Daily Endocrinology Research Analysis
Three studies stand out in endocrinology today: a mechanistic JCI paper maps cell-intrinsic hepatic insulin resistance in type 2 diabetes and identifies ROCK1/2 as actionable nodes; a European Journal of Endocrinology study shows that paradoxical bilateral aldosterone suppression during adrenal vein sampling largely reflects immunoassay artifacts resolvable by LC-MS/MS; and a JCEM population-genomics analysis reveals that MEN2 and PTEN hamartoma tumor syndrome are far more prevalent than previou
Summary
Three studies stand out in endocrinology today: a mechanistic JCI paper maps cell-intrinsic hepatic insulin resistance in type 2 diabetes and identifies ROCK1/2 as actionable nodes; a European Journal of Endocrinology study shows that paradoxical bilateral aldosterone suppression during adrenal vein sampling largely reflects immunoassay artifacts resolvable by LC-MS/MS; and a JCEM population-genomics analysis reveals that MEN2 and PTEN hamartoma tumor syndrome are far more prevalent than previously thought, with immediate implications for genetic testing strategies.
Research Themes
- Mechanistic mapping of hepatic insulin resistance and kinase reprogramming in T2D
- Diagnostic accuracy in primary aldosteronism: immunoassay vs LC-MS/MS in AVS
- Population genomics revising prevalence of endocrine cancer syndromes (MEN2, PHTS)
Selected Articles
1. Cell-intrinsic insulin signaling defects in human iPS cell-derived hepatocytes in type 2 diabetes.
Using iPSC-derived human hepatocytes and phosphoproteomics, the authors map widespread losses of canonical insulin signaling and the emergence of new phosphorylation programs in T2D, implicating ROCK1/2, MST4, and BCKDK. ROCK1/2 inhibition partially restores insulin action, nominating actionable kinase targets for hepatic insulin resistance.
Impact: Provides mechanistic, targetable insight into hepatic insulin resistance using human-relevant cells and state-of-the-art phosphoproteomics.
Clinical Implications: Suggests ROCK1/2 (and possibly MST4/BCKDK) as drug targets to restore hepatic insulin action; supports biomarker development based on phosphosite signatures for patient stratification.
Key Findings
- Over 300 phosphosites showed impaired insulin signaling in T2D hepatocytes, including losses in PI3K/AKT cascade targets.
- More than 500 emergent phosphorylation sites appeared in T2D on pathways such as Rho-GTPase, RNA metabolism, vesicle trafficking, and chromatin.
- Kinome inference implicated increased ROCK1/2 and MST4/BCKDK activity with reduced AKT2/3 signaling; ROCK1/2 inhibition partially rescued insulin action.
Methodological Strengths
- Human iPSC-derived hepatocyte model capturing patient-intrinsic signaling defects
- Comprehensive LC-MS/MS phosphoproteomics with kinome inference and functional rescue by kinase inhibition
Limitations
- Preclinical in vitro model without in vivo human validation
- Sample size and donor heterogeneity details are not fully delineated
Future Directions: Test ROCK1/2 and related kinase inhibitors in translational models and early-phase trials; develop phosphosite-based biomarkers to stratify hepatic insulin resistance phenotypes.
2. Population Prevalence of the Major Thyroid Cancer-Associated Syndromes.
Across All of Us and UK Biobank (>700,000 participants), MEN2 and PHTS are far more prevalent than previously thought, and many carriers (notably RET V804M/L) lack thyroid cancer diagnoses. These data support updating genetic testing and surveillance strategies, particularly for moderate-risk RET variants.
Impact: Population-scale genomics redefines baseline prevalence for endocrine cancer syndromes, directly informing screening and risk communication.
Clinical Implications: Consider broader germline testing and tailored surveillance for RET, PTEN, and APC variant carriers, with nuanced counseling for moderate-risk RET (e.g., V804M/L) given low penetrance for thyroid cancer.
Key Findings
- MEN2 (RET), PHTS (PTEN), and FAP (APC) were significantly associated with thyroid cancer in logistic regression.
- Estimated prevalence: MEN2 ~1:2172 (All of Us) and 1:2348 (UK Biobank); PHTS ~1:8764 and 1:13043; FAP ~1:8461 and 1:8238.
- RET V804M/L variants comprised 65% of MEN2 variants in All of Us; none of these carriers had diagnosed thyroid cancer.
Methodological Strengths
- Very large, population-based cohorts (All of Us and UK Biobank)
- Standardized variant classification using ClinVar with statistical association testing
Limitations
- Cross-sectional design with potential phenotype misclassification and incomplete clinical adjudication
- Reliance on ClinVar annotations; penetrance and expressivity not fully characterized
Future Directions: Prospective penetrance studies and guideline updates for genetic testing thresholds; evaluate outcomes of surveillance strategies in moderate-risk RET carriers.
3. Resolution of paradoxical bilateral aldosterone suppression with mass spectrometry.
In a cohort of 402 primary aldosteronism patients undergoing simultaneous AVS, 25% showed paradoxical bilateral aldosterone suppression by immunoassays, but LC-MS/MS remeasurement eliminated BAS in 79% of tested cases. Immunoassays misestimated cortisol and aldosterone, indicating that many BAS results are assay artifacts with major implications for PA subtyping.
Impact: Challenges a common AVS interpretation and provides a practical solution (LC-MS/MS), reducing misclassification risk in surgical decision-making for primary aldosteronism.
Clinical Implications: Use LC-MS/MS for cortisol/aldosterone quantitation in equivocal AVS (especially with BAS or partial cannulation) and avoid inferring contralateral suppression solely from immunoassay BAS.
Key Findings
- BAS prevalence by immunoassay was 25% (102/402) in AVS patients; occurred pre-/post-cosyntropin and both.
- LC-MS/MS remeasurement removed BAS in 79% (42/53) of cases with available serum, indicating assay artifacts.
- Immunoassays overestimated cortisol; for aldosterone, they overestimated low and underestimated high concentrations typical of adrenal veins.
Methodological Strengths
- Large single-center cohort with simultaneous AVS before/after cosyntropin
- Orthogonal confirmation using LC-MS/MS quantitation
Limitations
- Retrospective design; LC-MS/MS performed in a subset (53 patients)
- Single-center referral cohort may limit generalizability
Future Directions: Prospective studies standardizing LC-MS/MS in AVS workflows and defining thresholds to minimize misclassification; inter-lab harmonization of aldosterone/cortisol assays.