bims-medica 2025-01-26 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–01–26
29 papers selected by
Brett Chrest, Wake Forest University

Hyper-energy metabolism of Oxidative phosphorylation and enhanced glycolysis contributes to radioresistance in glioma cells.
Impaired oxidative phosphorylation drives primary tumor escape and metastasis.
Cryo-EM structure and regulation of human NAD kinase.
SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis.
Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
Randle Cycle in Practice: a student exercise to teach glucose- and fatty acid metabolism in fasted, fed and exercised states.
Fuel for thought: targeting metabolism in lung cancer.
Nutritional Counseling During Chemotherapy Treatment: A Systematic Review of Feasibility, Safety, and Efficacy.
Differential effects of β-hydroxybutyrate and α-ketoglutarate on HCT-116 colorectal cancer cell viability under normoxic and hypoxic low-glucose conditions: exploring the role of SRC, HIF1α, ACAT1, and SIRT2 genes.
Targeting Glutamine Metabolic Reprogramming in Pancreatic Cancer: Current Insights and Future Directions.
Tracing of Amino Acids Dynamics in Cell Lines Based on 18O Stable Isotope Labeling.
LDHAα, a lactate dehydrogenase A isoform, promotes glycolysis and tumor progression.
Development of a Genetically Encoded Sensor for Arginine.
Resistance Training and the Risk of Breast Cancer: A Population-Based Case-Control Study.
Metabolic interplays between the tumour and the host shape the tumour macroenvironment.
Dysfunctional mitochondrial bioenergetics sustains drug resistance in cancer cells.
Cancer cells 'poison' the immune system with tainted mitochondria.
Final Analysis of the Phase 1b Chemotherapy And Venetoclax in Elderly Acute Myeloid Leukaemia Trial (CAVEAT).
Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.
Purification and characterization of recombinant human mitochondrial proton-pumping nicotinamide nucleotide transhydrogenase.
FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells.
Glutamine, Serine and Glycine at Increasing Concentrations Regulate Cisplatin Sensitivity in Gastric Cancer by Posttranslational Modifications of KDM4A.
Chronic intermittent fasting impairs β cell maturation and function in adolescent mice.
V-ATPase in glioma stem cells: a novel metabolic vulnerability.
Inhibition of acyl-CoA synthetase long-chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction.
Preventive and Therapeutic effects of Metformin in Cancer: A Meta-Analysis of RCT and Cohort Studies.
Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease.
The effects of low-carbohydrate diet on glucose and lipid metabolism in overweight or obese patients with T2DM: a meta-analysis of randomized controlled trials.
Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial.

Free Radic Res. 2025 Jan 20. 1-14

Hyper-energy metabolism of Oxidative phosphorylation and enhanced glycolysis contributes to radioresistance in glioma cells.

Yogesh Rai, Ankit Kumar Tiwari, Rakesh Pandey, B S Dwarakanath, Anant Narayan Bhatt.

  PurposeThe concept of dual-state hyper-energy metabolism characterized by elevated glycolysis and OxPhos has gained considerable attention during tumor growth and metastasis in different malignancies. However, it is largely unknown how such metabolic phenotypes influence the radiation response in aggressive cancers. Therefore, the present study aimed to investigate the impact of hyper-energy metabolism (increased glycolysis and OxPhos) on the radiation response of a human glioma cell line.MethodsModulation of the mitochondrial electron transport chain was carried out using a 2,4-dinitrophenol (DNP). Metabolic characterization was carried out by assessing glucose uptake, lactate production, mitochondrial mass, membrane potential, and ATP production. The radiation response was examined by cell growth, clonogenic survival, and cell death assays. Macromolecular oxidation was assessed by DNA damage, lipid peroxidation, and protein carbonylation assay.ResultsHypermetabolic OPM-BMG cells exhibited a significant increase in glycolysis and OxPhos following irradiation as compared to the parental BMG-1 cells. Enhanced radioresistance of OPM-BMG cells was evidenced by the increase in α/β ratio (9.58) and D1 dose (4.18 Gy) as compared to 4.36 and 2.19 Gy in BMG-1 cells respectively. Moreover, OPM-BMG cells were found to exhibit increased resistance against radiation-induced cell death, and macromolecular oxidation as compared to BMG-1 cells. Inhibition of glycolysis and mitochondrial complex-II significantly enhanced the radiosensitivity of OPM-BMG cells compared to BMG-1 cells.ConclusionOur results demonstrate that the hyper-energy metabolism of increased glycolysis and OxPhos confer radioresistance. Consequently targeting glycolysis and OxPhos in combination with radiation may overcome therapeutic resistance in aggressive cancers like glioma.

Keywords:  2-DG; Cancer bioenergetics; Glioma; Hyper-energy metabolism; Malonate; OXPHOS; Radioresistance Glycolysis

DOI:  https://doi.org/10.1080/10715762.2025.2456740
bioRxiv. 2025 Jan 09. pii: 2025.01.08.631936. [Epub ahead of print]

Impaired oxidative phosphorylation drives primary tumor escape and metastasis.

Emily N Arner, Erin Q Jennings, Daniel R Crooks, Christopher J Ricketts, Melissa M Wolf, Matthew A Cottam, Emilie L Fisher-Gupta, Martin Lang, Nunziata Maio, Yuki Shibata, Evan S Krystofiak, Logan M Vlach, Zaid Hatem, Alexander M Blatt, Darren R Heintzman, Allison E Sewell, Emma S Hathaway, KayLee K Steiner, Xiang Ye, Samuel Schaefer, Zachary A Bacigalupa, W Marston Linehan, Kathryn E Beckermann, Frank M Mason, Kamran Idrees, W Kimryn Rathmell, Jeffrey C Rathmell.

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.

DOI: https://doi.org/10.1101/2025.01.08.631936
Sci Adv. 2025 Jan 24. 11(4): eads2664

Cryo-EM structure and regulation of human NAD kinase.

Prakash P Praharaj, Yang Li, Charline Mary, Mona H Soflaee, Kevin Ryu, Dohun Kim, Diem H Tran, Trishna Dey, Harrison J Tom, Halie Rion, Muriel Gelin, Andrew Lemoff, Lauren G Zacharias, João S Patricio, Thomas P Mathews, Zhe Chen, Corinne Lionne, Gerta Hoxhaj, Gilles Labesse.

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a crucial reducing cofactor for reductive biosynthesis and protection from oxidative stress. To fulfill their heightened anabolic and reductive power demands, cancer cells must boost their NADPH production. Progrowth and mitogenic protein kinases promote the activity of cytosolic NAD kinase (NADK), which produces NADP+, a limiting NADPH precursor. However, the molecular architecture and mechanistic regulation of human NADK remain undescribed. Here, we report the cryo-electron microscopy structure of human NADK, both in its apo-form and in complex with its substrate NAD+ (nicotinamide adenine dinucleotide), revealing a tetrameric organization with distinct structural features. We discover that the amino (N)- and carboxyl (C)-terminal tails of NADK have opposing effects on its enzymatic activity and cellular NADP(H) levels. Specifically, the C-terminal region is critical for NADK activity, whereas the N-terminal region exhibits an inhibitory role. This study highlights molecular insights into the regulation of a vital enzyme governing NADP(H) production.

DOI: https://doi.org/10.1126/sciadv.ads2664
EMBO J. 2025 Jan 17.

SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis.

Li Shi, Hao Chen, Yuxin Zhang, Donghao An, Mengyao Qin, Wanting Yu, Bin Wen, Dandan He, Haiping Hao, Jing Xiong.

  Metabolic requirements of dividing hepatocytes are prerequisite for liver regeneration after injury. In contrast to transcriptional dynamics during liver repair, its metabolic dependencies remain poorly defined. Here, we screened metabolic genes differentially regulated during liver regeneration, and report that SLC13A2, a transporter for TCA cycle intermediates, is decreased in rapid response to partial hepatectomy in mice and recovered along restoration of liver mass and function. Liver-specific overexpression or depletion of SLC13A2 promoted or attenuated liver regeneration, respectively. SLC13A2 increased cleavage of SREBP2, and expression of cholesterol metabolism genes, including LDLR and HMGCR. Mechanistically, SLC13A2 promotes import of citrate into hepatocytes, serving as building block for ACLY-dependent acetyl-CoA formation and de novo synthesis of cholesterol. In line, the pre-administration of the HMGCR inhibitor lovastatin abolished SLC13A2-mediated liver regeneration. Similarly, ACLY inhibition suppressed SLC13A2-promoted cholesterol synthesis for hepatocellular proliferation and liver regeneration in vivo. In sum, this study demonstrates that citrate transported by SLC13A2 acts as an intermediate metabolite to restore the metabolic homeostasis during liver regeneration, suggesting SLC13A2 as a potential drug target after liver damage.

Keywords:  ATP-citate Lyase; Cell Division; De Novo Cholesterol Synthesis; Metabolic Remodeling; Partial Hepatectomy; TCA Cycle

DOI:  https://doi.org/10.1038/s44318-025-00362-y
Nat Cancer. 2025 Jan 17.

Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.

Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

DOI: https://doi.org/10.1038/s43018-024-00895-x
Adv Physiol Educ. 2025 Jan 17.

Randle Cycle in Practice: a student exercise to teach glucose- and fatty acid metabolism in fasted, fed and exercised states.

Rikke Petersen, Mie Feldfoss Nørremark, Nils Færgeman.

  Here we describe an approach and overall concept on how to train undergraduate university students to understand basic regulation and integration of glucose and fatty acid metabolism in response to fasting, intake of carbohydrates and aerobic exercise. During lectures and both theoretical and practical sessions, the students read, analyse, and discuss the fundamentals of Randle cycle. They focus on how metabolism is regulated in adipose tissue, skeletal muscle, and liver at a molecular level under various metabolic conditions. Subsequently, students perform one of four different trials: 1) overnight fast followed by ingestion of jelly sandwiches and lemonade ad libitum; 2) overnight fast followed by ingestion of a chocolate bar and a soda; 3) overnight fast followed by ingestion of carrots and 4) light fast and aerobic exercise for 2 hours, while monitoring glucose- and fatty acid levels. The data from these trials clearly show that glucose levels are kept constant around 5 mM while fatty acid levels raise to 300-700 mM, after an overnight fast. Upon carbohydrate intake, glucose levels increase whereas fatty acid levels are reduced. In response to aerobic exercise, the glucose level is kept constant at 5 mM, while fatty acids levels increase over time. Collectively, the data clearly recapitulates the essence of Randle cycle. The exercise shows the great pedagogical value of experiments within practical courses to help students gain knowledge of energy metabolism and regulation of biochemical pathways. In an active learning environment, students successfully tackled physiological assignments, enhancing constructive communication and collaboration among peers.

Keywords:  Randle Cycle; energy metabolism; fatty acid metabolism; glucose metabolism; physical activity; postabsorptive; postprandial

DOI:  https://doi.org/10.1152/advan.00096.2024
Transl Lung Cancer Res. 2024 Dec 31. 13(12): 3692-3717

Fuel for thought: targeting metabolism in lung cancer.

Jaime L Schneider, SeongJun Han, Christopher S Nabel.

  For over a century, we have appreciated that the biochemical processes through which micro- and macronutrients are anabolized and catabolized-collectively referred to as "cellular metabolism"-are reprogrammed in malignancies. Cancer cells in lung tumors rewire pathways of nutrient acquisition and metabolism to meet the bioenergetic demands for unchecked proliferation. Advances in precision medicine have ushered in routine genotyping of patient lung tumors, enabling a deeper understanding of the contribution of altered metabolism to tumor biology and patient outcomes. This paradigm shift in thoracic oncology has spawned a new enthusiasm for dissecting oncogenotype-specific metabolic phenotypes and creates opportunity for selective targeting of essential tumor metabolic pathways. In this review, we discuss metabolic states across histologic and molecular subtypes of lung cancers and the additional changes in tumor metabolic pathways that occur during acquired therapeutic resistance. We summarize the clinical investigation of metabolism-specific therapies, addressing successes and limitations to guide the evaluation of these novel strategies in the clinic. Beyond changes in tumor metabolism, we also highlight how non-cellular autonomous processes merit particular consideration when manipulating metabolic processes systemically, such as efforts to disentangle how lung tumor cells influence immunometabolism. As the future of metabolic therapeutics hinges on use of models that faithfully recapitulate metabolic rewiring in lung cancer, we also discuss best practices for harmonizing workflows to capture patient specimens for translational metabolic analyses.

Keywords:  Lung cancer; immunometabolism; metabolism; resistance

DOI:  https://doi.org/10.21037/tlcr-24-662
Curr Oncol. 2024 Dec 24. pii: 3. [Epub ahead of print]32(1):

Nutritional Counseling During Chemotherapy Treatment: A Systematic Review of Feasibility, Safety, and Efficacy.

Shalet James, Alexie Oppermann, Kaitlin M Schotz, Mackenzie M Minotti, Gautam G Rao, Ian R Kleckner, Brenton J Baguley, Amber S Kleckner.

  Dietary interventions during chemotherapy hold promise for clinical and supportive care outcomes. We systematically investigated the feasibility, safety, and efficacy of nutritional counseling conducted during chemotherapy. Studies prospectively implemented nutrition counseling during chemotherapy. Articles were identified from three databases-EMBASE, Cochrane Library, and SCOPUS-from inception to 1 October 2024. Feasibility, safety, and efficacy of outcome data were extracted. Among 44 publications, 39 studies recruited 98 ± 80 participants (range 15-360); 38/39 (97%) were randomized controlled trials. One-third (31%) were among patients with breast cancer. Interventions were divided into individualized nutritional counseling (n = 21), nutrition counseling plus exercise (n = 13), and nutrient-specific dietary patterns (n = 10). Many had goals to achieve established nutrition guidelines. Feasibility was high based on attendance at counseling sessions, retention, and/or food log analysis. Overall, there were minimal adverse events related to the interventions. Many studies showed between-group differences favoring the intervention group for body weight (8/24, gain or loss, according to goals), nutritional status (8/9), quality of life (3/10 without and 6/9 with exercise), cancer-related fatigue (7/10), chemotherapy tolerance (6/11), and treatment responses (3/13). In conclusion, nutritional interventions were feasible and safe for patients undergoing chemotherapy and demonstrated preliminary efficacy to improve nutritional status, fatigue, chemotherapy tolerance, and other outcomes.

Keywords:  chemotherapy; diet; dietetics; intervention; oral intake

DOI:  https://doi.org/10.3390/curroncol32010003
Mol Genet Genomics. 2025 Jan 20. 300(1): 14

Differential effects of β-hydroxybutyrate and α-ketoglutarate on HCT-116 colorectal cancer cell viability under normoxic and hypoxic low-glucose conditions: exploring the role of SRC, HIF1α, ACAT1, and SIRT2 genes.

Parisa Badameh, Farideh Akhlaghi Tabar, Nima Mohammadipoor, Roya Rezaei, Roza Ranjkesh, Mohammad Hasan Maleki, Omid Vakili, Sayed Mohammad Shafiee.

  Recent therapeutic strategies have highlighted the potential of β-hydroxybutyrate (BHB) and α-ketoglutarate (α-KG) as effective anticancer agents, particularly for colon cancer. These metabolites can modulate cellular metabolism and induce epigenetic changes, inhibiting tumor growth. Nonetheless, certain cancer cells may utilize ketone bodies, like BHB as nutrient sources under hypoxic conditions, potentially reducing treatment efficacy. Understanding these mechanisms is crucial for optimizing cancer therapies. This study evaluated the effects of BHB and α-KG on HCT-116 colorectal cancer cell viability under normoxic and low-glucose hypoxic conditions. HCT-116 cell lines were treated with different doses of BHB and α-KG in normoxic and low-glucose hypoxic conditions, and then cell viability was assessed by the MTT assay. Moreover, the mRNA expression levels of SRC, hypoxia-inducible factor 1α (HIF-1α), acetyl-CoA acetyltransferase 1 (ACAT1), and sirtuin 2 (SIRT2) genes were determined using quantitative reverse transcriptase-polymerase chain reaction (q RT-PCR). BHB significantly increased the proliferation of HCT-116 colon cancer cells under low-glucose hypoxic conditions, while α-KG maintained cell viability in normoxic conditions but not in hypoxia. BHB treatment reduced SIRT2 mRNA levels and increased ACAT1, SRC, and HIF-1α expression. Conversely, α-KG decreased ACAT1, SRC, and HIF-1α expression and increased SIRT2 levels in normoxia but could not reverse gene expression during hypoxia. Our study demonstrated that BHB and α-KG exhibited complex interactions with colon cancer cell viability under varying oxygen and glucose conditions. While BHB promoted cell proliferation in hypoxic environments, α-KG showed protective effects in normoxic conditions. This research contributed to the growing body of evidence supporting the role of metabolic modulators in cancer therapy and emphasized the importance of understanding tumor microenvironments to optimize treatment outcomes. However, the need for further research into the metabolic pathways is underscored to enhance therapeutic strategies for cancer treatment.

Keywords:  Alpha-ketoglutarate; Beta-hydroxybutyrate; Colorectal cancer; Hypoxia

DOI:  https://doi.org/10.1007/s00438-024-02211-9
Curr Cancer Drug Targets. 2025 Jan 22.

Targeting Glutamine Metabolic Reprogramming in Pancreatic Cancer: Current Insights and Future Directions.

Yanhui Ma, Mingling Wang, Kexing Zhang, Fangbing Ren, Yuqun Wang, Wenqiang Zhang, Chengxia Kan, Fang Han, Hongxi Sun, Xiaodong Sun.

  Pancreatic Cancer (PC) is a devastating malignancy with a poor prognosis and in-creasing morbidity. Current treatment strategies have limited efficacy in improving patient survival. Metabolic reprogramming is a hallmark of cancer and plays a key role in the pro-gression and maintenance of PC. PC cells exhibit a unique glutamine metabolism that is dis-tinct from other cancer types. The non-classical pathway of glutamine metabolic reprogram-ming plays a "permissive role" in the survival and proliferation of PC cells, mainly by affect-ing the redox homeostasis of the cells. In this review, we compare and contrast the canonical and non-canonical glutamine metabolic pathways and highlight recent advances in targeting non-canonical glutamine metabolism for therapeutic intervention. This may provide novel in-sights and opportunities for exploiting glutamine metabolic reprogramming in PC treatment.

Keywords:  Pancreatic cancer; glutamine metabolism; glutamine metabolism inhibitors; metabolic reprogramming; targeted treat-ment.

DOI:  https://doi.org/10.2174/0115680096357993241206072609
Anal Chem. 2025 Jan 23.

Tracing of Amino Acids Dynamics in Cell Lines Based on 18O Stable Isotope Labeling.

Cemil Can Eylem, İpek Baysal, Samiye Yabanoğlu Çiftçi, Emirhan Nemutlu.

Metabolite levels and turnover rates are necessary to understand metabolomic dynamics in a living organism fully. Amino acids can play distinct roles in various cellular processes, and their abnormal levels are associated with pathological conditions, including cancer. Therefore, their levels, especially turnover rates, may provide enormous information about a phenotype. 13C- or 13C,15N-labeled amino acids have also been commonly used to trace amino acid metabolism. This study presented a new methodology based on 18O labeling for amino acids that relied on monitoring mass isotopologues to calculate the turnover rates of amino acids. The method optimization studies were carried over for selective amino acid monitoring. This methodology provides a rapid, robust, and simple GC-MS method for analyzing the fluxes of amino acid metabolism. The developed method was applied to fetal human colon (FHC) and human colon carcinoma (Caco-2) cell lines to determine cancer-induced shifts in the turnover rates of amino acids. These results defined metabolic reprogramming in Caco-2 cells through increased glutamate and serine turnovers and sharply decreased turnovers of aspartate, threonine, and methionine, therefore pointing to some metabolic vulnerabilities in the metabolism of cancerous cells. The simple mechanism of the developed methodology, the availability of affordable 18O-enriched water, and the ease of application can open a new arena in fluxomics analysis.

DOI: https://doi.org/10.1021/acs.analchem.4c05015
FEBS J. 2025 Jan 19.

LDHAα, a lactate dehydrogenase A isoform, promotes glycolysis and tumor progression.

Bingqing Huang, Wencui Shen, Yujiao Jia, Li Qin, Haoxu Wang, Qi Sun, Zhijian Xiao, Rongxin Zhang, Huijun Wang.

  Lactate dehydrogenase A (LDHA) is upregulated in multiple cancer types and contributes to the Warburg effect. Several studies have found that many tumor-related genes have subtypes and play important roles in promoting cancer development. Here, we identified a novel LDHA transcript, which produced a new protein 3 kDa larger than LDHA, which we named LDHAα. We found that multiple cancer cell lines express LDHAα, and ectopic expression of LDHAα led to a higher proliferation and migration rate in vitro. Ectopic expression of LDHAα could also promote tumor cell growth in vivo. Conversely, deletion of LDHAα by CRISPR-sgRNA significantly inhibited the growth of tumor cells. LDHAα was found to be mainly located in the cytoplasm, and overexpression or deletion of LDHAα could significantly affect the glucose uptake and lactate production of tumor cells. Further investigation showed that c-MYC and FOXM1 could markedly modulate the expression of both LDHA and LDHAα, especially c-MYC. We found that a small molecular compound targeting LDHA could also inhibit the enzyme activity of LDHAα. LDHAα, LDHA and c-MYC expression was significantly higher in human acute lymphocytic leukemia and colorectal cancer tissue specimens compared to normal controls. In conclusion, our study identified LDHAα as a subtype of LDHA and highlighted its critical role in tumor metabolism, providing a potential new therapeutic target for tumor diagnosis and treatment.

Keywords:  glycolysis; isoform; lactate dehydrogenase A; metabolism; tumor

DOI:  https://doi.org/10.1111/febs.17374
ACS Sens. 2025 Jan 21.

Development of a Genetically Encoded Sensor for Arginine.

Chun Wang, Xiaoxue Zhang, Haoyu Mao, Yi Xian, Yi Rao.

  The amino acid l-arginine (Arg) plays important roles in multiple metabolic and physiological processes, and changes in its concentration have been implicated in pathological processes. While it is important to measure Arg levels in biological systems directly and in real-time, existing Arg sensors respond to l-ornithine or l-lysine. Here we report ArgS1, a new Arg sensor. It showed a concentration-dependent increase in the ratio Ex488/405 for Arg with an apparent affinity of ∼64 μM and with a dynamic range (ΔR/R0) of 3. ArgS1 responds to Arg in both the cytoplasm and the subcellular organelles. ArgS1 monitored Arg levels in MDA-MB-231 cells, a breast cancer cell line deficient in a key enzyme for Arg synthesis (arginino-succinate synthetase1, ASS1) and amenable to Arg depletion therapy. We found that Arg levels in MDA-MB-231 cells decreased after depletion of extracellular Arg with a concomitant decline in cell viability. When ASS1 was overexpressed in the cells, Arg levels increased and cell viability was also enhanced. Thus, ArgS1 is an effective tool for real-time monitoring of Arg in human cells over a dynamic range of physiological and pathological relevance.

Keywords:  biosensor; cell imaging; fluorescent probe; fluorescent protein; l-arginine

DOI:  https://doi.org/10.1021/acssensors.4c03174
J Phys Act Health. 2025 Jan 17. 1-6

Resistance Training and the Risk of Breast Cancer: A Population-Based Case-Control Study.

Hiya Deepak Modi, Stephanie Byrne, L S Katrina Li, Terry Boyle.

   BACKGROUND: Convincing evidence supports that moderate to vigorous intensity physical activity decreases the risk of breast cancer. However, less is known about the role specific domains of physical activity play in breast cancer prevention, such as resistance training (RT). This case-control study investigated the association between RT and breast cancer risk.
METHODS: The Breast Cancer Environment and Employment Study was a population-based case-control study conducted in women aged 18-80 years in Western Australia from 2009 to 2011. Information about demographic, lifestyle, and clinical risk factors of breast cancer was collected via self-administered questionnaire. Participants retrospectively recalled their recreational physical activities for 3 different age periods: 15-24, 25-39, and 40+ years. Data were available from 1149 cases and 1710 controls. Logistic regression was used to examine the relationship between RT and breast cancer risk, after adjusting for a range of confounders.
RESULTS: The prevalence of RT ranged from 2% to 11% across the different age periods. Compared with doing none, engaging in RT versus during the age period of 15-24 years was associated with a 52% lower risk of breast cancer (adjusted odds ratio: 0.48; 95% confidence interval, 0.25-0.91). However, no associations were observed for the latter 2 age periods or lifetime RT.
CONCLUSION: These findings provide preliminary evidence that RT in early adulthood may be associated with a lower risk of breast cancer; however, there was no association between RT and breast cancer risk in the older age periods. Further research is required.

Keywords:  prevention; strength training; women

DOI:  https://doi.org/10.1123/jpah.2024-0327
Nat Rev Cancer. 2025 Jan 20.

Metabolic interplays between the tumour and the host shape the tumour macroenvironment.

Patricia Altea-Manzano, Amanda Decker-Farrell, Tobias Janowitz, Ayelet Erez.

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

DOI: https://doi.org/10.1038/s41568-024-00786-4
Am J Physiol Cell Physiol. 2025 Jan 24.

Dysfunctional mitochondrial bioenergetics sustains drug resistance in cancer cells.

Davide Gnocchi, Dragana Nikolic, Silvia Russo, Maria Laura Matrella, Rosa R Paparella, Sujeet Kumar, Subhas S Karki, Carlo Sabbà, Tiziana Cocco, Simona Lobasso, Antonio Mazzocca.

  Resistance to drugs is one of the major issues affecting the response to pharmacological treatments for tumors. Different mechanisms have been proposed to explain the development of cancer drug resistance (CDR), and several approaches to overcome it have been suggested. However, the biological basis of CDR remains unclear. Here, we investigated whether mitochondrial damage and consequent mitochondrial dysfunction are major causes of drug resistance in different tumors. To this end, we used cell lines from three tumors: hepatocellular carcinoma, breast cancer, and colon cancer. We then applied a protocol that recapitulates chemotherapy regimens in patients, rendering each cell line resistant to the drug commonly used in their respective treatments. The combination of cellular respiration analysis, gene expression analysis of cytochrome c oxidase isoforms, and mass spectrometry assessment of cardiolipin reveals that mitochondrial dysfunction is the underlying cause of the resistant phenotype. Importantly, we disclosed for the first time the rapid inhibition of oxidative phosphorylation (OXPHOS) by L-lactate, the major product of fermentation. Finally, we demonstrated that inhibition of lactic acid fermentation and activation of OXPHOS can increase drug sensitivity in all tested drug-resistant cancer cells. Taken together, our results suggest that inhibiting fermentation and enhancing mitochondrial function in cancer cells may be a concrete option to control the worrisome phenomenon of CDR.

Keywords:  Cancer drug resistance; L-lactate; cardiolipin; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1152/ajpcell.00538.2024
Nature. 2025 Jan 22.

Cancer cells 'poison' the immune system with tainted mitochondria.

Asher Mullard.



Keywords:  Cancer; Cell biology; Immunology

DOI:  https://doi.org/10.1038/d41586-025-00176-2
Blood Adv. 2025 Jan 18. pii: bloodadvances.2024014900. [Epub ahead of print]

Final Analysis of the Phase 1b Chemotherapy And Venetoclax in Elderly Acute Myeloid Leukaemia Trial (CAVEAT).

Chong Chyn Chua, Sun Loo, Chun Yew Fong, Stephen B Ting, Ing S Tiong, Shaun A Fleming, Natasha S Anstee, Adam Ivey, Michael Ashby, Tse-Chieh Teh, John Reynolds, Andrew W Roberts, Andrew H Wei.

Venetoclax plus azacitidine represents a key advance for older, unfit patients with acute myeloid leukemia (AML). The chemotherapy and venetoclax in elderly AML trial (CAVEAT) was first to combine venetoclax with intensive chemotherapy in newly diagnosed patients ≥65 years. In this final analysis, 85 patients (median age 71 years) were followed for a median of 41.8 months. The CAVEAT induction combined cytarabine and idarubicin with 5 dose levels of venetoclax (50-600 mg) for up to 14 days. Two additional cohorts explored adjusted-dose venetoclax (50 mg, 100 mg) with posaconazole. CAVEAT induction was well tolerated, with low mortality (4%) and limited high-grade gastrointestinal toxicity (4%). Delayed hematological recovery after consolidation was ameliorated by omitting idarubicin from post-remission therapy. The overall response rate (ORR: CR + CRh + CRi) was 75% with a median overall survival (OS) of 19.3 months (95% CI 11.1-31.3). Among de novo AML, ORR was 88% and median OS 33.1 months (95% CI 19.3-54.3). Almost one-third have not relapsed, many benefiting from prolonged treatment-free remission (median 17.9 months). CAVEAT induction was well tolerated and associated with high ORR that was durable, particularly for de novo AML. CAVEAT represents an effective time-limited treatment option for fit older patients with AML. (https://www.anzctr.org.au; ACTRN12616000445471).

DOI: https://doi.org/10.1182/bloodadvances.2024014900
Mol Cancer Ther. 2025 Jan 21.

Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.

Shan Lu, Xiao Pan, Eva Volckova, Anjali Shinde, Schuyler R Fuller, Regina Egan, Jianli Ma, Jong Kung, Christopher J Ott, Aaron N Hata, Cyril H Benes, Jing X Kang, Henning Willers.

Mutations in the KRAS oncogene can mediate resistance to radiation. KRAS mutation (mut) driven tumors have been reported to express cancer stem cell (CSC)-like features and may harbor metabolic liabilities through which CSC-associated radioresistance can be overcome. We established a radiation/drug screening approach that relies on the growth of 3D spheres under anchorage-independent and lipid-limiting culture conditions, which promote stemness and lipogenesis. In this format, we screened 32 KRASmut-enriched lung cancer models. As predicted from published data, CB-839, a glutaminase inhibitor, displayed the highest degree of radiosensitization in KRASmut models with LKB1 co-mutations. Radiosensitization by inhibition of stearoyl-CoA desaturase-1, SCD1, displayed a similar genotype preference though the data also implicated KEAP1 co-mutation and SCD1 expression as potential predictors of radiosensitization. In an isogenic model, KRASmut cells were characterized by increased SCD1 expression and a higher ratio of monounsaturated fatty acids (MUFA) to saturated fatty acids. Accordingly, pharmacological inhibition or depletion of SCD1 radiosensitized isogenic KRASmut but not wild-type cells. The radiosensitizing effect was notably small, especially compared to several DNA repair inhibitors. As an alternative strategy to targeting MUFA metabolism, adding polyunsaturated FAs (PUFA) phenocopied some aspects of SCD1 inhibition, suppressed tumor growth in vivo, and opposed the CSC-like phenotype of KRASmut cells. In conclusion, we report a 3D screening approach that recapitulates clinically relevant features of KRASmut tumors and can be leveraged for therapeutic targeting of metabolic vulnerabilities. Our data highlight pronounced inter-tumoral heterogeneity in radiation/drug responses and the complexity of underlying genomic dependencies.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0213
Biochim Biophys Acta Bioenerg. 2025 Jan 17. pii: S0005-2728(25)00006-4. [Epub ahead of print] 149540

Purification and characterization of recombinant human mitochondrial proton-pumping nicotinamide nucleotide transhydrogenase.

Sangjin Hong, Simone Graf, Christoph von Ballmoos, Robert B Gennis.

  The human mitochondrial nicotinamide nucleotide transhydrogenase (NNT) uses the proton motive force to drive hydride transfer from NADH to NADP+ and is a major contributor to the generation of mitochondrial NADPH. NNT plays a critical role in maintaining cellular redox balance. NNT-deficiency results in oxidative damage and its absence results in familial glucocorticoid deficiency. Recently it has also become clear that NNT is a tumor promoter whose presence in mouse models of non-small cell lung cancer results in enhanced tumor growth and aggressiveness. The presence of NNT mitigates the effects of oxidative stress and facilitates cancer cell proliferation, suggesting NNT-inhibition as a promising therapeutic strategy. The human NNT is a homodimer in which each subunit has a molecular weight of 114 kDa and 14 transmembrane spans. Here we report on the development of a system for isolating full-length recombinant human NNT using Escherichia coli. The purified enzyme is catalytically active, and the enzyme reconstituted into proteoliposomes pumps protons and generates a proton motive force capable of driving ATP synthesis by E. coli ATP synthase. The recombinant human NNT will facilitate structural and biochemical studies as well as provide a useful tool to develop and characterize potential anti-cancer therapeutics.

Keywords:  Cancer; Familial glucocorticoid deficiency; Heterologous overexpression; Human nicotinamide nucleotide transhydrogenase; Integral membrane protein

DOI:  https://doi.org/10.1016/j.bbabio.2025.149540
Blood. 2025 Jan 22. pii: blood.2024025886. [Epub ahead of print]

FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells.

Joana L Araújo, Elvin Wagenblast, Veronique Voisin, Jessica McLeod, Olga I Gan, Suraj Bansal, Liqing Jin, Amanda Mitchell, Blaise Gratton, Sarah Kristen Cutting, Andrea Arruda, Monica Doedens, Anthea Travas, Dennis Dong Hwan Kim, Jose-Mario Capo-Chichi, Sagi Abelson, Mark D Minden, Jean Cy Wang, Manuel A Sobrinho-Simões, Perpétua Pinto-do-Ó, Eric R Lechman, John E Dick.

Leukemic stem cells (LSCs) fuel acute myeloid leukemia (AML) growth and relapse, but therapies tailored towards eradicating LSCs without harming normal hematopoietic stem cells (HSCs) are lacking. FLT3 is considered an important therapeutic target due to frequent mutation in AML and association with relapse. However, there has been limited clinical success with FLT3 drug targeting, suggesting either that FLT3 is not a vulnerability in LSC, or that more potent inhibition is required, a scenario where HSC toxicity could become limiting. We tested these possibilities by ablating FLT3 using CRISPR/Cas9-mediated FLT3 knock-out (FLT3-KO) in human LSCs and HSCs followed by functional xenograft assays. FLT3-KO in LSCs from FLT3-ITD mutated, but not FLT3-wild type (WT) AMLs, resulted in short-term leukemic grafts of FLT3-KO edited cells that disappeared by 12 weeks. By contrast, FLT3-KO in HSCs from fetal liver, cord blood and adult bone marrow did not impair multilineage hematopoiesis in primary and secondary xenografts. Our study establishes FLT3 as an ideal therapeutic target where ITD+ LSC are eradicated upon FLT3 deletion, while HSCs are spared. These findings support the development of more potent FLT3-targeting drugs or gene-editing approaches for LSC eradication to improve clinical outcomes.

DOI: https://doi.org/10.1182/blood.2024025886
Mol Carcinog. 2025 Jan 21.

Glutamine, Serine and Glycine at Increasing Concentrations Regulate Cisplatin Sensitivity in Gastric Cancer by Posttranslational Modifications of KDM4A.

Junhao Fu, Yuqi Ni, Yuqing Hu, Wanfen Tang, Jianfei Fu, Yue Wang, Shian Yu, Wenxia Xu.

  Gastric cancer is a common digestive system tumor with a high resistance rate that reduces the sensitivity to chemotherapy. Nutrition therapy is an important adjuvant approach to favor the prognosis of gastric cancer. Dietary amino acids contribute greatly to gastric cancer progression by mediating tumor gene expressions, epigenetics, signal transduction, and metabolic remodeling. In the present study, 20 types of amino acids were screened and glutamine, glycine and serine were identified as the critical regulators of cisplatin (DDP) sensitivity in gastric cancer cells. Moreover, KDM4A acetylation drove the reduced chemotherapy sensitivity in gastric cancer cells by maintaining protein stability and activating DNA repair ability when the concentrations of glutamine (Gln), serine (Ser), and glycine (Gly) decreased. Conversely, Gln/Ser/Gly at increasing concentrations stimulated ubiquitination degradation of KDM4A, which in turn elevated the sensitivity of gastric cancer cells to chemotherapy. Our findings unveiled the role of amino acid nutrition in regulating chemotherapy sensitivity of gastric cancer and the underlying mechanism, thus providing a scientific basis for expanding the clinical significance of nutrition therapy for gastric cancer patients.

Keywords:  KDM4A; gastric cancer; glutamine; glycine; serine

DOI:  https://doi.org/10.1002/mc.23881
Cell Rep. 2025 Jan 18. pii: S2211-1247(24)01576-6. [Epub ahead of print]44(2): 115225

Chronic intermittent fasting impairs β cell maturation and function in adolescent mice.

Leonardo Matta, Peter Weber, Suheda Erener, Alina Walth-Hummel, Daniela Hass, Lea K Bühler, Katarina Klepac, Julia Szendroedi, Joel Guerra, Maria Rohm, Michael Sterr, Heiko Lickert, Alexander Bartelt, Stephan Herzig.

  Intermittent fasting (IF) is a nutritional lifestyle intervention with broad metabolic benefits, but whether the impact of IF depends on the individual's age is unclear. Here, we investigated the effects of IF on systemic metabolism and β cell function in old, middle-aged, and young mice. Short-term IF improves glucose homeostasis across all age groups without altering islet function and morphology. In contrast, while chronic IF is beneficial for adult mice, it results in impaired β cell function in the young. Using single-cell RNA sequencing (scRNA-seq), we delineate that the β cell maturation and function scores are reduced in young mice. In human islets, a similar pattern is observed in type 1 (T1D), but not type 2 (T2D), diabetes, suggesting that the impact of chronic IF in adolescence is linked to the development of β cell dysfunction. Our study suggests considering the duration of IF in younger persons, as it may worsen rather than reduce diabetes outcomes.

Keywords:  CP: Metabolism; Langerhans’ islets; diabetes; glucose metabolism; insulin; intermittent fasting; pancreas; weight loss; β cells

DOI:  https://doi.org/10.1016/j.celrep.2024.115225
J Exp Clin Cancer Res. 2025 Jan 17. 44(1): 17

V-ATPase in glioma stem cells: a novel metabolic vulnerability.

Alessandra Maria Storaci, Irene Bertolini, Cristina Martelli, Giorgia De Turris, Nadia Mansour, Mariacristina Crosti, Maria Rosaria De Filippo, Luisa Ottobrini, Luca Valenti, Elisa Polledri, Silvia Fustinoni, Manuela Caroli, Claudia Fanizzi, Silvano Bosari, Stefano Ferrero, Giorgia Zadra, Valentina Vaira.

   BACKGROUND: Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth.
METHODS: V-ATPase activity in GSC cultures was modulated using Bafilomycin A1 (BafA1) and cell viability and metabolic traits were analyzed using live assays. The GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Cell extracts, proximity-ligation assay and advanced microscopy was used to analyze subcellular presence of proteins. A metabolomic screening was performed using Biocrates p180 kit, whereas transcriptomic analysis was performed using Nanostring panels.
RESULTS: Perturbation of V-ATPase activity reduces GSC growth in vitro and in vivo. In GSC there is a pool of V-ATPase that localize in mitochondria. At the functional level, V-ATPase inhibition in GSC induces ROS production, mitochondrial damage, while hindering mitochondrial oxidative phosphorylation and reducing protein synthesis. This metabolic rewiring is accompanied by a higher glycolytic rate and intracellular lactate accumulation, which is not exploited by GSCs for biosynthetic or survival purposes.
CONCLUSIONS: V-ATPase activity in GSC is critical for mitochondrial metabolism and cell growth. Targeting V-ATPase activity may be a novel potential vulnerability for glioblastoma treatment.

Keywords:  Bafilomycin A1; Glioma; Glioma stem cell; Metabolism; V-ATPase

DOI:  https://doi.org/10.1186/s13046-025-03280-3
Mol Oncol. 2025 Jan 23.

Inhibition of acyl-CoA synthetase long-chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction.

Connor S Murphy, Heather Fairfield, Victoria E DeMambro, Samaa Fadel, Carlos A Gartner, Michelle Karam, Christian Potts, Princess Rodriguez, Ya-Wei Qiang, Habib Hamidi, Xiangnan Guan, Calvin P H Vary, Michaela R Reagan.

  Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long-chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpassSM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose- and time-dependent manner. RNA-sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma.

Keywords:  ACSL; Triacsin C; cell metabolism; fatty acid; hematological malignancies; multiple myeloma

DOI:  https://doi.org/10.1002/1878-0261.13794
Curr Cancer Drug Targets. 2025 Jan 22.

Preventive and Therapeutic effects of Metformin in Cancer: A Meta-Analysis of RCT and Cohort Studies.

Mikiyas Amare Getu, Xianbin Zhang, Jia Wang, Kunpeng Xu, Ying Ying, Li Ma, Peng Gong.

   BACKGROUND: There is discrepancy of results among various individual and me-ta-analytical studies about the effect of metformin on cancer risk and patients' survival. Therefore, we have conducted a comprehensive, updated meta-analysis to evaluate the preventive and therapeutic effects of metformin for cancer patients, as well as the inci-dence of adverse reactions, among metformin users.
METHODS: A total of 18 studies (10 cohort studies and 8 randomized controlled trials) in-volving 1,300,820 participants from Europe, North America, and Asia were included in this meta-analysis.
RESULTS: No significant association was found between metformin use and overall survival (Hazard ratio = 1.02; 95% CI, 0.80 - 1.30) and progressive-free survival (Hazard ratio = 1.00; 95% CI, 0.76 - 1.31). In addition, the summary risk estimates for adverse reactions of metformin were not statistically significant between intervention and control groups (Risk Ratio = 1.11; 95% CI, 0.94 - 1.31). However, metformin use was associated with a reduction in cancer risk (Hazard ratio = 0.90, 95% CI, 0.86 - 0.94).
CONCLUSION: Metformin does not significantly prolong the overall survival and progressive-free survival of cancer patients, but it may effectively reduce the risk of cancer occurrence.

Keywords:  Metformin; cancer; incidence; meta-analysis; survival; therapeutic.

DOI:  https://doi.org/10.2174/0115680096345507241030224210
Nat Cardiovasc Res. 2025 Jan 22.

Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease.

Gabriel K Adzika, Ricardo A Velázquez Aponte, Joseph A Baur.

DOI: https://doi.org/10.1038/s44161-024-00599-6
Front Nutr. 2024 ;11 1516086

The effects of low-carbohydrate diet on glucose and lipid metabolism in overweight or obese patients with T2DM: a meta-analysis of randomized controlled trials.

Wende Tian, Shuyu Cao, Yongxin Guan, Zihao Zhang, Qiyu Liu, Jianqing Ju, Ruixi Xi, Ruina Bai.

   Background: The dual burden of Type 2 Diabetes Mellitus (T2DM) and obesity is a critical public health issue. Low-carbohydrate diets have emerged as a potential intervention, yet clinical evidence remains inconclusive.
Purpose: This meta-analysis assesses the impact of low-carbohydrate diets on metabolic profiles in overweight or obese T2DM patients, aiming to guide clinical practice.
Methods: A systematic review identified randomized clinical trials (RCTs) comparing low-carbohydrate diets to control diets in T2DM patients from PubMed, Embase, and the Cochrane Library databases up to April 2023.
Results: Seventeen RCTs, encompassing 1,197 participants, demonstrated that low-carbohydrate diets significantly improved HbA1c levels and fasting plasma glucose (mean difference [MD] = -0.36, 95% CI -0.44 to -0.29, p < 0.00001; MD = -10.71, 95% CI -14.39 to -7.03, p < 0.00001). They also reduced triglycerides and increased HDL cholesterol (MD = -19.91, 95% CI -28.83 to -10.99, p < 0.00001; MD = 2.49, 95% CI 1.07-3.91, p = 0.0006), without affecting LDL and total cholesterol. Weight loss, reduced BMI, lower diastolic blood pressure, and decreased waist circumference were additional benefits.
Conclusion: Low-carbohydrate diets may enhance glycemic control and lipid profiles in overweight or obese T2DM patients, warranting consideration in T2DM management. However, the variability in diet definitions and methodologies underscores the necessity for further research to standardize dietary guidelines and evaluate long-term effects.

Keywords:  glucose and lipid metabolism; low-carbohydrate diet; obesity; overweight; type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fnut.2024.1516086
BMJ. 2025 Jan 22. 388 e081820

Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial.

Yuejun Liu, Ying Chen, Jianhua Ma, Jiayang Lin, Changqin Liu, Xuejun Li, Yong Xu, Hongyu Kuang, Lixin Shi, Yaoming Xue, Bo Feng, Dalong Zhu, Guang Wang, Jinkui Yang, Xinhua Xiao, Xuefeng Yu, Jiaqiang Zhou, Yuqian Bao, Qing Su, Minzhi Lyu, Xiaomu Li, Huijie Zhang, Xiaoying Li.

OBJECTIVE: To assess the effect of dapagliflozin plus calorie restriction on remission of type 2 diabetes.
DESIGN: Multicentre, double blind, randomised, placebo controlled trial.
SETTING: 16 centres in mainland China from 12 June 2020 to 31 January 2023.
PARTICIPANTS: 328 patients with type 2 diabetes aged 20-70 years, with body mass index >25 and diabetes duration of <6 years.
INTERVENTIONS: Calorie restriction with dapagliflozin 10 mg/day or placebo.
MAIN OUTCOME MEASURES: Primary outcome: incidence of diabetes remission (defined as glycated haemoglobin <6.5% and fasting plasma glucose <126 mg/dL in the absence of all antidiabetic drugs for at least 2 months); secondary outcomes: changes in body weight, waist circumference, body fat, blood pressure, glucose homoeostasis parameters, and serum lipids over 12 months.
RESULTS: Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002) over 12 months, meeting the predefined primary endpoint. Changes in body weight (difference -1.3 (95% CI -1.9 to -0.7) kg) and homoeostasis model assessment of insulin resistance (difference -0.8, -1.1 to -0.4) were significantly greater in the dapagliflozin group than in the placebo group. Likewise, body fat, systolic blood pressure, and metabolic risk factors were significantly more improved in the dapagliflozin group than in the placebo group. In addition, no significant differences were seen between the two groups in the occurrence of adverse events.
CONCLUSION: The regimen of dapagliflozin plus regular calorie restriction achieved a much higher rate of remission of diabetes compared with calorie restriction alone in overweight or obese patients with type 2 diabetes.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04004793.

DOI: https://doi.org/10.1136/bmj-2024-081820