Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis.

BACKGROUND: Recent studies suggest that tirzepatide, a dual glucose-dependent insulinotropic-peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA), has significant weight loss effects. This systematic review and meta-analysis aims to assess the efficacy and safety of tirzepatide for weight loss in patients with overweight or obesity. METHODS: Medline, Embase and Cochrane CENTRAL were searched for randomized controlled trials (RCTs) on tirzepatide's weight loss efficacy for these patients. A single arm meta-analysis of proportions estimated primary outcomes, ≥5%, ≥10%, and ≥15% weight loss, and adverse events (AEs); while meta-analysis of means estimated secondary outcomes. Comparative meta-analysis was conducted between tirzepatide and control arms where mean differences and odds ratios were estimated for continuous and dichotomous outcomes respectively. RESULTS: RCTs included in this study revealed that among 5800 patients, 78.22% (95% CI: 72.15% to 83.73%), 55.60% (95% CI: 46.54% to 64.47%), 32.28% (95% CI: 23.17% to 42.12%) achieved ≥5%, ≥10%, and ≥15% weight loss, respectively. Tirzepatide 5 mg demonstrated weight loss superiority relative to placebo (MD: -12.47 kg, 95% CI: -13.94 kg to -11.00 kg) and semaglutide (n = 1409, MD: -1.90 kg, 95% CI: -2.97 kg to -0.83 kg) with dose-dependent increase for 10 mg and 15 mg doses. The comparison between tirzepatide and semaglutide was examined in the SURPASS-2 trial that was included in this systematic review. For AEs, there was increase odds of experiencing gastrointestinal AEs with tirzepatide compared to placebo, but no significant difference with semaglutide. CONCLUSION: Tirzepatide has significant potential as a weight loss drug in patients with overweight and obesity, with little increase in AEs compared to other weight loss drugs. With its ability to concurrently target multiple aspects of metabolic syndrome, it should be considered as the next helm of weight loss therapies.

Barriers and Facilitators to Engagement With a Weight Management Intervention in Asian Patients With Overweight or Obesity: A Systematic Review.

OBJECTIVE: The obesity epidemic is a global health concern with Asian countries facing one of the most rapid rises in obesity rates. However, given the underwhelming long-term efficacy of weight loss strategies, especially in Asia, this review aimed to explore barriers and facilitators to weight management of patients with overweight and obesity in Asia. METHODS: Medline, CINAHL, PsycINFO, and Web of Science were searched for articles discussing barriers and facilitators of treatment to obesity from the perspectives of both health care professionals (HCPs) and patients. Qualitative and mixed method studies from Asia were included. Key quotes were extracted, coded, and thematically analyzed according to the methodology of Thomas and Harden. RESULTS: A total of 26 articles were included in this review. From patient perspectives, 3 main themes were identified: factors influencing poor eating behavior, inhibiting lifestyle modifications, and facilitating lifestyle modifications. Patients highlighted several barriers including the lack of social support, physiologic limitations to exercise, and low health literacy. Rigid sociocultural norms and lack of accessible health care services, exercise facilities, and healthy food exacerbated the barriers. Facilitators to lifestyle modifications consisted of strong support systems and high health literacy. HCPs agreed that low health literacy, lack of social support, and patient motivation impeded patients' weight loss attempts but were unaware of the other barriers they faced. CONCLUSION: There are discrepancies between ideas of barriers and facilitators of HCPs and patients. A mixture of population level, primary care, and personal interventions are required to address this disparity, and enhanced health literacy can improve weight loss outcomes.

Associations with metabolites in Chinese suggest new metabolic roles in Alzheimer's and Parkinson's diseases.

Metabolites are small intermediate products of cellular metabolism perturbed in a variety of complex disorders. Identifying genetic markers associated with metabolite concentrations could delineate disease-related metabolic pathways in humans. We tested genetic variants for associations with 136 metabolites in 1954 Chinese from Singapore. At a conservative genome-wide threshold (3.7 × 10-10), we detected 1899 variant-metabolite associations at 16 genetic loci. Three loci (ABCA7, A4GALT, GSTM2) represented novel associations with metabolites, with the strongest association observed between ABCA7 and d18:1/24:1 dihexosylceramide. Among 13 replicated loci, we identified six new variants independent of previously reported metabolite or lipid signals. We observed variant-metabolite associations at two loci (ABCA7, CHCHD2) that have been linked to neurodegenerative diseases. At SGPP1 and SPTLC3 loci, genetic variants showed preferential selectivity for sphingolipids with d16 (rather than d18) sphingosine backbone, including sphingosine-1-phosphate (S1P). Our results provide new genetic associations for metabolites and highlight the role of metabolites as intermediate modulators in disease metabolic pathways.

Long-Term Prognosis of Acute Myocardial Infarction Associated With Metabolic Health and Obesity Status.

OBJECTIVE: Emerging evidence supports the favorable cardiovascular health in nonobese subjects with healthy metabolism. However, little is known regarding the prognosis across the range of metabolic phenotypes once cardiovascular disease is established. We examined the prognosis of patients with acute myocardial infarction (AMI) stratified according to metabolic health and obesity status. METHODS: This is a retrospective study on consecutive patients with AMI admitted to a tertiary hospital between 2014 and 2021. Patients were allocated into the following 4 groups based on metabolic and obesity profile: (1) metabolically healthy obese (MHO), (2) metabolically healthy nonobese (MHNO), (3) metabolically unhealthy obese (MUO), and (4) metabolically unhealthy nonobese (MUNO). Metabolic health was defined in accordance to the Biobank Standardisation and Harmonisation for Research Excellence in the European Union Healthy Obese Project. The primary outcome was all-cause mortality. The Cox regression analysis examined the independent association between mortality and metabolic phenotypes, adjusting for age, sex, AMI type, chronic kidney disease, smoking status, and left ventricular ejection fraction. RESULTS: Of 9958 patients, the majority (68.5%) were MUNO, followed by MUO (25.1%), MHNO (5.6%), and MHO (0.8%). MHO had the lowest mortality (7.4%), followed by MHNO (9.7%), MUO (19.2%), and MUNO (22.6%) (P < .001). Compared with MHNO, MUO (hazard ratio [HR], 1.737; 95% confidence interval [CI], 1.282-2.355; P < .001) and MUNO (HR, 1.482; 95% CI, 1.108-1.981; P = .008) had a significantly higher mortality risk but not MHO (HR, 1.390; 95% CI, 0.594-3.251; P = .447), after adjusting for confounders. The Kaplan-Meier curves showed favorable survival in the metabolically healthy and obesity groups, with the highest overall survival in the MHO, followed by MHNO, MUO, and MUNO (P < .001). CONCLUSION: Metabolically healthy and obese patients with AMI have favorable prognosis compared with metabolically unhealthy and nonobese patients. It is equally important to prioritize intensive metabolic risk factor management to weight reduction in the early phase after AMI.

Antidiabetic Medications for Type 2 Diabetics with Nonalcoholic Fatty Liver Disease: Evidence From a Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are closely related, and antidiabetic medications have been shown to be potential therapeutics in NAFLD. Using a network meta-analysis, we sought to examine the effectiveness of antidiabetic agents for the treatment of NAFLD in patients with type 2 diabetes mellitus. METHODS: Medline and Embase were searched for randomized controlled trials relating to the use of antidiabetic agents, including sodium-glucose transport protein 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor gamma (PPARγ) agonists, biguanides, sulfonylureas and insulin, on NAFLD in patients with diabetes. The p-score was used as a surrogate marker of effectiveness. RESULTS: A total of 14 articles were included in the analysis. PPARγ agonists were ranked as the best treatment in steatosis reduction, resulting in the greatest reduction of steatosis. There was statistical significance between PPARγ agonists [mean difference (MD): -6.02%, confidence interval (CI): -10.37% to -1.67%] and SGLT2 inhibitors (MD: -2.60%, CI: -4.87% to -0.33%) compared with standard of care for steatosis reduction. Compared with PPARγ agonists, SGLT2 inhibitors resulted in a statistical significant reduction in fibrosis (MD: -0.06, CI: -0.10 to -0.02). Body mass index reduction was highest in SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists. Additionally, SGLT2 inhibitors were ranked as the best treatment for increasing high-density lipoprotein and reducing low-density lipoprotein. CONCLUSION: Glucagon-like peptide-1 receptor agonists and SGLT2 inhibitors were suitable alternatives for the treatment of NAFLD in those with type 2 diabetes mellitus with a reduction in body mass index, fibrosis, and steatosis. SGLT2 inhibitors also have the added benefit of lipid modulation.

Metabolic Associated Fatty Liver Disease Increases the Risk of Systemic Complications and Mortality. A Meta-Analysis and Systematic Review of 12 620 736 Individuals.

OBJECTIVE: The recent introduction of the term metabolic associated fatty liver disease (MAFLD) sought to reclassify nonalcoholic fatty liver disease (NAFLD). MAFLD is thought to improve the encapsulation of metabolic dysregulation. However, recent evidence has found significant differences between MAFLD and NAFLD, and prevailing knowledge has largely arisen from studies on NAFLD. Hence, we conducted a meta-analysis and systematic review of the outcomes associated with MAFLD. METHODS: MEDLINE and Embase databases were searched for articles relating to outcomes in MAFLD. Analysis was conducted in random effects with hazard ratios (HRs) to account for longitudinal risk assessment of mortality and systemic complications. RESULTS: A total of 554 articles were identified, of which 17 articles were included. MAFLD resulted in an increase in the overall mortality (HR, 1.24; confidence interval [CI], 1.13-1.34), cancer-related mortality (HR, 1.27; CI, 1.01-1.54), and cardiovascular disease mortality (HR, 1.28, 1.03-1.53; P = .04) compared with non-MAFLD. MAFLD also increases the risk of cardiovascular events (HR, 1.49; CI, 1.34-1.64; P < .01), stroke (HR, 1.55; CI, 1.37-1.73; P < .01), and chronic kidney disease (HR, 1.53; CI, 1.38-1.68). The presence of MAFLD was also associated with an increased risk of heart failure, obstructive sleep apnea, and malignancy. CONCLUSION: MAFLD can significantly elevate the risk of systemic diseases and mortality. The care of MAFLD thus requires interdisciplinary collaboration, and future clinical trials conducted on MAFLD should aim to reduce the incidence of end-organ damage aside from improving liver histology.

Branched-Chain Amino Acid Supplementation Does Not Preserve Lean Mass or Affect Metabolic Profile in Adults with Overweight or Obesity in a Randomized Controlled Weight Loss Intervention.

BACKGROUND: Branched-chain amino acid (BCAA) supplementation has been shown to increase muscle mass or prevent muscle loss during weight loss. OBJECTIVE: We aimed to investigate the effects of a BCAA-supplemented hypocaloric diet on lean mass preservation and insulin sensitivity. METHODS: A total of 132 Chinese adults (63 men and 69 women aged 21-45 y, BMI 25-36 kg/m2) were block randomly assigned by gender and BMI into 3 hypocaloric diet (deficit of 500 kcal/d) groups: standard-protein (14%) with placebo (control, CT) or BCAA supplements at 0.1 g · kg-1 body weight · d-1 (BCAA) or high-protein (27%) with placebo (HP). The subjects underwent 16 wk of dietary intervention with provision of meals and supplements, followed by 8 wk of weight maintenance with provision of supplements only. One-way ANOVA analysis was conducted to analyze the primary (lean mass and insulin sensitivity) and secondary outcomes (anthropometric and metabolic parameters) among the 3 groups. Paired t-test was used to analyze the change in each group. RESULTS: The 3 groups demonstrated similar significant reductions in body weight (7.97%), fat mass (13.8%), and waist circumference (7.27%) after 16 wk of energy deficit. Lean mass loss in BCAA (4.39%) tended to be lower than in CT (5.39%) and higher compared with HP (3.67%) (P = 0.06). Calf muscle volume increased 3.4% in BCAA and intramyocellular lipids (IMCLs) decreased in BCAA (17%) and HP (18%) (P < 0.05) over 16 wk. During the 8 wk weight maintenance period, lean mass gain in BCAA (1.03%) tended to be lower compared with CT (1.58%) and higher than in HP (-0.002%) (P = 0.04). Lean mass gain differed significantly between CT and HP (P = 0.03). Insulin sensitivity and metabolic profiles did not differ among the groups throughout the study period. CONCLUSIONS: BCAA supplementation does not preserve lean mass or affect insulin sensitivity in overweight and obese adults during weight loss. A higher protein diet may be more advantageous for lean mass preservation.

Use of sodium-glucose co-transporter-2 inhibitors in Asian patients with type 2 diabetes and kidney disease: An Asian perspective and expert recommendations.

Early onset of type 2 diabetes and a high prevalence of co-morbidities predispose the Asian population to a high risk for, and rapid progression of, diabetic kidney disease (DKD). Apart from renin-angiotensin system inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been shown to delay renal disease progression in patients with DKD. In this review article, we consolidate the existing literature on SGLT-2 inhibitor use in Asian patients with DKD to establish contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, data from studies on Asian patients with DKD, global trials (DAPA-CKD, CREDENCE and DELIGHT) and cardiovascular outcomes trials. In patients with DKD, SGLT-2 inhibitor therapy significantly reduced albuminuria and the risk of hard renal outcomes (defined as the onset of end-stage kidney disease, substantial decline in renal function from baseline and renal death), cardiovascular outcomes and hospitalization for heart failure. In all the cardiovascular and renal outcomes trials, there was an initial decline in the estimated glomerular filtration rate (eGFR), which was followed by a slowing in the decline of renal function compared with that seen with placebo. Despite an attenuation in glucose-lowering efficacy in patients with low eGFR, there were sustained reductions in body weight and blood pressure, and an increase in haematocrit. Based on the available evidence, we conclude that SGLT-2 inhibitors represent an evidence-based therapeutic option for delaying the progression of renal disease in Asian patients with DKD and preserving renal function in patients at high risk of kidney disease.

Increased oral processing and a slower eating rate increase glycaemic, insulin and satiety responses to a mixed meal tolerance test.

PURPOSE: Variations in specific oral processing behaviours may contribute to differences in glucose, insulin and satiety responses to a standardised test meal. This study tested how natural variations in oral processing between slower and faster eaters contribute to differences in post-prandial glucose (PP glucose), insulin response (PP insulin) and post-meal satiety for a standardised test meal. METHODS: Thirty-three participants with higher risk for type 2 diabetes consumed a standardised test-meal while being video recorded to derive specific oral processing behaviours. Plasma glucose, insulin and satiety measures were collected at baseline, during and post meal. Participants were split into slower and faster eaters using median split based on their eating rates and individual bolus properties were analysed at the point of swallow. RESULTS: There were large variations in eating rate (p < 0.001). While there was no significant difference in PP glucose response (p > 0.05), slower eaters showed significantly higher PP insulin between 45 and 60 min (p < 0.001). Slower eaters had longer oro-sensory exposure and increased bolus saliva uptake which was associated with higher PP glucose iAUC. Faster eating rate and larger bolus particle size at swallow correlated with lower PP glucose iAUC. A slower eating rate with greater chews per bite significantly increased insulin iAUC. Faster eaters also consistently rated their hunger and desire to eat higher than slower eaters (p < 0.05). CONCLUSIONS: Natural variations in eating rate and the associated oral processing contributed to differences in PP glucose, PP insulin and satiety responses. Encouraging increased chewing and longer oral-exposure time during consumption, may promote early glucose absorption and greater insulin and satiety responses, and help support euglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04522063.

Risk Factors of Thyroid Eye Disease.

OBJECTIVE: To examine risk factors that might be associated with thyroid eye disease (TED) in patients with Graves' disease (GD), which may guide physicians in the prevention and management of TED. METHODS: Medline and Embase were searched for articles discussing risk factors of TED. Comparisons were made between GD patients with and without TED, and between active and inactive TED GD patients. Weighted mean differences (WMDs) and odds ratios (ORs) were determined for continuous and dichotomous outcomes, respectively. Results were pooled with random effects using the DerSimonian and Laird model. RESULTS: Fifty-six articles were included in the analysis. Smoking, inclusive of current and previous smoking status, was a significant risk factor for TED (OR: 2.401; CI: 1.958-2.945; P < .001). Statistical significance was found upon meta-regression between male sex and the odds of smoking and TED (ß = 1.195; SE = 0.436; P = .013). Other risk factors were also examined, and patients with TED were significantly older than those without TED (WMD: 1.350; CI: 0.328-2.372; P = .010). While both age (WMD: 5.546; CI: 3.075-8.017; P < .001) and male sex (OR: 1.819; CI: 1.178-2.808; P = .007) were found to be significant risk factors for active TED patients compared to inactive TED patients, no statistical significance was found for family history, thyroid status, cholesterol levels, or body mass index. CONCLUSION: Factors such as smoking, sex, and age predispose GD patients to TED, and TED patients to active TED. A targeted approach in the management of GD and TED is required to reduce the modifiable risk factor of smoking.

Prevalence of thyroid eye disease in Graves' disease: A meta-analysis and systematic review.

OBJECTIVE: Thyroid eye disease (TED) is a debilitating condition that frequently manifests in patients suffering from Graves' disease (GD). This study aims to analyse the prevalence of TED among GD patients, with a focus on geographical region-specific rates. METHODS: Medline and Embase were searched for articles examining TED prevalence on April 2020, and articles were retrieved and sieved. Statistical analysis was performed after Freeman-Tukey double arcsine transformation. Thereafter, results were pooled with random effects by DerSimonian and Laird model. RESULTS: Fifty-seven articles involving 26,804 patients were included in the review. The overall pooled prevalence of TED was 40% (CI: 0.32 to 0.48) and by continent was 38% (CI: 0.31 to 0.46) for Europe, 44% (CI: 0.32 to 0.56) for Asia, 27% (CI: 0.06 to 0.56) for North America and 58% (CI: 0.55 to 0.61) for Oceania. The prevalence of TED in Southeast Asia was 35% (CI: 0.24 to 0.47) and Middle East 48% (CI: 0.19 to 0.78). Subgroup analysis showed regions with predominantly Caucasians (37%; CI: 0.28 to 0.46) had a lower prevalence of TED compared to Asians (45%; CI: 0.33 to 0.58). The pooled prevalence of lid retraction was 57% (CI: 0.39 to 0.74), proptosis 57% (CI: 0.48 to 0.65), diplopia 36% (CI: 0.24 to 0.48) and ocular hypertension 13% (CI: 0.06 to 0.19). CONCLUSION: A substantial proportion of patients with GD have TED and often manifest as lid retraction, proptosis and diplopia. Early detection through active screening might help to mitigate the progression of TED and its associated complications.

Plasma sphingolipids and risk of cardiovascular diseases: a large-scale lipidomic analysis.

INTRODUCTION: Sphingolipids are a diverse class of lipids with various roles in cell functions and subclasses such as ceramides have been associated with cardiovascular diseases (CVD) in previous studies. OBJECTIVES: We aimed to measure molecularly-distinct sphingolipids via a large-scale lipidomic analysis and expand the literature to an Asian population. METHODS: We performed a lipidomics evaluation of 79 molecularly distinct sphingolipids in the plasma of 2627 ethnically-Chinese Singaporeans. RESULTS: During a mean follow-up of 12.9 years, we documented 152 cases of major CVD (non-fatal myocardial infarction, stroke and cardiovascular death). Total ceramide concentrations were not associated with CVD risk [hazard ratio (HR), 0.99; 95% CI 0.81-1.21], but higher circulating total monohexosylceramides (HR, 1.22; 95% CI 1.03, 1.45), total long-chain sphingolipids (C16-C18) (HR, 1.22; 95% CI 1.02, 1.45) and total 18:1 sphingolipids (HR, 1.21; 95% CI 1.01, 1.46) were associated with higher CVD risk after adjusting for conventional CVD risk factors. CONCLUSIONS: Our results do not support the hypothesis that higher ceramide concentrations are linked to higher CVD risk, but suggest that other classes of sphingolipids may affect CVD risk.

Branched-Chain Amino Acid Oxidation Is Elevated in Adults with Morbid Obesity and Decreases Significantly after Sleeve Gastrectomy.

BACKGROUND: Plasma concentrations of branched-chain amino acids (BCAAs) are elevated in obese individuals with insulin resistance (IR) and decrease after bariatric surgery. However, the metabolic mechanisms are unclear. OBJECTIVES: Our objectives are to compare leucine kinetics between morbidly obese and healthy-weight individuals cross-sectionally, and to prospectively evaluate changes in the morbidly obese after sleeve gastrectomy. We hypothesized that leucine oxidation is slower in obese individuals and increases after surgery. METHODS: Ten morbidly obese [BMI (in kg/m2) ≥32.5, age 21-50 y] and 10 healthy-weight participants (BMI <25), matched for age (median ∼30 y) but not gender, were infused with [U-13C6] leucine and [2H5] glycerol to quantify leucine and glycerol kinetics. Morbidly obese participants were studied again 6 mo postsurgery. Primary outcomes were kinetic parameters related to BCAA metabolism. Data were analyzed by nonparametric methods and presented as median (IQR). RESULTS: Participants with obesity had IR with an HOMA-IR (4.89; 4.36-8.76) greater than that of healthy-weight participants (1.32; 0.99-1.49; P < 0.001) and had significantly faster leucine flux [218; 196-259 compared with 145; 138-149 µmol · kg fat-free mass (FFM)-1 · h-1], oxidation (24.0; 17.9-29.8 compared with 16.1; 14.3-18.5 µmol · kg FFM-1 · h-1), and nonoxidative disposal (204; 190-247 compared with 138; 129-140 µmol · kg FFM-1 · h-1) (P < 0.017 for all). After surgery, the morbidly obese had a marked improvement in IR (3.54; 3.06-6.08; P = 0.008) and significant reductions in BCAA concentrations (113; 95-157 µmol/L) and leucine oxidation (9.37; 6.85-15.2 µmol · kg FFM-1 · h-1) (P = 0.017 for both). Further, leucine flux in this group correlated significantly with IR (r = 0.78, P < 0.001). CONCLUSIONS: BCAA oxidation is not impaired but elevated in individuals with morbid obesity. Plasma BCAA concentrations are lowered after surgery owing to slower breakdown of body proteins as insulin's ability to suppress proteolysis is restored. These findings suggest that IR is the underlying cause and not the consequence of elevated BCAAs in obesity.

Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression.

PURPOSE: Metformin may have a role in reducing the incidence of colorectal cancer (CRC) and improving survival outcome. This meta-analysis explored the effect of metformin use on colorectal adenoma and cancer incidence, and colorectal oncological outcomes. METHODS: A database search was conducted on Medline, Embase and CNKI for studies comparing metformin vs. non-metformin users, metformin users vs. non-diabetics and metformin users vs. diabetics with diet-only treatment. Meta-analysis was done with DerSimonian and Laird with risk ratios (RR), and hazard ratios (HR) for survival outcomes. RESULTS: We included 58 studies and summarized incidences of colorectal adenoma and cancer, as well as cancer survival outcomes. Metformin users had a significant lower incidence of colorectal adenoma (RR 0.77, CI 0.67-0.88, p < 0.001), advanced adenoma (0.61, CI 0.42-0.88, p = 0.008) and CRC (RR 0.76, CI 0.69-0.84, p < 0.001) respectively compared with non-metformin users. Overall survival (HR 0.6, CI 0.53-0.67, p < 0.001) and CRC-specific survival (HR 0.66, CI 0.59-0.74, p < 0.001) were higher among metformin users compared with non-metformin users. Further analysis on overall survival of metastatic CRC patients revealed significantly higher survival rates in metformin users (HR 0.77, CI 0.68-0.87, p < 0.001). CONCLUSION: This meta-analysis showed that metformin use significantly reduces colorectal adenoma and cancer incidence and improves colorectal cancer outcomes.

Characteristics and genetic testing outcomes of patients with clinically suspected paraganglioma/pheochromocytoma (PGL/PCC) syndrome in Singapore.

BACKGROUND: Hereditary paraganglioma (PGL) and pheochromocytoma (PCC) syndromes are rare conditions, with limited data on spectrum of causative gene variants of these syndromes in Asian patients. METHODS: We describe the clinical characteristics and genetic testing outcomes of patients with suspected hereditary PGL/PCC who were referred to a tertiary cancer genetics clinic in Singapore. RESULTS: Among 2196 patients with suspected hereditary cancer syndrome evaluated at the cancer genetics clinic from 2000 to 2019, 13/2196 (0.6%) patients fulfilled clinical suspicion for hereditary PGL/PCC syndrome. After genetic counselling, 10 patients underwent multi-gene next generation sequencing and deletion/duplication analysis, including SDHAF2, SDHA, SDHB, SDHC, SDHD, VHL, NF1, RET, MAX, and TMEM127. Seven of 10 patients (70%) were identified to carry pathogenic variants, including 3 unrelated Chinese patients with head and neck PGL who carried the same SDHD: c.3G > C (p.Met1Ile) variant that was previously reported to be a possible founder variant in Chinese, and 3 patients with urogenital PGL and 1 patient with retroperitoneal PGL who carried different SDHB variants. Variant carriers were younger, more likely to present with multiple tumours, or have family history of paraganglioma or pheochromocytoma, than non- variant carriers. CONCLUSION: Hereditary PGL/PCC accounts for only 0.6% of patients seen in an adult cancer genetics clinic in Asia. SDHD and SDHB genes remain the most important causative genes of hereditary PGL/PCC in Asia even when patients are tested with multi-gene NGS panel.

The Consortium of Metabolomics Studies (COMETS): Metabolomics in 47 Prospective Cohort Studies.

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

Meal rich in carbohydrate, but not protein or fat, reveals adverse immunometabolic responses associated with obesity.

BACKGROUND: Obesity-related insulin resistance is linked to inflammation. Immunometabolic function differs between lean and obese subjects, but whether macronutrient composition of ingested meals affects these responses is not well known. We examined the effects of a single meal rich in fat, protein, or carbohydrate on immunometabolic responses. METHODS: Nine lean insulin sensitive (LIS) men and 9 obese insulin resistant (OIR) men ingested high-carbohydrate (HC), high-fat (HF) or high-protein (HP) mixed meals in random order. We assessed plasma glucose, insulin, and cytokine responses and cytokine gene expression in circulating mononuclear cells (MNC) at fasting and postprandial states (up to 6-h). RESULTS: Expression of NF-κB and TNFα genes were greater; whereas that of TGFß and IL-6 genes were lower, in the OIR compared to the LIS individuals. The differences were significantly greater after the HC meal, but not after the HP or HF meal. Similar results were obtained for plasma concentrations of TNFα and IL-6. CONCLUSIONS: Our findings indicate that a single HC meal has a distinct adverse effect on immunometabolic responses in the OIR individuals. The cumulative effect of such adverse responses to meals rich in carbohydrate may predispose the OIR individuals to a higher risk of cardiovascular disease.

Psychometric analysis of an eating behaviour questionnaire for an overweight and obese Chinese population in Singapore.

OBJECTIVES: Previous studies reveal that the Three-Factor Eating Questionnaire (TFEQ), which assesses eating behaviour, performs differently across population groups and cultures. We aimed to identify the factor structure that is most appropriate to capture eating behaviour in an overweight and obese Chinese population in Singapore. METHODS: TFEQ-51 was administered to 444 Chinese subjects pooled from four separate studies and scored according to various alternative versions of the TFEQ. Confirmatory factor analyses and goodness of fit indices were used to determine the most appropriate factor structure. Known-group validity analyses were conducted. RESULTS: Niemeier's Disinhibition Factors and the TFEQ-R18 factor structures were found to be the most applicable in our population based on goodness of fit indices, with a x(2)/df ratio of <3, RMSEA of ≤ 0.6 and a CFI value of >0.9 for both. Only two of three factors (Emotional Eating and Uncontrolled Eating) of the TFEQ-R18 showed good internal consistency, while none of Niemeier's Disinhibition Factors showed good internal consistency. Known-group validity showed that Emotional Eating and Internal Disinhibition were significantly associated with higher BMI. CONCLUSION: We found that the TFEQ-R18 factor structure is the most appropriate and practical for use in measuring eating behaviour in an overweight and obese Chinese population in Singapore.

Automated segmentation of visceral and subcutaneous (deep and superficial) adipose tissues in normal and overweight men.

PURPOSE: To develop an automatic segmentation algorithm to classify abdominal adipose tissues into visceral fat (VAT), deep (DSAT), and superficial (SSAT) subcutaneous fat compartments and evaluate its performance against manual segmentation. MATERIALS AND METHODS: Data were acquired from 44 normal (BMI 18.0-22.9 kg/m(2) ) and 38 overweight (BMI 23.0-29.9 kg/m(2) ) subjects at 3T using a two-point Dixon sequence. A fully automatic segmentation algorithm was developed to segment the fat depots. The first part of the segmentation used graph cuts to separate the subcutaneous and visceral adipose tissues and the second step employed a modified level sets approach to classify deep and superficial subcutaneous tissues. The algorithmic results of segmentation were validated against the ground truth generated by manual segmentation. RESULTS: The proposed algorithm showed good performance with Dice similarity indices of VAT/DSAT/SSAT: 0.92/0.82/0.88 against the ground truth. The study of the fat distribution showed that there is a steady increase in the proportion of DSAT and a decrease in the proportion of SSAT with increasing obesity. CONCLUSION: The presented technique provides an accurate approach for the segmentation and quantification of abdominal fat depots.

Effects of Roux-en-Y gastric bypass or diabetes support and education on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes.

OBJECTIVE: The long-term changes in insulin sensitivity and ß-cell function in morbidly obese patients with type 2 diabetes mellitus who undergo Roux-en-Y gastric bypass (RYGB) surgery or standard medical care remain unclear. We prospectively studied longitudinal changes of glucostatic parameters in morbidly obese patients with type 2 diabetes mellitus undergoing RYGB surgery or diabetes support and education (DSE). RESEARCH METHODS AND DESIGN: Sixty-one morbidly obese subjects (41.7 ± 0.6 kg/m) with type 2 diabetes mellitus were assigned to RYGB surgery (n = 30) or DSE (n = 31). They were matched for sex, age, and body weight. Insulin sensitivity index (Si) and acute insulin response (AIR) were derived from frequently sampled intravenous glucose tolerance test. Body composition was measured using dual-energy x-ray absorptiometry. General linear model with repeated measures was used to examine the longitudinal changes (baseline, 6 months, 12 months) in these parameters. RESULTS: At 12-month follow-up, significant improvement in obesity measures, body composition, glucose homeostasis, Si, and AIR was observed after RYGB surgery and weight loss. These outcomes were not influenced by preoperative insulin use. Although there were no significant changes in the body composition among DSE subjects, they experienced a decline in the Si and AIR, along with an increase in fasting glucose and HbA1c. The between-group differences in Si and AIR at 12-month follow-up were completely attenuated with adjustment to changes in body weight. CONCLUSIONS: The long-term effects of RYGB surgery on glucostatic parameters are partly dependent on weight loss. In morbidly obese patients with diabetes who were offered DSE, a progressive decline in the glucose homeostasis and glucostatic parameters is observed despite absence of weight gain. (NCT00787670).