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Implantation-caused foreign-body response (FBR) is a commonly encountered issue and can result in failure of implants. The high L-serine content in low immunogenic silk sericin, and the high D-serine content as a neurotransmitter together inspire us to prepare poly-DL-serine (PSer) materials in mitigating the FBR. Here we report highly water soluble, biocompatible and easily accessible PSer hydrogels that cause negligible inflammatory response after subcutaneous implantation in mice for 1 week and 2 weeks. No obvious collagen capsulation is found surrounding the PSer hydrogels after 4 weeks, 3 months and 7 months post implantation. Histological analysis on inflammatory cytokines and RNA-seq assay both indicate that PSer hydrogels show low FBR, comparable to the Mock group. The anti-FBR performance of PSer hydrogels at all time points surpass the poly(ethyleneglycol) hydrogels that is widely utilized as bio-inert materials, implying the potent and wide application of PSer materials in implantable biomaterials and biomedical devices. Implantation-caused foreign-body response is a commonly encountered issue and can result in failure of implants. Here, the authors demonstrate that a highly water soluble, biocompatible, and easily accessible poly-DL-serine hydrogel can mitigate foreign-body response.

Metabolic diseases are the most common and rapidly growing health issues worldwide. The massive population-based human genetics is crucial for the precise prevention and intervention of metabolic disorders. The China Metabolic Analytics Project (ChinaMAP) is based on cohort studies across diverse regions and ethnic groups with metabolic phenotypic data in China. Here, we describe the centralized analysis of the deep whole genome sequencing data and the genetic bases of metabolic traits in 10,588 individuals from the ChinaMAP. The frequency spectrum of variants, population structure, pathogenic variants and novel genomic characteristics were analyzed. The individual genetic evaluations of Mendelian diseases, nutrition and drug metabolism, and traits of blood glucose and BMI were integrated. Our study establishes a large-scale and deep resource for the genetics of East Asians and provides opportunities for novel genetic discoveries of metabolic characteristics and disorders.

Males are generally more susceptible to impaired glucose metabolism and type 2 diabetes (T2D) than females. However, the underlying mechanisms remain to be determined. Here, we revealed that gut microbiome depletion abolished sexual dimorphism in glucose metabolism. The transfer of male donor microbiota into antibiotics-treated female mice led the recipients to be more insulin resistant. Depleting androgen via castration changed the gut microbiome of male mice to be more similar to that of females and improved glucose metabolism, while reintroducing dihydrotestosterone (DHT) reversed these alterations. More importantly, the effects of androgen on glucose metabolism were largely abolished when the gut microbiome was depleted. Next, we demonstrated that androgen modulated circulating glutamine and glutamine/glutamate (Gln/Glu) ratio partially depending on the gut microbiome, and glutamine supplementation increases insulin sensitivity in vitro. Our study identifies the effects of androgen in deteriorating glucose homeostasis partially by modulating the gut microbiome and circulating glutamine and Gln/Glu ratio, thereby contributing to the difference in glucose metabolism between the two sexes. Male sex is a risk factor for impaired glucose metabolism and type 2 diabetes. Here the authors identify that androgen modulates the gut microbiome, which drives insulin resistance and contributes to sexual dimorphism in glucose metabolism in mice.

Aims/hypothesisThe cardiometabolic risk associated with metabolically healthy obesity (MHO) remains the subject of debate. It is unclear whether MHO is a transient condition that affects subclinical atherosclerosis risk. In this study, we aimed to investigate the association of MHO and its transition over time with incident subclinical atherosclerosis.MethodsA prospective study was conducted with 6220 Chinese adults who were free of cardiovascular disease (CVD) at baseline. Obesity was defined as BMI ≥25.0 kg/m2. Metabolic health was defined as an individual having fewer than two of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) criteria for components of the metabolic syndrome (excluding waist circumference). Subclinical atherosclerosis was measured by brachial–ankle pulse wave velocity, pulse pressure and albuminuria, separately or combined. Participants were cross-classified by BMI categories and by metabolic health status and its transition during follow-up. Inverse probability weighted logistic regression models were used to estimate ORs and 95% CIs for subclinical atherosclerosis.ResultsThe MHO phenotype accounted for 16.3% of the total population and 32.8% of the population with obesity at baseline. Baseline MHO was not significantly associated with incident subclinical atherosclerosis. During a follow-up period of 4.4 years, 46.8% of individuals with MHO developed a metabolically unhealthy status. Those with transient MHO had an increased risk of composite subclinical atherosclerosis compared with those in the metabolically healthy non-obesity reference group (OR 2.52 [95% CI 1.89, 3.36]). A transition from metabolically unhealthy to healthy status was shown to decrease the outcome risk. The relationship between BMI and subclinical atherosclerosis was partly mediated by BP and plasma glucose.Conclusions/interpretationMHO is not a stable condition and transient MHO conferred an increased risk of subclinical atherosclerosis, the early stage of CVD. Hence, individuals may benefit from early behavioural or medical management in order to avoid a deterioration of metabolic status and prevent atherosclerosis and CVD.

Composition of gut bacteria and serum metabolites in young, obese individuals is partially restored following weight loss surgery, including Bacteroides thetaiotaomicron , which decreases serum glutamate levels and fat mass gain in mice. Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron , a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.

Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides , thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella , those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment. The authors examine the effects of antidiabetic medication on the gut microbiome and bile acid composition and show that these data can be used to stratify treatment regimens for type 2 diabetes.

Protein acetylation has a crucial role in energy metabolism. Here we performed the first large-scale profiling of acetylome in rat islets, showing that almost all enzymes in core metabolic pathways related to insulin secretion were acetylated. Label-free quantitative acetylome of islets in response to high glucose revealed hyperacetylation of enzymes involved in fatty acid β-oxidation (FAO), including trifunctional enzyme subunit alpha (ECHA). Acetylation decreased the protein stability of ECHA and its ability to promote FAO. The overexpression of SIRT3, a major mitochondrial deacetylase, prevented the degradation of ECHA via decreasing its acetylation level in β-cells. SIRT3 expression was upregulated in rat islets upon exposure to low glucose or fasting. SIRT3 overexpression in islets markedly decreased palmitate-potentiated insulin secretion, whereas islets from SIRT3 knockout mice secreted more insulin, with an opposite action on FAO. ECHA overexpression partially reversed SIRT3 deficiency-elicited insulin hypersecretion. Our study highlights the potential role of protein acetylation in insulin secretion.

Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype (‘mvIR’), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes ( AKT1 , ERBB3 , FCGR1A , FGFR1 , LPL , NR1H3 ) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity. Insulin resistance contributes to cardiometabolic disease, but its genetic basis remains incompletely defined. Here, the authors identify 217 associated loci and highlight potential therapeutic targets, linking insulin resistance to multiple diseases and aging traits.

ABSTRACT Background The cardioprotective effects of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA)‐based therapies in nondiabetic individuals with overweight or obesity remain underexplored. This meta‐analysis evaluates their impact on cardiovascular events and metabolic parameters in this population. Methods A meta‐analysis was conducted using PubMed, Embase, Cochrane, and Web of Science databases from inception to June 18, 2024. Eligible studies were randomized controlled trials (RCTs) enrolling nondiabetic adults with overweight or obesity. These studies compared GLP‐1RA‐based therapies with placebo and reported cardiovascular events and metabolic parameters. Results A total of 29 RCTs involving 9 GLP‐1RA‐based drugs and 37 348 eligible participants were included. Compared to placebo, GLP‐1RA‐based therapies significantly reduced the risk of total cardiovascular events (relative risk: 0.81, 95% confidence interval [CI]: [0.76, 0.87]), major adverse cardiovascular events (0.80, [0.72, 0.89]), myocardial infarction (0.72, [0.61, 0.85]), and all‐cause mortality (0.81, [0.71, 0.93]). No significant differences were observed in cardiovascular death or stroke. Additionally, GLP‐1RA‐based therapies were associated with significant reductions in some cardiometabolic parameters. Among GLP‐1RA‐based therapies, orfroglipron demonstrated strong benefits in reducing systolic blood pressure (mean difference: −7.10 mmHg, 95% CI: [−11.00, −2.70]). Tirzepatide induced the greatest reduction in body mass index (−6.50 kg/m2, [−7.90, −5.10]) and hemoglobin A1c concentrations (−0.39%, [−0.52, −0.26]). Retatrutide and semaglutide were most effective in improving lipid profiles and reducing C‐reactive protein levels (−1.20 mg/dL, [−1.80, −0.63]), respectively. Conclusions In nondiabetic individuals with overweight or obesity, GLP‐1RA‐based therapies significantly reduce cardiovascular events and improve cardiometabolic parameters. These findings underscore the potential for individualized GLP‐1RA‐based therapies targeting cardiovascular risk factors.