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.
This study examined the involvement of fibroblast growth factor-23 (FGF-23) in primary aldosteronism (PA), a condition characterized by elevated aldosterone levels and hypertension. We recruited patients with unilateral PA (uPA) and observed increased levels of C-terminal FGF-23 (cFGF-23) and C-terminal to intact FGF-23 (iFGF-23) in patients with uPA compared with essential hypertension control participants. Elevated preoperative cFGF-23 levels were associated with adverse outcomes, including mortality and cardiovascular or kidney events. Plasma cFGF-23 levels demonstrated a nonlinear rise with aldosterone, but iFGF-23 levels were not correlated with plasma aldosterone concentration. Higher cFGF-23 levels independently predicted hypertension remission after adrenalectomy for patients with uPA. Patients with uPA, who exhibited elevated cFGF-23 levels, had decreased levels after adrenalectomy. In cell cultures, aldosterone enhanced cleavage of iFGF-23, leading to increased levels of cFGF-23 fragments, an effect mitigated by silencing of family with sequence similarity 20, member C (FAM20C). However, the enhancement of cFGF-23 levels remained unaffected by the furin inhibitor. The study suggests that aldosterone influences FGF-23 phosphorylation by interacting with FAM20C, with docking experiments indicating aldosterone's binding to FAM20C. This work highlights that patients with uPA with elevated cFGF-23 levels are associated with cardiovascular risks, and adrenalectomy reduces cFGF-23. Aldosterone likely promotes cFGF-23 production through FAM20C-mediated phosphorylation of iFGF-23.
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.
BACKGROUND: Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential antidepressant effects, population studies yield inconsistent results. OBJECTIVE: To compare the risk for depression in older adults with type 2 diabetes (T2D) initiating treatment with GLP-1RAs versus sodium-glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is). DESIGN: Target trial emulation study. SETTING: U.S. National Medicare administrative data from January 2014 to December 2020. PATIENTS: Adults aged 66 years or older with T2D initiating treatment with a GLP-1RA were matched 1:1 on propensity score with those initiating treatment with either an SGLT2i or a DPP4i. MEASUREMENTS: The primary end point was incident depression. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) with 95% CI within matched groups. RESULTS: A total of 14 665 matched pairs of older adults were included in the cohort for GLP-1RAs versus SGLT2is; the rate difference of depression between GLP-1RA users and SGLT2i users was 3.48 (95% CI, -0.81 to 7.78) per 1000 person-years, with an HR of 1.07 (CI, 0.98 to 1.18). In the cohort for GLP-1RAs versus DPP4is (13 711 matched pairs), the rate difference was -5.78 (CI, -10.49 to -1.07) per 1000 person-years, with an HR of 0.90 (CI, 0.82 to 0.98). LIMITATION: Unmeasured confounders (such as hemoglobin A CONCLUSION: Among older adults with T2D, the incidence of depression was relatively low. Use of GLP-1RAs was associated with a modestly lower risk for depression compared with use of DPP4is, but not SGLT2is. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
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.
INTRODUCTION: Cognition is reduced at low and high glucose, reflecting cognitive vulnerability to glucose (CVG) fluctuations. The impact of glucose fluctuations on the aging brain remains unclear. We examined whether CVG is associated with plasma biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration. METHODS: Participants included N = 114 adults with type 1 diabetes assessed for processing speed and sustained attention using ecological momentary assessment (EMA) combined with continuous glucose monitoring (CGM). We characterized associations between CVG and amyloid beta (Aβ) 42/40, phosphorylated tau (p-tau) 181 and 217, neurofilament light chain, and glial fibrillary acidic protein. RESULTS: CVG was associated with all plasma biomarkers, except Aβ 42/40. CVG for sustained attention exhibited strong associations with p-tau biomarkers that persisted across covariate specifications. DISCUSSION: CVG may be a useful digital phenotype of AD. It remains unclear whether CVG contributes to versus arises from neurodegeneration. We consider possible mechanisms linking cognitive vulnerability and long-term glucose variability to the development of neuropathology. HIGHLIGHTS: Cognitive vulnerability to glucose (CVG) may be a useful digital phenotype of neurodegeneration. We used cognitive ecological momentary assessment and continuous glucose monitoring to investigate CVG's associations with plasma biomarkers. Associations of CVG for sustained attention and phosphorylated tau 181 remained significant across covariates. We discuss possible mechanisms relating glucose variability, cognition, and neurodegeneration.