Lower Metabolic Risk Research Articles

Investigating a New Way to Assess Metabolic Risk in Pregnant Females with Prior RYGB Surgery.

Obesity in pregnancy is linked to adverse clinical outcomes such as gestational diabetes. Recently, a risk score calculated by different ceramide concentrations was recognized as a new way to investigate cardiovascular risk. The aim was to analyze if the ceramide risk score and cardiometabolic risk vary between normal-weight, obese, and females with prior Roux-en-Y bypass surgery (RYGB) during pregnancy. Three cohorts were investigated: first, 25 pregnant females with a history of RYGB; second, 19 with preconception BMI ≥ 35 kg/m2; and third, 19 normal-weight (preconception BMI < 25 kg/m2). Around the 24th to 28th weeks of gestation routine laboratory assessments, 3 h 75 g oral and intravenous glucose tolerance tests were carried out. The correlation of ceramide risk scores and ceramide ratios (Cer(d18:1/18:0)/Cer(d18:1/16:0)) with metabolic parameters was analyzed via Pearson correlation. The cohorts were compared via ANOVA and unpaired t-tests. The RYGB cohort had lower ceramide risk scores and ratios compared to obese pregnant females (7.42 vs. 9.34, p = 0.025; 0.33 vs. 0.47, p < 0.001). Ceramide risk score and ratio were found to correlate negatively with insulin sensitivity (measured with the Matsuda (r = -0.376, p = 0.031; r = -0.455, p = 0.008) and calculated sensitivity index (r = -0.358, p = 0.044; r = -0.621, p < 0.001) in females without RYGB. The ceramide risk score correlated positively with body fat in RYGB females (r = 0.650, p = 0.012). We found that females after RYGB have lower ceramide risk scores and ceramide ratios compared to obese pregnant females, possibly indicating lower metabolic risk.

Obesity and its association with self-efficacy and metabolic risk factors by region of birth among 40-year-olds participating in the Swedish targeted health dialogues

ObjectiveTargeted Health Dialogues (THD) is a public health intervention program that aims at preventing cardiovascular disease. THDs were implemented in the Swedish region Scania, in 2020, with the novelty of being conducted in a metropolitan area with a multiethnic population.This study investigated the prevalence of obesity among 40-year-old THD participants in Scania by region of birth, and its associations with self-efficacy and additional metabolic risk factors. MethodsCross-sectional data were retrieved from measurements in the THDs. Study participants included 1831 40-year-olds. Differences in characteristics by region of birth were assessed using chi-squared and ANOVA tests. The associations between overweight, obesity, and high waist-hip ratio (WHR) and self-efficacy and metabolic risk factors (blood pressure, LDL cholesterol, plasma glucose) were assessed using binominal and ordinal logistic regression, adjusted for sex and education and tested for interactions by region of birth. Results35.1 % of the participants were overweight (BMI 25–29.9), and 18.7 % were obese (BMI ≥30) with the highest levels among participants born outside Sweden (p = 0.005). Abdominal obesity was also more prevalent among participants born outside Sweden (p = 0.002). Obesity was associated with increased odds of having low self-efficacy (OR per BMI-level: 1.48 (CI 1.24–1.76) and additional metabolic risk factors. No interactions with region of birth were detected. ConclusionsThe prevalence of obesity differed between region of birth and obesity was associated with having low self-efficacy. These findings underline the need to customise lifestyle interventions in a multiethnic population to increase health equity.

Addressing olanzapine-induced diabetic ketoacidosis in a major depressive disorder case

This case study highlights a critical incidence of olanzapine-induced diabetic ketoacidosis (DKA) in a 36-year-old female patient treated for major depressive disorder with psychotic features. The patient developed severe DKA after the initiation of olanzapine, despite initially normal metabolic parameters and a low starting dose. This report underscores the acute metabolic derangement facilitated by olanza- pine, necessitating a comprehensive and urgent medical approach. The clinical intervention involved discontinuing olanzapine and initiating a multidisciplinary treatment strategy, which included medical management of DKA and psychiatric adjustments using alternatives with a lower metabolic risk. This case emphasizes the necessity for regular metabolic monitoring and the potential need for tailored psychiatric medication strategies to prevent severe side effects, highlighting the unpredictability of antipsychotic- induced metabolic disturbances and advocating for a holistic, patient-centered approach in psychiatric care.

Differential Associations of Erythrocyte Membrane Saturated Fatty Acids with Glycemic and Lipid Metabolic Markers in a Chinese Population: A Cross-Sectional Study.

Mounting evidence indicates a complex link between circulating saturated fatty acids (SFAs) and cardiovascular disease (CVD) risk factors, but research on erythrocyte membrane SFA associations with metabolic markers remains limited. Our study sought to investigate the correlations between erythrocyte membrane SFAs and key metabolic markers within glycemic and lipid metabolism in a Chinese population of 798 residents aged 41 to 71 from Guangzhou. Using gas chromatography-mass spectrometry, we assessed the erythrocyte membrane saturated fatty acid profile and performed multiple linear regression to evaluate the relationship between different SFA subtypes and metabolic markers. Our findings revealed that the odd-chain SFA group (C15:0 + C17:0) exhibited negative associations with fasting blood glucose (FBG), homeostatic model assessment for insulin resistance (HOMA-IR), and triglycerides (TG). Conversely, the very-long-chain SFA group (C20:0 + C22:0 + C23:0 + C24:0) exhibited positive associations with fasting insulins (FINS), HOMA-IR, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Furthermore, there was no evidence supporting an association between the even-chain group (C14:0 + C16:0 + C18:0) and metabolic markers. Our findings suggest that different subtypes of SFAs have diverse effects on glycemic and lipid metabolic markers, with odd-chain SFAs associated with a lower metabolic risk. However, the results concerning the correlations between even-chain SFAs and very-long-chain SFAs with markers of glycemic and lipid metabolism pathways are confusing, highlighting the necessity for further exploration and investigation.

Drugs and chemical substances inducing diabetes - review of the literature

A Type 3 of diabetes, classified as secondary diabetes, includes drug-induced or chemical-induced forms of diabetes. We distinguish many types of drugs that can indicate diabetes, among others commonly used glucocorticosteroids, β-blockers and diuretics, antidepressants and antipsychotics, statins, antiviral drugs. We aimed to evaluate the impact of chosen drugs and chemical substances on glycemic control, to analyse the mechanisms of development of drug-induced diabetes and to propose the therapeutic procedures. We conducted the literature review from the last 10 years using the Pubmed and Google Scholar. We analysed reviews, systematic reviews, meta-analysis, randomized controlled trials, clinical trials, observational studies published from 2013 to 2023. Mechanisms of diabetes development are various and complex. However, we need to underline the role of drug-induced weight gain. The duration of therapy is also important because longer therapy is usually associated with higher risk of development of diabetes. Drug-induced diabetes is a significant clinical problem. The benefits of using the drug often outweigh the side effects associated with poor glycemic control. Currently, pharmacotherapy of drug-induced diabetes is similar to the standards of treatment for other types of diabetes. Changing therapy to the drug with lower metabolic risk should be considered as far as possible.

Olanzapine, risperidone and ziprasidone differently affect lysosomal function and autophagy, reflecting their different metabolic risk in patients

The metabolic effects induced by antipsychotics in vitro depend on their action on the trafficking and biosynthesis of sterols and lipids. Previous research showed that antipsychotics with different adverse effects in patients cause similar alterations in vitro, suggesting the low clinical usefulness of cellular studies. Moreover, the inhibition of peripheral AMPK was suggested as potential aetiopathogenic mechanisms of olanzapine, and different effects on autophagy were reported for several antipsychotics. We thus assessed, in clinically-relevant culture conditions, the aetiopathogenic mechanisms of olanzapine, risperidone and ziprasidone, antipsychotics with respectively high, medium, low metabolic risk in patients, finding relevant differences among them. We highlighted that: olanzapine impairs lysosomal function affecting autophagy and autophagosome clearance, and increasing intracellular lipids and sterols; ziprasidone activates AMPK increasing the autophagic flux and reducing intracellular lipids; risperidone increases lipid accumulation, while it does not affect lysosomal function. These in vitro differences align with their different impact on patients. We also provided evidence that metformin add-on improved autophagy in olanzapine-treated cells and reduced lipid accumulation induced by both risperidone and olanzapine in an AMPK-dependent way; metformin also increased the production of bile acids to eliminate cholesterol accumulations caused by olanzapine. These results have different clinical implications. We demonstrated that antipsychotics with different metabolic impacts on patients actually have different mechanisms of action, thus supporting the possibility of a personalised antipsychotic treatment. Moreover, we found that metformin can fully revert the phenotype caused by risperidone but not the one caused by olanzapine, that still activates SREBP2.

Correlates of axonal content in healthy adult span: Age, sex, myelin, and metabolic health

As the emerging treatments that target grey matter pathology in Alzheimer's Disease have limited effectiveness, there is a critical need to identify new neural targets for treatments. White matter's (WM) metabolic vulnerability makes it a promising candidate for new interventions. This study examined the age and sex differences in estimates of axonal content, as well the associations of with highly prevalent modifiable health risk factors such as metabolic syndrome and adiposity. We estimated intra-axonal volume fraction (ICVF) using the Neurite Orientation Dispersion and Density Imaging (NODDI) in a sample of 89 cognitively and neurologically healthy adults (20–79 years). We showed that ICVF correlated positively with age and estimates of myelin content. The ICVF was also lower in women than men, across all ages, which difference was accounted for by intracranial volume. Finally, we found no association of metabolic risk or adiposity scores with the current estimates of ICVF. In addition, the previously observed adiposity-myelin associations (Burzynska et al., 2023) were independent of ICVF. Although our findings confirm the vulnerability of axons to aging, they suggest that metabolic dysfunction may selectively affect myelin content, at least in cognitively and neurologically healthy adults with low metabolic risk, and when using the specific MRI techniques. Future studies need to revisit our findings using larger samples and different MRI approaches, and identify modifiable factors that accelerate axonal deterioration as well as mechanisms linking peripheral metabolism with the health of myelin.

731-P: The Effect of Abatacept upon Glucose and C-Peptide Endpoints at One Year of Treatment and on Follow-up

The TrialNet abatacept randomized-controlled trial tested for the ability to delay the progression of T1D in Stage 1 [multiple autoantibody (Ab) positive and normal glucose on OGTT] individuals aged 6-45. No drug effect was detected on the primary endpoint of either dysglycemia or T1D (whichever came first). Based on evidence that C-peptide-based metabolic measures are more specific for T1D and detect an early impact of disease-modifying therapy, we performed post-hoc analyses using these variables and stratified on baseline metabolic profiles. In participants with lower baseline metabolic risk (Index60 &amp;lt;0.00) we assessed if changes in metabolic measures would differ between treatment groups. A favorable effect was evident for the combined glucose and C-peptide endpoints within 1 year of treatment (Table). Next we compared individuals with Index60&amp;lt;0.00 at baseline for exceeding an Index60 threshold of 1.00 on follow-up. 5-year risks were 38.9% for the placebo and 21.1% for the abatacept groups (p=0.016). In summary, for Stage 1 individuals with low baseline metabolic risk, combined glucose and C-peptide endpoints can detect a favorable abatacept effect at 1 year and, more conventionally, a decreased T1D progression risk on follow-up. Future trials of abatacept or other agents in Stage 1 T1D should include combined glucose and C-peptide measures as pre-specified endpoints. Disclosure E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. W.E.Russell: None. K.C.Herold: Board Member; NexImmune, Consultant; Provention Bio, Inc. J.Sosenko: None.

The impact of avocado intake on anthropometric measures among Hispanic/Latino children and adolescents: A cluster randomized controlled trial

While the association between avocado consumption and low metabolic risk has been shown in some studies conducted in adults, little is known about the potential effects of avocado consumption on health outcomes in children and adolescents. Thus, we investigated the impact of two levels of avocado allotment, plus a standard nutrition education, on measures of adiposity in children and adolescents (<18 years old). Children (aged 5-12, n=58) and adolescents (aged 13-17, n=32) in seventy-two families that self-identified as Hispanic, with at least 3 members over the age of 5 that resided in the same home, were free of severe chronic disease, and not on specific diets, were randomized to one of two levels of avocado allotment plus bi-weekly nutrition education sessions. Low allotment families received 3 avocados per week, while high allotment families received 14 avocados per week for 6 months. We performed an intention-to-treat analysis, using unpaired, 2-sided t-tests to test the mean changes in anthropometric measures of adiposity (body mass index (BMI), waist circumference, hip circumference, and weight) between children and adolescents from high and low allotment families after the 6-month intervention. At six months, there were no significant differences in body mass index, waist circumference, hip circumference, or waist circumference to weight ratio by avocado allotment group. In children, there was a significant difference in weight (difference in means: 1.10, 95% CI: 0.09, 2.10, p-value=0.03) and waist circumference to height ratio (difference in means: 0.27, 95% CI: 0.12, 0.41, p-value <0.01) between the avocado allotment groups at six months, but these did not remain significant after sensitivity analyses including per-protocol analyses. In adolescents only, there was a significant reduction in waist to hip circumference ratio in the high allotment group compared to the low allotment group after 6 months (difference in means:-0.05, 95% CI:-0.08, 0.00, p-value=0.04) that persisted after multiple sensitivity analyses. Different levels of avocado availability among children and adolescents does not appear to result in significant changes in anthropometric measures. Further study is needed to determine whether avocado consumption promotes metabolic health in this age group.

ANTECEDENTS, OUTCOMES, AND CORRELATES OF METABOLIC HEALTH IN OLDER AGE: A MULTIDISCIPLINARY PERSPECTIVE

Abstract Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease associated with reduced physical fitness, higher disease burden, and impaired cognitive functions in late life. Thus investigating antecedents, outcomes and correlates of metabolic health is a priority in order to promote healthier lifestyles and successful aging. This symposium compiles four empirical interdisciplinary studies that examine the role of metabolic health/risk on different timescales. Employing advanced modeling approaches to data obtained in large-scale studies, these reports will shed light on potential antecedents, correlates, and consequences thereof. First, Kalyani and colleagues will report data from the SPRING (Study of Physical Resilience IN Geriatrics) study on the interrelation between metabolic syndrome, glucose intolerance, and physical resilience.Second, Buchmann and colleagues examine the association of the metabolic syndrome and Lipoprotein(a) finding that hormonal aspects and in particular menopausal alterations seem to moderate theassociation between MetS and Lp(a). Third, Demuth and colleagues show how metabolic health is related to specific DNA methylation age acceleration as derived from five different epigenetic clocks, namely PhenoAge, and GrimAge.Fourth, Duezel and colleagues examine the neural correlates of metabolic risk in a sample of older adults finding that lower metabolic risk is linked to greater GMI in the prefrontal cortex. Conjointly, findings demonstrate the multifaceted nature of metabolic risk across adulthood and across different timescales. Walston will critically discuss the contributions from an aging perspective and discuss implications for future research.

A random forest-based metabolic risk model to assess the prognosis and metabolism-related drug targets in ovarian cancer

As one of the most common gynecologic malignant tumors, ovarian cancer is usually diagnosed at an advanced and incurable stage because of its early asymptomatic onset. Increasing research into tumor biology has demonstrated that abnormal cellular metabolism precedes tumorigenesis, therefore it has become an area of active research in academia. Cellular metabolism is of great significance in cancer diagnostic and prognostic studies. In this study, we integrated The Cancer Genome Atlas dataset with multiple Gene Expression Omnibus ovarian cancer datasets, identified 17 metabolic pathways with prognostic values using the random forest algorithm, constructed a metabolic risk scoring model based on metabolic pathway enrichment scores, and classified patients with ovarian cancer into two subtypes. Then, we systematically investigated the differences between different subtypes in terms of prognosis, differential gene expression, immune signature enrichment, Hallmark signature enrichment, and somatic mutations. As well, we successfully predicted differences in sensitivity to immunotherapy and chemotherapy drugs in patients with different metabolic risk subtypes. Moreover, we identified 5 drug targets associated with high metabolic risk and low metabolic risk ovarian cancer phenotypes through the weighted correlation network analysis and investigated their roles in the genesis of ovarian cancer. Finally, we developed an XGBoost classifier for predicting metabolic risk types in patients with ovarian cancer, producing a good predictive effect. In light of the above study, the research findings will provide valuable information for prognostic prediction and personalized medical treatment of patients with ovarian cancer.

Prevalence of hyperglycemia in masters athletes.

BackgroundAgeing is associated with decreased physical activity, obesity and subsequently an increased risk of developing type 2 diabetes mellitus (T2dm). Master athletes (MA) have initiated exercise or sport later in life or pursued a physically active lifestyle for an extended period. Subsequently, MAs have been proposed as a model of successful ageing as this active lifestyle is associated with health benefits including decreased health risk of chronic diseases and a reduction in premature mortality. Given long-term physical activity/exercise has previously been shown to be protective against hyperglycemia, a risk factor for T2dm, it is plausible that MA may have protective benefit against developing hyperglycemia. Therefore, the aim of this study was to investigate the prevalence of hyperglycemia via fasting plasma glucose (FPG) in MAs competing at the World Masters Games (WMG).MethodsThis cross-sectional, observational survey utilized an online survey using open-source web-based software was used to investigate MAs physiological and medical-related parameters. Over 28,000 MAs competed in the WMG, of which 8,072 MAs completed the survey. Of these MAs, a total of 486 (males 277, females 209; range 27 to 91 years, mean age 55.1 ± 10.2 years) attained recent pathology results which included FPG which was subsequently analyzed for this study. FPG and other outcome variables were compared between genders and to the Australian and United States general population.ResultsMean FPG for MAs was 5.03 mmol (±1.2, 95% CI [4.9–5.1] mmol) with majority (75.5%) of MAs reporting a normal (<5.5 mmol) FPG, followed by pre-diabetes (20.2%, >5.51 to <5.99 mmol) and abnormal (4.3%, >7.0 mmol). There was no significant difference (P = 0.333) in FPG between genders however, males had a slightly higher (+2.1%) FPG as compared to females (5.08 ± 1.2 mmol (95% CI [4.9–5.22] mmol) versus 4.98 ± 1.1 mmol (95% CI 4.8-5.1 mmol)). The majority of males (71.8%) and females (80.3%) were classified with a normal FPG. With regard to an abnormal FPG level, only 4.0% of males and 4.9% of females were classified abnormal which was suggestive of undiagnosed T2dm. With regard to age by decade, there was no significant difference (P = 0.06–1.00) between age groups and no relationship between the MAs’ age and FPG (r = .054, P = 0.24). As a group, MAs had a significantly lower FPG as compared to the Australian (−3.2%, P = 0.005) and United States general populations (−13.9%, P < 0.001).ConclusionsMost, however not all, MAs were found to have normal glycaemia, with only a small percentage indicating a risk of developing T2dm (i.e., impaired fasting glucose) and a smaller percentage identified with an abnormal FPG, suggestive of T2dm. These findings suggest MAs appear to be at low metabolic risk for developing T2dm based upon FPG and the physical activity/exercise they complete as MAs may indeed be protective against hyperglycemia whilst maintaining an active lifestyle.

Dose-response association between long-term weight loss in young adults and later-life metabolic health.

Long-term weight loss (LTWL) has been shown to be associated with lower metabolic risk in young adults with overweight/obesity. However, the dose-response association is uncertain. In a large-scale nationwide screening project in China, the participants aged 35 to 64 years who recalled overweight/obesity at age 25 years and experienced LTWL or maintained stable weight were included. The dose-response association between LTWL from age 25 to screening (35 to 64 years) and the odds of metabolic syndrome at screening were assessed using multivariable adjusted regression models with restricted cubic splines. A total of 40,150 participants (66.4% women) were included. The increment of LTWL was associated with continuously decreased odds of metabolic syndrome. The odds of metabolic syndrome were 0.64 (0.60 to 0.67), 0.42 (0.40 to 0.45), 0.27 (0.25 to 0.29), and 0.15 (0.13 to 0.17) for those with LTWL of 5% to 9.9%, 10% to 14.9%, 15% to 19.9%, and 20% or greater compared with <5% LTWL, respectively. Moreover, the incremental pattern was observed across all population subgroups. An incremental association between LTWL from young adulthood and odds of later-life metabolic syndrome was observed. Our findings highlight the effective ways to achieve LTWL to improve lifetime metabolic health for young adults with overweight/obesity.

Relationships between adiposity distribution and metabolic health in preconception women in South Africa.

ObjectiveAdipose tissue is a central regulator of metabolic health and a contributor to systemic inflammation. Patterns of adiposity deposition are important to understand for optimizing health. This study aimed to asses relationships between adiposity deposition and metabolic and inflammatory biomarkers in South African women prior to conception.MethodsNon‐pregnant, healthy women (n = 298) were recruited for this cross‐sectional study via home visits. Body composition was measured by Dual X‐ray Absorptiometry. Inflammation markers C‐reactive protein (CRP), alpha1‐acid glycoprotein (AGP), hemoglobin A1c (HbA1c), and blood pressure were scored according to risk. A summative metabolic health risk score was created for women with obesity. Generalized regression models assessed relationships between adiposity deposition and outcomes with adjustment for potential confounders.ResultsObesity was present in 22% of women (mean age = 20.93 years). Fat mass index was associated with inflammation and metabolic health risk (β = 0.58; p < 0.01). Visceral fat, trunk:limb ratio, android:gynoid ratio, body mass index, weight, and waist circumference were positively associated with CRP, AGP, and metabolic health risk (p < 0.01). Weight was associated with Hba1c (β < 0.01; p < 0.05). Participants with obesity and low metabolic health risk had lower fat mass index and visceral fat than participants with obesity and higher metabolic health risk.ConclusionsBlack South African women accumulated excess adipose tissue in abdominal regions. While fat mass and body mass were associated with inflammation and metabolic health risk, women with obesity and with lower fat mass index and lower visceral adipose tissue were metabolically protected. Identification of women at risk for metabolic disease preconception could help ensure future healthy pregnancies and prevent transference of risk to offspring.

Prognostic and predictive value of a metabolic risk score model in breast cancer: an immunogenomic landscape analysis.

Breast cancer is a kind of malignant tumor that occurs in breast tissue, which is the most common cancer in women. Cellular metabolism is a critical determinant of the viability and function of cancer cells in tumor microenvironment. In this study, based on the gene expression profile of metabolism-related genes, the prognostic value of 20 metabolic pathways in patients with breast cancer was identified. A universal risk stratification signature that relies on 20 metabolic pathways was established and validated in training cohort, two testing cohorts and The Cancer Genome Atlas pan cancer cohort. Then, the relationship between metabolic risk score subtype, prognosis, immune infiltration level, cancer genotypes and their impact on therapeutic benefit were characterized. Results demonstrated that the patients with the low metabolic risk score subtype displayed good prognosis, high level of immune infiltration and exhibited a favorable response to neoadjuvant chemotherapy and immunotherapy. Taken together, the work presented in this study may deepen the understanding of metabolic hallmarks of breast cancer, and may provide some valuable information for personalized therapies in patients with breast cancer.

Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia: State-of-the-art and future perspectives.

Metabolic disturbances and obesity are major cardiovascular risk factors in patients with schizophrenia, resulting in a higher mortality rate and shorter life expectancy compared with those in the general population. Although schizophrenia and metabolic disturbances may share certain genetic or pathobiological risks, antipsychotics, particularly those of second generation, may further increase the risk of weight gain and metabolic disturbances in patients with schizophrenia. This review included articles on weight gain and metabolic disturbances related to antipsychotics and their mechanisms, monitoring guidelines, and interventions. Nearly all antipsychotics are associated with weight gain, but the degree of the weight gain varies considerably. Although certain neurotransmitter receptor-binding affinities and hormones are correlated with weight gain and specific metabolic abnormalities, the precise mechanisms underlying antipsychotic-induced weight gain and metabolic disturbances remain unclear. Emerging evidence indicates the role of genetic polymorphisms associated with antipsychotic-induced weight gain and antipsychotic-induced metabolic disturbances. Although many guidelines for screening and monitoring antipsychotic-induced metabolic disturbances have been developed, they are not routinely implemented in clinical care. Numerous studies have also investigated strategies for managing antipsychotic-induced metabolic disturbances. Thus, patients and their caregivers must be educated and motivated to pursue a healthier life through smoking cessation and dietary and physical activity programs. If lifestyle intervention fails, switching to another antipsychotic drug with a lower metabolic risk or adding adjunctive medication to mitigate weight gain should be considered. Antipsychotic medications are essential for schizophrenia treatment, hence clinicians should monitor and manage the resulting weight gain and metabolic disturbances.

Joint association of modifiable lifestyle and metabolic health status with incidence of cardiovascular disease and all-cause mortality: a prospective cohort study.

We aimed to identify the joint associations of modifiable lifestyle and metabolic factors with the incidences of cardiovascular disease and all-cause mortality. We recruited 94,831 participants (men, 79.76%; median age, 51.60 [43.47-58.87]) without a history of cardiovascular disease from the Kailuan study during 2006 and 2007 and followed them until a cardiovascular disease event, or death occurred, or until December 31, 2017. Baseline metabolic health status was assessed using Adult Treatment Panel III criteria, and details of the lifestyles of the participants were recorded using a self-reported questionnaire. We used Cox proportional hazards models to evaluate the joint associations. During a median follow-up of 11.03 years, we recorded 6590 cardiovascular disease events and 9218 all-cause mortality. Participants with the most metabolic risk components and the least healthy lifestyle had higher risk of cardiovascular disease (hazard ratio 2.06 [95% confidence interval (CI) 1.77-2.39]) and mortality (HR 1.53 [95% CI 1.31-1.78]), than participants with fewer metabolic risk components and the healthiest lifestyle. Compared with those in participants with the healthiest lifestyle, the HRs for cardiovascular disease in participants with the least healthy lifestyle were 1.26 (95% CI 1.17-1.37), 1.16 (95% CI 1.03-1.31), and 1.07 (95% CI 0.90-1.27) for those with low, medium, and high metabolic risk, respectively. Healthy lifestyle is associated with a lower risk of cardiovascular disease and there is no significant interaction between metabolic risk and a healthy lifestyle. Therefore, a healthy lifestyle should be promoted, even for people with high metabolic risk.

190-LB: Using Genetics to Uncouple Higher Adiposity from Its Adverse Metabolic Effects

Type 2 diabetes is linked to higher risk of many non-metabolic conditions (e.g. cancers, neuropsychiatric and musculoskeletal disease) which all share a common risk factor: obesity. The causal pathways from excess weight to disease are unknown. We aimed to use specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects. Using metabolic biomarkers from 442,278 UK Biobank individuals, we identified two clusters of body fat % increasing alleles: a) 36 “favourable adiposity” (FA) alleles associated with a favourable metabolic profile (higher HDL and SHBG and lower triglyceride and liver enzymes); b) 38 “unfavourable adiposity” (UFA) alleles associated with an unfavourable profile (lower HDL and SHBG and higher triglyceride and liver enzymes). We used two-sample Mendelian randomization with 43 diseases from non-UK Biobank GWASs. We identified two sets of diseases. 1) Those where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here the FA and UFA clusters had an opposing effect on the risk of disease: type 2 diabetes (FA: 0.11 OR per 1 standard deviation higher body fat % [95%CI: 0.08, 0.16] vs. UFA: 5.50 [4.29, 7.05]), stroke (0.65 [0.52, 0.83] vs. 1.43 [1.23, 1.67]), gout (0.44 [0.29, 0.68] vs. 2.49 [1.88, 3.29]), breast cancer (1.12 [0.64, 1.94] vs. 0.52 [0.39, 0.68]) and colorectal cancer (0.67 [0.52, 0.85] vs. 1.20 [1, 1.50]). 2) Those where the mechanical excess weight (or other non-metabolic effects) is likely a cause of the disease. Here the FA cluster, despite having lower metabolic risk, and the UFA cluster were both associated with higher disease risk: venous thromboembolism (2.52 [1.82, 3.47] vs. 1.63 [1.25, 2.13]), osteoarthritis (1.45 [1.19, 1.76] vs. 2.20 [1.64, 2.95]), depression (2.85 [1.38, 5.89] vs. 2.59 [1.60, 4.21]). Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects in non-metabolic diseases pathophysiological mechanisms. Disclosure S. Martin: None. J. D. Bell: None. T. M. Frayling: None. H. Yaghootkar: None. J. Tyrrell: None. E. L. Thomas: None. M. Bown: None. J. T. Elder: None. C. Kabrhel: Research Support; Self; Diagnostica Stago, Grifols. N. Papadimitriou: None. M. Gunter: None. E. E. Vincent: None. Funding Diabetes UK (17/0005594)

A PNPLA3 Polymorphism Confers Lower Susceptibility to Incident Diabetes Mellitus in Subjects With Nonalcoholic Fatty Liver Disease

We investigated the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genotype and the risk of diabetes mellitus (DM) using a biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) cohort and a longitudinal observational cohort. Associations between genotypes and the prevalence of DM were evaluated with stratification according to the histological severity of NAFLD in the Boramae cohort (n= 706). A longitudinal cohort consisting of nondiabetic individuals with ≥2 health checkups was then selected to investigate the risk of incident DM according to the genotype (the GENIE cohort; n= 4998). Among subjects with NAFLD in the Boramae cohort, the G allele was independently associated with a lower prevalence of DM in both NAFL (odds ratio [OR] per 1 allele, 0.66; 95% confidence interval [CI], 0.46-0.97) and nonalcoholic steatohepatitis (OR per 1 allele, 0.59; 95% CI, 0.38-0.92). This result was replicated in the longitudinal GENIE cohort. The G allele was associated with a lower risk of incident DM during the median follow-up of 60 months in subjects with NAFLD (hazard ratio, 0.65; 95% CI, 0.45-0.93). In contrast, G allele carriers without NAFLD showed higher odds for DM in the context of the Boramae cohort (OR, 2.44; 95% CI, 1.00-5.95). These findings clarify conflicting results regarding the association between the PNPLA3 rs738409 genotype and the risk of DM, demonstrating a clear difference between subjects with and without NAFLD; this difference might be explained by the low metabolic risk in genetic NAFLD.

Metabolic disease and adverse events from immune checkpoint inhibitors.

Obese and overweight body mass index (BMI) categories have been associated with increased immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors (ICIs); however, the impact of being overweight in conjunction with related metabolic syndrome-associated factors on irAEs have not been investigated. We aimed to evaluate the impact of overweight and obese BMI according to metabolic disease burden on the development of irAEs. We conducted a retrospective observational study of patients receiving ICIs at a cancer center. Our main study outcome was development of ≥grade 2 (moderate) irAEs. Our main predictor was weight/metabolic disease risk category: (1) normal weight (BMI 18.5-24.9 kg/m2)/low metabolic risk (<2 metabolic diseases [diabetes, dyslipidemia, hypertension]), (2) normal weight/high metabolic risk (≥2 metabolic diseases), (3) overweight (BMI ≥25 kg/m2)/low metabolic risk, and (4) overweight/high metabolic risk. Of 411 patients in our cohort, 374 were eligible for analysis. Overall, 111 (30%) patients developed ≥grade 2 irAEs. In Cox analysis, overweight/low metabolic risk was significantly associated with ≥grade 2 irAEs (hazard ratio [HR]: 2.0, 95% confidence interval [95% CI]: 1.2-3.4) when compared to normal weight/low metabolic risk, while overweight/high metabolic risk (HR: 1.3, 95% CI: 0.7-2.2) and normal weight/high metabolic risk (HR: 1.5, 95% CI: 0.7-3.0) were not. Overweight patients with fewer metabolic comorbidities were at increased risk for irAEs. This study provides an important insight that BMI should be evaluated in the context of associated metabolic comorbidities in assessing risk of irAE development and ICI immune response.