Diabetes, Obesity & Metabolism最新文献

Aims/hypothesis: Pancreatic beta-cell dysfunction is pivotal in diabetes pathogenesis, with the NOD-like receptor protein 3 (NLRP3) inflammasome playing a crucial role. Dapansutrile (DAPA), a novel NLRP3 inhibitor, demonstrates promise in diabetes management.

Methods: The diabetic model of high-fat diet (HFD) + streptozotocin (STZ) mice was utilized to assess glucose metabolism indicators following DAPA intervention. Experiments involving pancreatic islets from normal mice or humans, as well as INS-1 cell lines, were conducted to evaluate CCK8, glucose-stimulated insulin secretion (GSIS), calcium ion imaging, vesicle fusion and mitochondrial function after exposure to palmitic acid (PA) and DAPA intervention. Additionally, the study explored the efficacy of islet transplantation in type 1 diabetes mice using islets treated with DAPA in vitro.

Results: This study showed that DAPA improved fasting blood glucose level, glucose tolerance and glucose metabolism in diabetes mice. The experimental work on pancreatic islets and INS-1 cells exposed to PA confirmed that DAPA enhanced GSIS, restored pancreatic function, improved calcium ion flux, mitochondrial dynamics and vesicle fusion. Notably, through the application of pancreatic islet transplantation technology, we illustrated that DAPA effectively addresses systemic glucose metabolism issues at the beta-cell level.

Conclusions/interpretation: DAPA targets the NLRP3 inflammasome in pancreatic beta cells of diabetic mice to preserve function, maintain mitochondrial homeostasis and offer potential avenues for diabetes management strategies.

Aims: Management of insulin therapy in elderly individuals with type 2 diabetes (T2D) residing in nursing homes is often challenging due to comorbidities, cognitive impairment and limited access to specialist care. Continuous glucose monitoring (CGM) and telemedicine may help optimise glycaemic control in this vulnerable population.

Materials and methods: In order to assess the efficacy and safety of a CGM and telemedicine-based management of insulin therapy in nursing home residents with T2D, a 12-week, randomised, controlled and open-label trial has been designed. Eighty-five patients on stable basal-bolus insulin therapy were assigned to either telemedicine-assisted insulin titration based on CGM data (intervention group) or standard care with capillary blood glucose monitoring (control group). The primary endpoint was the change in time in range (TIR, 70-180 mg/dL), with secondary outcomes including time below range (TBR), time above range (TAR), haemoglobin A1c (HbA1c), insulin dose and safety endpoints.

Results: TIR increased significantly in the intervention, but not in the control group, with a significant difference between study groups (p = 0.010). TBR showed a reduction in the intervention arm and an increase in the control arm with a significant difference between groups (p = 0.007). HbA1c and mean insulin daily units significantly also decreased in the intervention group, with significant differences between groups (p = 0.028 and p = 0.002, respectively). No safety issues potentially related to the intervention were identified during the study.

Conclusion: In conclusion, remote insulin dose adjustment based on interstitial glucose monitoring ameliorates glucose control in nursing home residents with T2D on basal-bolus insulin therapy.

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: Little is known about how the alignment between daily behaviours, such as physical activity and eating, and chronotype relates to glucose metabolism. We investigated whether alignment of physical activity and meal timing with chronotype was associated with glycaemic parameters and with prediabetes or type 2 diabetes (T2DM).

Materials and methods: In a cross-sectional analysis of 1384 participants from The Maastricht Study, we examined associations between behaviour-chronotype alignment and glucose metabolism. Physical activity timing was assessed by accelerometry and defined as the daypart with the highest step count. Meal timing, from a chrono-nutrition questionnaire, was defined as the daypart with the most eating occasions. Chronotype was estimated using the midpoint of sleep on free days corrected for sleep debt. Alignment reflected concordance between behaviour timing and chronotype. Confounder-adjusted logistic and linear regression models estimated associations with (pre)diabetes and with log-transformed fasting plasma glucose (FPG), 2-h post-load glucose (2hPLG), and haemoglobin A1c (HbA1c).

Results: Weekday alignment of physical activity timing with chronotype was associated with lower HbA1c (β per 20% more aligned weekdays: -0.48%, 95% CI -0.95, -0.02). Weekday meal timing alignment was associated with lower odds of prediabetes or T2DM (OR aligned vs. misaligned: 0.62, 95% CI 0.43-0.89). No significant associations were observed for weekend alignment, for FPG or 2hPLG, or for interactions between activity and meal timing alignment.

Conclusions: Weekday, but not weekend, alignment of physical activity and meal timing with chronotype was modestly associated with more favourable glucose metabolism. These findings suggest a potential role of behaviour-chronotype alignment in metabolic health, warranting confirmation in prospective and intervention studies.