Xinhua Xiao

Safiglipron is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered without fasting or dietary restrictions. We evaluated its efficacy and safety in OUTSTAND-1, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 46 sites in China. We randomized 284 adults with type 2 diabetes managed with diet and exercise alone (mean baseline HbA1c 7.95%, median diabetes duration 1.6 years, 33.1% women) to once-daily safiglipron 30 mg ( n = 70), 60 mg ( n = 70), 90 mg ( n = 72) or placebo ( n = 72) for 32 weeks, followed by a 20-week active-treatment extension. For the primary endpoint, placebo-adjusted treatment differences in HbA1c change from baseline to week 32 were −1.22% (95% CI, −1.53 to −0.91), −1.20% (95% CI, −1.52 to −0.89) and −1.45% (95% CI, −1.75 to −1.14) for 30 mg, 60 mg and 90 mg, respectively (all P < 0.0001; treatment policy estimand). Secondary outcomes showed HbA1c < 7.0% in 71.4−77.8% versus 25.0%, HbA1c ≤ 6.5% in 58.6−68.1% versus 16.7% and placebo-adjusted fasting plasma glucose differences of −1.58, −1.68 and −2.08 mmol l ^{− 1} , respectively (all P < 0.0001). Body weight differences were modest (−0.65%, −2.23% and −3.56% versus placebo). Other secondary outcomes generally favored safiglipron for HbA1c < 5.7% attainment, postprandial glycemia, homeostatic model assessment of β cell function (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), disposition index and waist circumference, with less rescue therapy use. Insulin and C-peptide responses varied by dose, and changes in treatment satisfaction were limited. Gastrointestinal adverse events were most common and mostly mild or moderate. Adverse events led to treatment discontinuation in 1.4%, 2.9%, 6.9% and 0% of participants receiving safiglipron 30 mg, 60 mg, 90 mg and placebo, respectively. These findings support once-daily oral safiglipron as an effective treatment option for type 2 diabetes. ClinicalTrials.gov identifier: NCT06672172 .

Aims: Rare GCK variants contribute to heterogeneous forms of monogenic diabetes, yet the molecular basis underlying their diverse functional consequences and pharmacological responsiveness remains incompletely understood. As glucokinase (GCK) serves as a central glucose sensor in pancreatic β‐cells and hepatocytes, defining the functional properties of individual variants may improve molecular diagnosis and inform the interpretation of potential therapeutic responses in GCK‐maturity‐onset diabetes of the young (GCK‐MODY, also called MODY2). Materials and Methods: We established a recombinant protein‐based functional platform to investigate two rare GCK variants, p.Leu88Pro and p.Val374Glu, identified in Chinese families with GCK‐MODY. Wild‐type and mutant GCK proteins were expressed and purified using a GST‐tagged prokaryotic system. Functional consequences were assessed by glucose‐response kinetics, pharmacological modulation with dorzagliatin, thermal stability analysis and structural stability prediction. Results: The p.Leu88Pro variant demonstrated impaired glucose sensing, with an increased S _0.5 value, together with reduced stability and a marked predicted destabilizing effect. The p.Val374Glu variant retained near‐normal glucose‐response kinetics under basal conditions but exhibited reduced thermal stability. Dorzagliatin markedly reduced the S _0.5 of p.Val374Glu with limited effects on maximal catalytic activity. Structural stability analysis further indicated reduced protein stability for both variants, with a greater predicted destabilizing effect for p.Leu88Pro than for p.Val374Glu. Conclusions: Rare GCK variants can cause heterogeneous biochemical defects and show differential responses to pharmacological activation. Integrating glucose‐response kinetics, protein stability assessment and drug‐response profiling provides complementary functional evidence for variant interpretation and highlights the molecular heterogeneity of GCK‐MODY and the potential for genotype‐dependent pharmacological responses.

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Aims: This study aims to systematically evaluate the efficacy of bimagrumab on body composition and glucose parameters in adults with obesity and metabolic dysfunction and its safety profile. Methods: We searched MEDLINE, PubMed, Embase, and the Cochrane Library on April 20, 2026, for randomized controlled trials (RCTs) assessing bimagrumab treatment in adults with obesity, insulin resistance, or type 2 diabetes mellitus (T2DM). The risk of bias was assessed using the Cochrane Risk of Bias tool (RoB 2), and meta‐analyses of efficacy and safety data were conducted using R software. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system was used to assess the strength of evidence. The study was registered with PROSPERO (CRD420261377110). Results: Of the 134 retrieved records, 4 RCTs (enrolling 268 participants) were included. The included population represented a broad spectrum of metabolic dysfunction, from obesity and nondiabetic insulin resistance to established T2DM. Compared with placebo, bimagrumab treatment significantly reduced total weight (mean difference [MD] –4.85 kg, 95% confidence interval [CI] –6.82 to −2.88), fat mass (−4.72 kg [−8.05 to −1.40]), and glycated haemoglobin (HbA1c) (−0.13% [−0.23 to −0.03]) and significantly increased total lean mass (1.66 kg [0.81 to 2.51]). However, bimagrumab led to an increase in low‐density lipoprotein (LDL) concentrations of 0.47 mmol/L [0.03 to 0.91] and significantly increased incidences of discontinuation (risk ratio [RR] 5.75 [1.61 to 20.46]), muscle spasms (RR 10.44 [4.23 to 25.75]), and diarrhoea (RR 4.91 [2.38 to 10.11]). Conclusion: Bimagrumab effectively reversed adverse effects on body composition in obese individuals, resulting in significant fat reduction, increased skeletal muscle mass, and improved glycemic control, suggesting that bimagrumab is a promising new target for personalized metabolic therapy.

Background/Objectives: The developmental origins of health and disease (DOHaD) theory suggests that intrauterine and early postnatal life represents a critical window for programming lifelong health trajectories and disease susceptibility in offspring. Maternal nutritional imbalance during this period is closely associated with obstetric complications and an elevated risk of metabolic disorders in children. As central metabolic hubs, mitochondria constitute a critical axis linking adverse in utero exposure to metabolic defects in offspring across generations. Methods: In this narrative review, we searched PubMed and Web of Science (up to 8 July 2026) for English-language literature linking maternal metabolic conditions and mitochondrial dysfunction. We included in vivo, in vitro, and clinical studies, explicitly excluding primary inherited mtDNA mutations and nonnutritional toxicant exposures to isolate nutritional programming effects. Results: Maternal metabolic stress induces multifaceted, tissue-specific mitochondrial alterations in the developing offspring. Rather than a uniform systemic decline, mitochondrial reprogramming exhibits profound spatial and cellular heterogeneity across critical metabolic organs, including the placenta, liver, skeletal muscle, heart, and hypothalamus. These developmental adaptations often manifest as molecular compensations, such as altered mitochondrial dynamics, perturbed biogenesis, and shifted OXPHOS capacity, ultimately leading to functional bioenergetic failure, oxidative stress, and the establishment of insulin resistance. Discussion: Organ-specific mitochondrial dysfunction drives the maternal transmission of metabolic syndrome. Targeting these mechanisms via dietary modifications, exercise, pharmacological agents, and mitochondrial transplantation offers promising strategies to rescue bioenergetics and prevent metabolic diseases in offspring.

Objective: To report a novel GCK variant (c.263T>C) identified in a patient with glucokinase-maturity-onset diabetes of the young (GCK-MODY) and to evaluate its pathogenicity and potential structural impact using in silico analyses. The proband had a paternal history of type 2 diabetes mellitus (T2DM) and was overweight with marked insulin resistance, presenting with clinical features suggestive of T2DM. She also exhibited transient glutamic acid decarboxylase antibody (GADA) positivity. Clinical characteristics were further evaluated to facilitate the differential diagnosis. Case presentation: A novel GCK missense variant was identified in a Chinese family, with the daughter as the proband. At 6 years of age, she presented with mild fasting hyperglycemia and initial GADA positivity and was misdiagnosed with type 1 diabetes mellitus (T1DM). However, her clinical features and family history were suggestive of MODY. Whole-exome sequencing revealed a heterozygous GCK c.263T>C variant, confirmed by Sanger sequencing in her mother, maternal grandmother, and maternal grandaunt. The variant was classified as likely pathogenic, establishing a diagnosis of GCK-MODY. Notably, she also exhibited obesity and a paternal family history of T2DM. During follow-up, GADA seroconverted to negative, with no evidence of persistent autoimmune diabetes. Conclusion: This case identifies a novel likely pathogenic GCK variant (c.263T>C) in a Chinese family and highlights the coexistence of GCK-MODY with insulin resistance within the same pedigree. The proband’s severe insulin resistance may be attributable to the combined effects of obesity and a paternal history of T2DM, contributing to a complex clinical phenotype. Transient GADA positivity was not associated with persistent autoimmune diabetes, suggesting it may reflect metabolic stress rather than true autoimmune pathogenesis.

Genetic predisposition and unhealthy lifestyles are well-known contributors to disorders of glucose and lipid metabolism, including type 2 diabetes, obesity, and metabolic dysfunction-associated fatty liver disease. However, these factors alone cannot fully explain the rapidly rising prevalence of these conditions. Emerging evidence highlights the pivotal role of the intrauterine environment in gestational diabetes mellitus (GDM) in shaping epigenetic modifications and metabolic reprogramming, thereby predisposing offspring to long-term metabolic complications. Exosomes have recently been identified as key mediators of maternal-fetal communication. In GDM, both the quantity and cargo (e.g., proteins, miRNAs) of exosomes are altered. These altered exosomes not only contribute to maternal glucose and lipid metabolic abnormalities but also act as a critical vector for transmitting adverse metabolic signals to the offspring. This exosome-mediated communication disrupts placental function and the development of fetal metabolic organs, ultimately programming the offspring for long-term metabolic disorders. In this review, we summarize the characteristic changes of maternal exosomes in GDM and explore the potential mechanism by which exosomes regulate offspring metabolism during maternal-fetal crosstalk. We also propose the possible direction of exosomes in application, providing insights into early-life strategies for the prevention of metabolic diseases.

Introduction: The global diabetes epidemic has brought gestational diabetes mellitus (GDM) and its long-term impacts on maternal-child health into sharp focus. Emerging evidence indicates that early-life metabolic programing, mediated significantly by gut microbiota, profoundly influences offspring glucose homeostasis. Notably, microbial-targeted nutritional interventions, including probiotic and prebiotic supplementation, have considerable potential as innovative therapeutic approaches. These strategies may effectively prevent intergenerational transmission of metabolic diseases by improving glucose metabolism in both mother and offspring. Methods: This narrative review synthesizes evidence from clinical trials and animal studies investigating the effects of maternal probiotic and prebiotic supplementation on glucose metabolism. We searched and analyzed literature focusing on glycemic outcomes in pregnant women with or without GDM and their offspring, as well as studies exploring underlying mechanisms including gut microbiota modulation, metabolite production, inflammatory pathways, and epigenetic regulation. Results: Clinical and animal studies have shown that probiotics and prebiotics can significantly alleviate metabolic parameters such as elevated fasting glucose and insulin resistance in patients with GDM, but their preventive effect on the incidence of GDM is unclear. In addition, maternal supplementation with probiotics or prebiotics may positively affect glucose metabolism in offspring through multiple interconnected mechanisms, which include the modulation of intestinal microbial ecology, the increased generation of microbial- derived metabolites such as short-chain fatty acids (SCFAs), the mitigation of inflammatory responses, and epigenetic regulation (e.g., DNA methylation, lncRNA and miRNA modification). Discussion: Despite some heterogeneity in the results of existing studies, there is overall support for the therapeutic potential of probiotic and prebiotic interventions in optimizing metabolic outcomes for both maternal and pediatric populations. Future studies need to further define the optimal type, dose and timing of intervention for probiotics and prebiotics and explore precise intervention strategies on the basis of individual gut microbiota characteristics. In conclusion, probiotic and prebiotic supplementation during pregnancy and lactation may become an adjunctive tool to improve glucose metabolism in mothers and infants, resulting in innovative approaches for the primary prevention of metabolic diseases.

Environmental factors, such as nutrition, hormones, and metabolites, which are present in early stages of life, have long-lasting effects throughout an organism’s lifespan, and an abnormal nutritional environment throughout gestation and lactation may significantly increase the possibility that offspring will develop chronic metabolic disorders. The important nutrients docosahexaenoic acid (C22:6n-3, DHA) and eicosapentaenoic acid (C20:5n-3, EPA), which are essential long-chain omega-3 polyunsaturated fatty acids, contribute to proper neurological and retinal development and exhibit both anti-inflammatory properties and lipid-reducing capabilities. Recent research has demonstrated that maternal diets supplemented with EPA and DHA may regulate lipid metabolism-related genes in the liver and adipose tissues and alter the intestinal microbial composition in offspring. These changes influence the progression of lipid metabolic disorders, including dyslipidemia, obesity, and MAFLD in the next generation. This narrative review illustrates the effects of maternal EPA and DHA intervention during the prenatal and breastfeeding period on lipid metabolism in the offspring and the underlying mechanisms. We also explore the directions for future research.