Insulin resistance (IR) is a risk factor for cardiovascular diseases and type 2 diabetes. Associations between DNA methylation (DNAm) and IR have been less studied in African ancestry (AA) populations than those of European ancestry (EA). We aimed to identify associations between whole blood DNAm and IR in up to 1,811 AA and 964 EA participants from the Atherosclerosis Risk in Communities (ARIC) study. We quantified IR using three surrogate measures: the homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride-glucose index (TyG), and the triglyceride glucose-body mass index (TyG-BMI). We used ancestry-stratified linear regression models to conduct epigenome-wide association studies of IR, adjusting for batch effects and relevant covariates. Among 484,436 tested CpG sites, 39 were significantly associated with IR, of which 31% (10 in AA and two in EA) were associated with TyG-BMI and not previously reported for IR or related traits. These include a positive association at cg18335991-SEMA7A in AA. SEMA7A inhibits adipogenesis of preadipocytes and lipogenesis of mature adipocytes. DNAm levels at cg18335991 have been reported to be negatively associated with SEMA7A expression in blood. After additionally adjusting for smoking and drinking status, 15 of the 39 significant CpG sites remained significant or suggestive. Our study identified novel IR-associated CpG sites, contributing to a broader understanding of the epigenetic mechanisms underlying IR in diverse populations.

Controversy remains as to which obesity measures better predict type 2 diabetes (T2D) risk in overweight or obese individuals. The objective of this study is to determine which commonly used obesity measures better reflect beta cell function and predict T2D risk in participants with overweight or obesity and to validate the findings using prospective cohort data.

Cross-sectional data from the Obesity Clinic of the Xiangya Hospital of the Central South University and prospective cohort from UK Biobank. BMI, waist circumference (WC), waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR) were measured. Primary outcomes included beta cell function indices in the cross-sectional study and the occurrence of diabetes obtained from UK Biobank data.

One thousand four hundred and ninety-seven participants with overweight or obesity (median age 29 years, 41% males) and 322,023 UK Biobank participants without diabetes at baseline (mean age 56.83 years, 50.4% males) were studied. WHpR had a stronger association with beta cell function and central body fat distribution than the other three obesity measures irrespective of glucometabolic states. WHpR associated positively with diabetes risk in participants using the hazard ratio scale (HR per SD increase of WHpR, 2.311, 95% CI 2.250-2.374).

WHpR is a superior index in reflecting central body obesity, estimating beta cell function, and predicting T2D risk in people with overweight or obesity compared to BMI, WC, and WHtR.

Burnout is caused by long term psychosocial stress and has, besides the fatigue and mental health burden, been associated with increased risk of adverse physical health, such as for example type 2 diabetes. This study aims to investigate the glucose and insulin levels in individuals with stress related burnout, by assessing these metabolic markers in response to a standard oral glucose tolerance test (OGTT). 38 cases with burnout (13 men and 25 women) and 35 healthy controls (13 men and 22 women) in the age 24-55 were included in the study. The burnout group overall did not differ from healthy controls in glucose or insulin levels during the OGTT. However, the burnout cases who reported more severe burnout symptoms exhibited significantly higher levels of both glucose and insulin levels during the OGTT compared to burnout cases reporting lower severity of symptoms. Furthermore, the group of burnout cases who reported symptoms of depression exhibited higher insulin levels during OGTT compared to the burnout cases without depressive symptoms. The observed higher levels in the burnout cases with most severe symptoms indicate an increased diabetic risk in these patients and it may be of importance to follow glucose and insulin levels in individuals with more severe symptoms of burnout i.e. to perform an OGTT.

Insulin resistance (IR) is an early marker of cardiometabolic deterioration which may develop heterogeneously in key metabolic organs, including the liver (LIR) and skeletal muscle (MIR). This tissue-specific IR is characterized by distinct metabolic signatures, but the role of the gut microbiota in its etiology remains unclear. Here, we profiled the gut microbiota, its metabolites and the plasma metabolome in individuals with either a LIR or MIR phenotype (n = 233). We observed distinct microbial community structures LIR and MIR, and higher short-chain fatty acid (SCFA) producing bacteria, fecal SCFAs and branched-chain fatty acids and a higher postprandial plasma glucagon-like-peptide-1 response in LIR. In addition, we found variations in metabolome profiles and phenotype-specific associations between microbial taxa and functional metabolite groups. Overall, our study highlights association between gut microbiota and its metabolites composition with IR heterogeneity that can be targeted in precision-based strategies to improve cardiometabolic health. Clinicaltrials.gov registration: NCT03708419.

Diabetes mellitus (DM) is a chronic metabolic disorder that can lead to serious complications, including testicular dysfunction. This dysfunction is considered a significant cause of male infertility. Quercetin (Que), a naturally existing flavonoid with versatile biological functions, has limited water solubility and low bioavailability. The current study was designed to develop a bioavailable formulation of Que. via encapsulating it in PEGylated liposomes (Que-PEG-Lip) and determine whether this formulation is effective in the treatment of alloxan-induced testicular injury via targeting Kisspeptin/Neurokinin B/Dynorphin/steroidogenesis signaling pathway. Thirty-two male Sprague Dawley rats were randomly divided into four groups: Control, alloxan-induced diabetes with testicular dysfunction (ALX), ALX + metformin (MET) and ALX + Que-PEG-Lip. The results showed that treatment of ALX group with Que-PEG-Lip significantly improved the alteration of glycemic index, serum reproductive hormones, testicular antioxidant status, testicular Kiss-1, androgen receptor (AR), and proliferation marker protein (ki67) immunoexpression in compared to ALX group. Moreover, the treatment of ALX group with Que-PEG-Lip regulated the Kisspeptin/Neurokinin B/Dynorphin/steroidogenesis pathway gene expression. Interestingly, the outcomes of the molecular docking analysis revealed a strong agonistic effect of Que. on the kisspeptin, neurokinin, and dynorphin receptors. In conclusion, Que-PEG-Lip mitigated the testicular dysfunction in alloxan-induced diabetic rats via regulation of hypothalamic-pituitary-gonadal axis signaling pathway and alleviation the testicular oxidative stress.

Cardiometabolic traits are heritable, and some display parent-of-origin effects, which indicates preferential inheritance from one parent or parental bias. Most studies of these phenomena have focused on adult populations. We aimed to investigate the heritability and parent-of-origin effects on cardiometabolic traits in a birth cohort with serial measurements to determine whether these patterns emerged early in life.

The Pune Maternal Nutrition Study comprises a birth cohort in which offspring and parents were studied from birth and followed up for 24 years. We investigated parent-of-origin effects on cardiometabolic traits cross-sectionally at available timepoints using linear regression, and longitudinally across the life course using mixed-effect regression. Maternal and paternal effects on offspring phenotype were modelled after adjusting for age, sex and BMI. Parent-of-origin effects were calculated based on the difference between maternal and paternal effects. We also investigated these effects in another birth cohort, that of the Pune Children's Study. Genetic parent-of-origin effects were assessed using generalised estimating equations after taking the parental origin of the alleles into account.

Birthweight showed a maternal parent-of-origin effect. At 24 years, maternal bias was seen for some obesity-related traits for daughters, while paternal bias was seen for WHR in sons. A shift from paternal bias at 6 years to maternal bias at 24 years for the skinfold thickness was observed in daughters. Fasting glucose and lipids showed maternal bias at 6, 12 and 24 years. For fasting insulin and HOMA2-S, a negative maternal effect at 6 years transitioned to a positive one at 12 years. For HOMA2-B, a paternal effect at 6 years transitioned to a maternal one at 12 years, and this remained so at 24 years. Some of these findings were also observed in the cohort from the Pune Children's Study. Longitudinal modelling revealed stronger paternal effects over time for fasting insulin and HOMA indices but maternal effects for glucose and lipids, reflecting their cumulative effect over time. Genetic variants at the KCNQ1 locus showed a maternal parent-of-origin effect on birthweight, on HOMA2-B at 12 years, and on lipids at 6 and 12 years.

Our study provides proof of concept of the existence of parent-of-origin effects on cardiometabolic traits from birth, through childhood and puberty, until adult age. Our results indicate a predominantly maternal influence on intrauterine, pubertal and reproductive-age metabolism in the offspring. While the longitudinal analysis indicated a maternal bias for the macronutrients (glucose and lipids), and a paternal bias for glucose-insulin metabolism, the cross-sectional analysis revealed a transition between parental influence across physiological stages. This dynamic relationship may have its origins in the life-history theory of evolution, and could inform strategies for primordial prevention aimed at curbing the rising burden of cardiometabolic disease. Further studies are needed to determine the mechanisms underlying such effects.

C-reactive protein (CRP) appears to improve the ability to detect cardiometabolic risk in young and middle-aged adults with mild-to-moderate obstructive sleep apnea (mmOSA). The aim of this study is to assess utility of CRP in identifying the risk of hypertension and insulin resistance across a wide age range including older patients with mmOSA. Adults (n = 216) of a wide age range (28-90 years old, mean age 52.64 ± 12.74) with mmOSA (5 ≤ AHI < 30) completed in-lab polysomnography or home sleep apnea testing, physical examination including blood pressure (BP) measures, structured medical history questionnaire, and blood draw for CRP and fasting glucose and insulin levels. In adults < 60 years, lnCRP but not the apnea-hypopnea index (AHI) was associated with greater odds for hypertension (odds ratio [OR] = 2.40, 95% CI = 1.20-4.84, p = 0.01; OR = 1.00, 95% CI = 0.92-1.08, p = 0.92, respectively) and with higher average systolic and diastolic BP. Also, in adults < 60 years lnCRP but not AHI, was associated with higher lnHOMA values. In contrast, in adults > 60 years neither lnCRP nor AHI were associated with greater odds for hypertension, average systolic and diastolic BP, and lnHOMA. Receiver-operating characteristics curves revealed that adding CRP to standard clinical factors (age, sex, and BMI) yielded moderately good risk models for hypertension in patients < 60 years (AUC = 0.721). In conclusion, CRP improves the ability to detect cardiometabolic risk in young and middle-aged, but not older adults with mmOSA, suggesting that inflammation may be a primary pathogenetic mechanism in younger patients with OSA.

Previous studies demonstrate that GDF15 and its related signaling activators may be affected by exercise training, leading to the suppression of inflammatory factors and the promotion of immune-metabolic balance. Therefore, the purpose of the study was to evaluate the effect of high-intensity interval training (HIIT) on amelioration of inter-organ crosstalk between liver and hypothalamus of the high-fat diet (HFD)-induced metabolic dysfunction-associated fatty liver disease (MAFLD) rats in a two-phase study. In this regard, rats were initially divided into two groups, the normal diet-inactive (NS) and the HFD groups. HFD course lasted 12 weeks to induce MAFLD in the latter group. After ensuring the induction of MAFLD, 25 rats were divided into three groups: the HFD-inactive group (HS), the HFD-HIIT group (HH), as well as the HFD-aerobic group (HA). The training interventions were consistently applied over a period of eight weeks, five days a week, with each session lasting 40-60 min, and the duration of the whole research was 21 weeks. The results of this study displayed that HIIT intervention promotes hypothalamic Gdf15 gene expression and there were similar alterations in genes expression of Foxo1 and Akt2. Moreover, our results confirmed that HIIT ameliorated hypothalamic NFKB gene expression and there was a similar trend in genes expression of Tnfa and Il1b following both HIIT as well as aerobic training protocols. Taking these findings together, it is concluded that interventions, particularly exercise training, uniquely contribute to the reduction of hypothalamic-associated inflammatory responses that result in prolonged and chronic increases in GDF15.

Energy-restricted (ER) diets promote weight loss and improve body composition and glycaemic control. Nut consumption also improves these parameters. However, less is known about the combined benefit of these two strategies. This scoping review implemented a systematic search of Medline, Embase and Scopus to identify randomised controlled trials evaluating the effect of ER diets with or without nuts on body mass, body composition and glycaemic control in adults. After reviewing titles and abstracts, twenty-nine full-text articles were screened, resulting in seven studies reported in eight papers that met the inclusion criteria. Energy restriction was achieved by prescribing a set energy target or reducing intake by 1000-4200 kJ from daily energy requirements. Interventions ranged from 4 to 52 weeks in duration and contained 42-84 g/d of almonds, peanuts, pistachios or walnuts. While all studies reported that energy restriction resulted in significant weight loss, the addition of nuts to ER diets demonstrated significantly greater weight loss in only approximately half of the included studies (4/7 studies). There was limited evidence to support additional benefits from nuts for body composition measures or glycaemic control. Although improvements in weight loss and glycaemia were not consistent when nuts were included in ER diets, no study revealed an adverse effect of nut consumption on health outcomes. Future studies could explore the effect of consuming different types and amounts of nuts, combined with various levels of energy restriction on weight, body composition and glycaemic control.

The important effects of variability of some physiological/biological characteristics (such as LDL cholesterol, blood pressure) on cardiovascular outcomes have been elucidated, while the role of insulin variability is undefined.

To investigate the associations of long-term fasting insulin variability during young adulthood before the onset of diabetes with subsequent cardiovascular outcomes in middle age.

We included 3,983 CARDIA (Coronary Artery Risk Development Study in Young Adults) participants aged 18 to 30 years with at least three fasting insulin measurements. Intra-individual fasting insulin variability was defined by the average real variability (ARV) of insulin and standard deviation (SD) of insulin during 30-year follow-up. The presence and the degree of coronary artery calcification (CAC) were assessed by computed tomography at year 25. Incident cardiovascular disease (CVD) and all-cause mortality were adjudicated.

After multivariable adjustment, comparing high versus low tertile of insulin ARV, the hazard of CVD increased by 65 % (HR, 1.65; 95 % CI, 1.13-2.39) and all-cause mortality by 97 % (HR, 1.97; 95 % CI, 1.38-2.82). Higher tertile of insulin ARV was associated with significantly worse degree of CAC (β =0.1; 95 % CI, 0.03-0.18) but not with the presence of CAC (P = 0.197). Similar results were also observed in insulin SD.

High long-term insulin variability in young adulthood before the onset of diabetes was associated with an increased risk of CVD and all-cause mortality in later life, independent of average FG, HOMA-IR and other established cardiovascular risk factors. Long-term insulin variability was associated with the degree but not the presence of CAC.

Glycaemic traits such as high fasting glucose levels and insulin resistance are positively associated with the risk of type 2 diabetes and other cardiometabolic diseases. Genetic association studies have identified hundreds of associations for each glycaemic trait, yet very few studies have involved continental African populations. We report the results of genome-wide association studies (GWASs) in a pan-African cohort for four glycaemic traits, namely fasting glucose, fasting insulin, insulin resistance (HOMA-IR) and beta cell function (HOMA-B), which are quantitative variables that affect the risk of developing type 2 diabetes.

GWASs for the four traits were conducted in approximately 10,000 individuals from the Africa Wits-INDEPTH Partnership for Genomics Studies (AWI-Gen) cohort, with participants from Burkina Faso, Ghana, Kenya and South Africa. Association testing was performed using linear mixed models implemented in BOLT-LMM, with age, sex, BMI and principal components as covariates. Replication, fine mapping and functional annotation were performed using standard approaches.

We identified a novel signal (rs574173815) in the intron of the ankyrin repeat domain 33B (ANKRD33B) gene associated with fasting glucose, and a novel signal (rs114029796) in the intronic region of the WD repeat domain 7 (WDR7) gene associated with fasting insulin. SNPs in WDR7 have been shown to be associated with type 2 diabetes. A variant (rs74806991) in the intron of ADAM metallopeptidase with thrombospondin type 1 motif 16 (ADAMTS16) and another variant (rs6506934) in the β-1,4-galactosyltransferase 6 gene (B4GALT6) are associated with HOMA-IR. Both ADAMTS16 and B4GALT6 are implicated in the development of type 2 diabetes. In addition, our study replicated several well-established fasting glucose signals in the GCK-YTK6, SLC2A2 and THORLNC gene regions.

Our findings highlight the importance of performing GWASs for glycaemic traits in under-represented populations, especially continental African populations, to discover novel associated variants and broaden our knowledge of the genetic aetiology of glycaemic traits. The limited replication of well-known signals in this study hints at the possibility of a unique genetic architecture of these traits in African populations.

The dataset used in this study is available in the European Genome-Phenome Archive (EGA) database ( https://ega-archive.org/ ) under study accession code EGAS00001002482. The phenotype dataset accession code is EGAD00001006425 and the genotype dataset accession code is EGAD00010001996. The availability of these datasets is subject to controlled access by the Data and Biospecimen Access Committee of the H3Africa Consortium. GWAS summary statistics are accessible through the NHGRI-EBI GWAS Catalog ( https://www.ebi.ac.uk/gwas/ ).

Postprandial hyperlipidaemia (PPL), characterized by elevated triglyceride (TG) concentrations after a meal, is common in type 2 diabetes (T2D) and is often recognized as an independent cardiovascular risk factor. Here, we aimed to assess the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition by alirocumab on PPL in patients with T2D.

EUTERPE is a randomized, double-blind, placebo-controlled cross-over trial conducted in male patients with T2D. Participants received sequentially two sequences of 10-week treatment (alirocumab 75 mg Q2W or placebo s/c) with a wash-out period of 10 weeks. The primary end-point was the percentage reduction in plasma TG response after an oral fat load (incremental area under the curve [iAUC]0-8h TG). Secondary end-points included mass spectrometry-based apolipoprotein measurements and nuclear magnetic resonance (NMR)-based lipoprotein profiling.

Fourteen participants were included: age 59 ± 9 years, BMI 32.8 ± 5.5 kg/m2, HbA1C 6.7 ± 0.5%. Compared to placebo, alirocumab did not reduce PPL (iAUC0-8h TG: -5% [CI 95%: -28, +25], p = 0.68). Alirocumab decreased fasting non-HDL cholesterol (-38.5 ± 5.6%, p = 0.0003), remnant cholesterol (-20.0 ± 13.3%, p = 0.04), apoB100 (-21.2 ± 6.4%, p = 0.004) and apoE (-15.3 ± 6.6%, p = 0.02) concentrations. NMR analyses showed that alirocumab decreased both postprandial VLDL2 cholesterol (-42% [-55, -25], p < 0.001) and IDL cholesterol (-26% [-38, -12], p = 0.0007), without effect on VLDL1 cholesterol or TG concentrations.

Inhibition of PCSK9 by alirocumab did not reduce PPL in T2D, confirming that PCSK9 controls remnant cholesterol catabolism rather than intestinal chylomicron production.

This investigation had two main objectives: (1) to compare the triglyceride-glucose (TyG) index with the homeostasis model assessment of insulin resistance (HOMA-IR) in relation to insulin-stimulated myocardial glucose metabolic rate (MrGlu), measured by a dynamic positron emission tomography (PET) scan using 18F-fluorodeoxyglucose (18F-FDG) coupled with a euglycemic-hyperinsulinemic clamp; and (2) to assess whether the TyG index correlates with myocardial mechano-energetic efficiency (MEE).

We evaluated MrGlu in 46 participants who had no prior diagnosis of coronary heart disease. Myocardial MrGlu was quantified by 18F-FDG PET during a euglycemic-hyperinsulinemic clamp. In a larger cohort of 1820 individuals, myocardial MEE per gram of left ventricular mass (MEEi) was measured echocardiographically. The TyG index was computed as the Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2].

When compared to HOMA-IR, the TyG index exhibited a stronger correlation with myocardial MrGlu (Pearson's r = -.566 for TyG vs. -.471 for HOMA-IR). Within the larger cohort, individuals in the highest TyG quartile showed significantly reduced MEEi compared to those in the lowest quartile (p < .001). Stepwise multivariate linear regression confirmed that the TyG index was the most significant determinant of MEEi, independent of traditional cardio-metabolic risk factors.

Our findings suggest that the TyG index is superior to HOMA-IR as an indicator of cardiac insulin resistance and that it independently correlates with MEEi. Thus, the TyG index may serve as a valuable, readily available tool to identify subjects at elevated cardiovascular risk.

Studies on prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and cardiometabolic health in childhood have produced inconsistent results. In this study, we evaluated associations between prenatal PFAS exposures, individually and as a mixture, and cardiometabolic outcomes including insulin resistance, beta cell function, blood lipids, blood pressure and central adiposity during middle childhood (7-9 years of age) in a Canadian maternal-child cohort (n = 281). We also explored effect measure modification based on child sex and physical activity. We quantified maternal second trimester plasma concentrations of six PFAS and measured 11 offspring cardiometabolic outcomes at a 7-9-year follow-up. In single-exposure models, ten-fold higher prenatal PFDA (β: -0.82, 95% CI: -1.36, -0.28), PFNA (β: -0.8, 95% CI: -1.41, -0.19), and PFOA (β: -0.69, 95% CI: -1.18, -0.19) concentrations were associated with lower diastolic blood pressure z-scores. This association did not persist when considering PFAS exposures as a mixture using quantile g-computation. Associations between PFAS exposures, individually or as a mixture, and other cardiometabolic outcomes were null. We observed no effect measure modification by child sex or physical activity (p-values for interaction ≥0.2). Our results contradict existing studies that suggest prenatal PFAS exposures are associated with adverse childhood cardiometabolic outcomes. Future studies should consider alternative markers of cardiometabolic health, trajectories in cardiometabolic health throughout childhood, and further explore potentially protective health behaviors.

Chronically transfused patients with sickle cell disease (SCD) and beta thalassemia major (TM) develop iron overload.

Determine the impact of iron overload on glucose regulation in SCD.

Prospective study of 28 patients with SCD and 38 patients with TM who underwent liver and pancreas R2* measurements and oral glucose tolerance tests.

Impaired fasting glucose (2 vs. 9, p = 0.27) and impaired glucose tolerance (1 vs. 11, p = 0.019) were less common in patients with SCD compared with patients with TM. No SCD patient had diabetes.

Iron-mediated glucose dysregulation is present but less common in SCD patients.

Insulin sensitivity is a key factor of the development of metabolic diseases, highly prevalent in adult survivors of childhood cancers. The aim of the Adapted Physical Activity for children treated for Cancer and Insulin-Sensitivity (APACIS) study is to investigate the effects of two exercise programs started as early as diagnosis on metabolic profile and physical health.

APACIS is a trial that includes children at diagnosis of all pediatric cancers which are randomly allocated to the Soft group - for low intensity physical activity - or to the Strong group - for mixed, high intensity exercise. Both programs are done at least twice weekly for 30 to 60 min over 6 months, adapted to the health status of the children, with a follow-up of 18 months. The primary objective is the change in insulin sensitivity measured by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at 0, 3, 6, 12 and 24 months between the two groups. The secondary objectives include changes in cholesterol, triglycerides and cortisol blood levels, state of undernourishment, cardiorespiratory fitness (based on peak rate of oxygen uptake of the 6 Minute Walk Test), flexibility (sit and reach flexibility test), fat mass distribution (Waist-to-Hip Ratio) and level of physical activity assessed by questionnaire at 0, 3, 6, 12 and 24 months. On-therapy metabolic adaptation in the different patient groups will also be evaluated by an integrated pipeline combining the detection of 150 metabolites, with metabolic pathway enrichment and network mapping. This approach will be complemented by an analysis of intestinal and oral microbiota, to identify the species impacted by treatments and the influence of exercise on these toxicities.

The APACIS study investigates the metabolic, motor, and nutritional effects in children with cancers performing low versus high intensity exercise with an innovative approach consisting of early practice since diagnosis. It will contribute to better personalize physical activity prescription during treatment of pediatric cancers.

The study has been registered on ClinicalTrials.gov (NCT05383092) the 7 of November, 2022.

Cardiometabolic index (CMI) is an index integrating visceral obesity and dyslipidemia. This study intends to scrutinize the connection between CMI and gallstone disease (GSD) and to elucidate the association between CMI and insulin resistance (IR) in patients with GSD.

To explore the potential nonlinear association and determine the inflection point, a restricted cubic spline (RCS) analysis was performed. Following categorization of CMI based on the identified inflection point, multivariate logistic regression models, subgroup analyses, and interaction tests were utilized to assess the connection between CMI and GSD, as well as between CMI and IR in GSD patients. The homeostasis model assessment for IR (HOMA-IR) and triglyceride-glucose (TyG) index was applied to evaluate IR. Spearman analysis was implemented to investigate the connection between CMI and HOMA-IR. The predictive performance of each indicator was evaluated by the receiver operating characteristic (ROC) curve and the area under the curve (AUC).

The study included 2311 individuals, with a GSD prevalence of 10.90%. RCS analysis revealed a nonlinear positive correlation between CMI and GSD (nonlinear P < 0.001), as well as between CMI and IR (nonlinear P < 0.001). In the fully adjusted multivariable logistic regression analysis of covariates, compared with the low-category CMI group, the high-category CMI was significantly associated with the risk of GSD (OR = 1.547, 95% CI: 1.143-2.092, P = 0.005), IR (OR = 4.990, 95% CI: 2.517-9.892, P < 0.001). Subgroup analysis demonstrated that the correlation between CMI and GSD was stronger in females. Spearman correlation analysis showed a positive association between CMI and HOMA-IR in GSD patients (r = 0.548, P < 0.001). The ROC curve demonstrated the predictive performance of the CMI model for GSD (AUC = 0.743), which was superior to conventional indicators such as Body Mass Index and Waist Circumference; the predictive performance of CMI (AUC = 0.772) for IR was consistent with that of TyG (AUC = 0.772).

Our research demonstrates that CMI exhibits a nonlinear positive correlation with the incidence of GSD and IR. This suggests that CMI may serve as a novel and valuable indicator for further investigating the intricate relationships among metabolic syndrome, obesity, and GSD.

Heart failure with preserved ejection fraction (HFpEF) has overtaken heart failure with reduced ejection fraction as the leading type of heart failure globally and is marked by high morbidity and mortality rates, yet with only a single approved pharmacotherapy: SGLT2i (sodium-glucose co-transporter 2 inhibitor). A prevailing theory for the mechanism underlying SGLT2i is nutrient deprivation signaling, of which ketogenesis is a hallmark. However, it is unclear whether the canonical ketogenic enzyme, HMGCS2 (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2), plays any cardiac role in HFpEF pathogenesis or therapeutic response.

We used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.

We demonstrate, for the first time, the intrinsic capacity of the human heart to produce ketones via HMGCS2. We found that increased acetylation of HMGCS2 led to a decrease in the enzyme's specific activity. However, this was overcome by an increase in the steady-state levels of protein. Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF. Critically, using a conditional, cardiomyocyte-specific HMGCS2 knockdown murine model, we revealed that the oxidized form of nicotinamide adenine dinucleotide is unable to rescue HFpEF in the absence of cardiomyocyte HMGCS2.

The canonical ketogenic enzyme, HMGCS2, mediates the therapeutic effects of the oxidized form of nicotinamide adenine dinucleotide repletion in HFpEF by restoring normal lipid metabolism and mitochondrial function.

Gestational diabetes mellitus (GDM), characterized by insulin resistance (IR) and β-cell dysfunction, is one of the most common complications of pregnancy with unmet needs of prevention methods.

To investigate the causal role of insulin resistance and metabolic pathways in the pathogenesis of GDM with our proposed high-dimensional systematic Mendelian randomization (hdsMR) framework.

Cases with GDM and controls with normal glucose tolerance were recruited at the University of Hong Kong-Shenzhen Hospital from 2015 to 2018. A total of 566 participants (aged > 18 years), including 274 with GDM, were enrolled after excluding subjects with major chronic diseases or long-term use of medications affecting glycolipid metabolism. Clinical characteristics and serum samples were collected during the GDM screening stage, and the genome and metabolome were tested. A novel hdsMR framework was proposed to estimate the causal role of IR index (Homeostasis Model Assessment of Insulin Resistance, HOMA-IR) and metabolic pathways in the pathogenesis of GDM.

Our hdsMR method confirmed that HOMA-IR was causal to GDM (odds ratio, 1.17; 95% confidence interval, 1.04-1.32) and revealed that two metabolic pathways (glyoxylate and dicarboxylate metabolism pathway and lysine degradation pathway) mediated 14.6% and 8.4%, respectively, between HOMA-IR and GDM. In an independent validation cohort comprising 255 pre-diabetic individuals, we showed that both pathways could be intervened through diet (P < 0.05). Furthermore, glyoxylate and dicarboxylate metabolism pathway was significantly associated with adverse pregnancy outcomes in GDM.

These results indicated that targeting specific metabolic pathways through dietary intervention is worth exploring as a possible GDM prevention approach, and hdsMR is more efficient in finding causal mediating metabolic pathways than traditional MR methods.

As the main active ingredient of the first FDA-approved phytochemical drug, epigallocatechin gallate (EGCG) can effectively alleviate glucolipid metabolic disorders. However, existing studies mainly focuses on the treatment of EGCG in disease models, with limited focus on its preventive effect on diseases in healthy models.

This study investigated how EGCG prevents and alleviates T2DM through gut microbiota and multi-organ interactions in Wistar healthy rats and GK T2DM rats.

The GK T2DM rat strain was established through repeated selective breeding of Wistar rats with glucose intolerance. Whether and how EGCG prevents and alleviates T2DM were evaluated, including glucose production and absorption efficiency, glucose transport, glucose metabolism, glucose excretion, T2DM-related tissue damage, gut microbiota, and liver transcriptome.

The health benefits of EGCG are primarily reliant on the involvement of the gut microbiota. Our study showed that although the specific microbial communities involved differ, the bidirectional interaction between EGCG and gut microbiota is widespread in healthy rats and T2DM rats. EGCG intervention elevated the relative abundance of specific microbial communities, which in turn promoted the metabolic processing of EGCG in the gut, producing numerous EGCG metabolites that may contribute to preventing and alleviating T2DM. In healthy rats, EGCG intervention selectively enhanced insulin secretion and serum insulin levels to prevent T2DM. In T2DM rats, EGCG intervention selectively lowered blood glucose levels, improved insulin resistance, delayed glucose production and absorption, and promoted urinary glucose excretion to alleviate T2DM. In both healthy and T2DM rats, EGCG intervention universally reduced gut microbiota-derived lipopolysaccharides, maintained systemic oxidative stress homeostasis, alleviated liver and kidney damage, increased muscle glycogen content, and promoted beige thermogenesis in white fat, thus demonstrating potential for preventing and alleviating T2DM.

As a natural active ingredient, EGCG could prevent and alleviate T2DM through gut microbiota and multi-organ interactions.

Insulin resistance (IR) can be optimally assessed using the euglycemic clamp, but practical clinical limitations necessitate surrogate markers. This study leveraged the Bayesian network analysis to evaluate three established IR markers: the Homeostatic Model Assessment of IR (HOMA-IR) using insulin level and fasting blood glucose (FBG), TG-Glucose (TyG) index using triglycerides (TG) and FBG, and TG-to-HDL ratio (TG/HDL ratio) using TG and high-density lipoprotein (HDL), based on the Korean National Health and Nutrition Examination Survey data (2019-2021). Our analysis revealed a sequential association pattern (TG/HDL ratio → TyG index → HOMA-IR), positioning the TyG index as a central connecting marker. The HOMA-IR exhibited strong predictive power for diabetes, while the TG/HDL ratio was most effective for assessing dyslipidemia. However, both had limited crossover utility. In contrast, the TyG index bridged this gap, demonstrating robust predictive capability for both conditions. The Markov blanket analysis illuminated the distinctive metabolic signatures of each marker: The TyG index displayed balanced glucose-lipid metabolic contributions, the HOMA-IR predominantly reflected glucose metabolism and obesity characteristics, and the TG/HDL ratio emphasized lipid metabolism. Notably, the TyG index's predictive performance showed significant enhancement when integrated with obesity information, contrasting with the HOMA-IR's minimal response owing to its inherent incorporation of obesity characteristics. These findings position the TyG index as a superior clinical marker, offering both comprehensive predictive capability and enhanced performance through synergistic integration with obesity measures. While each marker demonstrated reliability, the TyG index's unique combination of versatility and scalability establishes it as an effective tool for comprehensive metabolic risk assessment.

Obesity rates have surged since 1990 worldwide. This rise is paralleled by increases in pathological processes affecting organs such as the heart, liver, and kidneys, here termed systemic metabolic disorders (SMDs). For clinical management of SMD, the European Atherosclerosis Society proposes a pathophysiology-based system comprising three stages: Stage 1, where metabolic abnormalities such as dysfunctional adiposity and dyslipidaemia occur without detectable organ damage; Stage 2, which involves early organ damage manifested as Type 2 diabetes, asymptomatic diastolic dysfunction, metabolic-associated steatohepatitis (MASH), and chronic kidney disease (CKD); and Stage 3, characterized by more advanced organ damage affecting multiple organs. Various forms of high-risk obesity, driven by maintained positive energy balance, are the most common cause of SMD, leading to ectopic lipid accumulation and insulin resistance. This progression affects various organs, promoting comorbidities such as hypertension and atherogenic dyslipidaemia. Genetic factors influence SMD susceptibility, and ethnic disparities in SMD are attributable to genetic and socioeconomic factors. Key SMD features include insulin resistance, inflammation, pre-diabetes, Type 2 diabetes, MASH, hypertension, CKD, atherogenic dyslipidaemia, and heart failure. Management strategies involve lifestyle changes, pharmacotherapy, and metabolic surgery in severe cases, with emerging treatments focusing on genetic approaches. The staging system provides a structured approach to understanding and addressing the multi-faceted nature of SMD, which is crucial for improving health outcomes. Categorization of SMD abnormalities by presence and progression is aimed to improve awareness of a multi-system trait and encourage a tailored and global approach to treatment, ultimately aiming to reduce the burden of obesity-related comorbidities.

Polycystic ovary syndrome (PCOS) is associated with an increased risk of cardiovascular diseases (CVD). Plant-based diets are associated with reduced CVD risk factors. This study aimed to explore the associations between dietary phytochemical index (DPI) and asymmetric dimethylarginine (ADMA), lipid profile, atherogenic indices, and other metabolic biomarkers in women with PCOS.

In this cross-sectional study, 150 females aged 18-45 years diagnosed with PCOS were recruited. An interviewer-administered questionnaire was applied to gather the relevant demographic characteristics, detailed clinical information, and lifestyle habits of participants. A validated semi-quantitative food frequency questionnaire was used to assess dietary intake, and DPI was calculated accordingly. We used multiple linear regression to determine the association between serum concentrations of ADMA, total testosterone, sex hormone-binding globulin (SHBG), fasting serum glucose (FSG), insulin, and lipid profile, as well as atherogenic indices across quartiles of DPI.

There was a negative correlation between the DPI and serum levels of ADMA (p-trend = 0.022), triglycerides (TG) (p-trend = 0.003), oxidized low-density lipoprotein cholesterol (ox-LDL) (p-trend = 0.001), insulin (p-trend = 0.045) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p-trend = 0.018). Moreover, there was a tendency for visceral adiposity index (VAI) (p-trend = 0.005) and atherogenic index of plasma (AIP) (p-trend = 0.001) to decrease as the quartile categories of DPI increased. No significant regular trend was found for serum levels of FSG, SHBG, total testosterone, other lipid profiles, and lipid accumulation product (LAP).

These findings suggest that adherence to a phytochemical-rich diet decrease the CVD risk factors in PCOS patients.

This study aimed to explore the effects of hypoglycemic agents with weight loss effect plus a high protein diet and moderate exercise on weight loss and diabetes remission in adults with obesity and newly diagnosed prediabetes/type 2 diabetes (T2D).

Participants with obesity and newly diagnosed prediabetes or T2D (n = 61) were randomly allocated to standard treatment group (conventional medication and lifestyle guidance for 12 months) and intensive treatment group (in addition to conventional medication, a high protein diet and moderate exercise were given for 12 months).

By month 12, 60 (98.4%) participants completed the 12-month follow-up visit. In the intensive treatment group, 73.33% patients in the prediabetes subgroup returned to normoglycemia and the diabetes remission rate was 86.67% in the diabetes subgroup, which were much higher than the remission rate of prediabetes subgroup (7.69%) and diabetes subgroup (16.67%) in the standard treatment group (P < 0.001). The mean weight change was - 19.29 kg (95% CI, - 22.95 to - 15.63) in the intensive treatment group and - 1.52 kg (95% CI, - 5.12 to 2.07) in the standard treatment group from baseline after intervention. The weight change between the two groups was significantly different (net difference, - 17.77 kg; 95% CI, - 22.90 to - 12.64; P < 0.001). Percent of body fat, visceral fat area, and hepatic controlled attenuation parameter value reduced significantly in the intensive treatment group compared to the standard treatment group (P < 0.001).

Hypoglycemic agents with weight loss effect plus a high protein diet and moderate exercise could lead to a considerable proportion of patients with diabetes achieving diabetes remission.

chictr.org.cn ChiCTR2100044305.

In Japan, the guidelines for gestational weight gain (GWG) were revised in 2021. Under the new guidelines, pregnant women are recommended to increase their GWG. The aim of this study was to compare the incidence of adverse pregnancy outcomes (APOs), large for gestational age (LGA), and postpartum glucose tolerance in gestational diabetes mellitus (GDM) patients before and after the revised GWG standards. This retrospective cohort study enrolled 1,021 GDM patients who underwent prenatal glycemic control and a postpartum 75-g oral glucose tolerance test. The endpoint was the incidence of APOs, LGA, and postpartum impaired glucose tolerance (IGT) and diabetes mellitus (DM). There was no significant difference in the incidence of APOs and postpartum IGT and DM in GDM patients before and after the revised GWG standards. On the other hand, when the new GWG standards were applied to GDM patients, the incidence of LGA increased (adjusted odds ratio [aOR]; 1.764, 95% confidence interval [CI]; 1.180-2.637). In particular, when classified by pre-pregnancy body mass index, the incidence of LGA increased in the obese group (aOR; 5.944, 95% CI; 1.847-19.129). Future prospective cohort studies are needed to verify the efficacy and safety of appropriate GWG in Japanese GDM patients.

Research on the relationship between resistin levels, metabolic health, and obesity has produced inconsistent findings across different ethnic groups, making it unclear whether lower resistin levels are associated with these conditions in Mexican-Americans. This cross-sectional study investigated the relationship between resistin, metabolic health, and obesity in an adult Mexican-American cohort (n = 1511) using multivariable linear regression analysis. Related adipokines (leptin and adiponectin) were measured simultaneously. Participants were categorized into four groups by metabolic health (healthy/unhealthy) and obesity (obese/non-obese) status. "Metabolically unhealthy" was defined as ≥2 cardiometabolic abnormalities. Obesity was defined as a BMI ≥ 30 kg/m2. We also investigated the associations of related proinflammatory cytokines, demographic/anthropometric variables, and medications with each outcome variable of interest. The results showed no statistically significant differences in resistin levels between the groups. Leptin was higher and adiponectin was lower in groups with obesity and/or metabolically unhealthy status. The resistin findings contrast studies in other populations, while other leptin and adiponectin findings confirm those seen in many ethnic groups. Thiazolidinedione use was associated with lower resistin, confirming earlier research. These findings suggest that resistin's role in metabolic health may be different in Mexican-Americans compared to other populations.

Insulin sensitivity (IS) is a key determinant of metabolic health and may share genetic factors with obesity-related traits. Previous large-scale genetic studies have identified variants associated with IS as well as obesity related traits like body mass index (BMI) and waist-to-hip ratio (WHR). Notably, many of these associations are shared across traits, indicating a potential genetic overlap. However, the genetic intersection between IS and obesity-related traits remains underexplored. To explore this gap, we investigated associations between six IS indices, including fasting and post-glucose load measures, and genetic variants linked to BMI and WHR to determine their influence on IS and related cardiometabolic traits. To achieve this, we calculated six IS indices using fasting and oral glucose tolerance test (OGTT) data from 5,007 non-diabetic individuals, grouping them into fasting, OGTT0,120, and OGTT0,30,120 categories. A total of 678 BMI-associated and 265 WHR-associated genetic variants were analysed using linear regression, adjusting for age and sex, with sex-specific analyses for WHR. Analyses were conducted with and without BMI adjustments and corrected for multiple testing (padj). Additionally, we explored the relationship between IS-linked variants and their associations with type 2 diabetes (T2D), coronary artery disease (CAD) and stroke. Among the 678 BMI-associated variants, 100 showed nominal associations (p < 0.05) with at least one IS index; and 20 remained significant after multiple testing correction (padj < 0.05) when not adjusting for BMI. After adjusting for BMI, 70 variants retained nominal associations, and six remained significant (padj < 0.05). In sex-specific analyses of the 265 WHR-associated variants, 12 variants were associated in females when adjusted for BMI, whereas no significant associations were observed in males. Furthermore, BMI- and WHR-associated variants linked to decreased IS, such as those in FTO and VPS13C loci, were also associated with increased T2D and stroke risk, whereas IS-increasing variants, including those in VPS13C and PPARG, were linked to lower T2D and stroke risk, with some, like THADA, showing opposing effects on CAD. This study offers insights into genetic variants that influence both IS and obesity-related traits, revealing BMI- and WHR-associated variants with both positive and negative effects on IS and their potential impact on cardiometabolic health.

Introduction: Hyperinsulinemia and insulin resistance are strong predictors of cardiometabolic diseases, which disproportionately affect individuals across gender, racial/ethnic, and socioeconomic groups. We aim to estimate and test the temporal trends in the prevalence of hyperinsulinemia and insulin resistance (IR) by sociodemographic groups among nondiabetic adults in the United States from 1999 to 2018. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. We fitted linear and joinpoint logistic regression models to test the sample weighted and age-standardized time trends for linear and nonlinear trends in the prevalence of hyperinsulinemia and IR, respectively. Results: We included 17,310 nondiabetic men and nonpregnant women aged 20 years or older. The age-standardized prevalence of hyperinsulinemia increased from 28.2% in 1999-2000 to 41.4% in 2017-2018, with IR prevalence similarly rising from 24.8% in 1999-2000 to 38.4% in 2017-2018. Across the entire period examined, individuals who were male; non-Hispanic Black; Hispanic; or had a lower educational level or lower family income consistently had a higher prevalence of hyperinsulinemia and IR than other groups. We found increasing temporal trends in the prevalence of hyperinsulinemia and IR for all the sociodemographic subgroups, at least in some periods from 1999 to 2018. Conclusions: There was an increased age-standardized prevalence of hyperinsulinemia and IR among nondiabetic adults in the US across each defined sociodemographic group from 1999 to 2018. The difference in prevalence across subgroups underscores the need for designing personalized and targeted interventions to address disparities.

Background: Type 2 Diabetes Mellitus (T2DM) is associated with insulin resistance, hyperglycemia, and hyperlipidemia. Anthocyanins, which are natural antioxidants, have been reported to manage T2DM-related complications. However, the potential of anthocyanin-rich black wheat as a functional food for managing diabetes remains unexplored. Aim: This study aimed to investigate the effects of anthocyanin-rich black wheat on glucose metabolism, insulin sensitivity, lipid profile, oxidative stress, inflammation, and organ protection in high fat diet-streptozotocin (HFD-STZ) induced T2DM rats. Methods: T2DM was induced in rats using HFD-STZ. The rats were fed with either white wheat or anthocyanin-rich black wheat chapatti. Glucose metabolism, insulin sensitivity, lipid profile, antioxidant enzymes, inflammatory markers, and glucose transporters were assessed. Histopathological analysis of the liver, kidneys, and spleen was performed. Results: Compared to white wheat chapatti, black wheat chapatti exhibited higher α-amylase and α-glucosidase inhibitory activities. Black wheat chapatti consumption significantly reduced blood glucose and HbA1c levels, and improved insulin sensitivity, oral glucose tolerance, and insulin tolerance. Antioxidant enzyme (superoxide dismutase and catalase) activities were enhanced. Atherogenic dyslipidemia was attenuated, with improved high-density lipoprotein cholesterol levels. Inflammatory markers (TNF-α, IL-1β, leptin, resistin and cortisol) were reduced, while adiponectin (Acrp-30) levels increased. Black wheat chapatti activated adiponectin-AMPK and PI3K-AKT pathways, upregulating glucose transporters (GLUT-2 and GLUT-4). Histopathology revealed protective effects on the liver, kidneys, and spleen. Conclusions: Anthocyanin-rich black wheat chapatti ameliorates insulin resistance and associated complications in HFD-STZ-induced T2DM rats. It modulates key signaling pathways and glucose transporters, demonstrating its potential as a functional food for managing T2DM and its complications.

Hibiscus sabdariffa L. (HS) has been investigated as an alternative treatment for metabolic syndrome (MetS), as it affects all MetS components with low side effects simultaneously; however, clinical evidence regarding its efficacy compared with placebo is inconsistent. This study assessed how the aqueous calyx extract of HS influences insulin resistance and MetS parameters and examined the safety effects on liver, kidney, and hematological indexes in participants with abdominal obesity and mild MetS symptoms.

In this double-blind, randomized, placebo-controlled trial, 108 participants with MetS were randomly assigned to take 1000-mg HS (45.04mg/day in total polyphenols) or placebo daily for 12 weeks. Insulin resistance (HOMA-IR), glycemic markers, body mass index (BMI), waist circumference (WC), lipid profiles, and blood pressure were assessed at baseline, 6 weeks, and 12 weeks. Additionally, liver and kidney function indicators along with hematological parameters were evaluated.

Compared with placebo, HS did not significantly affect HOMA-IR, glycemic markers, BMI, WC, lipid profile, or blood pressure. Although HS did not significantly alter the lipid profile overall, serum low-density lipoprotein (LDL) levels decreased significantly at 12 weeks compared with baseline (-7.98mg/dL, [95% CI, -14.80, -1.15]). Additionally, HS did not cause significant liver or kidney function or hematological changes compared with placebo.

Taking 1000-mg HS daily for 12 weeks seems to be safe. Placebo and HS groups showed good clinical results, and the extract was not associated with improved metabolic parameters in individuals with abdominal obesity and mild MetS symptoms, with the exception of lower serum LDL.

The relationship between menopause and diabetes risk is unclear, with some studies indicating a weak association. This study examined changes in diabetes risk, β-cell function, and insulin sensitivity in relation to menopause.

In this community-based cohort study, data from 6684 visits to 1224 women over a 16-year follow-up were analyzed. Diabetes risk changes were assessed in relation to the different menopausal phases: premenopausal (≥3 years before menopause), perimenopausal (2 years before to 1 year after menopause), and postmenopausal (≥2 years after menopause). Changes in β-cell function and insulin sensitivity indices were tracked, and their relationship with diabetes risk was assessed. Generalized estimating equations and linear mixed models were used, adjusting for covariates including age at menopause and obesity.

Diabetes incidence was 18.6% among participants. The odds ratio (OR) of diabetes increased by 1.03 times annually during the premenopausal period (OR 1.03; 95% CI 1.02-1.04) and decreased during the postmenopausal period (OR 0.96; 95% CI 0.95-0.97). The incident diabetes groups showed a decline in insulin sensitivity and β-cell function, resulting in a decrease in the disposition indices over time. A large change in insulin sensitivity, especially during the period immediately before the onset of diabetes, increased the risk of diabetes (OR 1.88; 95% CI 1.33-2.67).

This study indicates an increased diabetes risk during the premenopausal periods, compared with that in the postmenopausal period, independent of age at menopause and obesity. Additionally, a decrease in insulin sensitivity followed by a subsequent decrease in β-cell function depending on the time of onset was related to the risk of diabetes. These findings enhance the understanding of diabetes risk and associated changes in insulin indices in relation to menopause, emphasizing the importance of health management and diabetes prevention for women in menopausal transition.

Sporadic Alzheimer's disease (AD), which accounts for the majority of cases, is sturdily influenced by lifestyle factors such as dietary habits, obesity, and diabetes, leading to its classification as Type 3 diabetes. To model this pathological link, our AD-like model was developed by feeding Wistar male rats a high-fat diet with fructose in drinking water (HFFD) for 8 weeks, followed by a single dose of lipopolysaccharide (LPS). This group was compared with a normal control group fed a standard diet and a β-hydroxybutyrate (BHB)-treated group (125 mg/kg, p.o.), administered starting 3 h after LPS and continuing for 1 week. The results demonstrate that BHB treatment illuminated cognitive gains, as indicated by the Y-maze, Morris water maze, and novel object recognition tests. In addition, it preserved hippocampal cytoarchitecture, reduced neurodegeneration, and attenuated amyloid plaques and phosphorylated Tau deposition. Cellularly, BHB restored critical molecular mechanisms, including increased lysosomal-associated membrane protein 2A (LAMP2A) hippocampal content as the main marker of chaperone-mediated autophagy (CMA), along with the chaperon protein Hsp70. Moreover, BHB alleviated neuroinflammation by inhibiting the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome activation alongside the downstream targets cleaved caspase-1 and IL-1β/IL-18 cytokines. BHB also reduced pyroptotic markers, caspase-11 and gasdermin-N, and microglia-induced inflammation as it shifted microglial polarization toward the neuroprotective M2 phenotype. Finally, BHB normalized hippocampal neurotransmitter levels of the inhibited acetylcholine and serotonin. These findings support BHB as a promising, multifaceted treatment for AD, highlighting the roles of CMA, Hsp70, and 5-HT in slowing disease progression and improving cognitive function.

It is debated that probiotics can improve glycolipid metabolism and slow the progression of prediabetes to diabetes mellitus. This study aimed to evaluate the effect of probiotics on lipid profile, glucose homeostasis, serum level of resistin, adiponectin, and vascular endothelial growth factor (VEGF) in prediabetic patients. This double-blind, randomized, placebo-controlled clinical trial was conducted on prediabetic patients in the Endocrinology clinic of Ghaem Hospital. Patients were randomly divided into two groups: the probiotics group was prescribed a daily 500-mg capsule of probiotics (109 colony-forming units), while the other received a placebo capsule with the same appearance. After 3 months, the effect of probiotic administration on laboratory parameters indicative of glycolipid metabolism, resistin, adiponectin, VEGF, body mass index (BMI), and blood pressure was compared between groups. This study was registered in the Iranian Registry of Clinical Trials (IRCT 20190801044405 N2). Fifty-two patients were included in the final analysis, with 26 patients in each group. The mean age of patients was 43.75 ± 8.45. At the beginning, both groups were similar in all demographic characteristics and measured serum levels of investigated biomarkers (p > 0.05 for all parameters). Both groups exhibited significant changes in BMI and fasting blood sugar (FBS). However, regarding FBS, the magnitude of change was significantly greater in patients treated with probiotics (p = 0.022). Our findings also revealed a significant increase in HDL (p = 0.001), adiponectin (p < 0.001), and VEGF (p = 0.024) serum levels and a significant decrease in HbA1c (p = 0.034), LDL (p = 0.002), TG (p < 0.001), and total cholesterol (p = 0.001) exclusively in the probiotics group. Probiotic supplementation efficiently improved glycolipid metabolism, adiponectin, and VEGF serum levels.