Weekly Endocrinology Research Analysis
This week in endocrinology saw advances spanning precision prescribing, adipose and mineral metabolism mechanisms, and novel diagnostic/prognostic markers. A Lancet real-world model offers a five-class decision tool to personalize glucose‑lowering therapy and improve 12‑month HbA1c. Translational studies highlighted LRP5 and BDH1 as actionable adipose and ketone‑epigenetic pathways influencing metabolic and cardiac outcomes, while clinical biomarker work (cFGF‑23, IA‑2A, anthropometric clusters)
Summary
This week in endocrinology saw advances spanning precision prescribing, adipose and mineral metabolism mechanisms, and novel diagnostic/prognostic markers. A Lancet real-world model offers a five-class decision tool to personalize glucose‑lowering therapy and improve 12‑month HbA1c. Translational studies highlighted LRP5 and BDH1 as actionable adipose and ketone‑epigenetic pathways influencing metabolic and cardiac outcomes, while clinical biomarker work (cFGF‑23, IA‑2A, anthropometric clusters) refines risk stratification and monitoring.
Selected Articles
1. LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity.
Integrated human genetics, Mendelian randomization, imaging, and adipose progenitor experiments show LRP5 drives lower‑body fat distribution and enhances systemic and adipocyte insulin sensitivity via WNT/β‑catenin signaling and VCP‑mediated proteostasis. Gain‑of‑function variants protect against age‑related lower‑body fat loss, nominating adipose‑selective LRP5 modulation as a therapeutic approach.
Impact: Provides convergent mechanistic and human genetic evidence that LRP5 controls metabolically favorable fat distribution and insulin sensitivity, identifying a tractable adipose‑specific target distinct from bone effects.
Clinical Implications: While preclinical-to-clinical translation remains needed, the findings support development of adipose‑selective LRP5/WNT modulators to preserve lower‑body fat and improve insulin sensitivity, potentially preventing metabolic syndrome in aging populations.
Key Findings
- LRP5 promotes lower‑body fat distribution and increases systemic/adipocyte insulin sensitivity independent of bone effects.
- LRP5 sustains adipose progenitor fitness via WNT/β‑catenin activation and VCP‑mediated proteostasis; expression declines with age.
- Gain‑of‑function LRP5 variants protect against age‑related lower‑body fat loss.
2. A five-drug class model using routinely available clinical features to optimise prescribing in type 2 diabetes: a prediction model development and validation study.
Using >100,000 drug initiations from the UK CPRD, authors developed and validated a five‑drug‑class model to predict 12‑month HbA1c effectiveness and identify an optimal glucose‑lowering class for individuals. Only ~15% of real‑world initiations matched the model's optimal recommendation, and model‑concordant treatment yielded lower observed 12‑month HbA1c.
Impact: Delivers a scalable precision‑prescribing tool with immediate translational relevance; embedding this model into EHR decision support could materially change initial/add‑on therapy selection in T2D.
Clinical Implications: Supports EHR‑integrated CDS to guide selection among SGLT2i, GLP‑1RA, DPP‑4i, TZDs, and sulfonylureas to maximize HbA1c reduction and reduce therapeutic inertia; prospective pragmatic trials and health‑economic evaluation are next steps.
Key Findings
- Developed/validated a five‑drug class prediction model from 100,107 drug initiations in CPRD to predict absolute 12‑month HbA1c.
- Only 15.2% of 212,166 initiations matched the model‑predicted optimal therapy in the combined cohort.
- Model‑concordant prescribing was associated with lower observed 12‑month HbA1c versus discordant prescribing.
3. C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism.
In unilateral primary aldosteronism, circulating C‑terminal FGF‑23 (cFGF‑23) is elevated, correlates nonlinearly with aldosterone, predicts adverse cardiovascular/kidney outcomes, and falls after adrenalectomy. Mechanistically, aldosterone enhances FAM20C‑dependent phosphorylation/cleavage of intact FGF‑23, increasing cFGF‑23 fragments, linking mineral metabolism to aldosterone biology.
Impact: Bridges clinical prognostication and mechanism by identifying an aldosterone–FAM20C–FGF‑23 axis with prognostic implications in primary aldosteronism, suggesting new biomarker and therapeutic entry points.
Clinical Implications: cFGF‑23 may be incorporated into risk stratification and perioperative monitoring for primary aldosteronism; targeting FAM20C‑mediated pathways could represent future therapeutic strategies to mitigate cardiovascular risk.
Key Findings
- cFGF‑23 levels are elevated in unilateral primary aldosteronism and show a nonlinear relationship with plasma aldosterone.
- Higher preoperative cFGF‑23 predicts mortality and cardiovascular/kidney events and decreases after adrenalectomy.
- Aldosterone enhances cleavage/phosphorylation of intact FGF‑23 via FAM20C in vitro; FAM20C silencing mitigates cFGF‑23 fragment increase.