Weekly Endocrinology Research Analysis
This week in endocrinology was dominated by high-impact translational and functional-genomic work: a comprehensive INSR deep-mutational map enables rapid functional classification of ~14,000 receptor variants and points to antibody-amenable defects for precision therapy. Human adrenocortical organoids demonstrate functional steroidogenesis, in vivo rescue of adrenal insufficiency, and disease modeling for PRKACA-driven Cushing’s, advancing regenerative approaches. Large human genetics work shows
Summary
This week in endocrinology was dominated by high-impact translational and functional-genomic work: a comprehensive INSR deep-mutational map enables rapid functional classification of ~14,000 receptor variants and points to antibody-amenable defects for precision therapy. Human adrenocortical organoids demonstrate functional steroidogenesis, in vivo rescue of adrenal insufficiency, and disease modeling for PRKACA-driven Cushing’s, advancing regenerative approaches. Large human genetics work shows MC4R loss-of-function uncouples obesity from atherogenic dyslipidemia and lowers cardiovascular risk, reshaping mechanistic targets for metabolic therapy.
Selected Articles
1. Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.
The authors functionally profiled ~14,000 extracellular INSR missense variants for cell-surface expression, insulin binding, and signaling to generate a sequence–function atlas that correlates with clinical insulin resistance syndromes and identifies variants amenable to monoclonal antibody activation.
Impact: Creates a translational resource that overcomes a major barrier in interpreting INSR variants, enabling rapid clinical classification and patient selection for receptor‑targeted therapies.
Clinical Implications: Clinicians and geneticists can use function scores to reclassify variants of uncertain significance, expedite diagnosis of genetic insulin resistance, and identify candidates for antibody-based activation trials.
Key Findings
- Function scores for ~14,000 INSR extracellular missense variants across expression, ligand binding, and signalling readouts.
- Strong correlation between function scores and clinical insulin resistance phenotypes, enabling variant stratification.
- Identification of variants responsive to monoclonal antibody agonism, highlighting translational therapeutic opportunities.
2. Human adrenocortical organoids for tissue regeneration and disease modeling.
This study establishes expandable human adrenocortical organoids that preserve zona fasciculata identity, secrete cortisol in response to physiological stimuli, rescue adrenalectomized mice, and model PRKACA L206R–driven cortisol-producing adenomas, providing a platform for regenerative therapy and tumor modeling.
Impact: First demonstration of human adrenocortical organoids with functional steroidogenesis and in vivo rescue advances regenerative strategies for adrenal insufficiency and enables precise disease modeling for therapeutic testing.
Clinical Implications: Provides a translational platform to explore autologous regenerative therapies for primary adrenal insufficiency and a preclinical system for testing drugs against cortisol-producing tumors driven by PRKACA mutations.
Key Findings
- Established expandable human adrenocortical organoids preserving zona fasciculata identity and cortisol secretion.
- Organoids responded to physiological stimuli and rescued adrenalectomized mice.
- Introduced PRKACA L206R to model cortisol-producing adenomas for Cushing’s syndrome research.
3. Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.
Large human cohorts show that adults with obesity due to MC4R loss-of-function have lower total/LDL-cholesterol and triglycerides and a reduced cardiovascular disease risk compared with weight-matched controls, indicating central melanocortin signaling can decouple obesity from atherogenic dyslipidemia.
Impact: Provides rare human evidence that central melanocortin pathways modulate lipid handling and cardiovascular risk independently of adiposity, reframing therapeutic opportunities for metabolic disease.
Clinical Implications: Suggests that targeting central melanocortin signaling could lower atherogenic lipids and CVD risk independent of weight loss; clinicians should consider MC4R genetic status when interpreting metabolic risk profiles.
Key Findings
- Adults with MC4R loss-of-function had lower total and LDL-cholesterol and lower triglycerides than weight-matched controls after adjusting for adiposity.
- Carriers showed reduced postprandial rises in triglyceride-rich lipoproteins and metabolomic signatures favoring adipose storage.
- In population datasets (e.g., UK Biobank), MC4R loss-of-function carriers had lower cardiovascular disease risk after accounting for body weight.