,5 1 Sichuan College of Traditional Chinese Medicine, Mianyang, Sichuan, People’s Republic of China 2 Department of Oncology, Karmanos Cancer Institute, Detroit, Michigan, USA 3 Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA 4 Karyopharm Therapeutics, Natick MA, USA 5 Hamad Medical Corporation, Doha, Qatar Correspondence: Ramzi M. Mohammad, email: // Keywords :Specific Inhibitors of Nuclear Export; Xpo1, Exportin 1, CRM1 inhibitor; Notch1; Fbw7; Apoptosis; Pancreatic Cancer Received : January 8, 2014 Accepted :March 19, 2014 Published : March 21, 2014 Abstract Chromosome maintenance region 1 (CRM1) also called Exportin 1 (Xpo1), a protein found elevated in pancreatic ductal adenocarcinoma (PDAC), blocks tumor suppressor protein (TSP) function through constant nuclear export. Earlier we had shown that targeting CRM1 by our newly developed specific inhibitors of nuclear export (SINE) leads to inhibition of pancreatic cancer cell proliferation and tumor growth arrest. In this paper we define the mechanism of SINE action. Our lead SINE KPT-185 inhibits PDAC cell growth, cell migration, tumor invasion and induces apoptosis and G2-M cell cycle arrest in low nano molar range (IC 50s ~150 nM). Mechanistically we demonstrate that the activity of KPT-185 is associated with nuclear retention of Fbw7; which degrades nuclear Notch-1 leading to decreased tumor promoting markers such as C-Myc, Cyclin-D1, Hes1 and VEGF. The orally bioavailable SINE (KPT-251) showed potent anti-tumor activity in a Colo-357 PDAC xenografts model; residual tumor analysis showed activation of Fbw7 concomitant with attenuation of Notch1 and its downstream genes. These results suggest that the antitumor activity of KPT-185 is in part due to nuclear retention of Fbw7 and consequent Notch1 degradation. The new CRM1 inhibitors, therefore, hold strong potential and warrant further clinical investigations for PDAC.

ObjectivesDiabetes Intervention Accentuating Diet and Enhancing Metabolism-I (DIADEM-I) is the first randomised controlled trial (RCT) in the Middle East and North Africa (MENA) region testing the effectiveness of an intensive lifestyle intervention (ILI) for weight loss and diabetes remission. We report on the recruitment process and baseline characteristics of the DIADEM-I cohort based on origin (Middle East vs North Africa), and waist circumference.DesignDIADEM-I is an open-label randomised, controlled, parallel group RCT recruiting young individuals (18–50 years) with early type 2 diabetes (≤3 years since diagnosis) originating from MENA. Individuals from primary care were randomised to usual medical care or ILI (total dietary replacement phase using meal replacement products, followed by staged food reintroduction and physical activity support). The primary outcome is weight loss at 12 months. Other outcomes are glycaemic control and diabetes remission.SettingPrimary care, Qatar.Participants147 (73% men) randomised within DIADEM-I who were included in the final trial data analysis.Outcome measuresRecruitment metrics, and baseline clinical and metabolic characteristics.ResultsOf 1498 people prescreened, 267 (18%) were invited for screening and 209 (78%) consented. 173 (83%) were eligible. 15 (7%) withdrew before randomisation and the remaining 158 were randomised. Mean age was 42.1 (SD 5.6) years and mean body mass index was: 36.3 (5.5) kg/m2 (women) and 34.4 (5.4) kg/m2 (men). Mean diabetes duration was 1.8 (1.0) years and mean glycosylated haemoglobin (HbA1c) was 7.0% (1.30) (52.5 mmol/mol (SD 14.3)). Participants originated from 13 countries. Those from North Africa reported greater physical activity and had lower family history of diabetes. 90% of subjects were taking diabetes medications and 31% antihypertensives. Those with greater waist circumference had significantly higher insulin resistance and lower quality of life.ConclusionRecruitment of participants originating from the MENA region into the RCT was successful, and study participation was readily accepted. While DIADEM-I participants originated from 13 countries, there were few baseline differences amongst participants from Middle East versus North Africa, supporting generalisability of RCT results.Trial registration numberISRCTN20754766; NCT03225339

ObjectiveTo define the epidemiological curve of COVID-19 in Qatar and determine factors associated with severe or critical illness.DesignCase series of first 5685 COVID-19 cases in Qatar.Setting and participantsAll confirmed COVID-19 cases in the State of Qatar between 28 February and 18 April 2020.Main outcome measuresNumber of total and daily new COVID-19 infections; demographic characteristics and comorbidity burden and severity of infection; factors associated with severe or critical illness.ResultsBetween 28 February and 18 April 2020, 5685 cases of COVID-19 were identified. Median age was 34 (IQR 28–43) years, 88.9% were male and 8.7% were Qatari nationals. Overall, 83.6% had no concomitant comorbidity, and 3.0% had three or more comorbidities. The overwhelming majority (90.9%) were asymptomatic or with minimal symptoms, with 2.0% having severe or critical illness. Seven deaths were observed during the time interval studied. Presence of hypertension or diabetes was associated with a higher risk of severe or critical illness, but age was not. The epidemiological curve indicated two distinct patterns of infection, a larger cluster among expatriate craft and manual workers and a smaller one among Qatari nationals returning from abroad during the epidemic.ConclusionCOVID-19 infections in Qatar started in two distinct clusters, but then became more widespread in the population through community transmission. Infections were mostly asymptomatic or with minimal symptoms and associated with very low mortality. Severe/critical illness was associated with presence of hypertension or diabetes but not with increasing age.

Introduction Diabetes is a well-known global public health challenge affecting millions globally. The aims of this study are to examine the community diabetes knowledge, perceptions, and awareness among the public in Qatar regarding (1) disease symptoms, risk factors, complications, prevention, and associated behaviors, and (2) local diabetes campaigns and available services or resources. Methods This study involved a total of 501 respondents selected through purposive sampling from major public malls and public places in Doha, Qatar between February and May 2015. Data were gathered by face-to-face interview utilizing a semi-structured questionnaire. Results were analyzed using count, percentage, median, chi-square test, z-test on proportion and logistic regression. The analysis was carried out at 5% level of significance using SPSS version 22 (IBM Corporation, Chicago, IL, USA). Results About 92% of participants knew at least one type of diabetes. Over 43.9% were physically active for 1–3 days per week. Highest proportion of the population perceived blindness (86%) as the top complication; frequent urination (58%) and excessive thirst (41%) as primary symptoms; hereditary factors (74%) and obesity (74%) as the top risk factors; and exercise (77%) and diet (72%) as among the preventive measures. Demographic overview of diabetes and lifestyle factors showed that the odds of obtaining screening tests were higher among females (OR=1.7, P=0.003), age 35–45 (OR=2.2, P=0.003), age ≥55 (OR=4.1, P

Background Chronic kidney disease (CKD) was a relative contraindication to hepatitis C virus (HCV) treatment in the interferon/ribavirin era. Aim To determine the efficacy, tolerability and safety of sofosbuvir/ledipasvir (SOF/LDV) and paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimens in persons with CKD. Methods We identified persons initiated on a SOF/LDV or PrOD regimen from October 30, 2014 to April 30, 2016. We excluded those with missing HCV genotype or eGFR values. We determined treatment completion and sustained virologic response (SVR) rates, and proportion developing worsening renal function or grade 3/4 haematologic toxicity. Results Among 13 663 persons on SOF/LDV±ribavirin, 14% and 1% persons had CKD Stage 3 and 4-5 respectively, 67.8% completed treatment, 98.2% achieved SVR. Treatment completion or SVR rates did not decline with advanced CKD or ribavirin administration. Among 3961 persons on PrOD±ribavirin, 9% and 3% persons had CKD Stage 3 and 4-5, respectively, 74.0% completed treatment and 98.2% achieved SVR. A decrease in treatment completion rates was seen in CKD stage 4-5 and those on ribavirin, but this did not impact SVR rates. A >10 mL/min/1.73 m2 drop in eGFR from baseline was observed in 30%-38% of persons with baseline eGFR ≥60 mL/min/1.73 m2 , but in only 0%-6% with CKD4-5. Grade 3/4 anaemia was more frequent in persons with CKD4-5, but ribavirin co-administration did not appear to affect this. Conclusions SOF/LDV and PrOD achieved high SVR rates in CKD population. Treatment completion rates were lower than expected. A decline in eGFR and development of anaemia were observed in a substantial proportion of persons, but the clinical implications remain unclear.

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. Electronic supplementary material The online version of this article (10.1186/s13063-018-2660-1) contains supplementary material, which is available to authorized users.

Insulin resistance, which plays a central role in the pathogenesis of type 2 diabetes (T2D), is an early indicator that heralds the occurrence of T2D. It is imperative to understand the metabolic changes that occur at the cellular level in the early stages of insulin resistance. The objective of this study was to determine the pattern of circulating lactate levels during oral glucose tolerance test (OGTT) and hyperinsulinemic euglycemic clamp (HIEC) study in normal nondiabetic subjects. Lactate and glycerol were determined every 30 minutes during OGTT and HIEC on 22 participants. Lactate progressively increased throughout the HIEC study period (P<0.001). Participants with BMI < 30 had significantly higher meanM-values compared to those with BMI ≥ 30 at baseline (P<0.05). This trend also continued throughout the OGTT. In addition, those with impaired glucose tolerance test (IGT) had significantly higher mean lactate levels compared to those with normal glucose tolerance (P<0.001). In conclusion, we found that lactate increased during HIEC study, which is a state of hyperinsulinemia similar to the metabolic milieu seen during the early stages in the development of T2D.

Recent studies have reported higher rates of hepatocellular carcinoma (HCC) in individuals treated with direct-acting antivirals (DAAs). However, making definitive conclusions has been challenging because of the heterogeneous populations and methodologies of these reports. We investigated whether DAA use is associated with higher rates of incident HCC compared to treatment with interferon (IFN)-based regimens. We performed a retrospective, population-based cohort study using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database. In a cohort of 17,836 persons, sustained virological response (SVR) was achieved by 66.6% and 96.2% of the IFN and DAA groups, respectively. Among all treated persons, risk of HCC was not higher in the DAA group compared to the IFN group (hazard ratio, 1.07; 95% confidence interval, 0.55, 2.08). Among persons with cirrhosis who achieved SVR, neither the HCC incidence rate nor HCC-free survival were significantly different in the DAA group compared to the IFN group (21.2 vs. 22.8 per 1,000 person-years; P = 0.78 and log-rank P = 0.17, respectively). Untreated persons with cirrhosis had a significantly higher HCC incidence rate (45.3 per 1,000 person-years) compared to those treated with either IFN or DAAs (P = 0.03). Both groups of treated persons had significantly lower probability of HCC development compared to untreated persons (log-rank, P = 0.0004). Conclusion DAA treatment is not associated with a higher risk of HCC in persons with cirrhosis with chronic HCV infection in the short term. Previously reported higher rates of HCC associated with DAA treatment may be explained by both the presence of relatively fewer baseline HCC risk factors in persons treated with IFN as well as selection bias, given that DAA regimens were used to treat persons at higher risk for developing HCC. (Hepatology 2018;67:2244-2253).

Background Higher risk of hepatitis B reactivation (HBV-r) has been reported in patients with hepatitis C treated with newer directly acting antiviral agents (DAAs). Aim To determine the proportion of persons who develop HBV-r and its clinical consequences among DAA treated vs pegylated interferon/ribavirin (PEG/RBV) treated persons. Methods We calculated the proportion of persons who developed HBV viral reactivation (HBV-r; new detectable HBV DNA or increase of >1 log10 ); serum alanine aminotransferase flare (>5 times baseline); all-cause mortality and hepatic decompensation in persons treated with a newer DAA regimen or PEG/RBV. Kaplan-Meier curves were used to demonstrate survival and hepatic decompensation by treatment group and HBV-r. Results In 34 632 persons treated with DAA and 23 475 treated with PEG/RBV, HBV-r rate per 1000 person-years was 30.04 (10.41, 49.67) and 25.42 (95% CI 17.23, 33.62) respectively (P = .8). When stratified by SVR or by baseline HBsAg status, HBV-r was not different between groups. Kaplan-Meier survival curves comparing each regimen stratified by presence or absence of HBV-r did not demonstrate a significant difference in incidence of hepatic decompensation over time. For overall survival, there was no difference between PEG/RBV treated persons with or without HBV-r. For DAA treated persons, those with HBV-r had a shortened survival, though the numbers at risk were small. Conclusions HBV-r is relatively uncommon after DAA therapy and not higher than among those treated with a PEG/RBV regimen. The small numbers of persons treated with a DAA regimen who do develop HBV-r have a shortened survival compared to those without HBV-r.

Background Proton pump inhibitors are among the most commonly prescribed medications in the United States. Their safety in cirrhosis has recently been questioned, but their overall effect on disease progression in noncirrhotic patients with chronic liver disease remains unclear. Aim To determine the impact of proton pump inhibitors on the progression of liver disease in noncirrhotic patients with hepatitis C virus (HCV) infection. Methods Using the electronically retrieved cohort of HCV-infected veterans (ERCHIVES) database, we identified all subjects who received HCV treatment and all incident cases of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Proton pump inhibitor use was measured using cumulative defined daily dose. Multivariate Cox regression analysis was performed after adjusting univariate predictors of cirrhosis and various indications for proton pump inhibitor use. Results Among 11 526 eligible individuals, we found that exposure to proton pump inhibitors was independently associated with an increased risk of developing cirrhosis (hazard ratio [HR]: 1.32; 95% confidence interval: [1.17, 1.49]). This association remained robust to sensitivity analysis in which only patients who achieved sustained virologic response were analysed as well as analysis excluding those with alcohol abuse/dependence. Proton pump inhibitor exposure was also independently associated with an increased risk of hepatic decompensation (HR: 3.79 [2.58, 5.57]) and hepatocellular carcinoma (HR: 2.01 [1.50, 2.70]). Conclusions In patients with chronic HCV infection, increasing proton pump inhibitor use is associated with a dose-dependent risk of progression of chronic liver disease to cirrhosis, as well as an increased risk of hepatic decompensation and hepatocellular carcinoma.

Background Risk of acute myocardial infarction (AMI) among hepatitis C virus (HCV)-positive versus HCV-negative persons with similar lipid levels is unknown. We determined incident AMI rates among HCV-positive and HCV-negative men among various lipid strata. Methods We created a propensity score matched (PSM) cohort and a low cardiovascular disease (CVD) risk cohort. Primary outcome was incident AMI rates by HCV status in each lipid strata using National Cholesterol Program guidelines for lipid strata. Results We identified 85863 HCV-positive and HCV-negative men in the PSM population. The incidence rates/1000 patient-years (95% confidence interval [CI]) for AMI among total cholesterol (TC) 200-239 stratum were 5.3 (4.89, 5.71) for HCV-positive versus 4.71 (4.42, 5) for HCV-negative men (P = .02) and for TC >240 mg/dL were 7.38 (6.49, 8.26) versus 6.17 (5.64, 6.71) (P = .02). For low-density lipoprotein cholesterol (LDL) of 130-159 mg/dL, AMI rates were 5.44 (4.97, 5.91) for HCV-positive and 4.81 (4.48, 5.14) for HCV-negative men (P = .03). The rise in risk with increasing lipid levels was greater in younger HCV-positive than in HCV-negative men (e.g., TC > 240 mg/dL: age >50 HR 1.38 [HCV-positive] and 1.12 [HCV-negative]; age ≤50 HR 1.6 [HCV-positive] and 1.29 [HCV-negative]), and more profoundly altered in HCV-positive men by lipid lowering therapy (change in HR with lipid-lowering therapy for TC >240 mg/dL from 1.82 to 1.19 [HCV-positive] from 1.48 to 1.03 [HCV-negative]). Conclusions HCV-positive men have a higher risk of AMI than HCV-negative men at higher TC/LDL levels; this risk is more pronounced at a younger age. Lipid lowering therapy significantly reduces this risk, with more profound reduction among HCV-positive versus HCV-negative men at similar lipid levels.

Objective: The incidence of diabetic ketoacidosis in pregnancy (DKP) varies from 0.5%, the lowest reported rate in western countries, to 8.9% in a study conducted in China. The associated fetal mortality is 9-36%. This study aimed to assess the current incidence, causes, and outcomes of diabetic ketoacidosis in pregnancy and identify factors associated with favorable outcomes. Methods: A retrospective chart review of 20 diabetic ketoacidosis hospital admissions of 19 pregnant women from 3,679 diabetic pregnancies delivered between June 2012 and May 2015 was conducted. Those with successful DKP management (group A) or with intrauterine fetal death or urgent delivery during diabetic ketoacidosis management (group B) were compared. Results: Thirteen cases had type 1 diabetes, and 6 cases had type 2 diabetes, including 2 new diagnoses. The most common precipitating factors were vomiting (55%) and insulin non-compliance (45%). Plasma glucose was

ObjectiveTo compare pregnancy outcomes in patients with early versus usual gestational diabetes mellitus (GDM).DesignA retrospective cohort study.SettingsThe Women’s Hospital, Hamad Medical Corporation, Qatar.ParticipantsGDM women who attended and delivered in the Women’s Hospital, between January and December 2016. GDM was diagnosed based on the 2013-WHO criteria. The study included 801 patients; of which, 273 E-GDM and 528 U-GDM. Early GDM (E-GDM) and usual GDM (U-GDM) were defined as GDM detected before and after 24 weeks’ gestation, respectively.OutcomesMaternal and neonatal outcomes and the impact of timing of GDM-diagnosis on pregnancy outcomes.ResultsAt conception, E-GDM women were older (mean age 33.5±5.4 vs 32.0±5.4 years, p2, p=0.0059) compared with U-GDM. The mean fasting, and 1-hour blood glucose levels were significantly higher in E-GDM vs U-GDM, respectively (5.3±0.7 vs 4.0±0.7 mmol/L, pConclusionOur data support the concept of early screening and treatment of GDM in high-risk patients. More data are needed to examine the optimal time for screening.

ObjectivesMetabolic syndrome is a cluster of conditions—increased blood pressure, a high blood sugar level, abdominal fat accumulation and abnormal cholesterol levels—that occur together, increasing the risk of heart disease, stroke and type 2 diabetes mellitus (T2DM). Mitochondria play a central role in the energy metabolism. Mitochondrial dysfunction contributes to the pathogenesis of metabolic disorders. Abnormality in mitochondrial function is a leading cause for development of insulin resistance and is promoted, at least partly, through lipid accumulation in ectopic tissues, including liver and skeletal muscle. Many growth and transcription factors involved in the regulation of mitochondrial gene expression also contribute to the pathophysiology of obesity, insulin resistance and type-2 diabetes. The role of mitochondria as functional organelles, and the signaling molecules produced by them are critical in the regulation of cellular energy metabolism and homeostasis. MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) encoding a 16-amino-acid peptide is a recently identified peptide. The skeletal muscle appears to be the main target organ for MOTS-c and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c increases glucose utilization, promotes insulin sensitivity and metabolic homeostasis through activation of AMPK dependent mechanisms in skeletal muscle. In rodent studies MOTS-c has been demonstrated to protect against insulin resistance induced by diet and ageing. However the role of MOTS-c in adipocytes is largely unknown. In this current study we aimed to study the effect of MOTS-c on adipocyte development and metabolism in cultured mouse adipocytes.Methods3T3L1 cells were grown in DMEM media containing 10% FBS. Cells were stimulated with various concentrations of MOTS-c (100 nM to 50 μM) to study the effect of MOTS-c on cell viability. For differentiation pre-adipocytes were grown in differentiation induction medium containing dexamethasone, IBMX and insulin for two days. The media was replaced with medium containing insulin only for the next six days. About 60–70% differentiation was achieved by day 8. For treatment group pre-adipocytes were pre-treated with MOTS-c for 24 hours, and then differentiated into adipocytes for eight days. Quantitative real-time PCR was used to investigate the effect of MOTS-c on adipogenic genes expression:, Peroxisome Proliferator-Activated Receptor Gamma (PPARg), AP2, adiponectin and leptin in mouse 3T3-L1 pre-adipocytes.ResultMOTS-c treatment did not induce any significant changes in cell viability at 24h following treatment. Pretreatment with MOTS-c prior to induction of differentiation down regulated expression of adipogenic markers including leptin, adiponectin, PPARg and PPARg-coactivator 1-alpha (PGC1a) mRNA levels, compared to differentiated adipocyte controls.ConclusionOur primary result indicates that MOTS-c inhibits adipogenesis through down-regulation of multiple genes involved in development of adipocytes, and this inhibition could contribute to the reduced abdominal adiposity. Future studies are currently in progress to further assess the effects of MOTS-c on adipocytes lipolysis, glucose uptake, glucose transporter (GLUT) family and other insulin-signaling pathway protein including GSK3B, IGF1R, IGF2R, and PIK3K are needed to understand the role of MOTS-c in mouse 3T3-L1 adipocytes.

SummaryInsulin resistance manifest in skeletal muscle, liver and adipocytes. Insulin stimulates muscle glucose uptake, suppresses the rate of hepatic glucose production (HGP) and restrains lipolysis. In insulin resistant individuals, insulin-stimulated glucose uptake is markedly reduced in skeletal muscle, impaired insulin-mediated suppression of hepatic glucose production (HGP) and inhibition of lipolysis. It is evident from human and animal studies that diabetes alters miRNAs expression in metabolically important organs (adipose, liver and skeletal muscle).micRNA are small non coding RNA molecules. However, they play critical role in the regulation of gene expression via post-transcriptional mechanisms. They are small in size (21?23 nucleotides) and recent studies have demonstrated that they play important role in many human complex diseases including diabetes. The ability of miRNA that simultaneously regulate many target genes makes them attractive candidates for regulating insulin production/secretion and action. mRNA are secreted to the circulation and are taken up from the circulation by several tissues, making them an attractive mechanism for inter-tissue signaling molecules. Thus, if micro RNA play role in the pathogenesis of insulin resistance or in communicating between insulin resistant tissues and the beta cell to regulate the level of beta cell function in concert with the prevailing level of insulin resistance, we anticipate a change in the circulatory profile of micro RNA in insulin resistant individuals compared to insulin sensitive individuals. Such a distinct circulatory profile of micro RNA in insulin sensitive versus insulin resistant individuals could provide a signature for the identification of insulin resistant individuals. Moreover, differentially expressed micro RNA molecules in insulin resistant individuals could serve signaling molecules which convey messages between insulin resistant tissues, i.e. liver, skeletal muscle and adipocytes and the beta cell. Insulin sensitivity is commonly assessed to predict the risk and evaluate the management of type 2 diabetes in clinical and research settings. Insulin sensitivity can be measured using a variety of techniques that are commonly employed in diabetes research and care. Among them, euglycemic hyperinsulemic clamp is the gold-standard method to quantify the sensitivity to insulin.The aim of the present study is to determine the profile of miRNA in the plasma in insulin sensitive Arab individuals and compare the result to that in insulin resistant Arab individuals.specific aims are;1. To discover the circulatory profile of microRNA in insulin sensitive and insulin resistant Arab individuals by using next generation sequencing technology.2. To identify novel microRNA/targets which are differentially expressed in insulin resistant individuals by real time Taq-Man PCR.3. To explore the effects changes of these miRNAs in insulin resistance diabetes β-Cell Biology. The experiments range from relevant tissue and cell cultures systems to human physiology. Design and methods: The circulating miRNA profile was assessed in a pilot study of 20 healthy volunteers whom glucose tolerance status was determined by the OGTT, and their insulin sensitivity was quantitated by the gold standard method the euglycemic hyperinsulemic clamp. Based on Glucose Infusion rate (GIR: mg/kg/min), before and after a 6-h hyperinsulinemeic euglycemic clamp, we selected two groups: 10 with high levels of GIR (insulin-sensitive group) and 10 with Very low levels of GIR (insulin resistant group).The serum samples was collected from the two groups for miRNA extraction and subsequent sequencing using the True-seq Illumina protocol. A small RNA library was generated from samples using the Illumina Truseq™ Small. The purified cDNA library was used for cluster generation on Illumina's Cluster Station and then sequenced on Illumina GAIIx following vendor's instruction for running the instrument. Raw sequencing reads (40 nts) were obtained using Illumina's Sequencing Control Studio software version 2.8 (SCS v2.8) following real-time sequencing image analysis and base-calling by Illumina's Real-Time Analysis version 1.8.70 (RTA v1.8.70). Result: Sequencing of the small circulating RNA isolated from insulin-resistant and insulin-sensitive healthy samples produced 69,559,764 raw reads. A total of 41,697,300 mappable reads was obtained after sequence filtering. Using a 2-fold expression difference as a cutoff, 33 miRNAs showed significally differential expression between insulin sensitive and insulin-resistant group. Among which, 10 were up-regulated and 22 were down-regulated. This RNA-seq discovery study shows that the most changes in miRNAs expression is in accordance with previous studies performed to explore circulating miRNAs in human insulin resistance or T2DM. Indeed, among the 54 selected miRNAs, we have identified the same changes in mir-126 expression that has described by Zampetaki and colleagues. This group reported that mir-126 is a unique plasma miRNA signature in 800 patients with T2D and observed that the reduced levels of mir-126 showed the strongest association with T2D. From the 33 miRNAs, a relative number of them are much documented to be associated with insulin resistance and type 2 diabetes. Nevertheless, some identified miRNAs are potential novel candidates and need to be deeply exploring during the event of the pathogenesis of T2D. Conclusion: This study provides a comparative profiling of circulating miRNAs in insulin-resistant versus insulin–sensitive subjects and the identification of specific miRNAs in circulation that changes are associated with insulin action. To our knowledge, this is the first study to investigate insulin resistance in Arab population using euglycemic hyperinsulemic clamp the gold-standard method to assess insulin sensitivity and aim to identify changes in circulating miRNAs expression associated to insulin action and signaling. The study also provides evidence that Insulin Resistance in human is related to changes in multiples microRNAs. Functional Validation studies of the differentially expressed miRNAs and relevant target and signaling pathways are ongoing.