Biology and Life Sciences

Abstract: A ketogenic diet (KD) is a low-carbohydrate, high-fat dietary approach. Beyond treating neurologic disorders, KD has attracted significant media attention for its potential to improve obesity and diabetes. The diet induces a metabolic shift from glucose toward fatty acid oxidation and ketone body production. This shift leads to ketosis, which may reduce hunger, cause weight loss, and improve glycaemic control and insulin sensitivity. In particular, the positive effects of KD lower insulin demand and may thereby improve β-cell function. However, the long-term efficacy, safety, and sustainability of KD, especially for diabetes, remain debated. This review offers current insights into the effects of ketogenesis and ketosis and the potential mechanisms underlying them. We examine the metabolic effects of KD in obesity and diabetes, drawing on preclinical and clinical studies, and suggest that combining KD with antidiabetic agents may provide synergistic benefits. We explore how KD alters the composition of the gut microbiota, thereby impacting host metabolism and systemic inflammation. We conclude by highlighting challenges and future directions for optimizing KD-based therapies through personalized nutrition and pharmacological combination treatments.

Abstract: Background: GLP-1 receptor agonists and related incretin-based therapies are effective pharmacological treatments for weight loss in adults with obesity and type 2 diabetes. However, weight regain after treatment discontinuation or attenuation remains a major clinical challenge. Appetite dysregulation may be one mechanism contributing to this regain. Objective: This systematic review aimed to evaluate whether appetite-related changes contribute to weight regain following GLP-1-based weight loss, with particular attention to the distinction between direct post-treatment evidence and indirect evidence from active-treatment studies. Methods: A systematic literature search was conducted in PubMed, Scopus, Embase, and the Cochrane Library for studies published between 2016 and 2026, following PRISMA 2020 guidelines. Eligible studies included adults with obesity, overweight, and/or type 2 diabetes receiving GLP-1 receptor agonists or related incretin-based therapies and reporting appetite-related outcomes, weight outcomes, weight maintenance, or weight regain. Randomized controlled trials, clinical trials, crossover studies, and observational studies were included. Findings were synthesized qualitatively. Results: Eighteen studies published between 2017 and 2026 met the inclusion criteria. Most studies reported that GLP-1-based therapy reduced appetite, hunger, food cravings, energy intake, or dietary intake, while increasing satiety and promoting weight loss during active treatment. Direct appetite measures were commonly reported using visual analogue scales, appetite questionnaires, food craving measures, and energy intake assessments. However, only a small number of studies directly evaluated appetite changes during treatment withdrawal, weight maintenance, or post-treatment weight regain. Therefore, the available evidence supports a plausible mechanistic link between loss of appetite regulation and weight regain, but the evidence remains largely indirect. Conclusion: GLP-1-based therapies consistently improve appetite regulation and promote weight loss during active treatment. However, direct evidence linking post-treatment appetite dysregulation to subsequent weight regain remains limited. Appetite dysregulation should therefore be interpreted as a plausible and clinically relevant contributor, rather than a definitively established causal driver.

Abstract: Background: Women with polycystic ovary syndrome (PCOS) have a substantially increased risk of endometrial cancer (EC), yet the biological mechanisms underpinning this association remain incompletely understood. Insulin-like growth factor (IGF)-associated signaling has been implicated, but existing evidence is conflicting. Methods: This feasibility and hypothesis-generating study combined a small clinical cohort with exploratory transcriptomics, in vitro and in silico analyses. Serum IGF1 and IGFBP-3 were measured in women with PCOS (n = 12 for IGF-1 and n = 6 for IGFBP-3) and controls (n = 24 for IGF1 and n = 7 for IGFBP-3). Pooled serum, stratified by IGF bioactivity, was applied to a human endometrial cancer cell line (HEC1A) to further assess effects on cell viability, cell cycle distribution, and downstream signaling, in addition to exploratory RNA sequencing (n=1 biological replicate per condition). Computational analysis of publicly available endometrial cancer datasets was used to contextualize experimental findings. Results: Serum IGF1 and IGFBP-3 levels did not differ significantly between PCOS and control groups. However, pooled PCOS serum increased EC cell viability and altered cell cycle progression compared with control serum. Pharmacological inhibition of IGF1R partially attenuated these effects, suggesting that IGF-associated pathways may contribute but are unlikely to act in isolation. Exploratory transcriptomic profiling of serum-treated EC cells supported enrichment of IGF-associated metabolic and growth programs (including mTORC1, PI3K/AKT/mTOR, glycolysis and oxidative phosphorylation), consistent with context-dependent modulation rather than IGF-only dependence. In silico analyses demonstrated frequent alterations in PI3K/AKT/mTOR-related genes in endometrial cancer, consistent with pathway-level vulnerability rather than IGF1-specific dependence. Conclusion: As a feasibility study, these findings suggest that PCOS serum contains factors that promote EC cell growth, with partial involvement of IGF signaling. However, multiple metabolic and hormonal pathways are likely to contribute. Larger, better-controlled studies incorporating insulin, sex steroids, and multiple EC models are required before causal inferences can be made.

Abstract: Cytochrome P450 oxidoreductase (POR) is the obligate electron donor for microsomal cytochrome P450 enzymes. Recessive mutations in the POR gene cause POR deficiency (PORD), a severe metabolic disorder characterized by skeletal malformations, ambiguous genitalia, and adrenal insufficiency. Because global POR knockout is embryonically lethal in mammalian models, the mechanistic study of PORD has historically been restricted to reconstituted biochemical assays or non-steroidogenic cellular backgrounds. Here, we describe complete biallelic POR knockout in human adrenal-derived NCI-H295R and human embryonic kidney HEK293T cells using CRISPR/Cas9. Transcriptomic and mass spectrometric steroid profiling of the adrenal clones revealed a blockade in canonical steroidogenesis, characterized by upstream accumulation of pregnenolone and progesterone, and severe depletion of downstream glucocorticoids and mineralocorticoids. Strikingly, knockout cells maintained low-level synthesis of dehydroepiandrosterone (DHEA) despite the complete absence of canonical CYP17A1 catalytic support, providing critical in vitro validation for the activation of alternative, CYP17A1-independent bypass steroidogenic pathways. Furthermore, utilizing the HEK293T platform, we evaluated the functional complementation of clinically relevant variants (A287P, R457H, P228L, and delP399_E401). Notably, the highly prevalent P228L variant exhibited selective preservation of CYP17A1 activity while severely impairing CYP19A1 aromatase function. A direct comparison between episomal overexpression and endogenous CRISPR prime editing of P228L highlighted critical differences in enzyme efficiency under native regulatory control. Finally, we establish a link between POR loss and altered intracellular Fe(II) storage, indicating perturbed ferroptotic susceptibility. These engineered human cell models provide a highly tractable platform for interrogating mutant-specific pharmacogenomics and developing targeted interventions.

Abstract: Castration-resistant prostate cancer (CRPC) survives androgen deprivation, a mechanism widely attributed to autonomous de novo steroidogenesis. Despite the clinical deployment of CYP17A1 inhibitors, the metabolic fidelity of the models underpinning this "tumor-as-gonad" dogma remains controversial. Here, integrating high-resolution liquid chromatography-mass spectrometry with transcriptomics across diverse prostate cancer models, we demonstrate that malignant cell lines universally lack autonomous steroidogenic capacity due to the transcriptional silencing of CYP17A1. Instead, these models operate as high-efficiency precursor "converters" by upregulating HSD3B1 and AKR1C3. Clinical stratification of 844 Prostate Adenocarcinoma patients corroborated this precursor-dependent phenotype. We identify a critical divergence: AR-High tumors rely on oxidative phosphorylation, whereas the transition to an AR-Low state is marked by extensive lineage plasticity. Strikingly, a neuroendocrine plasticity score inversely correlates with AR flux and independently predicts clinical progression (HR=2.41, p=0.024). Our findings redefine CRPC metabolism, dictating a therapeutic shift toward targeting downstream precursor conversion and adaptive lineage plasticity.

Abstract: Evidence suggests that physical activity promotes bone health through mechanical loading and biochemical signaling between bone and muscle tissues. A class of signaling molecules known as exerkines is a key mediator of bone–muscle crosstalk. Although exercise regulates osteokines, the acute exerkine responses across different exercise modalities remain unclear. This randomized repeated-measures crossover study compared acute changes in serum sclerostin (SCL), dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), osteopontin (OPN), brain-derived neurotrophic factor (BDNF), irisin, and interleukin 6 (IL-6) following circuit training (CT) (cycle ergometer, push-up, step-ups, medicine ball twist, and front squats with kettlebell for three sets) and traditional resistance (TR) exercise (3 sets 10 repetitions 80% 1RM for leg press, seated cable row, barbell bench press, dumbbell deadlifts, and dumbbell seated shoulder press) in healthy young adults (n=12). Participants performed two protocols separated by 2-week wash-out periods. Blood samples were analyzed before exercise training (pre), immediately post-exercise (IP), and 30 minutes post-exercise (30P) for all exerkines using ELISA. There was a significant interaction between protocol, timepoint, and sex (p=0.038) for SCL levels. There was a significant interaction between protocol, timepoint, and sex for SCL levels (p < 0.05). In males, SCL levels increased from Pre to IP under both training protocols (CT: 0.10 ± 0.02 ng/mL to 0.14 ± 0.02 ng/mL; TR: 0.20 ± 0.02 ng/mL to 0.21 ± 0.02 ng/mL). In both protocols, SCL levels decreased from IP to 30 P (CT: 0.14 ± 0.02 to 0.10 ± 0.01 ng/ml; TR: 0.22 ± 0.02 to 0.17 ± 0.02 ng/ml). In females, SCL levels increased from Pre to IP under both training protocols (CT: 0.03 ± 0.02 ng/mL to 0.06 ± 0.02 ng/mL; TR: 0.07 ± 0.02 ng/mL to 0.13 ± 0.02 ng/mL). There was a significant time effect for OPN and RANKL concentrations. Marginal means for the time point showed that OPN was significantly higher at the Pre time point. Post hoc analyses showed that OPN levels significantly decreased from 30P to Pre (18.84 ± 0.92 to 15.69 ± 1.32 pg/mL) (p=0.08). Similarly, RANKL showed a significant increase from Pre (0.38 ± 0.04 pg/mL) to 30P (0.57 ± 0.06 pg/mL) (p=0.02); otherwise, there were no significant differences between protocols or sexes. Irisin significantly decreased from Pre (28761.73 ± 238.52 pg/mL) to IP (2364.85 ± 243.79 pg/mL) in both protocols (p=0.01). DKK-1, BDNF, and IL-6 levels were only different between protocols (p< 0.01). SCL and BDNF levels were expressed higher in the TR protocol, whereas DKK-1, IL-6, and Irisin levels were expressed higher in the CT protocol. Overall, the findings suggest that SCL, RANKL, OPN, and irisin responded to the exercise bout, while the exerkines did not show meaningful changes over time.

Abstract: Alzheimer’s disease (AD) disproportionately affects women, with risk increasing sharply during and after the menopausal transition. While declines in estrogen have traditionally been emphasized, emerging evidence suggests that elevations in follicle-stimulating hormone (FSH) may represent a critical and underappreciated driver of neurodegenerative vulnerability. This review synthesizes current evidence linking reproductive aging to AD pathobiology, with a focus on endocrine, metabolic, and inflammatory mechanisms. We examine how sustained FSH elevation interacts with key molecular pathways implicated in AD, including C/EBPβ–δ-secretase signaling, mitochondrial dysfunction, impaired glucose metabolism, and disruptions in autophagic and lysosomal clearance. These processes converge to promote amyloid-β accumulation, tau pathology, and chronic neuroinflammation. In parallel, FSH influences apolipoprotein biology - particularly ApoE - through effects on lipid metabolism, protein lipidation, and clearance dynamics, thereby modulating both amyloid kinetics and inflammatory responses in an isoform-dependent manner. Reproductive aging is further characterized by systemic shifts in vascular integrity, blood–brain barrier function, and immunometabolic regulation, all of which may amplify susceptibility to neurodegenerative processes. Importantly, these upstream disturbances precede classical pathological hallmarks, reframing amyloid and tau accumulation as downstream manifestations of broader regulatory failure. Collectively, this work positions FSH not merely as a biomarker of ovarian decline, but as an active endocrine mediator of neurodegeneration. Targeting FSH signaling and its downstream pathways may therefore represent a promising and mechanistically grounded approach for mitigating AD risk, particularly in women.

Abstract: Milk quality is crucial for human health, and effective control of the supply chain—including services, processes, and products—is essential to maintain it. This study aimed to compare cholesterol and protein content, phospholipid composition, advanced glycation end products, and somatic cell count in milk from organic and conventional farming systems. Additionally, the impact of short versus long supply chains was evaluated. The results demonstrate that milk from organic farming has a better phos-pholipid and cholesterol composition and also a greater amount of protein than milk derived from traditional farming and that the long supply chain does not significantly change these properties, with the exception of phospholipids. Advanced glycation end products values were significantly higher in long supply chain, both in conventional and biological samples, but the long supply chain had a greater impact especially on the organic product. Finally, somatic cell count results show lower values in organic samples, suggesting particularly effective herd management and animal health protocols in these operations

Abstract: Weight regain following weight loss represents a major challenge in obesity management and is increasingly recognized as a biologically driven process rather than solely a consequence of behavioral non-adherence. A range of physiological adaptations, including reduced energy expenditure, neuroendocrine alterations in appetite regulation, and adipose tissue remodeling, act synergistically to promote weight restoration.In particular, changes in appetite-regulating hormones, such as decreased leptin and increased ghrelin levels, contribute to increased hunger and reduced satiety following weight loss. Additionally, emerging evidence highlights the role of adipose tissue remodeling and metabolic memory in sustaining susceptibility to weight regain.Nutritional factors may play a critical role in modulating these biological mechanisms. Dietary protein, fiber intake, glycemic responses, and overall dietary patterns have been shown to influence appetite regulation through interactions with gut-derived hormones, postprandial metabolism, and central appetite pathways. These effects suggest that dietary composition, beyond caloric restriction alone, may be a key determinant of long-term weight maintenance.Despite growing evidence, findings remain heterogeneous, and the long-term effectiveness of specific dietary strategies is not fully established. Future approaches should focus on integrating nutritional strategies with individual biological responses, including variability in hormonal regulation, metabolic adaptation, and gut–brain signaling.In conclusion, targeting appetite regulation and metabolic adaptation through personalized and sustainable nutritional strategies may represent a promising approach for reducing weight regain and improving long-term outcomes in obesity management.

Abstract: Background: Androgen deprivation therapy (ADT) is widely used in the management of prostate cancer (PCa) and remains a cornerstone of treatment across multiple disease settings. Although ADT con-tributes substantially to disease control, it also induces significant adverse metabolic and body composition changes. These alterations include loss of lean mass, increased fat mass, and deterio-ration in muscle quality, together contributing to a clinical phenotype consistent with sarcopenic obesity (SO). Importantly, ADT-induced SO is characterized not only by reductions in skel-etal muscle mass but also by impaired muscle quality, particularly fatty infiltration of skeletal muscle, or myosteatosis, an underrecognized but defining feature of this syndrome. Methods: This narrative review examines current evidence regarding interventions aimed at mitigating sar-copenic obesity in men treated with ADT for prostate cancer, identifies key gaps in the literature, and proposes a mechanism-driven path forward for intervention development. Results: Several exercise- and nutrition-based interventions have been evaluated in men receiving ADT and demonstrate improvements in selected outcomes such as muscle strength, body composition, and metabolic parameters. However, most studies have been limited by small sample sizes, short intervention durations, and a focus on isolated intervention components. Importantly, muscle quality and intramuscular fat infiltration (myosteatosis), a central component of sarcopenic obesity, have rarely been incorporated as biomarkers or endpoints in intervention trials targeting men re-ceiving ADT. Conclusion: Future interventions designed to mitigate SO and its associated metabolic abnormalities should evaluate comprehensive, bundled strategies initiated early during ADT and sustained long enough to capture clinically meaningful changes. Outcomes should include biomarkers of muscle mass, strength, and quality, including imaging-based measures of myosteatosis, along with metabolic syndrome markers, inflammatory mediators, functional outcomes, adherence, and quality of life. These changes should be correlated with underlying biological mechanisms such as NF-κB signal-ing and pro-inflammatory cytokines. Such data may inform future phase III trials and ultimately support clinical strategies to mitigate ADT-related sarcopenic obesity and its downstream cardi-ometabolic and oncologic consequences.

Abstract: Background: Vitamin K (VK) has emerging roles beyond coagulation, including potential involvement in glucose metabolism. While large cohorts report inverse associations between VK status and incident type 2 diabetes, less is known about its relation-ship with insulin resistance in general populations. Methods: We conducted a cross-sectional analysis of 23,247 adults from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Dietary VK intake was assessed using a 24-h recall and modeled as energy-adjusted nutrient density (µg/1000 kcal). Fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose, and HbA1c were analyzed using survey-weighted linear regression; models were adjusted for demographic, socioeconomic, lifestyle, and adiposi-ty-related factors. Effect modification by baseline metabolic status was evaluated, and sensitivity analyses assessed robustness. Results: Higher energy-adjusted VK intake was independently associated with lower fasting insulin and HOMA-IR, but not with fasting glucose or HbA1c. Each SD increase in VK intake was associated with 1.4% lower fasting insulin (95% CI -2.4% to -0.4%) and 1.3% lower HOMA-IR (95% CI -2.3% to -0.3%) in fully adjusted models. Associations were attenuated but remained signif-icant after adjustment for adiposity. Effect modification by baseline metabolic status was observed, with stronger associations among normoglycemic individuals. Findings were robust across sensitivity analyses. Conclusions: In this nationally representative sample of U.S. adults, higher VK intake was modestly associated with lower insulin resistance markers. Dietary VK intake may contribute to maintenance of insulin sensitivity, particularly in metabolically intact states. Prospective studies incorporating comprehensive VK biomarkers and dynamic measures of insulin sensitivity are warrant-ed.

Abstract: Obesity is a chronic inflammatory, multifactorial disease characterized by excessive fat accumulation driven by an imbalance between energy intake and energy expenditure. Despite the implementation of public health strategies and individual therapeutic interventions, overweight and obesity affect more than two billion people worldwide. While the distinction between preclinical (PCO) and clinical obesity (CO) has been conceptually established, tools capable of translating this distinction into clinical diagnostics remain lacking. Current approaches typically use quality-of-life questionnaires as outcome measures rather than diagnostic criteria. In this study, we proposed a novel diagnostic framework in which the SF-36 Role-Physical (RP) domain functions as a screening tool to identify CO. We integrated anthropometric criteria (BMI, waist circumference), organ dysfunction (comorbidities), and objectively defined physical limitations (RP domain cutoffs). Results demonstrated that stratifying patients based on this functional model successfully isolated a phenotype characterized by a distinct pro-inflammatory profile. Individuals classified as having CO exhibited significantly increased IL-6 and IL-17A levels compared to PCO and overweight groups, providing biological validation that the SF-36 RP domain can effectively distinguish pathological adiposity from simple weight gain.

Abstract: Type 2 diabetes mellitus (T2DM) is a major driver of cardiovascular disease (CVD), yet current risk stratification tools fail to capture underlying molecular dysregulation. This study aimed to characterize an integrated molecular signature associated with cardiovascular risk in T2DM. A total of 128 individuals (96 T2DM and 32 controls) were evaluated. Circulating miR-34a expression was quantified by RT–qPCR, and protein biomarkers including SIRT1, inflammatory markers (IL-6, TNF-α, hs-CRP), oxidative stress markers (MDA, total antioxidant capacity), and endothelial dysfunction markers (VCAM-1, ICAM-1) were measured by ELISA. Cardiovascular risk was assessed using the Framingham Risk Score. miR-34a expression was significantly elevated in T2DM, particularly in individuals with high cardiovascular risk (p < 0.001). This was accompanied by reduced SIRT1 levels and a progressive increase in inflammatory, oxidative, and endothelial dysfunction markers. Integrated analysis revealed strong correlations between miR-34a upregulation, SIRT1 suppression, and systemic pathophysiological alterations. Multivariate regression identified miR-34a, SIRT1, IL-6, and MDA as independent predictors of high cardiovascular risk. A combined biomarker model demonstrated excellent discriminative performance (AUC = 0.92), outperforming individual markers. These findings support the existence of a coordinated miR-34a/SIRT1-driven molecular axis linking inflammation, oxidative stress, and endothelial dysfunction to cardiovascular risk in T2DM. This integrated biomarker approach may improve risk stratification and support precision cardiometabolic medicine.

Abstract: Diabetes mellitus affects an estimated 589 million adults globally, and cutaneous manifestations occur in up to 70% of affected individuals during the course of the disease. While the impaired wound healing associated with diabetes has been extensively studied, the aesthetic implications of diabetic skin disease remain comparatively underexplored. Individuals with diabetes frequently exhibit features of accelerated cutaneous aging, including premature wrinkling, dyschromia, xerosis, alopecia, and other cosmetically significant dermatoses that may negatively impact quality of life. In parallel, the demand for aesthetic dermatologic procedures among patients with diabetes has increased substantially; however, evidence-based recommendations guiding the safe and effective use of cosmetic interventions in this population remain limited. Diabetic skin demonstrates accelerated biological aging driven by complex pathophysiological mechanisms, including the accumulation of advanced glycation end products, chronic low-grade inflammation, oxidative stress, microvascular dysfunction, and neuropathy. These processes partially overlap with chronological aging and photoaging but are mechanistically distinct and may influence tissue repair, inflammatory responses, and the safety profile of commonly performed aesthetic procedures such as chemical peels, laser resurfacing, dermal fillers, neuromodulators, and microneedling. Emerging regenerative approaches, including platelet-rich plasma, platelet lysate, and mesenchymal stromal cell-derived products such as exosomes and secretomes, have attracted increasing attention as biologically targeted strategies for cutaneous rejuvenation. Nevertheless, clinical evidence specifically addressing aesthetic interventions in diabetic populations remains limited. A diabetes-informed approach to aesthetic dermatology that considers metabolic status, procedure selection, and post-procedural monitoring is therefore essential to optimize safety and therapeutic outcomes.

Abstract:

Introduction Overactive bladder (OAB) frequently co-occurs with cardiovascular-kidney-metabolic (CKM) syndrome; however, the complex interplay of systemic inflammation, psychological distress, and metabolic dysregulation driving this connection remains poorly defined. This study aimed to elucidate these multidimensional associations and identify shared metabolic patterns between OAB and CKM-related conditions. Methods We analyzed data from 11,836 participants in the National Health and Nutrition Examination Survey (2005–2018). CKM stages were classified using American Heart Association criteria, while OAB severity, systemic inflammation, and depression were assessed via the Overactive Bladder Symptom Score, neutrophil-to-high-density lipoprotein cholesterol ratio (NHR), and Patient Health Questionnaire-9, respectively. We utilized survey-weighted multivariable regression and mediation analysis. Furthermore, two-sample Mendelian randomization (MR) analyses using genome-wide association study datasets were conducted to identify causal metabolites. Results Higher CKM stages were significantly associated with increased OAB severity. Elevated NHR and depression scores were independently linked to OAB. Notably, a significant synergistic interaction was observed: moderate inflammation amplified the impact of depressive symptoms on OAB. Mediation analyses demonstrated that NHR, depression, and their interaction significantly mediated the relationship between CKM stage and OAB. MR analysis identified specific causal lipid, amino acid, and energy-related metabolites for OAB, exhibiting substantial overlap with CKM metabolic signatures. Discussion & Conclusion CKM progression, systemic inflammation, and depression are robustly associated with OAB, linked through neuro-inflammatory and psychological pathways. OAB appears to be a manifestation of systemic dysregulation shared with CKM syndrome, necessitating integrated management strategies addressing cardiometabolic health and psychological well-being.

Abstract: Since the pioneering work of Dean P. M. and Matthew E. K. (1970), four decades have elapsed without any consensus on the mechanism responsible for the oscillations of the plasma membrane voltage exhibited by pancreatic β-cells stimulated by glucose. In this review, the different hypothesis dealing with the cause of voltage oscillations that lead to insulin secretion pulsatility will be commented. The earliest explanation attributed the voltage oscillations (bursting) to glycolytic oscillations, taking as a reference skeletal muscle glycolysis oscillations. Later, the scientific interest moved to glucose oxidation after discovering that some mitochondrial parameters also oscillated in synchrony with membrane voltage oscillations. As [Ca2+]cyt increases resultant from membrane depolarization oscillated in synchrony with membrane bursting, it competed with metabolic oscillations (e.g. cytosolic ATP/ADP) for being the cause or the effect of insulin pulsatility; it was demonstrated that metabolic oscillations preceded [Ca2+]cyt oscillations. We are contributing with the hypothesis attributing the cause of voltage oscillations to a sequential competition of two β-cell plasma membrane channels: K+ATP channel and Cx36 hemichannel (Cx36H). Whereas increased glucose metabolism (increased ATP/ADP) closures K+ATP channels and depolarizes the plasma membrane (active phase of a bursting), Cx36Hs are opened and repolarize the membrane potential with a certain delay by inhibiting glucose metabolism (silent phase of a bursting). Repolarization, in turn, closes Cx36H and allows the recovery of glucose oxidation and beginning of a new active phase.

Abstract: Background: Vitamin D (25(OH)D) deficiency affects over one billion people globally and is associated with type 2 diabetes (T2D) and cardiometabolic diseases. However, causal relationships remain unclear, as vitamin D supplementation have shown limited benefit in reducing T2D risk. Genetic studies have identified variants influencing circulating 25(OH)D levels, but whether genetically determined vitamin D status predicts cardiometabolic outcomes is still uncertain. We therefore used bidirectional Mendelian randomization with genome-wide polygenic scores to evaluate the causal relationship and directionality between vitamin D status and T2D. Methods and Results: We analyzed multi-ethnic populations from the UK Biobank (N = 471,861), and 3,486 participants from the Asian Indian Diabetic Heart Study/Sikh Diabetes Study with serum 25(OH)D measures and genome-wide genotype data. A global polygenic score of vitamin D–raising alleles did not significantly reduce the risk of T2D, coronary artery disease, stroke, or other cardiometabolic risk factors. In contrast, a higher T2D polygenic risk score (PRS) was strongly associated with increased risk for 25(OH)D deficiency (<50 nmol/L). Genetically instrumented analyses showed per SD increase in T2D PRS significantly reduced circulating 25(OH)D levels (β = −8.9 nmol/L; 95% CI: −9.3 to −8.5; p = 3.6 × 10⁻²⁸). Conclusions: Our findings suggest low circulating vitamin D levels are unlikely to causally predict T2D risk but may serve as a marker for secondary prevention in endocrine and cardiovascular health. Instead, genetic susceptibility to T2D appears to contribute to reduced vitamin D levels. Further studies are needed to clarify the mechanisms underlying vitamin D deficiency in diabetes.

Abstract: The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated nuclear transcription factor belonging to the nuclear receptor superfamily. Although classically characterised as the master regulator of hepatic fatty acid oxidation (FAO) and lipid catabolism, accumulating evidence positions PPARα as an indispensable molecular conductor at the feto-maternal interface. Within the human placenta, PPARα is expressed in both cytotrophoblast and syncytiotrophoblast layers throughout gestation, where it governs mitochondrial and peroxisomal β-oxidation, orchestrates pro-resolution inflammatory signalling, modulates trophoblast differentiation and invasion, and participates in epigenetic programming of the developing fetus. Derangements of placental PPARα activity are increasingly identified in major obstetric complications, including preeclampsia, gestational diabetes mellitus, and intrauterine growth restriction, where aberrant lipid accumulation, heightened oxidative stress, and amplified pro-inflammatory cytokine signalling converge. This review synthesises current knowledge on the molecular biology and genomic targets of PPARα in the placenta, its integration with maternal metabolic adaptations of pregnancy, its role in nutrient sensing and fetal programming, and the consequences of its dysregulation in pregnancy pathology. We further discuss emerging therapeutic implications of PPARα modulation and outstanding questions in this rapidly evolving field.

Abstract: Childhood obesity is a globally pervasive condition driven not only by lifestyle and environmental factors but also by complex molecular mechanisms. These mechanisms involve genetic predisposition, epigenetic regulation, hormonal signaling pathways, adipose tissue biology, immuno-inflammatory responses, and interactions with environmental endocrine disruptors. This review synthesizes current evidence from scientific articles, systematic reviews, and mechanistic studies to elucidate how molecular processes shape the development, onset, and progression of obesity in children. Understanding these pathways is critical for developing precise prevention strategies and targeted interventions.

Abstract: Background/Objectives: Sweeteners and sweetness enhancers (S&SEs) have been proposed to potentially impair appetite regulation by stimulating sweet taste receptors beyond the perception of sweetness, similar to caloric sweeteners. The evidence is, however, not clear. Methods: This sub-study investigated the acute effects of a mixture of acesulfame potassium and cyclamate (Ace-K/Cyc) versus water on postprandial appetite sensations and energy intake at baseline, after a 2-month weight loss period, and after a 4–month weight loss maintenance period, including (S&SE group) or ex-cluding S&SEs (Sugar group) in the diet. A total of 26 participants (18-65 years; BMI≥25.0 kg/m2) were recruited from the 1-year randomized controlled SWEET trial. Subjective appetite sensations were measured via visual analogue scales fasting and 9 times during a 250-minute postprandial period. During this period first a standardized breakfast (0-10 minutes) and 2 hours later a test drink containing either Ace-K/Cyc or water (120-130 minutes) were given. After 265 minutes, an ad libitum test meal was served. Results: The S&SEs group rated lower feelings of hunger, prospective con-sumption, and desire to eat something sweet after the test drink with Ace-K/Cyc com-pared to the Sugar group consuming water (p< 0.05). This was true for all 3 test days. Adjusting for taste of the test drinks removed the differences for hunger. Ad libitum energy intake did not differ (p>0.05). Conclusions: Ace-K/Cyc compared to water re-duced feelings of prospective consumption and desire to eat something sweet acutely, after 2 months weight loss, and after 4 months weight loss maintenance.