Daily Endocrinology Research Analysis
Analyzed 83 papers and selected 3 impactful papers.
Summary
Analyzed 83 papers and selected 3 impactful articles.
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 an endogenous GLP-1 secretagogue, the authors show that GLP-1 cooperates with insulin to activate left-sided vagal afferents, acutely enhancing insulin action and improving glycemia comparably to GLP-1RAs. This identifies a physiological GLP-1/insulin–vagal axis that can be leveraged for therapeutic or nutritional strategies in type 2 diabetes.
Impact: Reveals a previously underappreciated neuroendocrine mechanism by which endogenous GLP-1 augments insulin action via vagal afferents, with immediate translational implications for non-pharmacologic and pharmacologic interventions.
Clinical Implications: Supports investigating d-allulose or other GLP-1 secretagogues, and neuromodulatory approaches targeting the GLP-1/insulin–vagal pathway, to enhance insulin sensitivity without increasing insulin secretion burden in type 2 diabetes.
Key Findings
- d-Allulose triggers intestinal GLP-1 release that cooperates with insulin to activate left-sided vagal afferents.
- The mechanism enhances insulin action (not secretion), acutely improving glycemic control.
- Glycemic improvement in type 2 diabetes was comparable to GLP-1 receptor agonists, suggesting therapeutic targeting of GLP-1/insulin–vagal signaling.
Methodological Strengths
- Physiologic dissection of a neuroendocrine reflex using a selective endogenous GLP-1 secretagogue.
- Mechanistic differentiation of insulin action versus secretion effects via vagal pathway activation.
Limitations
- Predominantly preclinical mechanistic work; generalizability to diverse human populations requires clinical trials.
- Short-term, acute effects were emphasized; durability and metabolic outcomes over time remain unknown.
Future Directions: Human interventional studies testing d-allulose dosing, meal timing, and neuromodulation of left vagal afferents; biomarker development to monitor GLP-1/insulin–vagal tone and insulin action.
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. A lipid-immune network signature defines susceptibility to asparaginase-associated pancreatitis.
Longitudinal lipidomic/proteomic profiling in two pediatric ALL cohorts identified a reproducible LPC-centered lipid–immune network disruption in patients who develop AAP. A post-induction IL-18/LPC ratio stratified AAP risk in a protocol-defined very high-risk subgroup (AUC 0.81), supporting systems biomarkers for prevention strategies.
Impact: Provides pre-injury, reproducible molecular features of AAP susceptibility and a translatable lipid–cytokine ratio with subgroup-level discrimination, addressing a major toxicity barrier in curative ALL therapy.
Clinical Implications: Supports prospective validation of IL-18/LPC-based risk stratification to guide monitoring and mitigation (e.g., dose modification, early symptom surveillance) for high-risk ALL subgroups receiving asparaginase.
Key Findings
- A reproducible LPC-centered signature with attenuated therapy-associated LPC responses and disrupted co-regulation was observed across two cohorts.
- Lipid–cytokine coupling was altered, including a case–control flip in associations between LPC species and IL-18.
- Elevated post-induction IL-18/LPC ratios identified AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81).
Methodological Strengths
- Prospective, paired sampling before exposure capturing pre-injury biology and longitudinal changes.
- Cross-cohort reproducibility with integrated lipidomics–proteomics and network analyses.
Limitations
- Risk discrimination (IL-18/LPC) was demonstrated in a protocol-defined very high-risk subgroup, requiring broader validation.
- Clinical utility thresholds and integration with existing clinical risk factors remain to be established.
Future Directions: Prospective, multi-center validation trials incorporating IL-18/LPC ratios into risk-adapted asparaginase dosing and monitoring; mechanistic studies on LPC–inflammasome/IL-18 pathways in pancreatic injury.
BACKGROUND: Asparaginase is essential for curing acute lymphoblastic leukemia (ALL), but its use is limited by asparaginase-associated pancreatitis (AAP), a severe and unpredictable toxicity lacking validated prospective biomarkers. We sought to define early systemic molecular features of susceptibility to AAP. METHODS: We performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (n = 161; 79 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and at the end of induction therapy (including a single dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. We applied differential abundance and network-based analyses, and integrated lipid-cytokine associations using proteomics. RESULTS: Across cohorts, we identified a reproducible lysophosphatidylcholine (LPC)-centered signature characterized by attenuated induction therapy-associated LPC responses and disruption of LPC co-regulation at the network level. Proteomic profiling revealed enrichment of cytokine signaling pathways, and integrative analyses demonstrated altered lipid-cytokine coupling, including a flip in association direction for LPC species and interleukin-18 (IL-18) between cases and controls. Although IL-18/LPC ratios do not differ globally, elevated post-induction IL-18/LPC ratios identify AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81). CONCLUSION: These findings support a systems-level model in which failure of coordinated lipid-immune responses under therapeutic stress confers vulnerability to AAP, providing a framework for validation and mitigation strategies. TRIAL REGISTRATION: NCT00400946; NCT01574274; NCT03020030 (parent trials). FUNDING: Servier Pharmaceuticals (IIT-95014-027-USA); SDRC (P30DK116074); Stanford SPARK; Fonds de Recherche du Québec - Santé; Fondation Charles-Bruneau; The Leukemia & Lymphoma Society of Canada.
3. Hepatoma-Derived Growth Factor Coordinates STAT3 Pathway and Exosome-Mediated Intrahepatic Crosstalk to Control Hepatic Steatosis and MASLD.
HDGF is identified as a nodal regulator that couples lipogenesis (via S6K1-dependent STAT3 Ser727 phosphorylation) to exosome-mediated macrophage activation in MASLD. Hepatic HDGF deficiency and pharmacologic STAT3 inhibition protect against steatosis/inflammation, and human HDGF levels correlate with disease progression, nominating the HDGF–STAT3–exosome axis as a therapeutic target.
Impact: Uncovers a unifying mechanism linking hepatocellular lipogenesis and intrahepatic inflammatory crosstalk with human correlation, providing dual actionable nodes (STAT3 phosphorylation and exosomal HDGF secretion).
Clinical Implications: Supports development of agents targeting HDGF secretion or STAT3 Ser727 phosphorylation to reduce steatosis and inflammation in MASLD; HDGF may serve as a biomarker for disease activity and treatment response.
Key Findings
- Hepatic HDGF deficiency protects mice from diet-induced steatosis and hepatic inflammation.
- HDGF promotes lipogenesis via S6K1-dependent STAT3 Ser727 phosphorylation; STAT3 inhibitor S3I-201 abrogates HDGF-induced steatosis.
- HDGF Ser165 phosphorylation is required for exosomal secretion that activates proinflammatory macrophages; human hepatic/serum HDGF levels correlate with MASLD progression.
Methodological Strengths
- Multi-level mechanistic validation (genetic deficiency, pharmacologic inhibition, exosome biology) with in vivo and in vitro concordance.
- Human translational relevance via serum and hepatic HDGF measurements correlating with disease stage.
Limitations
- Predominantly preclinical; specificity and safety of targeting STAT3 Ser727 or HDGF exosomal export require evaluation.
- Human data are correlative; interventional human studies are needed to establish causality and therapeutic efficacy.
Future Directions: Design selective inhibitors of HDGF Ser165 phosphorylation/exosomal release and STAT3 Ser727 modulation; evaluate HDGF as a stratification biomarker and pharmacodynamic readout in early-phase MASLD trials.
Metabolic dysfunction-associated steatotic liver disease has become a predominant cause of chronic liver disease worldwide and represents a major clinical management challenge owing to the scarcity of effective therapeutic interventions. However, the molecular mechanisms driving MASLD progression remain incompletely understood. Here, we identify hepatoma-derived growth factor (HDGF) as a key regulator that integrates lipogenesis with intrahepatic inflammation in MASLD pathogenesis. Hepatic HDGF deficiency profoundly protects mice from high-fat, high-sucrose diet-induced hepatic steatosis and inflammation. Mechanistically, HDGF promotes lipogenesis and hepatic steatosis by facilitating S6K1-dependent phosphorylation of STAT3 at Ser727. Consistently, pharmacological inhibition of STAT3 by S3I-201 abolishes HDGF-induced lipogenic gene expression and hepatic steatosis in mouse models. Importantly, phosphorylation of HDGF at Ser165 is essential for its exosomal secretion from hepatocytes, thereby triggering proinflammatory macrophage activation. In humans, both serum and hepatic levels of HDGF are elevated and positively correlated with MASLD progression. Together, these findings uncover a mechanism that couples hepatic lipogenesis to intrahepatic macrophage activation, driving both steatosis and inflammation in MASLD. Targeting the HDGF-STAT3 pathway and exosomal HDGF secretion may represent a potential therapeutic strategy for ameliorating metabolic dysfunction and hepatic inflammation in MASLD and related disorders.