Daily Endocrinology Research Analysis
Analyzed 114 papers and selected 3 impactful papers.
Summary
Plasma proteomics from the EXSCEL trial yielded a modifiable multi-protein score that improves prediction of major adverse cardiovascular events in type 2 diabetes and is responsive to GLP-1 receptor agonist therapy. A large UK Biobank imaging cohort shows MRI-defined fatty pancreas independently associates with incident type 2 diabetes, chronic kidney disease, and cardiovascular events, supporting its role in the cardio-kidney-metabolic continuum. A mechanistic study identifies presenilin-1 as a regulator of beta-cell glycolysis, linking neurodegeneration biology to islet function.
Research Themes
- Precision cardiometabolic risk stratification using modifiable plasma proteomics
- Ectopic fat (fatty pancreas) as an independent cardio-kidney-metabolic risk factor
- Cross-disease mechanisms linking beta-cell metabolism and neurodegeneration
Selected Articles
1. A Validated, Modifiable Proteomic Score from the EXSCEL Trial Predicts Cardiovascular Events in Diabetes.
Using baseline and 12-month plasma proteomics from the randomized EXSCEL trial, the authors derived a supervised machine-learning multi-protein score that improved MACE risk discrimination beyond clinical factors and was externally validated in independent cohorts. The score and top-ranked protein tetranectin were modified by GLP-1 RA therapy, and decreases in the score associated with better outcomes, indicating a treatment-responsive, modifiable biomarker for precision prevention.
Impact: Demonstrates a generalizable, treatment-responsive proteomic risk score for cardiovascular events in T2D, moving beyond static clinical models toward precision prevention.
Clinical Implications: Enables refined cardiovascular risk stratification and potentially dynamic monitoring of GLP-1 RA treatment response in T2D; could guide therapy intensification and trial enrichment, pending clinical implementation studies.
Key Findings
- A supervised multi-protein plasma score improved MACE risk discrimination beyond clinical factors in the EXSCEL cohort.
- External validation in Cardiovascular Health Study and PROMISE confirmed generalizability across cohorts with and without diabetes.
- The proteomic score and top-ranked protein tetranectin were modified by GLP-1 RA treatment; reductions associated with improved outcomes.
Methodological Strengths
- Longitudinal proteomics within a randomized trial framework (baseline and 12-month sampling).
- External validation across two independent cohorts; supervised ML with multivariable adjustment.
Limitations
- Post hoc biomarker analysis; potential overfitting and platform-specific effects.
- Causality cannot be inferred; sample sizes per cohort and ancestry diversity are not detailed in the abstract.
Future Directions: Prospective implementation studies to assess clinical utility, cost-effectiveness, and decision impact; assay standardization; testing score-guided therapy intensification and monitoring strategies.
Adults with type 2 diabetes mellitus (T2DM) are at increased risk for stroke, myocardial infarction, and cardiovascular death, yet individual risk is heterogeneous and incompletely captured by clinical models. In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), adults with T2DM were randomized to a GLP-1 RA (exenatide) or placebo and followed longitudinally for major adverse cardiovascular events (MACE). High-throughoput discovery proteomics was done in plasma collected at baseline and 12-months. Proteins associated with time-to-MACE were identified using multivariable regression and incorporated into supervised machine lea
2. Fatty Pancreas and Risk of Type 2 Diabetes, Chronic Kidney Disease and Cardiovascular Events: Evidence From a Population-Based Cohort.
In 19,255 UK Biobank participants, MRI-PDFF–defined fatty pancreas categorized by consensus thresholds was independently associated with prevalent and incident T2D, incident CKD, and modestly with MACE, after adjustment for BMI, visceral fat, and covariates. Each 5% increase in pancreatic PDFF increased odds/hazard of T2D, positioning fatty pancreas within the cardiovascular-kidney-metabolic continuum.
Impact: Establishes clinically interpretable MRI thresholds for fatty pancreas that predict incident diabetes, kidney disease, and cardiovascular events beyond adiposity, supporting risk stratification.
Clinical Implications: Where MRI-PDFF is available, pancreatic fat quantification could augment cardiometabolic risk assessment and identify individuals needing intensified prevention for T2D and CKD.
Key Findings
- Moderate-to-severe fatty pancreas (PDFF ≥16%) associated with prevalent and incident T2D (OR 3.25; HR 2.72) and incident CKD (HR 1.82).
- Modest associations with MACE were observed (prevalent OR 1.26; incident HR 1.30).
- Each 5% increase in pancreatic PDFF increased T2D risk (OR 1.16; HR 1.17), independent of BMI, visceral adiposity, and covariates.
Methodological Strengths
- Large population-based imaging cohort (N=19,255) with MRI-derived PDFF.
- Use of international consensus thresholds and multivariable models adjusting for obesity and visceral fat.
Limitations
- Observational design limits causal inference; potential residual confounding.
- European-ancestry sample may limit generalizability; MRI access limits immediate scalability.
Future Directions: Evaluate PDFF-guided prevention algorithms, assess generalizability to diverse ancestries, and test whether pancreatic fat reduction modifies risk.
BACKGROUND: Fatty pancreas is a metabolically active ectopic fat depot, but its cardiometabolic implications have been assessed using heterogeneous thresholds. We investigated the association of fatty pancreas, quantified using MRI-derived proton density fat fraction (PDFF) and categorised according to 2026 international consensus thresholds, with prevalent and incident type 2 diabetes (T2D), chronic kidney disease (CKD) and major adverse cardiovascular events (MACE). METHODS: We analysed 19,255 European-ancestry participants from the UK Biobank imaging sub-study. Pancreatic PDFF was categorised as normal (< 6%), mild (6 to < 16%) and moderate-to-severe fatty pancreas (≥ 16%). Outcomes were ascertained through nati
3. Presenilin-1 controls glycolysis and identity of pancreatic beta cells.
Across multiple beta-cell models, PS1 emerged as a key regulator of glycolytic flux via control of sub-mitochondrial Ca2+, linking an Alzheimer’s disease protein to beta-cell metabolism and early-phase insulin secretion. This reveals a cross-disease mechanistic axis and a potential target for restoring beta-cell function in diabetes.
Impact: Uncovers a previously unappreciated role for presenilin-1 in beta-cell glycolysis, bridging neurodegeneration and islet biology and opening avenues for metabolic intervention.
Clinical Implications: Suggests PS1-dependent pathways as therapeutic targets to enhance early insulin secretion and beta-cell metabolic resilience; may inform comorbidity links between dementia and diabetes.
Key Findings
- PS1 regulates glycolytic flux in pancreatic beta cells by controlling sub-mitochondrial Ca2+.
- PS1 function is fundamental for early-phase glucose-stimulated insulin secretion, linking AD-related proteins to islet metabolism.
Methodological Strengths
- Mechanistic interrogation across multiple beta-cell model systems.
- Integration of calcium signaling and metabolic flux analyses to define causal pathways.
Limitations
- Abstract provides limited detail on in vivo validation and effect sizes.
- Translational applicability to human disease requires further confirmation.
Future Directions: Define PS1-mediated nodes suitable for pharmacologic modulation, validate in vivo in diabetes models, and examine PS1–beta-cell pathways in human islets and clinical phenotypes.
Presenilin-1 (PS1) is an endoplasmic reticulum protein, most known for its role in pathogenesis of familial Alzheimer's Disease (AD). PS1 has been attributed roles in intracellular calcium homeostasis in the brain, as well as in the pancreatic beta cells, where it has been shown to be fundamental for the initial phase of glucose-induced insulin secretion. To gain mechanistic insight into beta cell autonomous function of PS1, we have examined various beta cell models and found that PS1 controls glycolytic flux of pancreatic beta cells by regulating sub-mitochondrial Ca