Diabetes, Obesity & Metabolism最新文献

Aim: To synthesise evidence from RCTs investigating the effectiveness of nutrition interventions on depression, anxiety, stress, and/or diabetes distress outcomes in adults living with diabetes.

Methods: Six online databases were searched using key words between 2000 and February 2024. Included studies were conducted in adult populations (≥18 years), with Type 1 (T1D) or Type 2 Diabetes (T2D), investigating impacts of nutrition interventions on mental health outcomes. Random effects meta-analyses were undertaken for mental health outcomes.

Results: Thirty publications met inclusion criteria, all included adults with T2D, with one including both T1D and T2D. The most common interventions were nutrition supplements (n = 17, 57%) and altering macronutrient intakes (n = 5, 17%). Most studies reported on depression (n = 26) and anxiety (n = 14) outcomes, with fewer examining stress (n = 7) or diabetes-related distress (n = 8). Meta-analyses indicated nutrition supplementation when compared to control improved scores for depression (Beck Depression Inventory (BDI): WMD = -3.13; 95% CI: -5.09, -1.17) and anxiety (Beck Anxiety Inventory: WMD = -1.30; 95% CI: -2.08, -0.52) but not for stress. Meta-analyses confirmed that altering macronutrient composition significantly lowered diabetes-related distress (Problem Areas in Diabetes (PAID): WMD = -4.20; 95% CI: -8.18, -0.22).

Conclusion: This review provides evidence that nutrition interventions, particularly supplement use or altered macronutrient composition, improve depression and anxiety for those with T2D. Future research should evaluate the impact of whole dietary patterns on mental health in adults with diabetes, especially T1D, to inform effective food-based nutrition advice, rather than focusing on individual supplements.

Aims: Emerging evidence suggests that indole-3-propionic acid (IPA), a gut microbiota-derived tryptophan metabolite, confers metabolic benefits in type 2 diabetes (T2D). However, its direct role in preserving pancreatic β-cell function and the underlying molecular mechanisms remains largely undefined. This study aimed to investigate the role and underlying mechanisms of IPA in preserving β-cell function and alleviating endoplasmic reticulum (ER) stress under diabetogenic conditions.

Materials and methods: High-fat diet-fed and db/db mice were treated with IPA via oral gavage. Glucose homeostasis, islet morphology, and insulin secretion were evaluated. In vitro studies in MIN6 cells and isolated islets assessed IPA's effects on ER stress, insulin secretion, and apoptosis. Proteomics, molecular docking, luciferase reporter assays, and gene expression analyses were conducted to identify key molecular targets.

Results: IPA significantly preserved islet architecture and enhanced insulin secretion. Proteomic analysis revealed downregulation of ER stress pathways and upregulation of SGPP1 upon IPA treatment. SGPP1 was essential for IPA-mediated suppression of ER stress and β-cell apoptosis through direct interaction with HSPA5. IPA stabilized and activated the transcription factor FOXA1, which in turn transcriptionally upregulated SGPP1 expression.

Conclusion: IPA protects pancreatic β-cells by activating the FOXA1-SGPP1-HSPA5 signalling pathway, thereby alleviating ER stress and enhancing β-cell survival.

Aims: To evaluate the pharmacokinetics (PK) and safety of HR17031 (a fixed-ratio combination of INS068 and Noiiglutide) in subjects with hepatic impairment.

Materials and methods: This open-label, single-dose, nonrandomised, parallel-design trial enrolled 24 subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and normal hepatic function (n = 8 each). Participants received a single subcutaneous injection of HR17031 (10 U/0.024 mg). PK parameters of INS068 and Noiiglutide were determined by liquid chromatography-tandem mass spectrometry, free drug fractions were assessed by ultracentrifugation, and serum C-peptide concentrations were measured. Safety was monitored throughout.

Results: PK profiles of INS068 and Noiiglutide in subjects with mild hepatic impairment were comparable to those with normal function, while modest reductions were observed in moderate impairment (INS068 AUC_0-∞ geometric mean ratio [GMR]: 0.814 [0.703-0.944]; Noiiglutide AUC_0-∞ GMR: 0.713 [0.574-0.886]). Unbound fractions of both components and C-peptide concentrations showed no significant differences across groups. HR17031 was well tolerated, and there were no serious adverse events.

Conclusions: HR17031 demonstrated PK profiles of INS068 and Noiiglutide comparable between subjects with mild or moderate hepatic impairment and those with normal hepatic function, with modest reductions in moderate impairment. The treatment was well tolerated with a favourable safety profile, and no significant differences in C-peptide concentrations were observed across groups.

The kidneys play a vital role in maintaining systemic homeostasis by eliminating waste products, modulating metabolic homeostasis, and performing endocrine functions. Aging, characterized by hallmarks including oxidative stress, chronic inflammation, and metabolic dysregulation, constitutes a major predisposing factor for the pathogenesis of renal diseases. Amino acids serve as critical regulators of cellular metabolism, stress responses, and immune regulation, rendering amino acid metabolism intimately linked to the aging process. This review focuses on the multifaceted interplay between amino acid metabolism and renal aging, with particular emphasis on its implications in chronic kidney disease and related disorders: In senescent cells, accumulated branched-chain amino acids activate the mammalian target of rapamycin complex 1 (mTORC1), while tryptophan metabolites activate the aryl hydrocarbon receptor (AhR). Taurine deficiency impairs mitochondrial function and antioxidant defenses. Glutamine metabolism regulates the clearance of senescent cells through mechanisms including modulation of lysosomal pH and apoptosis. Glycine enhances glutathione synthesis and mitigates oxidative and inflammatory damage. In addition to modulating the aging process, urea cycle amino acids exhibit altered levels in kidney diseases and frequently serve as indicators of disease severity. Furthermore, we propose several promising therapeutic strategies, including nutritional interventions directed at specific amino acids and pharmacological therapies that target the modulation of amino acid metabolism. The relationship between amino acid availability and aging in kidney disease is not merely linear but involves a complex and dynamic interplay. Elucidating these mechanisms with advanced methods is key to developing novel clinical interventions and building a theoretical foundation for translational research.

Aims: This trial aimed to evaluate the impact of different subcutaneous injection regions on the pharmacokinetics and safety of the once-weekly basal insulin GZR4 in healthy Chinese participants.

Materials and methods: This randomized, open-label, three-period crossover trial enrolled 24 healthy participants. Each participant received a single subcutaneous injection of GZR4 (3 nmol/kg) in the thigh, abdomen, and deltoid region of the upper arm (upper arm), respectively. This was followed by a four-week observation period, with an additional one-week interval between each injection. Blood samples were collected regularly to assess the pharmacokinetic (PK) characteristics of GZR4. The primary endpoint was the area under the concentration-time curve from 0 to 672 h after a single dose (AUC_0-672h) across injection regions. Secondary endpoints included additional PK parameters, safety, and immunogenicity.

Results: The GZR4 exposure (AUC_0-672h) was comparable across injections in the thigh, abdomen, and upper arm. The geometric mean AUC_0-672h ratio (90% CI) for abdomen/upper arm was 104.8% (96.5%, 113.9%), for abdomen/thigh was 102.6% (94.5%, 111.4%), for thigh/upper arm was 102.2% (94.1%, 110.9%); all within the predefined equivalence range of 80.0%-125.0%. A total of 22 participants (91.7%) experienced 51 treatment-emergent adverse events (TEAEs), and all TEAEs were mild or moderate in severity. No hypoglycaemic events, serious adverse events, or deaths were reported.

Conclusions: In healthy Chinese participants, subcutaneous injection of GZR4 in the thigh, abdomen, or upper arm displayed comparable drug exposure, with no clinically meaningful differences observed among the injection regions.

Background: Since obesity and its associated metabolic dysregulation are recognized risk factors for cognitive decline, this study investigated whether semaglutide, a glucagon-like peptide-1 receptor agonist proven to have cardiometabolic benefits, could provide potential neuroprotective effects on brain structure and function.

Methods: In a prospective, single-arm intervention study, 26 adults with overweight or obesity received 1.0 mg semaglutide weekly for 24 weeks. Multimodal assessments were performed pre- and post-intervention, including structural and functional MRI for analysing grey matter volume (GMV), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo). Cognitive function was evaluated using standardized computerized tasks (the Flanker and N-back). Additionally, comprehensive metabolic profiles were assessed, including markers of glucose and lipid metabolism along with inflammatory cells.

Results: Semaglutide treatment significantly improved systemic metabolic health, inducing weight loss and reducing glycolipid levels and leukocyte counts. Neuroimaging revealed targeted neurobiological effects in the left temporal lobe: specifically, increased GMV in the left inferior temporal gyrus and decreased fALFF in the left middle and superior temporal gyri alongside reduced ReHo in the left middle temporal gyrus. These neural changes occurred despite no significant improvement in cognitive task performance. Importantly, the alterations in brain structure and function were not statistically correlated with the degree of weight loss or metabolic improvement.

Conclusions: A 24-week semaglutide intervention induces significant neurobiological remodelling in the left temporal lobe of adults with overweight or obesity. These central effects are independent of the drug's systemic metabolic improvements, offering new evidence for its potential neuroprotective role.

Aims: The aim of this study was to quantify the interaction between hypertension and diabetes on cardiovascular disease risk in elderly adults, using data from the CHARLS and HRS cohorts. Competing risk models accounting for mortality were employed in the analysis.

Materials and methods: This is a prospective analysis of 18 647 participants aged ≥60 years, drawn from two major longitudinal studies: the China Health and Retirement Longitudinal Study (CHARLS, n = 9823, 2011-2020) and the Health and Retirement Study (HRS, n = 8824, 2010-2020). Participants had no baseline cardiovascular disease. The primary endpoints included stroke, myocardial infarction, heart failure, and cardiovascular mortality. Interactions between hypertension and diabetes were assessed using Cox proportional hazards and Fine-Grey competing risk models, with both multiplicative and additive approaches applied.

Results: Over median follow-up of 7.8 years (CHARLS) and 8.2 years (HRS), 1909 cardiovascular events occurred. Comorbid hypertension-diabetes showed elevated risk versus neither condition. Significant additive interactions emerged consistently: RERI 0.75 (95% CI: 0.19-1.31) in CHARLS and 0.84 (95% CI: 0.21-1.47) in HRS, with 28-31% excess risk attributable to interaction. Synergy indices confirmed super-additive effects. Stroke showed strongest interaction (RERI ~0.9, SI ~1.8), while myocardial infarction demonstrated minimal synergy. Effects were amplified in participants aged 60-74 and females.

Conclusions: This analysis shows that hypertension and diabetes together increase cardiovascular risk in elderly individuals by about 30%. The findings are consistent across different ethnic groups and healthcare systems, suggesting universal biological mechanisms. This supports updating risk assessments and enhancing preventive strategies, especially for cerebrovascular risks in the elderly.

Aims: Adjunctive therapies to insulin for type 1 diabetes mellitus (T1DM), including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), may improve glycaemic control and reduce insulin requirements; however, safety concerns remain, particularly for diabetic ketoacidosis (DKA).

Materials and methods: PubMed, Ovid MEDLINE, Embase, Web of Science, Scopus and the Cochrane Library through 26 September 2025. Data were pooled using a random-effects model. Risk of bias analyses were performed.

Results: Ninety studies met inclusion criteria. GLP-1RAs produced modest improvements in glycaemic control, lowering glycated haemoglobin (HbA1c) (-0.56%) and increasing time-in-range (TIR), while reducing total and basal daily insulin requirements, body weight (-3.6 kg) and body mass index (BMI) (-1.05 kg/m²). Severe hypoglycaemia and DKA were rare; gastrointestinal adverse effects were the most common adverse effects; renal and cardiovascular outcomes were neutral. SGLT2is significantly improved HbA1c (-0.38%), TIR (+8.6 pp), insulin requirements (-4.7 U/day), body weight (-2.5 kg) and BMI (-0.82 kg/m²). Severe hypoglycaemia was uncommon, while DKA risk was increased (risk ratios = 2.19, 95% confidence interval 1.16-4.17), primarily in predictable clinical settings. Renal parameters remained stable or improved, and cardiovascular events were infrequent. Across drug classes, mortality and hospitalisations were rare.

Conclusions: Adjunctive GLP-1RAs and SGLT2is provide modest clinical improvements in adults with type 1 diabetes. These benefits must be balanced against class-specific safety concerns, especially the increased risk of DKA with SGLT2-based therapies. Larger, long-term trials are needed to define their optimal use in routine care.

Aims: Randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors have yielded inconsistent findings regarding mortality benefits. It remains unclear whether, and in which subgroups, SGLT2 inhibitors confer survival benefits in older adults with diabetic kidney disease (DKD).

Materials and methods: We emulated a target trial using a nationwide claims and health checkup database in Japan to compare all-cause mortality between SGLT2 and dipeptidyl peptidase-4 (DPP4) inhibitor initiators among 5371 adults aged ≥65 years with DKD. The primary outcome was all-cause mortality. Hazard ratios (HRs) were estimated using propensity score overlap weighting and Cox proportional hazards models in an intention-to-treat analysis. A per-protocol analysis with inverse probability of censoring weighting was conducted as sensitivity analysis. Effect modification by age, body mass index (BMI) and Charlson comorbidity index (CCI) was assessed using restricted cubic spline models.

Results: During a median follow-up of 2.23 (IQR, 1.07-3.49) years, 437 deaths occurred. SGLT2 inhibitor use was associated with significantly lower all-cause mortality than DPP4 inhibitors (HR, 0.51; 95% confidence interval, 0.38-0.70), with consistent results in the per-protocol analysis (HR, 0.50; 95% confidence interval, 0.35-0.73). Survival benefit was evident up to about 80 years of age and among individuals with BMI ≥22 kg/m², irrespective of CCI.

Conclusions: In this target trial emulation study, SGLT2 inhibitors were associated with lower mortality in older adults with DKD, particularly those under 80 years and with BMI ≥22 kg/m². These findings support personalized treatment decisions for this high-risk population in clinical practice.

Aims: This study investigated changes in how people living with obesity (PwO) perceive weight-related discussions with healthcare professionals (HCPs) in Denmark from 2022 to 2024, a period marked by shifts in obesity treatment options as well as the broader understanding of obesity.

Materials and methods: A cross-sectional online survey was conducted among adult PwO in Denmark, building on the 2022 Awareness, Care, and Treatment In Obesity maNagement-Denmark survey with a few modifications. Data were collected via representative online panels from September to October 2024. Adjusted logistic regression models were performed.

Results: A total of 1005 PwO participated in the 2024 survey, compared to 879 in the 2022 survey. The proportion of PwO discussing weight with HCPs increased significantly from 38% in 2022 to 58% in 2024. The percentage of PwO reporting positive feelings after weight consultations did not change significantly. PwO in 2024 still refrained from discussing weight due to fear of prejudice (23%), previous negative experiences (17%) and the belief that reducing weight was their own responsibility (46%). Subgroup analyses in 2024 revealed that those currently using weight loss medications reported the most positive perceptions of weight-related discussions with their HCP.

Conclusions: Overall increased engagement of PwO regarding weight-related discussions with HCPs was observed from 2022 to 2024. However, barriers persist, since some PwO avoid interactions with HCPs due to previous experiences with stigma or the fear of being judged. Continued efforts are essential to address these barriers, enhance HCP education about weight-related bias, and foster a supportive environment for PwO in healthcare settings.