Diabetes, Obesity & Metabolism最新文献

Aims: Higher cardiorespiratory fitness is associated with reduced type 2 diabetes mellitus (T2D) risk, but the underlying mechanisms remain incompletely understood. We investigated whether biological aging mediates the association between maximal oxygen uptake (VO₂max) and incident T2D risk.

Materials and methods: This prospective cohort study included 54 418 UK Biobank participants aged 39-70 years without baseline diabetes. VO₂max was estimated using a validated algorithm incorporating resting heart rate, physical activity, age, sex and body mass index. Biological age (BA) and phenotypic age (PhenoAge) were calculated from clinical biomarkers. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sociodemographic, lifestyle and clinical factors. Linear regression analyses assessed cross-sectional associations between VO₂max and standardised glycaemic and lipid biomarkers. Mediation analysis quantified the proportion of association explained by biological aging measures.

Results: During 694 986 person-years of follow-up, 2628 participants developed T2D (incidence rate: 3.78 per 1000 person-years). Compared to the lowest VO₂max quartile, participants in the highest quartile had a 56% lower T2D risk (HR 0.44, 95% CI = 0.39-0.50). Each standard deviation increase in VO₂max was associated with a 28% lower risk (HR 0.72, 95% CI = 0.68-0.76). BA acceleration mediated 8.2% (95% CI = 6.1%-10.8%) and PhenoAge acceleration mediated 9.1% (95% CI = 6.8%-12.1%) of the VO₂max-T2D association. Protective associations were consistent across sex, age, ethnicity and genetic risk subgroups. VO₂max showed strong inverse correlations with glucose (β = -0.32), glycated haemoglobin (β = -0.28), triglycerides (β = -0.31) and a positive correlation with high-density lipoprotein (HDL) cholesterol (β = 0.29).

Conclusions: Higher cardiorespiratory fitness demonstrates robust protective associations against T2D incidence, with biological aging mechanisms partially mediating this relationship.

Aims: To comprehensively assess the efficacy and safety of liraglutide on metabolic and hepatic outcomes in patients with non-alcoholic fatty liver disease (NAFLD), with or without type 2 diabetes mellitus (T2DM), based on randomised controlled trials (RCTs).

Materials and methods: Electronic databases (PubMed, Web of Science, Cochrane Library and Embase) were systematically searched for randomised RCTs evaluating liraglutide in the treatment of NAFLD. Outcome measures included body mass index (BMI), glycated haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and adverse events (AEs).

Results: Eight RCTs (with an overall moderate risk of bias as assessed by the Cochrane Risk of Bias tool) involving 478 participants were included in the analysis. The meta-analysis results demonstrated that liraglutide significantly improved BMI (standardised mean difference [SMD]: -0.85; 95% confidence interval [CI]: -1.04 to -0.66), FPG (SMD: -1.22; 95% CI: -1.97 to -0.46), and GGT (SMD: -1.10; 95% CI: -1.48 to -0.72; p < 0.00001) in patients with NAFLD, regardless of T2DM comorbidity. Furthermore, liraglutide showed positive effects on ALT (SMD: -0.44; 95% CI: -0.80 to -0.08) and TG (SMD: -1.08; 95% CI: -1.97 to -0.19) specifically in patients with NAFLD comorbid with T2DM. However, the effect of liraglutide on HbA1c was not statistically significant (SMD: 0.14; 95% CI: -0.39 to 0.67). Regarding safety, liraglutide was associated with a higher incidence of adverse events, primarily gastrointestinal disorders such as nausea and diarrhoea, though these were mostly transient.

Conclusions: Liraglutide demonstrates beneficial effects on BMI, FPG and GGT in patients with NAFLD with or without comorbid T2DM. It also shows positive effects on ALT and TG in patients with NAFLD and T2DM. While the treatment was associated with a higher burden of mostly manageable gastrointestinal adverse events, the findings of this study warrant further validation in prospective high-quality studies.

Aims: Obesity involves both metabolic and neural dysfunction, yet the temporal dynamics of brain connectivity remain unclear. This study applied dynamic functional network connectivity (dFNC) analysis to reveal time-varying brain network patterns in obesity.

Materials and methods: Eighty-three individuals with obesity and 40 normal-weight controls underwent resting-state functional magnetic resonance imaging. After preprocessing and group independent component analysis, dFNC was estimated using a sliding-window approach and clustered into distinct connectivity states. Temporal metrics (fraction time, dwell time and transitions) were compared between groups, and correlations with clinical characteristics were analysed.

Results: Three recurring connectivity states were identified. Compared with controls, individuals with obesity showed enhanced coupling among the default mode, attention and visual networks, with reduced network flexibility-manifested as prolonged dwell time and fewer transitions. Uncontrolled eating correlated positively with time spent in maladaptive states, whereas cognitive restraint was negatively associated with participation in integrative states.

Conclusions: Obesity is characterised by state-dependent reorganisation of large-scale brain networks and diminished temporal flexibility. These dynamic connectivity alterations are closely related to eating behaviour and metabolic characteristics, suggesting that dFNC provides a valuable neuroimaging framework for understanding impaired self-regulation in obesity and for guiding future intervention studies.

Aims: Mixed evidence exists on whether metformin adds to or attenuates the insulin-sensitising effects of exercise. To date, no studies have tested whether metformin differentially impacts exercise training intensity-mediated insulin sensitivity. We tested the hypothesis that metformin would blunt metabolic insulin sensitivity and carbohydrate oxidation in an intensity-based manner among adults with metabolic syndrome (MetS) risk.

Materials and methods: In a double-blind, placebo-controlled trial, participants were randomised to low-intensity exercise plus placebo (~55% VO₂max 5 days/week, LoEx + PL, n = 22) or metformin (2000 mg/day, LoEx + Met, n = 21) and high-intensity exercise plus placebo (~85% VO₂max 5 days/week, HiEx + PL, n = 24) or metformin (HiEx + Met, n = 24) for 16 weeks. A 120-min euglycaemic-hyperinsulinemic clamp (40 mU/m²/min, 90 mg/dL) was conducted pre- and post-treatment to assess metabolic insulin sensitivity (M-value/insulin). Fasting and insulin-stimulated carbohydrate oxidation was also assessed using indirect calorimetry. Adipokines (leptin, high molecular weight (HWM), and total adiponectin) were measured at 0 and 120 min of the clamp. Aerobic fitness (VO₂max) and body composition (DXA) were also analysed.

Results: HiEx + PL increased metabolic insulin sensitivity (p = 0.017) while HiEx + Met, LoEx + PL, or LoEx + Met did not. HiEx + PL also raised insulin-stimulated carbohydrate oxidation and decreased fat oxidation compared with LoEx + Met (both, p = 0.008). Increased metabolic insulin sensitivity related to reductions in fasting glucose (r = -0.41, p = 0.025), VO₂max (r = 0.55, p = 0.002), fasting leptin (r = -0.54, p = 0.01), and weight loss (r = -0.60, p < 0.001) after exercise and placebo, but not exercise and metformin.

Conclusions: Metformin attenuated metabolic insulin sensitivity and insulin-stimulated carbohydrate oxidation after high-intensity exercise training in adults at risk for MetS.

Aims: Obesity is a growing global health crisis; pharmacotherapies such as tirzepatide combined with multidisciplinary lifestyle support have shown promise but real-world evidence in digital weight-loss services (DWLSs) is limited. This retrospective study evaluated 6- and 12-month weight loss, adherence and predictors of outcomes in an Australian cohort using a tirzepatide-supported medicated DWLS.

Materials and methods: All patients initiating tirzepatide through the Juniper AU DWLS between 1 September 2024 and 23 April 2025 (n = 4309) were analysed. The study population was predominantly female (92.9%) and Caucasian (81.9%), with a mean age of 41.46 years and a mean baseline body mass index of 32.9 kg/m². Primary endpoints were programme adherence at 6 and 12 months and mean percentage weight loss among adherent patients. Adherence required ≥5 medication orders and a weight entry at 173-193 days after programme initiation (6 months), or ≥10 orders and a weight entry 355-375 days post-initiation (12 months). Full cohorts were analysed using last observation carried forward imputation.

Results: At 6 months, 31.7% met adherence criteria; mean weight loss among adherent patients was 16.9% (±8.6; 95% CI 16.6-17.2), with 98.0% achieving ≥5% weight reductions. At 12 months, 16.1% were adherent; mean weight loss was 22.7% (±7.2; 95% CI: 19.8-22.6) and 100% of patients reached the ≥5% milestone. Multivariable models identified 1-month weight loss as the strongest predictor of 6- and 12-month outcomes; sustained weekly weight tracking and health coach messaging were strongly associated with both retention and greater weight loss. Paradoxically, very frequent weight tracking in month one correlated with poorer outcomes and reduced retention. Side effects were common but mostly mild/moderate and did not correlate with weight loss or programme retention.

Conclusions: Tirzepatide plus multidisciplinary digital care yields large clinically meaningful weight loss among engaged users, but low adherence limits population-level effectiveness. Early clinical response and sustained engagement are key drivers of adherence; however, interventions are needed to manage early weight-loss expectations.

Aims: The timing of physical activity may influence metabolic health through interactions with circadian rhythms, yet its role in type 2 diabetes mellitus (T2DM) development is unclear. We investigated associations between time-of-day-specific physical activity and incident T2DM, and whether theoretically reallocating activity from morning to later in the day was associated with changes in T2DM risk.

Materials and methods: We included 4615 participants from The Maastricht Study cohort without diabetes (age 59.2 ± 8.6 years; 56.3% women). Device-based physical activity was measured over 7 days using activPAL monitors and classified into light-intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA), for morning (06:00-11:59 AM), afternoon (12:00-17:59 PM), evening (18:00-23:59 PM) and night (00:00-05:59 AM). Incident T2DM was assessed during a median 8.2-year follow-up. Cox proportional hazard and isotemporal substitution models were used, adjusted for sociodemographic and lifestyle factors, including diet, employment and sleep duration.

Results: During follow-up, 168 participants (3.6%) developed T2DM. Each additional 10 min/day of afternoon LPA or MVPA was associated with lower T2DM risk (LPA: hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.70-0.97; MVPA: HR 0.85, 95% CI 0.72-1.00). Evening MVPA was also inversely associated with T2DM risk (0.65; 0.45-0.93), whereas night-time MVPA was associated with an increased risk (3.64; 1.30-10.17). No significant associations were found of morning LPA and MVPA or evening and night LPA with T2DM incidence. Substitution analyses indicated that reallocating 10 min of morning LPA to afternoon LPA (HR 0.71; 0.54-0.95) or morning MVPA to evening MVPA (HR: 0.64; 0.43-0.96) was associated with a lower T2DM risk, while no other significant associations were observed.

Conclusions: Later-day physical activity, particularly in the afternoon, was associated with a lower incidence of T2DM, independent of intensity. This highlights the potential relevance of activity timing in relation to T2DM incidence.

Aims: Heart failure (HF) may develop in type 2 diabetes without prior cardiovascular disease (CVD). This study aimed to identify risk factors that distinguish CVD that presents first as a HF event versus CVD that presents first as an atherosclerotic event (ASCVD), among people with type 2 diabetes.

Materials and methods: ORIGIN and REWIND trial participants with type 2 diabetes but free of CVD (N = 6175; 64 ± 7 years, 50.1% female) were followed for ~5.8 years for incident CVD presenting first as either a HF event (HF hospitalization or HF death), ASCVD (myocardial infarction, unstable angina, stroke, or revascularization), or other cardiovascular death. Multi-state models characterised event-specific associations of risk factors with each possible first CVD event.

Results: HF was the first event in 16.8% of 1024 incident CVD cases. Older age, higher BMI, and higher urine albumin:creatinine ratio were more strongly associated with CVD manifesting first as HF, rather than as ASCVD or other cardiovascular death. ASCVD as the first event (65.2% of cases) was more strongly associated with worse LDL-cholesterol and HbA1c. These unique associations of risk factors with HF versus ASCVD translated to variable probabilities of HF as the first CVD event, depending on the clinical profile (32.0% for a profile enriched with HF-specific risk factors versus 5.1% for a profile enriched with ASCVD-specific risk factors).

Conclusions: CVD that presents first as a HF event is common in type 2 diabetes and its risk factors are distinct from those associated with CVD that presents first as an ASCVD event.

Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents one of the most common chronic liver disorders worldwide, and its incidence continues to rise each year. Serine β-lactamase-like protein (LACTB) is a serine protease that plays a crucial role in lipid metabolism and hepatocellular carcinoma, but its function in MASLD remains unclear. Therefore, the study aims to elucidate the effect and mechanism of LACTB in the progression of MASLD.

Materials and methods: The expression of LACTB in liver tissues from MASLD patients and high-fat diet (HFD) fed mice was assessed. Both in vivo and in vitro models were established to examine the role and molecular mechanisms of LACTB in MASLD.

Results: LACTB protein levels were upregulated in the liver tissues from MASLD patients and HFD-fed mice. LACTB overexpression exacerbated hepatic steatosis, insulin resistance, and inflammation in HFD-fed mice. Conversely, LACTB knockdown improved these phenotypes. Mechanistically, LACTB interacted with CPT2 and promoted its ubiquitin-mediated degradation. The effect of LACTB in hepatocellular lipid metabolism was dependent on CPT2.

Conclusions: Our findings indicate that LACTB is a novel regulatory factor in MASLD by influencing the ubiquitin-mediated degradation of CPT2 to participate in disease progression. These findings may provide a novel potential therapeutic strategy for MASLD.