Burden Of Metabolic Diseases Research Articles

8780 The Role of Nuclear Receptor Corepressors 1 and 2 on Intestinal Carbohydrate Transport in Mice

Abstract Disclosure: M.J. Ritter: None. I. Amano: None. A.H. van der Spek: None. H.E. Daniel: None. A.N. Hollenberg: None. The nuclear receptor corepressors NCoR1 and NCoR2 are two critical regulators of metabolism that are required for maintaining metabolic homeostasis. Both NCoR1 and NCoR2 (also known as the silencing mediator of retinoic acid and thyroid hormone receptors; SMRT) recruit histone deacetylase 3 (HDAC3) to their deacetylase domain (DAD) to repress nuclear receptor (NR) target gene expression. Interruption of the DAD of NCoR1 in mice leads to lower body weight, decreased whole-body fat mass, insulin sensitization with altered oscillatory patterns of key metabolic genes (1). On the other hand, total body knock-out (KO) of SMRT leads to weight gain, insulin resistance, and hepatic steatosis with an increase in hepatic lipogenesis (2). Previously, we showed that the KO of NCoR1 and SMRT in tandem from adult mice led rapidly to weight loss, hypoglycemia, hypothermia and was lethal. Reductions in intestinal carbohydrate transporters were seen, including sodium-glucose linked transporter-1 (SGLT1), glucose transporter 2 (GLUT2), and glucose transporter 5 (GLUT5) (3). Thus, we hypothesized that NCoR1 and SMRT play unique roles in regulating intestinal carbohydrate metabolism, in turn controlling metabolic parameters including body mass and glucose levels. We then generated a novel model to enable KO of NCoR1 and SMRT throughout intestinal epithelial cells (IECs) in adult mice using a tamoxifen inducible cre under control of the villin 1 promoter. Mice were injected with tamoxifen and body weight and glucose were monitored daily. This was followed by both oral and intraperitoneal glucose tolerance testing (GTT) and metabolic phenotyping. Preliminary data showed that NCoR1 and SMRT KO leads to sustained weight loss and hypoglycemia with 50% survivability. Metabolic phenotyping confirmed reduction in body mass without concomitant reduction in food intake. Oral GTT showed a blunted peak in response to glucose gavage compared to intraperitoneal administration. Gene expression analysis showed reduction in SGLT1, GLUT2, and GLUT5 in addition to changes in metabolic pathways associated with fatty acid metabolism. Here, we show that NCoR1 and SMRT are critical regulators of body mass and glucose in part via their actions on carbohydrate transporters in the intestine. With the global burden of metabolic diseases, including obesity and diabetes, ever-rising, NCoR1 and SMRT represent an overlooked but important area of study to better our understanding of disease processes and identify new targets for treatment. We next aim to determine the functional mechanism by which weight loss and hypoglycemia develop in addition to identifying molecular targets and pathways regulated by NCoR1 and SMRT in IECs.

Global burden of metabolic diseases, 1990–2021

BackgroundCommon metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global health burden in the last three decades. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) data enables the first insights into the trends and burdens of these metabolic diseases from 1990 to 2021, highlighting regional, temporal and differences by sex. MethodsGlobal estimates of disability-adjusted life years (DALYs) and deaths from GBD 2021 were analyzed for common metabolic diseases (T2DM, hypertension, obesity, hypercholesterolemia, and MASLD). Age-standardized DALYs (mortality) per 100,000 population and annual percentage change (APC) between 1990 and 2021 were estimated for trend analyses. Estimates are reported with uncertainty intervals (UI). ResultsIn 2021, among five common metabolic diseases, hypertension had the greatest burden (226 million [95 % UI: 190–259] DALYs), whilst T2DM (75 million [95 % UI: 63–90] DALYs) conferred much greater disability than MASLD (3.67 million [95 % UI: 2.90–4.61]). The highest absolute burden continues to be found in the most populous countries of the world, particularly India, China, and the United States, whilst the highest relative burden was mostly concentrated in Oceania Island states. The burden of these metabolic diseases has continued to increase over the past three decades but has varied in the rate of increase (1.6-fold to 3-fold increase). The burden of T2DM (0.42 % [95 % UI: 0.34–0.51]) and obesity (0.26 % [95 % UI: 0.17–0.34]) has increased at an accelerated rate, while the rate of increase for the burden of hypertension (−0.30 % [95 % UI: −0.34 to −0.25]) and hypercholesterolemia (−0.33 % [95 % UI: −0.37 to −0.30]) is slowing. There is no significant change in MASLD over time (0.05 % [95 % UI: −0.06 to 0.17]). ConclusionIn the 21st century, common metabolic diseases are presenting a significant global health challenge. There is a concerning surge in DALYs and mortality associated with these conditions, underscoring the necessity for a coordinated global health initiative to stem the tide of these debilitating diseases and improve population health outcomes worldwide.

Celiac artery mesenteric fat measurement with endosonography (CAMEUS) reliably correlates with obesity and related comorbidities.

Visceral fat represents a metabolically active entity linked to adverse metabolic sequelae of obesity. We aimed to determine if celiac artery mesenteric fat thickness can be reliably measured during endoscopic ultrasound (EUS), and if these measurements correlate with metabolic disease burden. This was a retrospective analysis of patients who underwent celiac artery mesenteric fat measurement with endosonography (CAMEUS) measurement at a tertiary referral center, and a validation prospective trial of patients with obesity and nonalcoholic steatohepatitis who received paired EUS exams with CAMEUS measurement before and after six months of treatment with an intragastric balloon. CAMEUS was measured in 154 patients [56.5% females, mean age 56.5 ± 18.0 years, body mass index (BMI) 29.8 ± 8.0 kg/m2] and was estimated at 14.7 ± 6.5 mm. CAMEUS better correlated with the presence of non-alcoholic fatty liver disease (NAFLD) (R2 = 0.248, P < 0.001) than BMI (R2 = 0.153, P < 0.001), and significantly correlated with metabolic parameters and diseases. After six months of intragastric balloon placement, the prospective cohort experienced 11.7% total body weight loss, 1.3 points improvement in hemoglobin A1c (P = 0.001), and a 29.4% average decrease in CAMEUS (-6.4 ± 5.2 mm, P < 0.001). CAMEUS correlated with improvements in weight (R2 = 0.368), aspartate aminotransferase to platelet ratio index (R2 = 0.138), and NAFLD activity score (R2 = 0.156) (all P < 0.05). CAMEUS is a novel measure that is significantly correlated with critical metabolic indices and can be easily captured during routine EUS to risk-stratify susceptible patients. This station could allow for EUS access to sampling and therapeutics of this metabolic region.

The immediate impact of a balanced, very low-calorie diet on the metabolic health of Indian subjects - A prospective longitudinal study

Problems consideredGlobal challenges posed by obesity, type 2 diabetes mellitus (T2DM), hypertension, and related metabolic diseases necessitate effective interventions. Pharmacotherapy often falls short, leading to a demand for innovative approaches. This study delves into the effects of an organized diet featuring a readily available food substitute blend over an eight-week span. MethodsThe study implemented a low-calorie diet (800–830 calories), comprising three shakes, non-starchy vegetables, soups, reduced buttermilk, and limited fat. Assessments covered NCDs like T2DM, hypertension, dyslipidemia, and non-alcoholic fatty liver disease. WHO STEPS protocol guided anthropometric measures and blood pressure readings, while INBODY 230 Analyser determined body composition. SPSS 16 software facilitated analysis of baseline and two-month follow-up data. ResultsParticipants with an average baseline BMI of 31.9 kg/m2 witnessed substantial improvements. Weight, BMI, waist and hip circumferences, neck, arm, and thigh circumferences, and body fat percentage registered significant decreases. Positive changes were observed in diabetes indicators, including reduced HbA1c (7.2%–6.1%) and fasting/post-prandial blood glucose (p < 0.001). Noteworthy enhancements extended to blood pressure, triglycerides, and NAFLD markers (p < 0.001), indicating favorable shifts in obesity-related markers and metabolic irregularities. ConclusionThe study underscores the potential of reversal diet in real-world clinical settings, offering promise in ameliorating metabolic disorders linked to obesity. Intriguingly, these benefits extended to individuals of South Asian region, accentuating its broad relevance. However, sustaining these improvements necessitates further exploration through extended interventions with larger participant cohorts. The findings kindle optimism in addressing mounting burden of metabolic diseases on a global scale.

Metabolic PET/CT analysis of aggressive Non-Hodgkin lymphoma prior to Axicabtagene Ciloleucel CAR-T infusion: predictors of progressive disease, survival, and toxicity

PET/CT is used to evaluate relapsed/refractory non-Hodgkin lymphoma (NHL) prior to chimeric antigen receptor T-cell (CAR-T) infusion at two time points: pre-leukapheresis (pre-leuk) and pre-lymphodepletion chemotherapy (pre-LD). We hypothesized that changes in PET/CT between these time points predict outcomes after CAR-T. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and other metrics were calculated from pre-leuk and pre-LD PET/CT scans in patients with NHL who received axicabtagene ciloleucel, and assessed for association with outcomes. Sixty-nine patients were analyzed. While single time point PET/CT characteristics were not associated with risk of PD or death, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p < 0.05 for all). LASSO analysis identified increasing extranodal MTV and increasing TLG of the largest lesion as strong predictors of death (AUC 0.74). Greater pre-LD total MTV was associated with higher risk of grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS) (p = 0.042). Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of progression and death. A two variable risk score stratifies prognosis prior to CAR-T infusion and may inform risk-adapted strategies.

Disparities in ethnicity and metabolic disease burden in referrals to nephrology.

The profile of patients referred from primary to tertiary nephrology care is unclear. Ethnic Malay patients have the highest incidence and prevalence of kidney failure in Singapore. We hypothesised that there is a Malay predominance among patients referred to nephrology due to a higher burden of metabolic disease in this ethnic group. This is a retrospective observational cohort study. From 2014 to 2018, a coordinator and physician triaged patients referred from primary care, and determined co-management and assignment to nephrology clinics. Key disease parameters were collated on triage and analysed. A total of 6,017 patients were studied. The mean age of patients was 64 ± 16 years. They comprised 57% men; 67% were Chinese and 22% were Malay. The proportion of Malay patients is higher than the proportion of Malays in the general population (13.4%) and they were more likely than other ethnicities to have ≥3 comorbidities, including diabetes mellitus, hypertension, hyperlipidaemia, coronary artery disease and stroke (70% vs. 57%, P < 0.001). Malay and Indian patients had poorer control of diabetes mellitus compared to other ethnicities (glycated haemoglobin 7.8% vs. 7.4%, P < 0.001). Higher proportion of Malay patients compared to other ethnicities had worse kidney function with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 on presentation (28% vs. 24%, P = 0.003). More ethnic Malay, Indian and younger patients missed appointments. A disproportionately large number of Malay patients are referred for kidney disease. These patients have higher metabolic disease burden, tend to miss appointments and are referred at lower eGFR. Reasons underpinning these associations should be identified to facilitate efforts for targeting this at-risk population, ensuring kidney health for all.

Impact of Liver Transplantation on Adipose Tissue Compartments and Its Association With Metabolic Sequela.

Loss of skeletal muscle can be accompanied by an increase in adipose tissue leading to sarcopenic obesity. There are limited data on how liver transplantation (LT) might impact adipose tissue compartments, particularly among patients with metabolically active disease, such as nonalcoholic steatohepatitis (NASH) and subsequent metabolic sequela. Skeletal muscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were measured using cross-sectional imaging performed in 190 patients pre-LT, 6 mo post-LT and 12 mo post-LT. Changes in adipose tissue and their impact on metabolic diseases were determined in patients transplanted for NASH versus non-NASH. Skeletal muscle, VAT, and SAT were similar in patients with NASH and non-NASH pre-LT despite a higher burden of metabolic diseases in patients with NASH. Following LT, no significant differences between skeletal muscle and SAT were observed in the entire cohort and among patients with NASH (versus non-NASH). LT recipients with the highest muscle mass pre-LT were at the greatest risk for muscle loss post-LT. A time-dependent increase in VAT was noted post-LT, which was more robust among patients with a history of NASH cirrhosis. In adjusted multivariate analysis, NASH versus non-NASH was a strong predictor of post-LT increase in VAT (β-coefficient 3.00, P = 0.04). Pre-LT VAT was an independent predictor of post-LT serum triglycerides (β-coefficient 5.49 ± 2.78, P = 0.05) and low-density lipoprotein cholesterol (β-coefficient 1.80 ± 0.75, P = 0.02). A trend between pre-LT VAT and diabetes was noted but did not reach statistical significance. VAT but not SAT increases rapidly after LT, especially among patients transplanted for NASH cirrhosis and predicts future metabolic burden.

Exposure to outdoor artificial light at night increases risk and burden of metabolic disease in Ningxia, China.

Nearly a quarter of the world's land has already been polluted by artificial light. And numerous human and animal studies have corroborated that light at night can disrupt metabolism. Therefore, we aimed to estimate the association between outdoor artificial light at night (ALAN) and the presence of metabolic disease. Daily hospital admission cases from Ningxia, China, between 2014 and 2020 were included. Cumulative associations between outdoor ALAN and metabolic disease were estimated using logistic regression and distributed lagged non-linear models (DLNM) with lags of 0-30 days and stratified analysis by age groups and gender. The results suggest that 26.80% of metabolic disease cases in Ningxia can be attributed to outdoor ALAN and that men, especially in men aged 46-59 years, are more susceptible to lighting. Policymakers need to develop measures and facilities in corresponding areas, such as universal access to indoor blackout curtains. In particular, men should be urged to minimize going outside at night and to develop protective measures specifically for men.

284-OR: An Alternative Downstream Translational Start Site in PPARG Produces a Novel Protein That Rescues Loss-of-Function Mutations in Humans

PPARG is the target of thiazolidinediones (TZD) and plays a central role in glucose and lipid metabolism. Loss-of-function (LOF) mutations in PPARG increase the risk of type 2 diabetes (T2D) and cause Mendelian lipodystrophy. In population-scale sequencing studies, we identified protein-truncating variants in PPARG expected to cause lipodystrophy, but surprisingly showing no burden of metabolic disease in their human carriers. To further understand this finding, we use CRISPR/CAS9 to systematically target deletions to every exon of PPARG revealing that mutations causing deleterious frameshifts in exons 1 and 2 resulted in cells with intact PPARG responses. We subsequently constructed a library of PPARG transgenes encoding termination sequences at every possible codon (1-505) in the PPARG2 cDNA and tested them for transactivation function. We found that PPARG transgenes encoding termination sequences prior to codon 135 (c.ATG402-404) corresponding to exon 2 in the genomic DNA (chr3:12381414 Hg38) retained transactivation activity. We hypothesized that c.ATG402-404 served as an alternative translational start site that generates a PPARG isoform lacking the N-terminus but retaining DNA-binding, ligand-binding, and transactivation properties. Indeed, cells engineered to disrupt PPARG prior to chr3:12381414 retained TZD responsiveness and produced a 40 kDa protein recognized by antibodies targeting the C-terminus but not the N-terminus of PPARG. Analysis of the global transcriptional activity of the PPARG p.M135-505 compared to full-length PPARG revealed that p.M135-505 produced a similar TZD-induced upregulation of known PPARG targets and gene sets. In summary, PPARG p.M135-505 is a truncated but fully functional protein that responds to PPARG agonists and may rescue disruptive mutations that would otherwise cause lipodystrophy. Disclosure K.Mendez lara: None. X.Du: None. K.Glass: None. R.Hernandez: None. C.De arruda saldanha: None. S.Heinz: Research Support; Hologic Inc., Stock/Shareholder; Leash Laboratories. A.R.Majithia: None. Funding National Institutes of Health (RDK01DK123422)

MOSUNETUZUMAB DEMONSTRATES DURABLE RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: UPDATED ANALYSIS OF A PIVOTAL PHASE II STUDY

MOSUNETUZUMAB DEMONSTRATES DURABLE RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: UPDATED ANALYSIS OF A PIVOTAL PHASE II STUDY

The global burden of metabolic disease: Data from 2000 to 2019

Global estimates of prevalence, deaths, and disability-adjusted life years (DALYs) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were examined for metabolic diseases (type 2 diabetes mellitus [T2DM], hypertension, and non-alcoholic fatty liver disease [NAFLD]). For metabolic risk factors (hyperlipidemia and obesity), estimates were limited to mortality and DALYs. From 2000 to 2019, prevalence rates increased for all metabolic diseases, with the greatest increase in high socio-demographic index (SDI) countries. Mortality rates decreased over time in hyperlipidemia, hypertension, and NAFLD, but not in T2DM and obesity. The highest mortality was found in the World Health Organization Eastern Mediterranean region, and low to low-middle SDI countries. The global prevalence of metabolic diseases has risen over the past two decades regardless of SDI. Urgent attention is needed to address the unchanging mortality rates attributed to metabolic disease and the entrenched sex-regional-socioeconomic disparities in mortality.

The global syndemic of metabolic diseases in the young adult population: A consortium of trends and projections from the Global Burden of Disease 2000–2019

BackgroundA significant proportion of premature deaths globally are related to metabolic diseases in young adults. We examined the global trends and mortality of metabolic diseases in individuals aged below 40 years using data from the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2019. MethodsFrom 2000 to 2019, global estimates of deaths and disability-adjusted life years (DALYs) were described for metabolic diseases (type 2 diabetes mellitus [T2DM], hyperlipidemia, hypertension, obesity, non-alcoholic fatty liver disease [NAFLD]). Subgroup analyses were performed based on sex, geographical regions and Socio-Demographic Index (SDI). Age-standardised death and DALYs were presented per 100,000 population with 95 % uncertainty intervals (UI). Projections of mortality and DALYs were estimated using regression models based on the GBD 2019 data and combining them with Institute for Health Metrics and Evaluation projection counts for years up to 2050. ResultsIn 2019, the highest age-standardised death rates were observed in hypertension (133·88 [121·25–155·73]), followed by obesity (62·59 [39·92–89·13]), hyperlipidemia (56·51 [41·83–73·62]), T2DM (18·49 [17·18–19·66]) and NAFLD (2·09 [1·61–2·60]). Similarly, obesity (1932·54 [1276·61–2639·74]) had the highest age-standardised DALYs, followed by hypertension (2885·57 [2580·75–3201·05]), hyperlipidemia (1207·15 [975·07–1461·11]), T2DM (801·55 [670·58–954·43]) and NAFLD (53·33 [40·73–68·29]). Mortality rates decreased over time in hyperlipidemia (−0·6 %), hypertension (−0·47 %), NAFLD (−0·31 %) and T2DM (−0·20 %), but not in obesity (1·07 % increase). The highest metabolic-related mortality was observed in Eastern Mediterranean and low SDI countries. By 2050, obesity is projected to contribute to the largest number of deaths (102·8 % increase from 2019), followed by hypertension (61·4 % increase), hyperlipidemia (60·8 % increase), T2DM (158·6 % increase) and NAFLD (158·4 % increase), with males continuing to bear the greatest burden across all metabolic diseases. ConclusionThe growing burden of metabolic diseases, increasing obesity-related mortality trends, and the sex-regional-socioeconomic disparities evident in young adulthood, underlie the concerning growing global burden of metabolic diseases now and in future.

Global burden of metabolic diseases: data from Global Burden of Disease 2000-2019. A cosortium of metabolic disease

Abstract Funding Acknowledgements Type of funding sources: None. Background The growing prevalence of metabolic diseases is a major concern. We sought to examine the global trends and mortality of metabolic diseases using estimates from the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2019. Methods Global estimates of prevalence, deaths, and disability-adjusted life year (DALYs) from 2000-2019 were examined for metabolic diseases (type 2 diabetes mellitus [T2DM], hypertension, and nonalcoholic fatty liver disease [NAFLD]). For metabolic risk factors (hyperlipidemia and obesity), estimates were limited to mortality and DALYs. Death rates was compared across sex, World Health Organisation regions and Socio-demographic Index (SDI) quintiles. Age-standardised prevalence and death rates were presented per 100,000 population with 95% uncertainty intervals (UI). Findings From 2000 to 2019, prevalence rates increased for all metabolic diseases, with the most pronounced increase in high SDI countries. In 2019, the mean (95%UI) age-standardised prevalence per 100,000 population was estimated to be 15,023 (13,493-16,764) for NAFLD, 5,283 (4,864–5,720) for T2DM and 234 (171-313) for hypertension. The highest age-standardised death rates were observed in obesity (62·59 [39·92-89·13]; males, 66·55 [39·76-97·21]; females. 58·14 [38·53-81·39]), followed by hyperlipidemia (56·51 [41·83-73·62]; males, 67·33 [50·78-86·43]; females, 46·50 [32·70-62·38]), T2DM (18·49 [17·18-19·66], males, 67·33 [50·78-86·43]; females, 46·50 [32·70-62·38]), hypertension (15·16 [11·20-16·75]; males, 14·95 [10·32-16·75]; females, 15·05 [11·51-17·09]) and NAFLD (2·09 [1·61-2·60]; males, 2·38 [1·82-3·02]; females, 1·82 [1·41-2·27]). Mortality rates decreased over time in hyperlipidemia (-154%), hypertension (-52%) and NAFLD (-52%), but not in T2DM and obesity. The highest mortality for metabolic diseases was found in Eastern Mediterranean, and low to low-middle SDI countries. Conclusion The global prevalence of metabolic diseases has risen over the past two decades regardless of SDI. Attention is needed to address the unchanging mortality rates attributed to metabolic disease and the regional, socioeconomic, and sex disparities in mortality from metabolic disease.

The global syndemic of metabolic diseases in the young adult population: a consortium from the Global Burden of Disease 2000-2019

Abstract Funding Acknowledgements Type of funding sources: None. Background A large proportion of premature deaths are related to metabolic diseases in the young adult population. We examined the global trends and mortality of metabolic diseases using estimates from the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2019 in individuals aged below 40 years. Methods From 2000-2019, global estimates of prevalence, deaths, and disability-adjusted life years (DALYs) were described for metabolic diseases (type 2 diabetes mellitus [T2DM], hypertension, non-alcoholic fatty liver disease [NAFLD]). Global estimates were limited to mortality and DALYs for risk factors (hyperlipidemia and obesity). Subgroup analyses were performed based on sex, geographical regions and Socio-Demographic Index (SDI). Age-standardized prevalence, death, and DALYs were presented per 100,000 population with 95% uncertainty intervals (UI). Findings The prevalence for all metabolic diseases increased from 2000-2019, with the most pronounced increase in males and high SDI countries. In 2019, the highest age-standardised death rates were observed in hypertension (133·88 [121·25-155·73]; males, 160·13 [138·91-180·79]; females, 119·66 [102·33-136·86]), followed by obesity (62·59 [39·92-89·13]; males, 66·55 [39·76-97·21]; females, 58·14 [38·53-81·39]), hyperlipidemia (56·51 [41·83-73·62]; males, 67·33 [50·78-86·43]; females, 46·50 [32·70-62·38]), T2DM (18·49 [17·18-19·66]; males, 19·94 [18·50-21·32]; females, 17·30 [15·62-18·70]) and NAFLD (2·09 [1·61-2·60]; males, 2·38 [1·82-3·02]; females, 1·82 [1·41-2·27]). Similarly, obesity (1932·54 [1276·61-2639·74]) had the highest age-standardised DALYs, followed by hypertension (2885·57 [2580·75-3201·05]), hyperlipidemia (1207·15 [975·07-1461·11]), T2DM (801·55 [670·58-954·43]) and NAFLD (53·33 [40·73-68·29]). Mortality rates decreased over time in hyperlipidemia (-60%), hypertension (-47%), NAFLD (-31%) and T2DM (-20%), but not in obesity (107% increase). The highest metabolic-related mortality was observed in the Eastern Mediterranean and low SDI countries. Conclusion The growing prevalence of metabolic diseases, increasing obesity-related mortality trends, and the sex-regional-socioeconomic disparities evident in young adulthood, present the concerning global burden of metabolic diseases now and in the years ahead.

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Benefits Versus Risk.

With the growing burden of metabolic disease, cardiovascular disease, and diabetes mellitus, there is an implication for new pharmacological intervention. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of drugs that work on SGLT2 receptors in the kidneys to decrease glucose reabsorption. Lowering glucose levels mainly aids those with type 2 diabetes (T2DM), but they also have many other effects on the body. This article will investigate the impact of SGLT2i on six relevant organ systems; to establish current knowledge and potential benefits and risk for SGLTi in clinical practice. The medications that inhibit SGLT2 suffix with flozins are known to help decrease hypertension, acute cardiac failure, and bradycardia in the cardiovascular system. Flozins were found to aid with acute pulmonary edema, asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) in the pulmonary system. SGLT2 is also found in the blood-brain barrier (BBB), andas such, SGLT2i can also affect the central nervous system (CNS). They reduced reactive oxygen species (ROS), BBB leakage, microglia burden, and acetylcholinesterase (AChE) levels. In the liver, this class of drugs can also assist with non-alcoholic fatty liver disease (NAFLD), hepatotoxicity, and weight loss. In the pancreas, SGLT2i has been shown to help with primarily diabetes and hyperglycemia. Finally, SGLT2i's are known to aid in decreasing nephrotoxicity and stopping the progression of the glomerular filtration rate (GFR) decrease. New studies have shown that the flozin drugs have been helpful for those who were receiving kidney transplants. Despite the positive effects, there are some concerns about SGLT2i and its notable adverse effects. Flozin drugs are known to cause urinary tract infections (UTIs), dehydration, orthostatic hypotension, postural dizziness, syncope, hypotension, hyperkalemia-induced cardiac arrest, and pancreatitis. This literature review will discuss, in detail, the benefits and risks that SGTL2i have on different organ systems and implicate the role they may play in clinical practice.

Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study

ObjectiveTo investigate the potential causal effects of long term plasma caffeine concentrations on adiposity, type 2 diabetes, and major cardiovascular diseases.DesignTwo sample mendelian randomisation study.SettingGenome-wide association study summary data for...

Sedentary patterns and cardiometabolic risk factors in Mexican children and adolescents: analysis of longitudinal data

BackgroundSedentary behavior is a modifiable risk factor for cardiometabolic health; however, the assessment of total sedentary time may not capture youth’s highly active and interrupted activity patterns. This study examined the associations between sedentary activity patterns and cardiometabolic risk factors among Mexican youth, who have a disproportionate burden of metabolic diseases, using a repeated measure design out of a longitudinal data.Methods570 subjects in the Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) birth cohort, who were followed up to three-time points during adolescence, were included. Bout duration, and frequency and percentages of waking time spent in specific intensities of activity, were quantified using ActiGraph wGT3X-BT wrist accelerometers. Self-reported questionnaires were used to query the usual duration of different sedentary behaviors. Outcomes were fasting lipid profile, markers for glucose homeostasis, anthropometry, and blood pressure. Associations were modeled using linear mixed-effects models, and isotemporal substitution approach was additionally used to assess the effect of replacing objectively assessed sedentary activity with other activity intensities, adjusting for potential confounders.ResultsEach hour of self-reported screen-based time was positively associated with diastolic blood pressure (mm Hg) [β = 0.30, 95% confidence interval (95% CI) = 0.10, 0.51], and an hour of other sedentary time was associated with log serum glucose (mg/dL) [β = 0.01, 95% CI = 0.004, 0.017]. Substitution models showed that replacing 5% of sedentary time with moderate to vigorous physical activity (MVPA) was associated with lower waist circumference (cm) [β = − 1.35, 95% CI = − 1.91, − 0.79] and log serum triglycerides (mg/dL) [β = − 0.11, 95% CI = − 0.18, − 0.03]. Substituting one uninterrupted sedentary bout with light activity was associated with lower insulin (μIU/mL) [β = − 0.06, 95% CI = − 0.10, − 0.02].ConclusionsSedentary time was associated with cardiometabolic risk factors in Mexican youth in a context-specific manner. Replacing sedentary time with higher intensities was associated with improvements in some cardiometabolic markers.

Diabetes in HIV: the Link to Weight Gain.

The burden of metabolic diseases, including type 2 diabetes mellitus (T2DM), is rising among persons with HIV (PWH) on antiretroviral therapy (ART). This increase coincides with an aging population and a greater proportion who are overweight/obese. This review summarizes the changing epidemic of T2DM on contemporary ART, the role of weight gain, and therapeutic options. Recent studies confirm that PWH face an epidemic of obesity and T2DM, similar to the general population. Contemporary ART is associated with greater weight gain and may contribute to the risk of T2DM. Recent advances in medical weight loss therapy offer a way forward in the prevention and treatment of weight-associated T2DM. Weight gain is one of the biggest contributors to T2DM in PWH. Future studies on the role of adipose tissue distribution, adipose tissue function and clinical use of effective weight loss medications may change the paradigm of care for PWH.

Time for better time-restricted eating trials to lessen the burden of metabolic diseases

Optimizing the quality, quantity, and timing of nutrition holds immense potential to improve health and prevent disease. The results of a recent randomized controlled trial1 have been widely misrepresented with the incorrect interpretation that optimizing the timing of food intake imparts no health benefits.

Race-specific associations of urinary phenols and parabens with adipokines in midlife women: The Study of Women's Health Across the Nation (SWAN)

Adipokines, cytokines secreted by adipose tissue, may contribute to obesity-related metabolic disease. The role of environmental phenols and parabens in racial difference in metabolic disease burden has been suggested, but there is limited evidence. We examined the cross-sectional associations of urinary phenols and parabens with adipokines and effect modification by race. Urinary concentrations of 6 phenols (bisphenol-A, bisphenol-F, 2,4-diclorophenol, 2,5-diclorophenol, triclosan, benzophenone-3) and 4 parabens (methyl-paraben, ethyl-paraben, propyl-paraben, butyl-paraben) were measured in 2002–2003 among 1200 women (mean age = 52.6) enrolled in the Study of Women's Health Across the Nation Multi-Pollutant Study. Serum adipokines included adiponectin, high molecular weight (HMW)-adiponectin, leptin, soluble leptin receptor (sOB-R). Linear regression models were used to estimate the adjusted percentage change in adipokines per inter-quantile range (IQR) increase in standardized and log-transformed levels of individual urinary phenols and parabens. Bayesian kernel machine regression (BKMR) was used to evaluate the joint effect of urinary phenols and parabens as mixtures. Participants included white (52.5%), black (19.3%), and Asian (28.1%) women. Urinary 2,4-dichlorophenol was associated with 6.02% (95% CI: 1.20%, 10.83%) higher HMW-adiponectin and urinary bisphenol-F was associated with 2.60% (0.48%, 4.71%) higher sOB-R. Urinary methyl-paraben was associated with lower leptin in all women but this association differed by race: 8.58% (−13.99%, −3.18%) lower leptin in white women but 11.68% (3.52%, 19.84%) higher leptin in black women (P interaction = 0.001). No significant associations were observed in Asian women. Additionally, we observed a significant positive overall effect of urinary phenols and parabens mixtures in relation to leptin levels in black, but not in white or Asian women. Urinary bisphenol-F, 2,4-dichlorophenol and methyl-paraben may be associated with favorable profiles of adipokines, but methyl-paraben, widely used in hair and personal care products, was associated with unfavorable leptin levels in black women. Future studies are needed to confirm this racial difference.