Effects and interaction of single nucleotide polymorphisms at the pharmacokinetic/pharmacodynamic site: insights from the Rotterdam study into metformin clinical response and dose titration
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Reversal of metformin’s anti-proliferative effect in fission yeast efr3 and dnm1 (DRP1) mutants with elongated mitochondria
Metformin is a well-tolerated drug frequently prescribed for managing type 2 diabetes. Extended metformin use has been linked to a significant decrease in cancer incidence across both diabetic and non-diabetic populations. Here we investigate the anti-proliferative effects of metformin on fission yeast S. pombe. Our findings demonstrate that metformin’s inhibitory impact on cell proliferation is effective in the absence of AMP-activated protein kinase (AMPK). Using an unbiased genetic screen we identified the plasma membrane signalling scaffold Efr3, critical for phosphatidylinositol signalling and the generation of PI4Ps, as a key determinant of resistance to the anti-proliferative effect of metformin. Deletion of efr3 resulted in both AMPK-dependent and AMPK-independent resistance to metformin. We show that Efr3 does not influence cell proliferation by controlling Ras1 activity or its cellular localization in yeast. We observe that dnm1 (DRP1) mutants with elongated mitochondria are also resistant to the anti-proliferative effect of metformin and that metformin treatment promotes mitochondrial fusion. Metabolic measurements after prolonged metformin exposure demonstrated a reduction in respiration in both wild type and the efr3 deletion, however, that reduction is less pronounced in the efr3 deletion, which also contained elongated mitochondria. It is likely that mitochondrial fusion enhances yeast fitness in response to metformin exposure. Together we provide a new perspective on the cellular response to metformin.
Metformin-regulated glucose flux from the circulation to the intestinal lumen
Through a retrospective analysis of existing FDG PET-MRI images, we recently demonstrated that metformin increases the accumulation of FDG in the intestinal lumen, suggesting that metformin stimulates glucose excretion into the intestine. However, the details of this phenomenon remain unclear. We here investigate the detailed dynamics of intestinal glucose excretion, including the rate of excretion and the metabolism of excreted glucose, in both the presence and absence of metformin.
Energy metabolism in health and diseases
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
Intelligent shipping: integrating autonomous maneuvering and maritime knowledge in the Singapore-Rotterdam Corridor
Designing safe and reliable routes is the core of intelligent shipping. However, existing methods for industrial use are inadequate, primarily due to the lack of considering company preferences and ship maneuvering characteristics. To address these challenges, here we introduce a methodological framework that integrates maritime knowledge and autonomous maneuvering model. Based on historical maritime big data, the framework offers customized routes for companies with specific routing preferences. The autonomous maneuvering model then evaluates the safety and reliability of the routes by considering ship motion characteristics and ocean hydrodynamics. We validate its effectiveness on the world’s longest Green and Digital Shipping Corridor between Singapore and Rotterdam. Results demonstrate that our model can provide customized route design for companies and enhance safety for shipping. The framework could serve as a fundamental structure to build a fully digitalized platform for route customization and evaluation for global shipping, optimizing operational decision-making and safety assurance.
Longitudinal associations of dietary fiber and its source with 48-week weight loss maintenance, cardiometabolic risk factors and glycemic status under metformin or acarbose treatment: a secondary analysis of the March randomized trial
To examine longitudinal and dose-d ependent associations between dietary fiber intake and various clinical outcomes over 48 weeks of pharmacological treatment in T2DM patients.
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