Metabolic Comorbidities Research Articles

Comorbidities in multiple sclerosis and their influence on the choice of treatment

Clinical trials of disease-modifying therapies (DMTs) for people with multiple sclerosis (pMS) are conducted in selected populations, excluding patients with comorbidities or concomitant medications. However, a large percentage of pMS have some additional disease, which could affect the response and choice of the DMT. The objective of this review is to assess how concurrent pathologies can impact the choice of DMTs. Relevant articles were selected through a systematic search in PubMed. Comorbidities were grouped for better classification into autoimmune, chronic infections, cardiovascular and metabolic, oncological and neuropsychiatric. In autoimmune pathologies, it is key to take into account the effects of TME on them and the possibility of interaction with their specific treatments. Immunomodulatory therapies are safe for people with chronic infections. Immunosuppressive treatments are generally contraindicated in people with active infections. In cardiovascular and metabolic comorbidities, infusion reactions associated with monoclonal antibodies, and the phenomena of starting treatment with S1P modulators, must be taken into account. DMTs with an immunosuppressive effect are contraindicated in people with active malignancies. Although psychiatric pathology per se does not preclude the use of DMTs, caution should be exercised when new psychiatric symptoms appear. For these reasons, among the multiple factors that must be considered when starting or changing a DMT in pMS, comorbidities constitute a decisive element.

The link between alterations in circadian rhythms and lipid metabolism in bipolar disorder: the lipid droplets hypothesis.

Bipolar disorder (BD) is a neuropsychiatric illness characterized by recurrent episodes of mania and depression, leading to profound cognitive and functional impairments, psychiatric and metabolic comorbidities, and substantial healthcare costs. Due to its complex nature and absence of specific biomarkers, BD presents significant daily challenges for clinicians. Therefore, advancing our understanding of BD pathophysiology is essential to identify novel diagnostic biomarkers and potential therapeutic targets. Although its neurobiology remains unclear, disruption of circadian rhythms and lipid alterations have emerged as key hallmarks of BD. As essential components of the brain, lipids play a pivotal role in regulating synaptic activity and neuronal development. Thus, alterations in brain lipids may contribute to the neuroanatomical changes and reduced neuroplasticity observed in BD. The levels of toxic lipids inside the cell are buffered by lipid droplets that regulate the storage of neutral lipids. These dynamic organelles adapt to cellular needs, and their dysregulated accumulation has been linked to various pathological conditions. Notably, lipid droplets and various lipid classes display rhythmic oscillations throughout the 24-hour cycle, suggesting a link between lipid metabolism, circadian rhythms and lipid droplets. In this review, we explore the impairment of circadian rhythms and lipid metabolism in BD, along with evidence demonstrating that circadian clocks regulate the accumulation of lipid droplets. Importantly, we propose the "lipid droplets hypothesis for BD" that considers that the compromised lipid metabolism in BD is intimately associated with alterations in the lipid droplets homeostasis, which can be driven by disturbances in the circadian clocks.

The impacts of biologic treatment on metabolic profiling in psoriasis.

Psoriasis is an immune-mediated inflammatory disease commonly accompanied by various metabolic disorders. It is widely known that biologics could affect the metabolic status and comorbidities in psoriasis patients, however, the effects of biologics on metabolism in psoriasis patients remain poorly understood. The aim of this study was to elucidate the characteristic changes of metabolic profiling in psoriasis vulgaris (PsV) patients before and after applying biologics. Plasma samples were collected from a retrospective cohort of 43 PsV patients. Non-targeted metabolomics analyses were performed using liquid chromatography-mass spectrometry (LC-MS) to compare the metabolic profiles before and after applying adalimumab (ADA) or ixekizumab (IXE) for 4 weeks. Additionally, correlation analyses were conducted to investigate the associations between metabolite expression levels and clinical characteristics. The biologics significantly affected the metabolic profiles of PsV patients especially in glycerophospholipids (GPs). First, phosphatidylcholine (PC), unsaturated lysophosphatidylcholine (LPC), unsaturated lysophosphatidic acid (LPA) and unsaturated lysophosphatidylethanolamine (LPE) were significantly up-regulated, whereas phosphatidylethanolamine (PE), saturated LPC, saturated LPA and saturated LPE were predominantly down-regulated after biologic treatment. What is more, the changes in PE and LPA were mainly observed after applying IXE instead of ADA. Second, we also found GPs including PC, unsaturated LPC, unsaturated LPA and unsaturated LPE were primarily negatively correlated with disease severity, whereas, PE, saturated LPC, saturated LPA and saturated LPE displayed inverse correlations. Biologics could affect GP metabolism and facilitate the transition of metabolic status from a pro-inflammatory to an anti-inflammatory phenotype in PsV patients.

Lack of awareness and ethnic polarity is a major cause of metabolic associated fatty liver disease in high-risk diabetes population in South London.

Metabolic associated fatty liver disease (MAFLD) stands as the leading cause of chronic liver disease globally. Notably, individuals with metabolic risk factors, such as diabetes and obesity, exhibit a staggering prevalence of MAFLD, with estimates reaching up to 70%. However, despite its widespread occurrence, there's a noticeable gap in understanding and awareness about MAFLD among these high-risk groups. The main objective of this study was to assess the awareness and prevalence of MAFLD among diabetic patients who regularly receive secondary care focusing particularly on how multiethnic backgrounds and associated lifestyle preferences influence these health outcomes. Cross-sectional study. Patients with type 2 diabetes (T2D) who regularly attend Lambeth Diabetes Intermediate Care Team clinics were invited to undergo MAFLD screening using FibroScan. Those who agreed to participate were provided with structured questionnaires on diet, physical activity, and MAFLD knowledge by a hepatologist. For each participant, anthropometric data, medical history, liver stiffness measurement, and controlled attenuation parameter (CAP) were documented. Steatosis was identified with a CAP value of ⩾275 dB/m, and advanced fibrosis was flagged at values of ⩾8 kPa. The FibroScan data was valid in 96.4% (215), 53.5% (115/215) had steatosis and 26.2% (58/215) had liver fibrosis in this multiethnic high-risk group. Awareness of MAFLD was notably low at 30.9%. Alarmingly, 69% of patients diagnosed with liver fibrosis were unfamiliar with the condition. Additionally, understanding of MAFLD showed variation among different ethnic groups with highest levels were demonstrated in the Caucasian/White population (46%). Majority (96%) of these subjects were receiving specific lifestyle advice from healthcare professionals due to metabolic conditions and comorbidities. However, most patients preferred diets that were rich in carbohydrates (65.8%) and only 43% subjects performed moderate exercise daily highlighting lack of understanding regarding MAFLD and lifestyle management. There's a pressing need for increased awareness of MAFLD, especially in multiethnic high-risk groups. Additionally, the development of cost-effective strategies to stratify risk is essential to address this growing health concern.

Management of non-alcoholic fatty liver disease-associated hepatocellular carcinoma.

In recent years, with the decline in HBV and HCV infections, there has been a corresponding reduction in both the morbidity and mortality of virus-associated HCC. Nevertheless, rising living standards, coupled with the increasing prevalence of metabolic disorders like diabetes and obesity, have led to a rapid surge in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) incidence. The mechanisms underlying the progression from NAFLD to NAFLD-HCC are multifaceted and remain incompletely understood. Current research suggests that genetic predisposition, metabolic dysregulation, lipotoxicity, oxidative stress, and inflammation are key contributing factors. Given the complexity of these mechanisms and the frequent occurrence of metabolic comorbidities like type 2 diabetes mellitus (T2DM) and cardiovascular disease in NAFLD-HCC patients, there is a pressing need for tailored therapeutic strategies, along with novel prevention, monitoring, and treatment approaches that are personalized to the patient's pathophysiology. Due to the limited depth of research, incomplete understanding of pathogenesis, and insufficient clinical data on NAFLD-HCC treatment, current therapeutic approaches largely rely on tumor staging. In this review, we synthesize current research on the pathogenesis, surveillance, diagnosis, treatment, and prevention of NAFLD-HCC, and offer perspectives for future studies, particularly regarding its underlying mechanisms.

Bariatric Surgery in Obesity: Metabolic Quality Analysis and Comparison of Surgical Options.

Obesity is a constantly growing health problem which reduces quality of life and life expectancy. Bariatric surgery (BS) for obesity is considered when all other conservative treatment modalities have failed. Comparison of the multidisciplinary programs with BS regarding to the weight loss showed that substantial and durable weight reduction have been achieved only with bariatric surgical treatments. Although laparoscopic sleeve gastrectomy is the most popular BS, it has high long-term failure rates, and it is claimed that one of every three patients will undergo another bariatric procedure within a 10-year period. Although BS provides weight loss and improvement of metabolic comorbidities, in long-term follow-up, weight gain is observed in half of the patients, while decrease in bone mass and nutritional deficiencies occur in up to 90%. Moreover, despite significant weight loss, several psychological aspects of patients are worsened in comparison to preoperative levels. Nearly one-fifth of postoperative patients with "Loss-of-eating control" meet food addiction criteria. Therefore, the benefits of weight loss following bariatric procedures alone are still debated in terms of the proinflammatory and metabolic profile of obesity.

A review of dolutegravir-associated weight gain and secondary metabolic comorbidities.

Dolutegravir is an integrase inhibitor and is recommended by the World Health Organization as the preferred first-line and second-line human immunodeficiency virus treatment in all populations. Excessive weight gain associated with dolutegravir-based regimens is an emerging issue; however, the long-term metabolic consequences of this effect have not been fully understood. Growing evidence shows that this leads to a higher incidence of hyperglycemia, hypertension, and metabolic syndrome, along with elevated cardiovascular risk. Dolutegravir-based regimens, also associated with greater adipocyte differentiation and greater expression of markers associated with lipid storage, continue to be a problem among patients living with human immunodeficiency virus. The mechanisms by which certain antiretroviral therapy agents differentially contribute to weight gain remain unknown. Some clinical investigators speculate that dolutegravir could interfere with central nervous system appetite regulation (melanocortin-4 receptor) and insulin signaling, or may have better penetration of adipose tissue where they could exert a direct impact on adipose tissue adipogenesis, fibrosis, and insulin resistance. This review summarizes our current understanding of weight gain and fat changes associated with dolutegravir and its possible secondary metabolic comorbidities.

Adverse socio-economic conditions associated with the presence of obesity and its metabolic comorbidities in adults in San Luis, Argentina

The prevalence of obesity depends on biopsychosocial and environmental factors and represents a risk factor for communicable and non-communicable diseases. Objectives: To determine the association between demographic, socioeconomic and lifestyle characteristics and the presence of obesity and its metabolic comorbidities (MC) in adults in San Luis City, Argentina. Observational population-based cross-sectional study of 306 individuals aged 18-85 years from San Luis, Argentina, selected by multistage random sampling, with an overweight prevalence of 35% and a 0.05 margin of error. Socioeconomic, demographic, and lifestyle variables were assessed, and multiple logistic regression models were fitted with the presence of obesity and MC as outcomes and sociodemographic and lifestyle characteristics as covariates. Obesity was found in 17.3% of participants, diabetes in 3%, high blood pressure (HBP) in 11%, dyslipidemia in 3.3% and coronary ischemic complications (CIC) in 13%. The proportion of residents with at least one of these conditions was 26.8%. Low Educational level (EL) was positively associated with the presence of obesity (OR 3.58; IC95% 1.04-12.24; p=0,04), and its MC (OR 5.25; IC95% 1.05-26.23; p=0.04) with respect to high EL. Similarly, the possibility of presenting CIC was increased in people with medium EL (OR 5.8; IC95% 1.12-30.19; p=0.03). On the other hand, the possibility of presenting diabetes increased by 17% with increasing body mass index (BMI) (OR 1.17; IC95% 1.03-1.34; p=0.01). Finally, women were more likely to present HBP (OR 3.71; IC95% 1.01-13.72; p=0.04) and CIC (OR 3,43; IC95% 1,06-11,10; p=0,03). Conclusion: the increase in age, female sex and medium and low NI are factors and conditions of vulnerability that predispose an increase in the prevalence of MC in adults from San Luis, Argentina.

Sweetener Food Additives: A Synoptical Overview on Their Chemical Properties, Applications in Food Products and Side Effects

The increase of obesity and its metabolic comorbidities have led to a growing consumption of sugar-free products, where sucrose is replaced by low-calorie sweeteners. Since the discovery of the synthesis of saccharin, progressively more non-nutritive sweeteners have been produced and consumed, as they release none or only very small amounts of energy. In this context, traditional synthetic food sweeteners are largely used, because they have a higher sweetener power than most of the sweeteners of natural origin. Yet, due to their potential risks, some of them are being replaced by those obtained from natural origins with high sweetening power, such as thaumatins and neohesperidin DC, or by synthetic sweeteners with an even greater sweetener power, with advantame as the one with the highest sweetening power. Yet, numerous side effects of synthetic sweeteners have been reported (namely, stomach and liver problems, allergic reactions, nausea, vomiting, changes in behaviour, cognitive problems, genotoxicity and carcinogenic effects), whereas those naturally derived seem to have less important health problems associated. Moreover, some sweeteners of natural origin, such as polyols, have a low sweetening power, which makes them less effective, but have other functions in food processing. To further understand the implications of using synthetic and natural-derived food sweeteners, this review aims to provide a synoptical approach on chemical characteristics, properties, uses and side effects of those which are currently allowed and applied during food processing mostly considering the authorized sweeteners in European Union.
 Keywords: Side effects of sweeteners; Sweetener food additives; Sweeteners of natural origin; Sweeteners of synthetic origin; Sweeteners applications

Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions.

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.

Patients' perspective on the medical pathway from first symptoms to diagnosis in genetic lipodystrophy.

Underdiagnosis is an important issue in genetic lipodystrophies, which are rare diseases with metabolic, cardiovascular, gynecological, and psychological complications. We aimed to characterize the diagnostic pathway in these diseases from the patients' perspective. Cross-sectional study conducted through a self-reported patient questionnaire. Patients with genetic lipodystrophy were recruited throughout the French national reference network for rare diseases of insulin secretion and insulin sensitivity. Patients completed a self-reported questionnaire on disease symptoms, steps leading to the diagnosis, and healthcare professionals involved. Descriptive analyses were conducted. Out of 175 eligible patients, 109 patients (84% women) were included; 93 had partial familial lipodystrophy and 16 congenital generalized lipodystrophy. Metabolic comorbidities (diabetes 68%, hypertriglyceridemia 66%, hepatic steatosis 57%), cardiovascular (hypertension 54%), and gynecologic complications (irregular menstruation 60%) were frequently reported. Median age at diagnosis was 30 years (interquartile range [IQR] 23-47). The overall diagnostic process was perceived as "very difficult" for many patients. It extended over 12 years (IQR 5-25) with more than five different physicians consulted by 36% of respondents, before diagnosis, for lipodystrophy-related symptoms. The endocrinologist made the diagnosis for 77% of the patients. Changes in morphotype were reported as the first symptoms by the majority of respondents. Diagnostic pathway in patients with genetic lipodystrophy is rendered difficult by the multisystemic features of the disease and the lack of knowledge of non-specialized physicians. Training physicians to systematically include adipose tissue examination in routine clinical evaluation should improve diagnosis and management of lipodystrophy and lipodystrophy-associated comorbidities.

From NAFLD to MASLD: When metabolic comorbidity matters

Introduction and ObjectivesIn a recent development, a cohort of hepatologists has proposed altering the nomenclature of non-alcoholic fatty liver disease (NAFLD) to metabolic-associated steatotic liver disease (MASLD), accompanied by modified diagnostic criteria. Our objective was to investigate the effect of the revised definition on identifying significant hepatic fibrosis. Patients and MethodsFrom Jan 2009 to Dec 2022, a total of 428 patients with biopsy-proven hepatic steatosis were diagnosed with NAFLD. Patients were classified into subgroups according to MASLD and Cryptogenic-SLD diagnostic criteria. The clinical pathological features were compared between these two groups. Risk factors for significant fibrosis were analysed in the MASLD group. In total, 329 (76.9 %) patients were diagnosed with MASLD, and 99 (23.1 %) were diagnosed with Cryptogenic-SLD. ResultsThose with MASLD exhibited a higher degree of disease severity regarding histology features than Cryptogenic-SLD. The prevalence of significant fibrosis increased from 13 % to 26.6 % for one and two criteria present to 42.5 % for meeting three or more cardiometabolic risk factor (CMRF) criteria (p = 0.001). ALB (aOR:0.94,95 %CI:0.90-1.00; p = 0.030), lower levels of PLT (aOR:0.99, 95 %CI:0.99-1.00; p < 0.001), and more metabolic comorbidities (aOR:1.42,95 %CI:1.14-1.78; p = 0.012) were independent risk factors of significant fibrosis in MASLD. ConclusionsThe new nomenclature of MASLD and SLD is more applicable to identifying significant fibrosis than NAFLD. Patients with three or more cardiometabolic risk factors are at higher risk of fibrosis.

Is Glycemic Control the Primary Goal in Diabetes Treatment?

The prevalence of Diabetes is steadily increasing, raising public health concerns. Hyperglycemia leads to microvascular and macrovascular diseases through several metabolic and biochemical pathways. Previous clinical trials and observational studies have demonstrated that tight glycemic control can reduce the incidence of diabetic complications, with the greatest benefit shown in younger patients with diabetes of shorter duration and those who have no prior history of cardiovascular disease. Moreover, previous studies highlight the concept of metabolic memory and legacy effect, since controlling diabetes early can have an impact on long-term prognosis of the disease. As to whether it is time to consider shifting the treatment focus for patients with type 2 diabetes from a glucose-centric to a weight-centric or a cardio-centric approach, the dilemma remains theoretical; glucose control, weight loss and effective treatment of metabolic and cardio-vascular co-morbidities are interrelated components of an integrated plan of care that should be addressed simultaneously and effectively.

Endocrine and metabolic comorbidities in primary cicatricial alopecia: A nationwide population-based study.

Primary cicatricial alopecia (PCA) is a rare, scarring, hair loss disorder. Due to its low incidence, little is known about endocrine and metabolic comorbidities in patients with PCA. Thus, we aimed to investigate the association between PCA and endocrine and metabolic disorders. This nationwide, population-based, cross-sectional study included patients diagnosed with PCA or non-cicatricial alopecia (NCA) and normal individuals without history of alopecia registered in the Korean National Health Insurance Service database between January 1, 2011, and December 31, 2020. We calculated the odds ratios of endocrine and metabolic comorbidities of patients with PCA compared to all patients or age- and sex-matched patients with NCA or normal individuals using multivariable logistic regression models. A total of 3 021 483 individuals (mean age [SD], 38.7 [15.0] years, 1 607 380 [53.2%] men), including 11 956 patients with PCA, 601 852 patients with NCA, and 2 407 675 normal participants, were identified. Patients with PCA had an increased risk for dyslipidemia (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.06-1.24), diabetes (aOR 1.38, 95% CI 1.24-1.53), and hypertension (aOR 1.10, 95% CI 1.02-1.19) compared to matched patients with NCA. Regarding PCA subtypes, lichen planopilaris/frontal fibrosing alopecia was positively associated with hypothyroidism (aOR 2.03, 95% CI 1.44-2.86) compared to NCA. Folliculitis decalvans and dissecting cellulitis were positively associated with dyslipidemia (aOR 1.16, 95% CI 1.05-1.28 and aOR 1.16, 95% CI 1.04-1.29, respectively), diabetes (aOR 1.38, 95% CI 1.20-1.58 and aOR 1.52, 95% CI 1.32-1.74, respectively), and hypertension (aOR 1.10, 95% CI 1.00-1.20 and aOR 1.14, 95% CI 1.02-1.27, respectively). Similar trends were observed when each PCA subgroup was compared with the normal control group. This study demonstrates that patients with PCA are more likely to have endocrine and metabolic comorbidities than patients without PCA. Further research on these comorbidities may improve the understanding of PCA.

Racial, ethnic, and biologic sex disparities in outpatient laboratory monitoring of isotretinoin use: a cross-sectional study.

Isotretinoin is commonly used for the treatment of acne. Despite high efficacy, isotretinoin has a side effect profile that prompts regular outpatient laboratory monitoring. Emerging evidence suggests clinically significant lab abnormalities are rare. Racial, ethnic, and biologic sexdisparities in laboratory monitoring of isotretinoin have yet to be characterized. This study explores disparities in laboratory monitoring of patients prescribed isotretinoin, factoring in the COVID-19 pandemic given its impacts on laboratory monitoring. Two populations were evaluated: all patients taking isotretinoin, and patients taking isotretinoin with no metabolic, cardiovascular, hematologic, hepatic, or renal comorbidities. The latter population was included to screen out patients who might receive increased laboratory testing for conditions besides isotretinoin use. Our data reveal that African-American, Asian, and Hispanic patients prescribed isotretinoin were more likely than Caucasian patients to receive orders for outpatient laboratory monitoring. These disparities persisted independent of comorbidities that may prompt additional testing, suggesting that non-Caucasian patients bear an additional testing burden even when their comorbidities were matched to their peers. Disparities persisted in the setting of reduced laboratory monitoring due to the COVID-19 pandemic. These data reveal that patients of color are more likely to receive outpatient laboratory monitoring for isotretinoin prescriptions. There is an opportunity for testing standardization to improve medication access, decrease burden and costs for patients and the healthcare system, and decrease racial disparities in prescribing and monitoring of isotretinoin. Dermatology clinics may benefit from standard operating procedures outlining for whom regular monitoring is needed.

Liver Bacterial Colonization in Patients with Obesity and Gut Dysbiosis.

Recently, the link between gut microbiota, liver inflammation, and obesity has become an interesting focus of research. The aim of this study is to show the possible relation between gut microbiota dysbiosis in patients with obesity and the presence of bacterial genomes in their liver biopsies. A prospective study on patients undergoing bariatric surgery was carried out. Anthropometric and metabolic data, comorbidities, stool samples, and hepatic biopsies were collected and analyzed at the time of surgery. The V3-16S rRNA region was sequenced using the Ion Torrent new-generation sequencing platform. In each of the 23 patients enrolled, the bacterial population was analyzed both in the stools and liver. In eight patients (34.7%), Prevotella (62.5%), Bacteroides (50%), Streptococcus (12.5%), and Dalister (12.5%) were found in both samples, simultaneously; in 15 cases, the liver was free from colonization. The statistically significant difference between groups was a Roseburia intestinalis reduction in fecal samples of patients with liver biopsies colonized by bacteria (1% vs 3%; p = 0.0339). To the best of our knowledge, this is the first study reporting the presence of bacterial genome in a liver biopsy on bariatric patients, instead of the microbe-associated molecular patterns. Notably, in literature, the presence of Roseburia intestinalis in stool samples has been shown to prevent intestinal inflammation playing its role in the gut barrier integrity. In our population, the Roseburia reduction was associated with the presence of bacterial genome in the liver, probably related to a greater permeability of the gut and vascular barriers.

Effect of Roux-en-Y Gastric Bypass on circulating oxylipin profile in women with obesity and type 2 diabetes

Background & Aims: Chronic inflammation associated with obesity directly contributes to metabolic comorbidities, including type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for obesity-associated T2D. We investigated the effect of RYGB on the circulating profile of oxylipins derived from arachidonic (ARA), eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids as a potential mechanism underlying the metabolic benefits of the surgery. Methods: Plasma samples were collected from 28 women with obesity and T2D before and 3 months after RYGB. Circulating levels of oxylipins and their precursors, along with biochemical markers of glucose homeostasis, were evaluated using untargeted mass spectrometry and routine biochemical techniques, respectively. Results: No significant changes were observed in the levels of oxylipins derived from EPA and DHA. However, there was an increase in ARA and its derived oxylipins, TXB2 (an inert derivative of TXA2) and PGD2 (Wilcoxon, p ≤ 0.05). Positive correlations were observed between hemoglobin A1c levels and TXB2 as well as ARA levels (Spearman, p ≤ 0.05). Conclusions: Our data suggest that the anti-inflammatory oxylipins derived from EPA and DHA may not be involved in the metabolic benefits associated with RYGB. However, the findings indicate that the pro-inflammatory oxylipin TXA2 and its precursor ARA may negatively impact glucose homeostasis both before and after RYGB.

Sleeve gastrectomy for the treatment of adolescent obesity in children aged 13 and under: a retrospective study

BackgroundSleeve gastrectomy (SG) induces weight reduction and improves metabolic co-morbidities in children with severe obesity but remains underutilized, especially for young adolescents and preadolescents. ObjectiveWe hypothesized there would be no differences in weight loss or co-morbidity resolution at 1 year post-SG in children who underwent SG at 13 years or younger compared to children who underwent SG at 17–18 years old. SettingAcademic medical center, United States. MethodsMedical records of children who underwent laparoscopic SG at a quaternary academic center from September 2014 to October 2022 were reviewed. A cohort of 15 patients, ≤13 years of age, was compared to a matched cohort of 15 older adolescent patients. Preoperative characteristics and postoperative outcomes were collected. ResultsBoth cohorts had similar baseline characteristics. Median preoperative body mass index (BMI) was 51.8 kg/m2 for the ≤13 cohort compared to 50.9 kg/m2 in the older cohort (P = .87). Time to postoperative enteral feeds and length of stay were similar between both groups, and there were no 30-day readmissions or immediate postoperative complications. Median percentage excess BMI loss at 1 year postoperation was 54% (IQR, 25.5%–94.5%) for the ≤13 cohort compared with 44% (IQR, 34.0%–51.0%) for the older cohort (P = .34). Two of 11 patients were lost to follow-up in the younger group compared to 4 of 15 in the older group (P = .61). Both groups demonstrated significant improvement in metabolic syndrome co-morbidities after SG. ConclusionSG in younger children is associated with successful postsurgical outcomes compared with adolescents, with effective weight loss and improvement of obesity-related metabolic co-morbidities.

Metabolically ‘extremely unhealthy’ obese and non-obese patients with diabetes and the risk of cardiovascular events: a French nationwide cohort study

BackgroundNon-obese patients with diabetes mellitus (DM) are becoming more prevalent, but their cardiovascular risk (CV) especially when accompanied with cardio-renal-metabolic co-morbidities (hypertension, chronic kidney disease, hyperlipidemia) is not well characterised. The aim of the study was to assess the CV risk among patients with DM in relation to obesity and cardio-renal-metabolic co-morbidities.Materials and methodsThis was a cohort study of all patients with DM without a history of major adverse cardiovascular event who were hospitalized for any reason in France in 2013 with at least 5 years of follow-up. They were categorized by the presence of obesity vs no obesity, as well as three cardio–renal–metabolic co-morbidities: hypertension, chronic kidney disease, hyperlipidemia. ‘Extremely unhealthy’ patients with DM were defined as those having all 3 co-morbidities.ResultsThere were 196,112 patients (mean age 65.7 (SD 13.7) years; 54.3% males) included into the analysis. During a mean follow-up of 4.69 ± 1.79 years, when adjusted for multiple covariates, the non-obese and ‘extremely unhealthy’ obese patients had the highest risk of CV death [aHR 1.40 (95% CI, 1.22–1.61) and 1.48 (95% CI, 1.25–1.75), respectively]. The ‘extremely unhealthy’ obese had the highest risk of MACE-HF [aHR 1.84 (95% CI, 1.72–1.97)] and new-onset AF [aHR 1.64 (95% CI, 1.47–1.83)].ConclusionBoth non-obese and obese patients with DM with associated cardio-renal-metabolic co-morbidities are an ‘extremely unhealthy’ phenotype with the highest risk of CV death and CV events.Graphical abstract

Differential Mortality Outcomes in Real-world Patients with Lean, Nonobese, and Obese Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is commonly associated with obesity but can develop in normal-weight people (lean NAFLD). We compared outcomes in lean, overweight, and obese NAFLD. This retrospective chart review included patients at Stanford University Medical Center with NAFLD confirmed by imaging between March 1995 and December 2021. Lean, overweight, and obese patients had body mass index of <25.0, >25.0 and <29.9, and ≥30.0 kg/m2 for non-Asian and >23.0 and ≥27.5 for overweight and obese Asian patients. A total of 9061 lean (10.2%), overweight (31.7%), and obese (58.1%) patients were included. Lean patients were 5 years older than obese patients (53±17.4 vs. 48.7±15.1 years), more were female (59.6% vs. 55.2%), white (49.1% vs. 46.5%), had NASH (29.2% vs. 22.5%), cirrhosis (25.3% vs.19.2%), or nonliver cancer (25.3% vs. 18.3%). Fewer had diabetes (21.7% vs. 35.8%) or metabolic comorbidities (all p<0.0001). Lean NAFLD patients had liver-related mortality similar to other groups but higher overall (p=0.01) and nonliver-related (p=0.02) mortality. After multivariable model adjustment for covariates, differences between lean and obese NAFLD in liver-related, nonliver-related, and overall mortality (adjusted hazard ratios of 1.34, 1.00, and 1.32; p=0.66, 0.99, and 0.20, respectively) were not significant. Lean NAFLD had fewer metabolic comorbidities but similar adverse or worse outcomes, suggesting that it is not benign. Healthcare providers should provide the same level of care and intervention as for overweight and obese NAFLD.