Metabolism: clinical and experimental最新文献

Background: The role of cardiovascular health (CVH) factors and their associated proteomic profiles in the progression and prognosis of cardiovascular-kidney-metabolic (CKM) syndrome among individuals at stages 0-3 remains unclear.

Methods: This study analyzed data from 10,351 Chinese adults (China Health and Retirement Longitudinal Study [CHARLS]), 224,352 British adults (UK Biobank [UKB]), and 20,726 American adults (National Health and Nutrition Examination Survey [NHANES]). Cox proportional hazards models were used to assess the associations of CVH score and proteomic panel with incident CVD and in CKM stages 0-3 individuals.

Results: The median follow-up periods were 13.6 years in UKB, 9.4 years in CHARLS, and 7.5 years in NHANES. Among individuals with CKM stages 0-3, those with optimal CVH had reduced risks of overall CVD compared with those with low CVH (UKB, HR = 0.58, 95% CI: 0.55-0.62; CHARLS, HR = 0.77, 95% CI: 0.64-0.92), and all-cause mortality (UKB, HR = 0.45, 95% CI: 0.42-0.49; CHARLS, HR = 0.60, 95% CI: 0.47-0.76; NHANES, HR = 0.34, 95% CI: 0.26-0.44). These protective associations were similarly observed across CVD subtypes and cause-specific mortality. An ENM-selected panel of 722 proteins was associated with 41% lower overall CVD risk and 54% lower all-cause mortality. Meanwhile, circulating proteins mediated the associations between CVH score and CKM syndrome progression and prognosis, particularly ALPP.

Conclusions: Optimal cardiovascular health behaviors and factors are key to halting the progression and improving the prognosis of CKM syndrome, with the associated proteins potentially serving as biomarkers and molecular targets for interventions.

The global escalation of obesity necessitates therapeutic interventions that transcend the efficacy ceilings of current mono-target pharmacotherapies. Amycretin, a novel unimolecular co-agonist targeting glucagon-like peptide-1 (GLP-1) and amylin receptors, has emerged as a promising candidate for weight management. In this review, we examine the developmental rationale of amycretin, elucidating how its dual-agonist mechanism synergistically engages hindbrain-mediated satiety pathways and delays gastric emptying to overcome metabolic plateaus. We summarize pivotal findings from recent clinical trials, highlighting that amycretin elicits profound weight reduction-demonstrating up to 13.1% loss with oral administration (12 weeks) and 24.3% with subcutaneous delivery (36 weeks)-with a safety profile consistent with incretin-based classes. Furthermore, we explore the strategic potential of combining amycretin with insulin-independent agents, such as SGLT2 inhibitors, to optimize cardio-renal outcomes. These insights provide a theoretical framework for positioning amycretin in the future management of adiposity-based chronic diseases.

Homeotherms maintain a steady body temperature through thermoregulation, a process critical for survival during fasting, in which the brain has to defend energy-costly body temperature while reducing energy expenditure to conserve energy reserve; however, the neural basis for defending body temperature remains unclear. Here, we demonstrated that AgRP neuron lesion led to lethality during time-restricted feeding on chow but not on HFD, and caused no obvious impact on HFD-induced obesity or obesity-reducing responses to glucagon-like peptide-1 receptor agonism. The lesion disrupted adaptive feeding behaviors during time-restricted feeding and reduced motivational feeding on chow. Notably, the lethality was caused by hypothermia instead of reduced food intake. The lesion also caused failure in body temperature maintenance during acute fasting in cold. Fasting-induced activation in AgRP neurons was abrogated when mice were placed in a warm environment. Our results identify the physiological role for AgRP neurons in defending body temperature during restricted availability of low-calorie diets but dispensable for body weight regulation with food ad libitum.

Background: Insulin GZR4 (GZR4) is a once-weekly insulin currently under development. This phase 2 trial assessed the efficacy and safety of once-weekly (QW) GZR4 versus once-daily (QD) insulin degludec (IDeg) in Chinese people with type 2 diabetes (T2D).

Methods: This 16-week, randomized, open-label, multicenter, treat-to-target phase 2 trial consisted of 2 cohorts: Cohort A enrolled insulin-naïve people; Cohort B enrolled people previously treated with basal insulin. Participants were randomly assigned (1:1) to receive GZR4 or IDeg. The primary outcome was the change in HbA1c from baseline to week 16.

Results: Between August 22, and September 22, 2023, 179 participants were enrolled and allocated to Cohort A (n = 83) and Cohort B (n = 96). The estimated mean change in HbA1c from baseline to week 16 was -1.50 percentage points in the GZR4 group vs -1.48 percentage points in the IDeg group in Cohort A (estimated treatment difference [ETD] of -0.02 percentage points [95% CI -0.34 to 0.30], p = 0.902), -1.26 percentage points in the GZR4 group vs -0.87 percentage points in the IDeg group in Cohort B (ETD -0.38 percentage points [95% CI -0.66 to -0.11], p = 0.007). At week 16, GZR4 and IDeg group showed a similar proportion of participants achieving HbA1c targets. The treatment-emergent adverse events did not differ between two groups. The incidence of hypoglycemia (mostly level 1) was slightly higher in participants receiving GZR4 than IDeg, particularly in Cohort B. No severe hypoglycemia (level 3) was reported.

Conclusions: In this phase 2 trial, once-weekly GZR4 demonstrated effective glycemic control over 16 weeks in both insulin-naïve patients and those previously treated with basal insulin. The incidence of hypoglycemia was slightly higher with GZR4, particularly in the basal insulin-treated group, though no severe hypoglycemic events were reported. These findings warrant further investigation in larger phase 3 trials, which will utilize an adjusted, more precise molar-dose potency of GZR4 to fully characterize its benefit-risk profile.