Aberrant liver fibrosis is frequently observed in and contributes to the pathogenesis of end-stage liver diseases including cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSCs) trans-differentiate into E...Aberrant liver fibrosis is frequently observed in and contributes to the pathogenesis of end-stage liver diseases including cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSCs) trans-differentiate into ECM-producing myofibroblasts to mediate liver fibrosis. In the present study we investigated the role of sterol response element binding protein 2 (SREBP2) in this process focusing on epigenetic mechanism and translational potential. We report that HSC-specific deletion or myofibroblast-restricted SREBP2 depletion attenuated liver fibrosis in mice. Integrated transcriptomic analysis combining RNA-seq and CUT&Tag-seq identified acyl-coenzyme A synthetase short-chain family member 2 (ACSS2) as a novel SREBP2 target; SREBP2 directly bound to the ACSS2 promoter to activate ACSS2 transcription. Over-expression of ectopic ACSS2 partially rescued the deficiency of HSC-myofibroblast transition when SREBP2 was depleted. In contrast, ACSS2 deletion in HSCs or myofibroblasts ameliorated liver fibrosis in mice. Mechanistically, SREBP2-dependent ACSS2 trans-activation stimulated histone H3K9/H3K27 acetylation necessary for the expression of pro-fibrogenic genes in HSCs. Importantly, a small-molecule ACSS2 inhibitor (ACSS2i) mitigated liver fibrosis in mice. Finally, relevance of the SREBP2-ACSS2 axis was validated in biopsy specimens from patients with chronic liver disease. In conclusion, our data uncover a previously unappreciated role for SREBP2 in HSC activation and provide proof-of-concept for targeting ACSS2 in the intervention of liver fibrosis.
García-Gavilán JF, Paz-Graniel I, Pérez-Acosta JA
… +20 more, Ruiz-Canela M, Li J, Clish C, Razquin C, Yun H, Corella D, Estruch R, Ros E, Fitó M, Wang F, Fiol M, Lapetra J, Gómez-Gracia E, Liang L, Denis C, Babio N, Guasch-Ferré M, Martínez-González MÁ, Hu FB, Salas-Salvadó J
OBJECTIVE: This study aimed to identify metabolomic profiles associated with type 2 diabetes and insulin resistance (HOMA-IR) and relate them to the risk of total mortality. METHODS: A longitudinal study was conducted in...OBJECTIVE: This study aimed to identify metabolomic profiles associated with type 2 diabetes and insulin resistance (HOMA-IR) and relate them to the risk of total mortality. METHODS: A longitudinal study was conducted in a subset of participants from a diabetes case-cohort study (mean age, 66.5 years; 62% women; 176/699 with incident T2D) within the PREDIMED trial. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year follow-up (validation sample). Multi-metabolite profile scores for type 2 diabetes and HOMA-IR, respectively, were derived using elastic net regression. Cox proportional hazards were fitted to assess the association between metabolomic profiles and total mortality, adjusting for potential confounders. External validation was performed in the NHS/HPFS cohorts. RESULTS: A total of 31 metabolites were associated with type 2 diabetes and 105 with HOMA-IR. Both metabolomic profiles were significantly associated with a higher risk of total mortality (type 2 diabetes HR = 1.52, 95%CI: 1.04-2.25; HOMA-IR HR = 1.33, 95%CI: 1.00-1.75) in the PREDIMED cohort. Shared metabolites between both metabolomic signatures, including glycine, SDMA, DMGV, and phosphocreatine, were associated with mortality. These associations were replicated in a pooled analysis of three independent American cohorts (type 2 diabetes HR = 1.09, 95%CI: 1.05-1.13; HOMA-IR HR = 1.04, 95%CI: 1.00-1.09). CONCLUSIONS: In an older population at high cardiometabolic risk, metabolomic scores of type 2 diabetes and insulin resistance were associated with total mortality risk, potentially explaining some mechanisms behind the increased risk of mortality observed in epidemiological studies for individuals with glycemic dysregulations.
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 remai...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 mortality 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 pe...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 t...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.
AIMS: Hepatocellular carcinoma (HCC) exhibits aberrant lipid metabolism, notably increased de novo fatty acid synthesis and reduced fatty acid oxidation. PDAP1, a cancer-associated RNA-binding protein, is overexpressed i...AIMS: Hepatocellular carcinoma (HCC) exhibits aberrant lipid metabolism, notably increased de novo fatty acid synthesis and reduced fatty acid oxidation. PDAP1, a cancer-associated RNA-binding protein, is overexpressed in multiple malignancies, yet its specific contribution to fatty acid metabolic reprogramming and HCC progression remains undefined. METHODS: The expression pattern and prognostic relevance of PDAP1 were investigated using public datasets and validated in clinical specimens. To evaluate the functional role of PDAP1, a series of in vitro assays, including CCK-8, colony formation, EdU, wound healing, transwell invasion, and flow cytometry experiments were conducted. In vivo studies were performed using multiple mouse models, including subcutaneous tumor, orthotopic liver tumor, as well as lung and liver metastasis models. The underlying mechanisms of PDAP1 were elucidated through bulk and single-cell RNA sequencing and further validated by RNA immunoprecipitation, RNA pull-down assays, and lipid metabolism-related assays. RESULTS: PDAP1 was markedly upregulated in HCC and correlated with poor overall and progression-free survival. Functional assays demonstrated that PDAP1 knockdown inhibited HCC cell proliferation, migration, and invasion, while promoting apoptosis. Conversely, PDAP1 overexpression exerted the opposite effects. In vivo, PDAP1 also showed promoting effect on HCC growth and metastasis. Mechanistically, PDAP1 stabilized HSPA8 mRNA, activating the ERK/MAPK pathway, which enhanced SREBP1-mediated fatty acid synthesis and suppressed PPARα-driven fatty acid oxidation, thereby driving fatty acid metabolic reprogramming and malignant transformation of HCC. CONCLUSIONS: PDAP1 stabilizes HSPA8 mRNA as an RNA-binding protein to activate ERK/MAPK signaling, which further modulates the expressions of the SREBP1 and PPARα, ultimately driving HCC progression and metastasis through fatty acid metabolism reprogramming. Targeting PDAP1 may provide a promising therapeutic strategy for HCC.
Catecholamine resistance in adipose tissue encompasses an articulated network of cellular and molecular adaptations to inflammatory and neuroendocrine signals in obesity. By dampening adrenergic signaling, these adaptati...Catecholamine resistance in adipose tissue encompasses an articulated network of cellular and molecular adaptations to inflammatory and neuroendocrine signals in obesity. By dampening adrenergic signaling, these adaptations may serve a protective role, shielding tissues from excessive catecholamine stimulation and the metabolic stress induced by inflammatory signals. However, reduced adrenergic responsiveness also constrains lipolysis and thermogenesis in adipose tissue, limiting the ability to mobilize fat during caloric restriction or increased energy demand. Thus, while initially adaptive, catecholamine resistance under conditions of nutrient excess may reinforce energy storage and promote weight persistence in obesity. In this work, we examine the neuro-endocrine framework underlying catecholamine resistance in adipose tissue, with the aim of elucidating its implications for metabolic homeostasis and body weight regulation in obesity.
BACKGROUND: To systematically evaluate microRNAs (miRNAs) associated with microvascular complications of type 1 diabetes mellitus (T1D), quantify differential expression using complementary frequentist and Bayesian meta-...BACKGROUND: To systematically evaluate microRNAs (miRNAs) associated with microvascular complications of type 1 diabetes mellitus (T1D), quantify differential expression using complementary frequentist and Bayesian meta-analytic frameworks, and contextualize dysregulated signals through integrative multi-database pathway analysis. METHODS: A systematic search of Medline, Embase, Scopus, and Web of Science was conducted through February 2025 to identify observational studies reporting miRNA expression in diabetic nephropathy (DN) or diabetic retinopathy (DR). Effect sizes (Hedges' g) were pooled using random-effects models and Bayesian hierarchical meta-analysis to account for within-study dependence. Experimentally validated and predicted targets were retrieved via multiMiR and mapped to Gene Ontology, KEGG, and Reactome pathways to evaluate biological convergence. RESULTS: Nine studies comprising 34 contrasts and 19 unique miRNAs met inclusion criteria. miR-29a-3p (g = -0.99; 95% CI -1.33 to -0.65; I = 0.00) and miR-204-5p (g = -0.88; 95% CI -1.06 to -0.70; I = 0.00) were consistently downregulated in DN. Bayesian models corroborated frequentist estimates, demonstrated robust convergence, and showed minimal sensitivity to prior specification. No universal circulating miRNA signature emerged across complications, reflecting substantial biological and methodological heterogeneity. Enrichment analyses of validated targets indicated convergence on pathways related to autophagy, Wnt signaling, fibrosis, and apoptosis. CONCLUSION: Current evidence does not support a unified circulating miRNA signature for T1D microvascular complications. However, reproducible downregulation of miR-29a-3p and miR-204-5p highlights candidate signals warranting validation in adequately powered longitudinal and diagnostic-accuracy studies. By integrating quantitative synthesis with pathway-level interpretation, this study clarifies the present evidentiary landscape and provides a framework to guide future translational research in T1D microangiopathy.
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...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.
Metformin (dimethyl biguanide) is a primary pharmacotherapy to treat hyperglycemia in type 2 diabetes. It counters the effects of insulin resistance, improves glucose homeostasis, assists weight control and avoids overt...Metformin (dimethyl biguanide) is a primary pharmacotherapy to treat hyperglycemia in type 2 diabetes. It counters the effects of insulin resistance, improves glucose homeostasis, assists weight control and avoids overt hypoglycemia via reduced hepatic gluconeogenesis, increased splanchnic glucose turnover and greater peripheral glucose utilization. The underlying cellular actions of metformin differ between tissues and drug exposures. High concentrations of metformin (e.g. millimolar in the intestine) can interrupt the mitochondrial respiratory chain at complex 1, increase cytosolic NADH (favouring pyruvate conversion to lactate), decrease ATP synthesis, raise cytosolic AMP and activate AMP-activated protein kinase (AMPK). Lesser concentrations of metformin in liver can interrupt the respiratory chain at complex 4, which inhibits mitochondrial glycerol-3-phosphate dehydrogenase and impedes the mitochondrial glycerophosphate shuttle. Low concentrations of metformin (e.g., ∼10 μM) can activate AMPK by a lysosomal pathway without interrupting oxidative metabolism. While AMPK implements many of the metabolic effects of metformin, other contributing mechanisms include separate effects on metabolic pathways (e.g. inhibiting fructose-1,6-bisphosphatase) and signalling intermediates (e.g. inhibiting phosphatases) to reinforce the actions of insulin. Thus, the antidiabetic effects of metformin reflect diverse concentration-dependent cellular actions on nutrient metabolism and energetics in different tissues. The breadth of cellular actions of metformin encourages investigation of potential opportunities to assist in the management of cardiovascular, inflammatory, neoplastic and neurodegenerative disorders.
Exercise performance and skeletal muscle homeostasis are influenced by myofiber type composition. Cysteine and glycine-rich protein 3 (CSRP3) is highly expressed in the oxidative fiber-rich mammalian soleus muscle. Howev...Exercise performance and skeletal muscle homeostasis are influenced by myofiber type composition. Cysteine and glycine-rich protein 3 (CSRP3) is highly expressed in the oxidative fiber-rich mammalian soleus muscle. However, the mechanistic basis of CSRP3's involvement in skeletal muscle development and myofiber type specification remains unclear. Here, we used various exercise training (aerobic/anaerobic) bioinformatics datasets and experimental model systems involving live mice and cell lines to determine the role of CSRP3 in driving mitochondrial metabolic reconfiguration, skeletal muscle fiber type remodeling, and improved exercise endurance. CSRP3 promotes the formation of oxidative myofibers while suppressing glycolytic myofiber differentiation. It enhances mitochondrial biogenesis, oxidative phosphorylation capacity, and elevates mitochondrial membrane potential. Conversely, AAV-mediated CSRP3 knockdown perturbs mitochondrial energy metabolism, compromises exercise performance, and reduces the proportion of oxidative myofibers. Mechanistically, CSRP3 binds to D-lactate dehydrogenase (LDHD) via a specific 33-amino acid region, promoting D-lactate metabolism in skeletal muscle. This interaction regulates mitochondrial morphology, biogenesis, oxidative phosphorylation efficiency, and TCA cycle activity, ultimately driving skeletal muscle mitochondrial energy metabolic rewiring and skeletal muscle fiber type remodeling.
BACKGROUND: The latest data release from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2023 has enabled us to conduct an updated analysis of the trends and burdens of common metabolic diseases/risk...BACKGROUND: The latest data release from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2023 has enabled us to conduct an updated analysis of the trends and burdens of common metabolic diseases/risk factors from 1990 to 2023 in the Asia-Pacific region. We aimed to highlight disparities across geographic regions, over time, and by sex, while incorporating a predictive assessment of future trends through 2030. METHODS: We analyzed estimates of disability-adjusted life years (DALYs) and mortality for five common metabolic diseases and risk factors in the Asia-Pacific region (type 2 diabetes mellitus [T2DM], high systolic blood pressure [SBP], high body mass index [BMI], high LDL cholesterol, and metabolic dysfunction-associated steatotic liver disease [MASLD]). We also used Bayesian age-period-cohort (BAPC) models to project disease burdens through 2030. RESULTS: In 2023, in Asia-Pacific region, high SBP accounted for the largest burden (~138 million DALYs; 6.27 million deaths), followed by high BMI (~55 million DALYs; 1.33 million deaths), high LDL cholesterol (~53 million DALYs; 2.02 million deaths), T2DM (~49 million DALYs; 1.13 million deaths), and MASLD (~1.26 million DALYs; 47 thousand deaths). From 1990 to 2023, total DALYs increased 1.7- to 3.7- fold, with absolute burdens highest in China, India, and Indonesia, and relative burdens concentrated in Pacific Islands. Projected trends through 2023 suggest that the burden of all metabolic diseases/risk factors, except MASLD, is likely to continue rising, with high SBP remaining the dominant contributor. CONCLUSION: Analysis of the GBD 2023 and 2030 projections show that metabolic diseases/risk factors will remain a persistent challenge for the Asia-Pacific region, with substantial increases in DALYs and mortality. These findings call for coordinated, intensified global actions to address interconnected metabolic conditions and can have positive implications for the United Nations' 2030 health-related goals.
Epidemiological evidence indicates that hyperinsulinemia is an independent risk factor for albuminuria and renal impairment, yet its molecular basis remains unclear. In prediabetic db/db mice, hyperinsulinemia coincided...Epidemiological evidence indicates that hyperinsulinemia is an independent risk factor for albuminuria and renal impairment, yet its molecular basis remains unclear. In prediabetic db/db mice, hyperinsulinemia coincided with albuminuria, podocyte injury, and impaired glomerular insulin signaling, characterized by insulin receptor exhaustion and hypoactivity of the IRS1/PI3K/Akt insulin signaling. This led to diminished inhibitory phosphorylation of GSK3β in podocytes, denoting GSK3β hyperactivity. Notably, GSK3β co-localized and physically interacted with IRS1 in glomerular podocytes, phosphorylating IRS1 as a direct substrate. In cultured podocytes, prolonged high insulin exposure induced insulin receptor depletion, GSK3β hyperactivity, and increased inhibitory phosphorylation of IRS1, forming a self-perpetuating cycle of insulin desensitization and podocyte injury. GSK3β appears to play a key role, as ectopic expression of a constitutively active GSK3β mutant GSK3β enhanced inhibitory phosphorylation of IRS1, desensitized insulin signaling, and exacerbated podocyte injury. In contrast, forced expression of a kinase-dead mutant of GSK3β or inhibition of GSK3β with a selective small-molecule inhibitor tideglusib abrogated inhibitory phosphorylation of IRS1, restored insulin sensitivity and protected podocytes. In vivo, GSK3β knock-in mice exhibited impaired insulin signaling and podocyte injury with albuminuria. Conversely, tideglusib treatment in prediabetic db/db mice attenuated podocyte injury and insulin resistance, thereby improving albuminuria. Collectively, hyperinsulinemia directly elicits albuminuria and renal impairment via a cascade of molecular events involving insulin receptor exhaustion, reduced insulin signaling, and GSK3β hyperactivity, which promotes IRS1 inhibition and thereby forms a self-amplifying GSK3β-IRS1 circuit of insulin desensitization and podocyte injury. Targeting GSK3β could disrupt this pathogenic loop and mitigate hyperinsulinemia-induced renal injury.
BACKGROUND: Cardiovascular-Kidney-Metabolic (CKM) syndrome integrates metabolic risk factors, chronic kidney disease (CKD), and cardiovascular dysfunction, and is closely linked to cardiovascular disease (CVD) risk. We a...BACKGROUND: Cardiovascular-Kidney-Metabolic (CKM) syndrome integrates metabolic risk factors, chronic kidney disease (CKD), and cardiovascular dysfunction, and is closely linked to cardiovascular disease (CVD) risk. We aimed to evaluate sex-specific differences in prevalence, components, and outcomes of CKM syndrome to inform strategies for personalized cardiovascular prevention. METHOD: We included 6563 participants without established CVD from the Multi-Ethnic Study of Atherosclerosis (MESA). CKM stages were defined according to American Heart Association criteria. We assessed sex-specific prevalence, component distributions, and incidence of coronary heart disease (CHD), heart failure (HF), stroke, and mortality. Incidence rates (IR) per 1000 person-years and Fine-Gray subdistribution hazard ratios (SHR) were estimated. RESULTS: Among 3095 men and 3468 women (mean age: 62 ± 10 years), men had a higher CKM Stage 3 prevalence (42.4% vs. 36.4% in women). Within Stage 3, subclinical atherosclerotic CVD (coronary artery calcium [CAC] score ≥ 100 Agatston unit) predominated in men (70.5%), whereas subclinical HF (elevated cardiac biomarkers) was more frequent in women (70.1%). During a median follow-up of 13.7 years (IQR 9.0-15.5 years), CHD incidence was higher in men (IR: 20.9 vs. 8.9 in women), followed by HF (IR: 7.2 vs. 4.5) and stroke (IR: 6.7 vs. 6.3). Using women as the reference, SHRs (95% CI) for men were 2.28 (1.84, 2.82) for CHD, 1.66 (1.20, 2.30) for HF, and 1.07 (0.80, 1.43) for stroke. CONCLUSIONS: Men exhibited a higher prevalence of advanced CKM Stages and a substantially greater CHD burden, while women showed a higher subclinical HF phenotype within CKM Stage 3. These findings support sex-specific, stage-based CKM assessment as an actionable framework for early risk stratification and tailored cardiovascular prevention.
BACKGROUND: Prior research on circadian rhythms have primarily focused on the risk of diabetes, with limited evidence on their impact in glycemic control among individuals with type 2 diabetes. This study investigated th...BACKGROUND: Prior research on circadian rhythms have primarily focused on the risk of diabetes, with limited evidence on their impact in glycemic control among individuals with type 2 diabetes. This study investigated the association between Fitbit-derived circadian rhythm parameters and continuous glucose monitoring (CGM) metrics. METHOD: Data were analyzed from 122 insulin-treated patients with type 2 diabetes who concurrently wore real-time CGM devices (Dexcom G6) and activity trackers (Fitbit Inspire 2) for 10 days. Cosinor analyses were used to derive circadian parameters from wearable-based heart rate data. Associations between time-of-day-specific activity metrics and CGM outcomes were evaluated using partial Spearman correlations and multivariable logistic regression. RESULTS: Stronger circadian rhythmicity-characterized by greater amplitude and higher goodness-of-fit (R2)-was significantly associated with improved glycemic outcomes and reduced glucose variability. Higher daytime step counts and lower sedentary time were associated with reduced hyperglycemia and variability. Longer sleep duration was inversely associated with hypoglycemia (TBR <70) and glucose variability indices. Notably, circadian robustness (R2) and afternoon step counts emerged as independent predictors of achieving comprehensive CGM-based targets after adjusting for key clinical and behavioral confounders. CONCLUSIONS: In this cross-sectional exploratory analysis, greater daytime physical activity and stronger circadian rhythmicity were associated with improved glycemic control and reduced glucose variability. These findings are hypothesis-generating and support the need for prospective trials testing circadian-aligned behavioral interventions.
G protein-coupled receptors (GPCRs) in the central nervous system, particularly in the hypothalamus, are promising therapeutic targets for the treatment of obesity and related metabolic disorders. However, the developmen...G protein-coupled receptors (GPCRs) in the central nervous system, particularly in the hypothalamus, are promising therapeutic targets for the treatment of obesity and related metabolic disorders. However, the development of anti-obesity drugs targeting GPCRs in hypothalamus has been significantly constrained by their propensity to induce a range of adverse effects. An alternative strategy is to directly target the G protein subunits downstream of GPCRs, potentially biasing GPCR signaling away from harmful pathways while preserving those essential for normal cellular functions. The G protein βγ (Gβγ) subunits have emerged as a potential therapeutic target, but its role in obesity is largely unknown. In this study, we found that gallein, a Gβγ inhibitor, can ameliorate diet-induced obesity (DIO) and related metabolic dysfunction by suppressing appetite. Given the critical role of hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons in maintaining whole-body energy balance, we further demonstrated that gallein suppressed appetite by inhibiting AgRP neuronal activity. More importantly, specific inhibition of Gβγ subunits in AgRP neurons can inhibit the activation of AgRP neurons, thereby reducing food intake and ameliorating DIO and related metabolic dysfunction. Conversely, overexpression of Gβγ in AgRP neurons promoted hyperphagia and obesity. Mechanistically, we discovered that Gβγ subunits increase AMPK activity to promote mitochondrial fatty acid oxidation and ATP production, ultimately increasing the activity of AgRP neurons and related peptide expression. In conclusion, our study demonstrates that Gβγ subunits regulate feeding and metabolism through multiple bioenergetic processes in AgRP neurons. Gallein, the small-molecule inhibitor of Gβγ subunits emerges as a promising therapeutic candidate for obesity and its associated comorbidities.