Daily Endocrinology Research Analysis
Three impactful endocrinology papers span mechanistic, prognostic, and comparative-effectiveness research. A Cell Reports Medicine study identifies PGK1 as a dual-mode driver of diabetic kidney disease and reports small-molecule antagonists. TrialNet data in Diabetes Care delineate age-specific progression patterns to type 1 diabetes, and a meta-analysis shows GLP-1 receptor agonists improve kidney outcomes vs DPP4i/sulfonylureas/insulin but are inferior to SGLT2 inhibitors.
Summary
Three impactful endocrinology papers span mechanistic, prognostic, and comparative-effectiveness research. A Cell Reports Medicine study identifies PGK1 as a dual-mode driver of diabetic kidney disease and reports small-molecule antagonists. TrialNet data in Diabetes Care delineate age-specific progression patterns to type 1 diabetes, and a meta-analysis shows GLP-1 receptor agonists improve kidney outcomes vs DPP4i/sulfonylureas/insulin but are inferior to SGLT2 inhibitors.
Research Themes
- Diabetic kidney disease mechanisms and therapeutic targets
- Age-specific progression and staging in type 1 diabetes
- Comparative kidney outcomes of incretin-based therapies versus SGLT2 inhibitors
Selected Articles
1. Phosphoglycerate kinase 1 contributes to diabetic kidney disease through enzyme-dependent and independent manners.
This mechanistic study identifies PGK1 as a central driver of DKD via dual modes: enzymatic 3-PG–GPX1–NLRP3 activation and non-enzymatic Aldh1l1–UNC5CL inflammation. Genetic manipulation in renal tubules and small-molecule antagonists (including an FDA-approved drug) ameliorated DKD in models, nominating PGK1 as a druggable target.
Impact: It uncovers a novel, targetable metabolic–inflammatory axis in DKD and provides immediate translational leads (three antagonists) that prevented DKD in vivo.
Clinical Implications: PGK1 inhibition could complement current DKD therapies by targeting tubular metabolic–inflammasome pathways. Repurposing oxantel pamoate warrants early-phase clinical testing with biomarkers (3-PG, inflammasome readouts).
Key Findings
- PGK1 is upregulated in DKD patients and mice; tubular PGK1 knockout mitigates DKD, while overexpression worsens it.
- Enzymatic 3-PG production inhibits GPX1, activating NLRP3 inflammasome; non-enzymatic PGK1 binds Aldh1l1 to promote UNC5CL-mediated inflammation.
- PAX5 drives PGK1 upregulation in DKD; small-molecule antagonists (C-16, lirinidine, oxantel pamoate) prevent DKD in models.
Methodological Strengths
- Integrated human and mouse evidence with metabolomics, genetics, and pharmacology
- Cell type–specific manipulation of PGK1 in renal tubules with in vivo phenotyping
Limitations
- Preclinical study; no human interventional data
- Potential off-target effects and long-term safety of antagonists remain unknown
Future Directions: Phase 1/2 trials of oxantel pamoate with tubular injury and inflammasome biomarkers; medicinal chemistry to optimize PGK1-selective antagonists; patient stratification by PGK1/PAX5/3-PG signatures.
2. Contrasting Adult and Pediatric Populations in a Cohort of At-Risk Relatives in The T1D TrialNet Pathway to Prevention Study.
Among at-risk relatives, adults more often have single autoantibody and slower progression at stage 1, but stage 2 progression matches children (≈78% at 5 years). Adults progressing from single GAD positivity show distinct genetic risk profiles, and HbA1c/risk indices better identify adult progressors.
Impact: These findings support age-tailored monitoring: adults with stage 2 require intensive follow-up similar to children, whereas earlier stages may allow less frequent surveillance.
Clinical Implications: Screening programs should stratify by age and stage: prioritize rapid follow-up and trial enrollment for adults with stage 2 T1D; use HbA1c/metabolic risk scores for adult progression prediction; educate that single GAD positivity in adults is not benign.
Key Findings
- Adults had more single autoantibody positivity (4.0% vs 2.6%) and less multiple autoantibodies (0.83% vs 2.8%).
- Five-year progression risk was lower in adults at single autoantibody and stage 1 (8.2% and 17%) but identical at stage 2 (78%).
- Adult progressors were more often single GAD-positive with lower T1D but higher T2D genetic risk; HbA1c/risk indices performed better in adults.
Methodological Strengths
- Very large multicenter cohort with standardized staging and comparisons across age groups
- Evaluation of genetic risk scores and metabolic indices alongside autoantibody profiles
Limitations
- Observational design with potential selection bias (family-based screening)
- Follow-up intervals and timing heterogeneity; generalizability beyond relatives uncertain
Future Directions: Prospective age-tailored surveillance algorithms; interventional trials targeting stage 2 in adults; refine risk scores integrating genetics, HbA1c, and autoantibodies.
3. Kidney Outcomes With Glucagon-Like Peptide-1 Receptor Agonists Versus Other Glucose-Lowering Agents in People With Type 2 Diabetes: A Systematic Review and Meta-Analysis of Real-World Data.
Across 31 observational studies (n≈1.6M), GLP-1 RAs yielded better kidney outcomes than DPP4 inhibitors, sulfonylureas, and basal insulin but were inferior to SGLT2 inhibitors for AKI, kidney-related hospitalizations, and ≥40% eGFR decline. Effects on ≥50% eGFR decline and ESKD were similar to SGLT2 inhibitors.
Impact: Provides comparative-effectiveness evidence to guide agent selection in T2D with kidney risk, reinforcing SGLT2 inhibitors as first-line for renal protection and positioning GLP-1 RAs as preferable to DPP4i/sulfonylureas/insulin when SGLT2i are unsuitable.
Clinical Implications: Prefer SGLT2 inhibitors for renal protection when possible; if contraindicated, GLP-1 RAs may confer renal benefit over DPP4i/sulfonylureas/insulin. Monitor AKI risk and hospitalization, especially when GLP-1 RAs are used instead of SGLT2 inhibitors.
Key Findings
- Versus SGLT2 inhibitors, GLP-1 RAs were associated with higher AKI (HR 1.12), kidney-related hospitalizations (HR 1.66), and ≥40% eGFR decline (HR 1.40).
- Versus DPP4 inhibitors, GLP-1 RAs reduced ≥50% eGFR decline (HR 0.84), kidney-related hospitalizations (HR 0.73), and ESKD (HR 0.70).
- Benefits similar when compared to sulfonylureas; versus basal insulin, GLP-1 RAs reduced albuminuria progression (HR 0.89).
Methodological Strengths
- Large-scale synthesis with multiple active comparators; PROSPERO-registered protocol
- Random-effects models and hazard ratio pooling across 31 observational cohorts
Limitations
- Observational data subject to confounding by indication and residual bias
- High heterogeneity across studies; outcome definitions and adjustment sets vary
Future Directions: Head-to-head pragmatic trials and target trial emulation comparing GLP-1 RAs vs SGLT2 inhibitors for renal endpoints; subgroup analyses in CKD stages and albuminuria strata.