Daily Endocrinology Research Analysis
Analyzed 83 papers and selected 3 impactful papers.
Summary
Three papers stood out today: an individual participant data analysis of 137,488 adults maps age-related thyroid function trajectories and links them to mortality; a mechanistic Diabetes study shows that endogenous GLP-1 released by the rare sugar d-allulose cooperates with insulin to activate left-sided vagal afferents and enhance insulin action; and translational work connects specific circulating ceramides (C18:0, C24:1) to impaired myogenesis and sarcopenia across cell, animal, and human data.
Research Themes
- Age-related endocrine physiology and mortality risk
- Gut–brain–pancreas signaling in glucose homeostasis
- Lipid mediators as drivers and biomarkers of musculoskeletal decline
Selected Articles
1. Gut-Derived GLP-1 Released by Rare Sugar d-Allulose Cooperates With Insulin to Activate Left-Sided Vagal Afferents and Enhance Insulin Sensitivity.
Using d-allulose as a physiological probe, the authors show that endogenous intestinal GLP-1, in concert with insulin, activates left-sided vagal afferents to potentiate insulin action rather than secretion, acutely improving glycemia. This gut–insulin–vagal axis provides a mechanistic basis for nutritional or neuromodulatory interventions to enhance insulin sensitivity.
Impact: It uncovers a directional, left-sided vagal mechanism through which endogenous GLP-1 and insulin cooperate to enhance insulin action, suggesting testable, nonpharmacologic strategies (e.g., rare sugar intake, vagal modulation).
Clinical Implications: Supports dietary d-allulose as an adjunct to improve postprandial glycemia via neural mechanisms and motivates exploration of left vagal neuromodulation in insulin-resistant states.
Key Findings
- d-Allulose triggered intestinal GLP-1 release that, together with insulin, activated left-sided vagal afferents.
- This pathway enhanced insulin action (not secretion), improving glycemic control acutely in type 2 diabetes.
- GLP-1/insulin–vagal signaling achieved glucose-lowering comparable to GLP-1 receptor agonists.
Methodological Strengths
- Physiological probing of endogenous GLP-1 using a noncaloric secretagogue (d-allulose)
- Neurovisceral mechanism identified with laterality (left-sided vagal afferents) and functional readouts
Limitations
- Preclinical/physiological study; human interventional confirmation is needed
- Short-term effects; durability and safety of chronic d-allulose intake or neuromodulation remain to be established
Future Directions: Translate to controlled human trials testing d-allulose on postprandial glycemia and insulin action, and evaluate targeted left-vagal neuromodulation in insulin resistance.
Compared with glucagon-like peptide 1 (GLP-1) receptor agonists, the physiological roles and mechanisms of endogenous, short-lived GLP-1 in glucose metabolism remain poorly understood. We used the rare sugar d-allulose, a noncaloric GLP-1 secretagogue, as a tool to elucidate the physiological actions of endogenous GLP-1. d-allulose-induced intestinal GLP-1 release cooperates with insulin to activate left-side vagal afferents, enhancing insulin action rather than insulin secretion and thereby regulating glycemic control. Because this acute mechanism improved hyperglycemia in type 2 diabetes to an extent comparable to that observed with GLP-1 receptor agonists, targeting GLP-1/insulin-vagal signaling may inform novel therapies and dietary or nutritional interventions for type 2 diabetes.
2. Natural history of thyroid function in ageing: an individual participant data analysis of 137 488 participants from 31 prospective cohort studies.
Across 31 cohorts (137,488 participants), TSH increased with age in longitudinal analyses irrespective of iodine status, with greater variability in older adults; cross-sectional TSH patterns differed by regional iodine sufficiency. Patterns of changing thyroid function were associated with all-cause mortality, informing age- and context-specific interpretation of TSH.
Impact: Provides high-quality, IPD-based quantification of age-related thyroid trajectories and their mortality links, directly informing age-appropriate TSH reference interpretation and overtreatment avoidance.
Clinical Implications: Supports cautious interpretation of mildly elevated TSH in older adults and suggests considering regional iodine status and longitudinal trends rather than single thresholds to guide management.
Key Findings
- Longitudinally, TSH increases with age across iodine contexts; cross-sectional TSH differs by iodine sufficiency.
- Older adults exhibit greater variability in TSH trajectories.
- Patterns of thyroid function change are associated with all-cause mortality.
Methodological Strengths
- Individual participant data meta-analysis across 31 prospective cohorts
- Stratification by sex and regional iodine status; linear mixed modeling
Limitations
- Observational design limits causal inference for mortality associations
- Heterogeneity in assay methods and follow-up across cohorts
Future Directions: Define age- and iodine-adjusted TSH reference intervals and test management strategies that incorporate longitudinal thyroid trajectories in randomized pragmatic trials.
BACKGROUND: Evidence regarding thyroid function changes with ageing remains inconsistent and the implications of potential changes are unclear. We aimed to investigate ageing-related thyroid function changes and their associations with mortality. METHODS: In this individual participant data (IPD) analysis, prospective population-based cohorts were eligible for inclusion when data on thyroid function measurements and mortality were available in individuals aged 18 years and older. Eligible datasets were identified through a systematic search of PubMed. We excluded cohorts of participants with only thyroid disease or thyroid-altering medications, or pregnant individuals. We requested data from all eligible cohorts that agreed to participate in the study. Linear mixed models were used to investigate associations between age and thyroid function, stratified for sex and regional iodine status. Annual changes in thyroid-stimulating hormone (TSH) and free thyroxine (FT
3. Elevated Circulating Ceramides 18:0 and 24:1 as a Risk Factor for Sarcopenia: In Vitro, Animal, and Clinical Evidence.
Ceramides C18:0 and C24:1 impair myogenesis via ROS, suppress ITGB1–FAK–AKT signaling, activate FoxO catabolic programs, and reduce muscle mass and function in mice. In older adults, higher circulating C18:0 and C24:1 associate with significantly increased sarcopenia risk, nominating these lipids as biomarkers and potential intervention targets.
Impact: Triangulates mechanism and human association, advancing lipidomic targets for sarcopenia prevention and treatment.
Clinical Implications: Supports measuring specific ceramides as risk markers and exploring ceramide-lowering or antioxidant strategies to mitigate age-related muscle decline.
Key Findings
- C18:0 and C24:1 ceramides impaired myogenic differentiation via ROS, downregulating myogenic markers and ITGB1–FAK–AKT signaling while activating FoxO pathways.
- Antioxidant N-acetylcysteine attenuated ceramide-induced myogenic defects.
- In mice, both ceramides reduced muscle fiber cross-sectional area and strength; in humans (n=165), higher circulating levels associated with greater sarcopenia risk.
Methodological Strengths
- Convergent evidence across in vitro, in vivo, and human cohort data
- Quantitative lipidomics with LC–MS/MS and functional muscle assessments
Limitations
- Human cohort size is modest and cross-sectional, limiting causal inference
- Mouse model uses exogenous ceramide administration, which may not fully recapitulate endogenous pathophysiology
Future Directions: Prospective studies to validate ceramide thresholds for risk stratification and interventional trials targeting ceramide metabolism or ROS pathways to prevent sarcopenia.
BACKGROUND: Ceramides have garnered considerable attention as pro-aging bioactive lipids implicated in both metabolic dysfunction and musculoskeletal decline. Among these, C18:0 and C24:1 ceramides may play a role in the pathophysiology of sarcopenia, a key manifestation of age-related deterioration. However, their specific contributions to muscle degeneration remain poorly defined. METHODS: C2C12 myoblasts and primary myoblasts were treated with C18:0 or C24:1 ceramides during differentiation to assess myotube formation, migration and intracellular reactive oxygen species (ROS) levels. Three-month-old C57BL/6 mice received daily intraperitoneal injections of C18:0 or C24:1 ceramides for 4 weeks to evaluate muscle morphology and function. In a human cohort of 165 community-dwelling older adults (≥ 65 years), serum ceramide levels were measured via LC-MS/MS and analysed in relation to sarcopenia parameters. RESULTS: Both C18:0 and C24:1 ceramides significantly impaired myogenic differentiation in vitro, as evidenced by reduced myotube number, total myotube area, average area per myotube, nuclei count per myotube and fusion index, through ROS-mediated mechanisms (with up to an 8.6-fold increase in ROS production). Consistently, C18:0 and C24:1 ceramides markedly downregulated key myogenic markers and inhibited ITGB1-FAK-AKT signalling while promoting nuclear activation of FoxO-associated catabolic pathways. These deleterious effects were attenuated by treatment with the antioxidant N-acetylcysteine. In mice, systemic administration of either ceramide resulted in reduced muscle fibre cross-sectional area in the tibialis anterior (by 20.5% and 20.9% for C18:0 and C24:1, respectively) and soleus muscles (by 18.1% and 16.1%), accompanied by decreased grip strength, shorter grid hanging times and reduced latency to fall in the rotarod test. Clinically, in a cohort of 165 older adults (80.6% female; mean age 75.2 ± 5.2 years in controls and 79.7 ± 4.8 years in the sarcopenia group), serum levels of C18:0 and C24:1 ceramides were 27% and 14% higher, respectively, in individuals with sarcopenia compared to controls (p = 0.001 and 0.018). Furthermore, each standard deviation increase in serum C18:0 and C24:1 ceramide levels was associated with a 2.0- and 1.6-fold increased risk of sarcopenia, respectively (p = 0.003 and 0.040). CONCLUSIONS: Our findings reveal that circulating C18:0 and C24:1 ceramides are significantly associated with sarcopenia in older adults, while experimental models demonstrate they promote muscle atrophy through oxidative stress-induced impairment of myogenesis and muscle function. These ceramides may serve as minimally invasive biomarkers and potential therapeutic targets for age-related muscle decline. Interventions aimed at modulating ceramide metabolism could offer new avenues for sarcopenia prevention and treatment in aging populations.