Prediabetes is a highly prevalent and increasingly common condition affecting a significant proportion of the global population. The heterogeneous nature of prediabetes presents a challenge in identifying individuals who...Prediabetes is a highly prevalent and increasingly common condition affecting a significant proportion of the global population. The heterogeneous nature of prediabetes presents a challenge in identifying individuals who particularly benefit from lifestyle or other therapeutic interventions aiming at preventing type 2 diabetes (T2D) and associated comorbidities. The phenotypic characteristics of individuals at risk for diabetes are associated with both specific risk profiles for progression and a differential potential to facilitate prediabetes remission and reduce the risk of future T2D. This review examines the current definition and global prevalence of prediabetes and evaluates the potential of prediabetes remission to reduce the alarming increase in the global burden of T2D.
Cardiovascular disease (CVD) remains a significant global health concern, with obesity recognized as a prominent risk factor. The 'obesity paradox' (OP) suggests that obesity does not always lead to adverse outcomes, par...Cardiovascular disease (CVD) remains a significant global health concern, with obesity recognized as a prominent risk factor. The 'obesity paradox' (OP) suggests that obesity does not always lead to adverse outcomes, particularly in heart failure (HF). In this forum, we discuss the relevance of the OP in the current therapeutic landscape for cardiometabolic diseases.
Identification of exendin-4 (a glucagon-like peptide-1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one of the most serendipitous discoveries of recent times. GLP-1RAs are now an established therap...Identification of exendin-4 (a glucagon-like peptide-1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one of the most serendipitous discoveries of recent times. GLP-1RAs are now an established therapeutic approach in type 2 diabetes (T2D), body weight management, and cardiovascular (CV) risk protection. Furthermore, there is a growing platform of evidence that GLP-1RA has extended benefit in renal, hepatic, respiratory, and neurological diseases. One can speculate on the biological advantage of exendin-4 to the Gila monster, but for humankind GLP-1RAs are peptides with significant potential to improve disease-related outcomes. We report on the latest evidence and mechanisms for GLP-1RA-mediated end-organ protection that uniquely highlight its future development potential across multiple disease areas.
Trends Endocrinol Metab
· 2025 Mar · PMID 39880788
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Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox dema...Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.
Recent advances in lineage-tracing technologies have significantly improved our understanding of pancreatic cell biology, particularly in elucidating the ontogeny and regenerative capacity of pancreatic cells. A deeper a...Recent advances in lineage-tracing technologies have significantly improved our understanding of pancreatic cell biology, particularly in elucidating the ontogeny and regenerative capacity of pancreatic cells. A deeper appreciation of the mechanisms underlying pancreatic cell identity and plasticity holds the potential to inform the development of new therapeutic modalities for conditions such as diabetes and pancreatitis. With this goal in mind, here we summarize advances, challenges, and future directions in tracing pancreatic cell origins and fates using lineage-tracing technologies. Given their essential role for blood glucose regulation, we pay particular attention on the insights gained from endocrine cells, especially β-cells.
Liver fibrosis and biological sex variably modulate the risks of hepatocellular carcinoma (HCC) and extrahepatic cancers (EHCs) arising in the context of metabolic dysfunction-associated steatotic liver disease (MASLD)....Liver fibrosis and biological sex variably modulate the risks of hepatocellular carcinoma (HCC) and extrahepatic cancers (EHCs) arising in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we highlight how these variables may have implications in the setting of chemoprevention and precision medicine approaches in MASLD and guide additional research.
Primary aldosteronism (PA) is a common, salt-sensitive form of endocrine hypertension. Compared with essential hypertension (EH), PA is more susceptible to cardiorenal complications and metabolic risks. However, PA has a...Primary aldosteronism (PA) is a common, salt-sensitive form of endocrine hypertension. Compared with essential hypertension (EH), PA is more susceptible to cardiorenal complications and metabolic risks. However, PA has a low screening rate and a poor response to mineralocorticoid receptor antagonists (MRAs). In addition to somatic ion channel mutations and epigenetic alterations, which contribute to excessive production of aldosterone, cholesterol, as a crucial precursor for aldosterone biosynthesis, may be involved in PA pathogenesis. Abnormal adrenal cholesterol uptake and steroidogenesis have been found in patients with PA. Therefore, we propose that a statin-based therapeutic strategy may be pivotal for antagonizing PA-related comorbidities by targeting cholesterol-dependent adrenal steroidogenesis.
Cachexia is a complex metabolic disorder characterized by negative energy balance due to increased consumption and lowered intake, leading to progressive tissue wasting and inefficient energy distribution. Once considere...Cachexia is a complex metabolic disorder characterized by negative energy balance due to increased consumption and lowered intake, leading to progressive tissue wasting and inefficient energy distribution. Once considered as passive bystander, metabolism is now acknowledged as a regulator of biological functions and disease progression. This shift in perspective mirrors the evolving understanding of cachexia itself, no longer viewed merely as a secondary consequence of cancer but as an active process. However, metabolic dysregulations in cachexia are currently studied in an organ-specific manner, failing to be fully integrated into a comprehensive framework that explains their functional roles in disease progression. Thus, in this review, we aim to provide a general overview of the various metabolic alterations with a potential systemic impact.
Respiratory infections and diseases pose significant challenges to society and healthcare systems, underscoring the need for preventative and therapeutic strategies. Recent research in rodent models indicates that short-...Respiratory infections and diseases pose significant challenges to society and healthcare systems, underscoring the need for preventative and therapeutic strategies. Recent research in rodent models indicates that short-chain fatty acids (SCFAs), metabolites produced by gut bacteria, may offer medicinal benefits for respiratory conditions. In this opinion, we summarize the current literature that highlights the potential of SCFAs to enhance immune balance in humans. SCFAs have demonstrated the potential to decrease the risk of primary and secondary respiratory infections, modulate allergic airway exacerbations, and improve overall epithelial pathogen defenses. Therefore, we suggest that systemic SCFA levels could be targeted to support gut and respiratory health in specific groups, such as patients in hospital, women and their offspring, children, older adults, and athletes/military personnel.
With the rising prevalence of type 2 diabetes mellitus (T2DM) and obesity, several previously under-recognised complications associated with T2DM are becoming more evident. The most common of these emerging complications...With the rising prevalence of type 2 diabetes mellitus (T2DM) and obesity, several previously under-recognised complications associated with T2DM are becoming more evident. The most common of these emerging complications are metabolic dysfunction-associated steatotic liver disease (MASLD), cancer, dementia, sarcopenia, and frailty, as well as other conditions involving the lung, heart, and intestinal tract. Likely causative factors are chronic inflammation and insulin resistance, whereas blood glucose levels appear to play a lesser role. We discuss these complications and the new approaches being developed to prevent and manage them, especially incretin-based therapies. We argue that these new interventions may work in a complementary way to other proven cardiorenal protective therapies to reduce the burden of T2DM complications.
Trends Endocrinol Metab
· 2025 Sep · PMID 39753502
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Prostate cancer (PC) is a notoriously immune-cold tumor in that it often lacks substantial infiltration by antitumor immune cells, and in advanced diseases such as neuroendocrine PC, it could be devoid of immune cells. A...Prostate cancer (PC) is a notoriously immune-cold tumor in that it often lacks substantial infiltration by antitumor immune cells, and in advanced diseases such as neuroendocrine PC, it could be devoid of immune cells. A majority of PC patients thus have, unfortunately, been unable to benefit from recent advances in immunotherapies. What causes this immunosuppressive microenvironment around PC? In this review, we discuss various genetic and epigenetic regulators intrinsic to prostate tumor cells that could have profound effects on the tumor microenvironment, thus contributing to this immune-cold status. It will be essential to target the cancer cells themselves in order to change the tumor microenvironment to harness existing and developing immunotherapies that had great success in other tumors.
An J, Thorson AS, Wasserman DH
… +2 more, Stafford JM, Zhu L
Trends Endocrinol Metab
· 2025 Sep · PMID 39743402
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Premenopausal women and endurance-trained individuals of either sex have reduced cardiovascular disease (CVD) risk. Endurance training shifts fuel selection towards fats to spare carbohydrates; interestingly, women prior...Premenopausal women and endurance-trained individuals of either sex have reduced cardiovascular disease (CVD) risk. Endurance training shifts fuel selection towards fats to spare carbohydrates; interestingly, women prioritize fats as an energy resource more than men do during exercise. Relying on fats during exercise drives whole-body lipolysis and promotes lipid uptake and oxidation capacity in skeletal muscles. These metabolic adaptations during exercise result in protection against diet-induced obesity, a healthy body fat distribution, and reduced plasma triacylglycerol (TG) concentrations. Here, we analyze how sex differences and endurance training mediate changes in skeletal muscles, including exercise-induced lipolysis, lipid uptake and β-oxidation, intramuscular TG storage, and postexercise lipid metabolism, and discuss how regulating this processes affects CVD risk.
Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct sp...Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.
Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder, affecting approximately 11-13% of women of reproductive age. Women with PCOS experience a higher prevalence of infertility, pregnancy comp...Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder, affecting approximately 11-13% of women of reproductive age. Women with PCOS experience a higher prevalence of infertility, pregnancy complications, and cardiometabolic disorders such as obesity, insulin resistance, and type 2 diabetes mellitus. Furthermore, psychiatric comorbidities, including depression and anxiety, significantly impact the quality of life in this population. Although obesity exacerbates these health risks, the exact etiology and pathophysiology of PCOS remain complex and only partially understood. Emerging research suggests potential transgenerational inheritance through genetic and epigenetic mechanisms, highlighting the possibility of PCOS-related risks affecting subsequent generations, including sons. This review synthesizes recent findings on PCOS inheritance patterns and underscores areas for future clinical and research exploration.
Ferroptosis has been implicated in several reproductive disorders, but the underlying mechanisms remain unknown; thus, interventions targeting this pathway are lacking. Here we summarize the emerging findings on ferropto...Ferroptosis has been implicated in several reproductive disorders, but the underlying mechanisms remain unknown; thus, interventions targeting this pathway are lacking. Here we summarize the emerging findings on ferroptosis in reproductive biology and corresponding disorders, and highlight perspectives and challenges on future ferroptosis research with potential clinical applications.
Circadian rhythms are highly conserved biorhythms of ~24 h that govern many fundamental biological processes, including cardiovascular (CV) homeostasis. Disrupting the timing of cellular oscillators promotes cellular str...Circadian rhythms are highly conserved biorhythms of ~24 h that govern many fundamental biological processes, including cardiovascular (CV) homeostasis. Disrupting the timing of cellular oscillators promotes cellular stress, and induction of pathogenic pathways underpins the pathogenesis of many CV diseases (CVDs). Thus, shift work, late eating, sleep disturbances, and other disruptors can result in an elevated risk of heart disease and increased incidence of adverse CV events. Here, we discuss the importance of circadian rhythms for CV homeostasis, recent developments in understanding the impact of disrupted circadian rhythms on CV health and disease progression, and how understanding the interactions between circadian and CV physiology is crucial for improving interventions to mitigate CVD, especially in populations impacted by disrupted circadian rhythms.