Daily Endocrinology Research Analysis
Three studies advance endocrine science across cardio-renal, neuropsychiatric, and neurodegenerative interfaces: (1) Aldosterone drives C-terminal FGF-23 production via FAM20C in primary aldosteronism, linking mineral metabolism to cardiovascular risk; (2) In older adults with type 2 diabetes, GLP-1 receptor agonists show a modestly lower depression risk versus DPP-4 inhibitors but not versus SGLT2 inhibitors; (3) Cognitive vulnerability to glucose fluctuations associates with plasma phosphoryla
Summary
Three studies advance endocrine science across cardio-renal, neuropsychiatric, and neurodegenerative interfaces: (1) Aldosterone drives C-terminal FGF-23 production via FAM20C in primary aldosteronism, linking mineral metabolism to cardiovascular risk; (2) In older adults with type 2 diabetes, GLP-1 receptor agonists show a modestly lower depression risk versus DPP-4 inhibitors but not versus SGLT2 inhibitors; (3) Cognitive vulnerability to glucose fluctuations associates with plasma phosphorylated tau biomarkers, suggesting a digital phenotype of neurodegeneration.
Research Themes
- Aldosterone–FGF-23 coupling and cardio-renal endocrinology
- Metabolic therapeutics and mental health (GLP-1RA, depression)
- Digital phenotyping of neurodegeneration via glucose variability
Selected Articles
1. C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism.
In unilateral primary aldosteronism, circulating cFGF-23 is elevated, tracks nonlinearly with aldosterone, predicts adverse outcomes, and decreases after adrenalectomy. Mechanistically, aldosterone enhances FAM20C-dependent phosphorylation/cleavage of iFGF-23, increasing cFGF-23 fragments. These data link mineral metabolism to aldosterone biology and suggest cFGF-23 as a prognostic biomarker.
Impact: This study bridges mechanism and clinic by identifying an aldosterone–FAM20C–FGF-23 axis with prognostic relevance in primary aldosteronism, potentially reshaping risk stratification and therapeutic targeting.
Clinical Implications: cFGF-23 measurement may aid prognostication and postoperative monitoring in primary aldosteronism, while highlighting FAM20C signaling as a potential therapeutic target alongside adrenalectomy.
Key Findings
- cFGF-23 levels were elevated in unilateral primary aldosteronism and showed a nonlinear increase with aldosterone, whereas iFGF-23 did not correlate with aldosterone.
- Higher preoperative cFGF-23 predicted adverse outcomes (mortality, cardiovascular/kidney events) and decreased after adrenalectomy.
- Aldosterone enhanced iFGF-23 cleavage via FAM20C in vitro; silencing FAM20C mitigated cFGF-23 fragment increase, while furin inhibition had no effect.
Methodological Strengths
- Integration of clinical biomarker analyses with mechanistic in vitro experiments and pre/post-surgical assessments
- Use of fragment-specific FGF-23 measures (cFGF-23 vs iFGF-23) enabling pathway resolution
Limitations
- Observational clinical associations without randomized intervention; sample size not specified in abstract
- In silico docking supports but does not prove direct aldosterone–FAM20C binding in vivo
Future Directions: Validate cFGF-23 as a prognostic biomarker in larger, multi-center cohorts; dissect in vivo FAM20C regulation by aldosterone and test pharmacologic modulation of the FAM20C–FGF-23 axis.
2. Glucagon-Like Peptide-1 Receptor Agonists and Risk for Depression in Older Adults With Type 2 Diabetes : A Target Trial Emulation Study.
In Medicare-insured adults aged ≥66 years with type 2 diabetes, GLP-1RAs were associated with a modestly lower depression risk versus DPP-4 inhibitors (HR 0.90) but not versus SGLT2 inhibitors (HR 1.07). Results derive from a large target trial emulation with 1:1 propensity score matching.
Impact: Addresses a timely safety/benefit question about GLP-1RAs and mental health using robust causal inference methods in real-world data.
Clinical Implications: Findings are reassuring that GLP-1RAs do not increase depression risk versus SGLT2 inhibitors and may be preferable to DPP-4 inhibitors regarding depression in older adults, informing agent selection alongside metabolic benefits.
Key Findings
- GLP-1RA vs SGLT2i: HR for incident depression 1.07 (95% CI 0.98–1.18), indicating no significant difference.
- GLP-1RA vs DPP-4i: HR 0.90 (95% CI 0.82–0.98) and rate difference −5.78 per 1000 person-years, indicating modestly lower risk.
- Overall depression incidence was relatively low in older adults with T2D in Medicare data.
Methodological Strengths
- Target trial emulation with active comparator new-user design and 1:1 propensity score matching
- Large national administrative dataset with time-to-event modeling
Limitations
- Residual confounding (e.g., glycemic control such as HbA1c) and misclassification inherent to claims data
- Generalizability limited to older (≥66 years) Medicare beneficiaries
Future Directions: Incorporate clinical covariates (HbA1c, PHQ-9) and patient-reported outcomes, examine dose/formulation effects, and assess younger cohorts and mechanistic psychiatric endpoints.
3. Cognitive vulnerability to glucose fluctuations: A digital phenotype of neurodegeneration.
Among 114 adults with type 1 diabetes, cognitive vulnerability to glucose fluctuations (via EMA+CGM) associated with plasma biomarkers of neurodegeneration, especially phosphorylated tau (p-tau181/217), independent of covariates. CVG did not associate with Aβ42/40, suggesting specificity to tau-related pathology.
Impact: Introduces a scalable, real-world digital phenotype linking glycemic dynamics to AD-relevant pathology, bridging endocrinology and neurodegeneration.
Clinical Implications: Highlights the importance of mitigating glucose variability to protect cognition; supports integrating CGM-informed cognitive monitoring in high-risk patients.
Key Findings
- CVG was associated with plasma biomarkers of neurodegeneration (p-tau181/217, NfL, GFAP) but not with Aβ42/40.
- Associations between sustained attention CVG and phosphorylated tau biomarkers remained significant across covariate specifications.
- EMA combined with CGM provides a practical, ecological approach to quantify CVG as a potential digital phenotype.
Methodological Strengths
- Integration of continuous glucose monitoring with ecological momentary cognitive assessment
- Use of plasma AD and neurodegeneration biomarkers with covariate-robust associations
Limitations
- Cross-sectional observational design in a modest sample (N=114) limits causal inference
- Generalizability limited to adults with type 1 diabetes
Future Directions: Longitudinal and interventional studies to test whether reducing glucose variability attenuates tau-related biomarker trajectories and cognitive decline.