Susana Rovira-Llopis

Brief daily “exercise snacks” improved metabolic health, cardiorespiratory fitness, and muscle oxygenation in sedentary women. These changes were accompanied by modulation of PBMC mitochondrial dynamics, autophagy-related markers, and neutrophil-endothelial interactions. Our findings provide mechanistic support for time-efficient exercise as a feasible strategy to counteract sedentary-induced cardiometabolic dysfunction.

Diabetic kidney disease (DKD) is a frequent complication of type 2 diabetes and is closely linked to systemic inflammation. Peripheral blood mononuclear cells (PBMCs) are markers of systemic inflammatory and metabolic stress. It is unknown if metabolism-related transcriptomic alterations in these cells is associated with DKD. Using the nCounter® Human Metabolic Pathways Panel we profiled PBMC metabolic transcripts in individuals with type 2 diabetes or DKD and in controls ( n = 12/group), and integrated transcriptomic data with clinical, inflammatory, and mitochondrial parameters. Patients with DKD showed increased inflammatory biomarkers and reduced PBMC mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Metabolism-related transcriptomic profiling identified 13 differentially expressed genes across groups. DKD subjects displayed downregulation of SLC7A11 versus controls and HLA-DQA1 versus type 2 diabetes, and upregulation of CPT1A and GBA1 versus controls. CPT1A upregulation was confirmed by RT-qPCR and supported by external GEO datasets, though ROC analyses indicated a limited discriminatory performance. Pathway analyses revealed enrichment of immune-related, fatty acid oxidation, and fructose-6-phosphate pathways and reduced cell proliferation pathways in DKD patients. Inflammatory markers correlated positively with energy-regulating pathways and negatively with anabolic processes. In conclusion, these findings suggest that PBMCs reflect immunometabolic remodeling in response to DKD, thus highlighting an association between systemic inflammation, mitochondrial dysfunction, and altered energy metabolism in circulating immune cells.

Introduction: Obesity is associated with disruptions in circadian rhythms and emotional well-being that can contribute to metabolic and psychological health issues. This study aimed to investigate the effects of weight loss by a dietary intervention on circadian gene expression and emotional state in individuals with obesity. Methods: Fifty subjects with obesity followed a dietary intervention for 6 months. Anthropometric and biochemical parameters were assessed. Sleep quality was measured using a sleep questionnaire and Rosemberg Self-Esteem Scale, Beck Depression Inventory and State-Trait Anxiety Inventory (STAI) were used. PBMCs’ RNA was analyzed for circadian-related gene expression. Results: Participants lost 11.3% body weight, along with reductions in lipid, carbohydrate metabolism and inflammation markers. Sleep quality improved; as poor sleep frequency was reduced, though sleep duration was similar. Self-esteem did not significantly increase; however, the proportion of participants with high self-esteem rose from 62 to 69% ( χ ² = 12.5, p < 0.05). State anxiety decreased (STAI-S, p < 0.01), though trait anxiety remained stable. Several circadian genes were upregulated, including CLOCK , ARNTL , CRY1 , DBP , and NR1D1 ; with associations found between CLOCK and lower state anxiety at baseline, and between CRY2 and higher self-esteem and lower depression at baseline ( p < 0.05). Conclusion: The dietary intervention influenced positively the metabolic, psychological, and circadian rhythm marker profile, highlighting potential interconnections between metabolism, circadian gene expression, and mental well-being. Clinical Trial Registration: Identifier NCT06279780

Purpose: This study evaluates and compares the effects of continuous and interval training on inflammatory and adhesion molecules in subjects with Type 1 diabetes mellitus (T1D) and healthy controls. Methods: Using Luminex X-MAP, serum inflammatory and adhesion molecules were measured in 50 non-obese, sedentary adults (78% women; mean age 34 years), including 27 with T1D and 23 healthy controls. Results: Subjects with T1D exhibited a tendency towards decreased interleukin 10 (IL-10) levels and increased intercellular adhesion molecule (ICAM1) levels compared to controls. Exercise training, specifically high-intensity interval training (HIIT), increased IL-10 levels in the T1D group. Among controls, we observed a decrease in vascular cell adhesion molecule 1 (VCAM1) after continuous training, and in platelet selectin (P-selectin) after HIIT. The correlation studies revealed that subjects with higher baseline maximal oxygen uptake (VO ₂ max) achieved greater reductions in P-selectin levels with training and that levels of VCAM1 were further reduced by training in subjects with higher baseline metabolic equivalents (METS). Conclusion: Our findings show that the effects of exercise on inflammatory cytokines and adhesion molecules vary depending on the training modality and the population studied. Additionally, our data suggest that physical activity and fitness levels influence individual responses to exercise in relation to adhesion molecules in healthy and subjects with T1D.

Aims/hypothesis: Alterations in circadian rhythms increase the likelihood of developing type 2 diabetes and CVD. Circadian rhythms are controlled by several core clock genes, which are expressed in nearly every cell, including immune cells. Immune cells are key players in the pathophysiology of type 2 diabetes, and participate in the atherosclerotic process that underlies cardiovascular risk in these patients. The role of the core clock in the leukocytes of people with type 2 diabetes and the inflammatory process associated with it are unknown. We aimed to evaluate whether the molecular clock system is impaired in the leukocytes of type 2 diabetes patients and to explore the mechanism by which this alteration leads to an increased cardiovascular risk in this population. Methods: This is an observational cross-sectional study performed in 25 participants with type 2 diabetes and 28 healthy control participants. Clinical and biochemical parameters were obtained. Peripheral blood leukocytes were isolated using magnetic bead technology. RNA and protein lysates were obtained to assess clock-related gene transcript and protein levels using real-time PCR and western blot, respectively. Luminex XMAP technology was used to assess levels of inflammatory markers. Leukocyte–endothelial interaction assays were performed by perfusing participants’ leukocytes or THP-1 cells (with/without CLK8) over a HUVEC monolayer in a parallel flow chamber using a dynamic adhesion system. Results: Participants with type 2 diabetes showed increased BMAL1 and NR1D1 mRNA levels and decreased protein levels of circadian locomotor output cycles kaput (CLOCK), cryptochrome 1 (CRY1), phosphorylated basic helix-loop-helix ARNT like 1 (p-BMAL1) and period circadian protein homologue 2 (PER2). Correlation studies revealed that these alterations in clock proteins were negatively associated with glucose, HbA_1c, insulin and HOMA-IR levels and leukocyte cell counts. The leukocyte rolling velocity was reduced and rolling flux and adhesion were enhanced in individuals with type 2 diabetes compared with healthy participants. Interestingly, inhibition of CLOCK/BMAL1 activity in leukocytes using the CLOCK inhibitor CLK8 mimicked the effects of type 2 diabetes on leukocyte–endothelial interactions. Conclusions/interpretation: Our study demonstrates alterations in the molecular clock system in leukocytes of individuals with type 2 diabetes, manifested in increased mRNA levels and decreased protein levels of the core clock machinery. These alterations correlated with the impaired metabolic and proinflammatory profile of the participants with type 2 diabetes. Our findings support a causal role for decreased CLOCK/BMAL1 activity in the increased level of leukocyte–endothelial interactions. Overall, our data suggest that alterations in core clock proteins accelerate the inflammatory process, which may ultimately precipitate the onset of CVD in patients with type 2 diabetes. Graphical

The purpose of the study was to determine the impact of weight loss through calorie restriction on metabolic profile, and inflammatory and oxidative stress parameters in metabolically healthy (MHO) and unhealthy (MUHO) obese individuals. A total of 74 subjects (34 MHO and 40 MUHO) received two cycles of a very low-calorie diet, alternating with a hypocaloric diet for 24 weeks. Biochemical, oxidative stress, and inflammatory markers, as well as serum metabolomic analysis by nuclear magnetic resonance, were performed at baseline and at the end of the intervention. After the diet, there was an improvement in insulin resistance, as well as a significant decrease in inflammatory parameters, enhancing oxidative damage, mitochondrial membrane potential, glutathione, and antioxidant capacity. This improvement was more significant in the MUHO group. The metabolomic analysis showed a healthier profile in lipoprotein profile. Lipid carbonyls also decrease at the same time as unsaturated fatty acids increase. We also display a small decrease in succinate, glycA, alanine, and BCAAs (valine and isoleucine), and a slight increase in taurine. These findings show that moderate weight reduction leads to an improvement in lipid profile and subfractions and a reduction in oxidative stress and inflammatory markers; these changes are more pronounced in the MUHO population.

Daily rhythms of metabolic function are supported by molecular circadian clock systems that are strongly regulated by feeding and fasting. Intermittent fasting diets have been associated with weight loss and improved metabolism. However, the effects of time-restricted eating (TRE) on glycemic parameters are still under debate. In this review, we aim to systematically analyze the effects of TRE on glycemic parameters. We searched on PubMed, EMBASE, and the Cochrane Library for controlled studies in which subjects followed TRE for at least 4 weeks. 20 studies were included in the qualitative systematic review, and 18 studies (n = 1169 subjects) were included in the meta-analysis. Overall, TRE had no significant effect on fasting glucose (Hedges’s g = -0.08; 95% CI:-0.31,0.16; p = 0.52), but it did reduce HbA1c levels (Hedges’s g = -0.27; 95% CI: -0.47, -0.06; p = 0.01). TRE significantly reduced fasting insulin (Hedges’s g = -0.40; 95% CI: -0.73,-0.08; p = 0.01) and showed a tendency to decrease HOMA-IR (Hedges’s g = -0.32; 95% CI:-0.66,0.02; p = 0.06). Interestingly, a cumulative analysis showed that the beneficial effects of TRE regarding glucose levels were less apparent as studies with later TRE windows (lTRE) were being included. Indeed, a subgroup analysis of the early TRE (eTRE) studies revealed that fasting glucose was significantly reduced by eTRE (Hedges’s g = -0.38; 95% CI:-0.62, -0.14; p < 0.01). Our meta-analysis suggests that TRE can reduce HbA1c and insulin levels, and that timing of food intake is a crucial factor in the metabolic benefit of TRE, as only eTRE is capable of reducing fasting glucose levels in subjects with overweight or obesity.PROSPERO registration number CRD42023405946.