Weekly Endocrinology Research Analysis
This week’s endocrinology literature emphasized human-to-mechanism translation and clinical risk stratification. A JCI paper identified a common glucocorticoid receptor variant (rs6190) that drives hypercholesterolemia and atherosclerosis via hepatic PCSK9/BHLHE40 with sex-specific effects, pointing to actionable lipid targets. A Molecular Metabolism study established complete PAX4 loss as a novel cause of transient neonatal diabetes and mapped PAX4-regulated islet networks using CRISPR‑iPSC and
Summary
This week’s endocrinology literature emphasized human-to-mechanism translation and clinical risk stratification. A JCI paper identified a common glucocorticoid receptor variant (rs6190) that drives hypercholesterolemia and atherosclerosis via hepatic PCSK9/BHLHE40 with sex-specific effects, pointing to actionable lipid targets. A Molecular Metabolism study established complete PAX4 loss as a novel cause of transient neonatal diabetes and mapped PAX4-regulated islet networks using CRISPR‑iPSC and CUT&RUN. An IPD meta-analysis in Lancet Diabetes & Endocrinology linked low maternal FT4 / isolated hypothyroxinaemia to increased gestational diabetes risk, suggesting FT4 inclusion in antenatal risk assessment.
Selected Articles
1. The human glucocorticoid receptor variant rs6190 increases blood cholesterol and promotes atherosclerosis.
This study links a nonrare GR coding SNP (rs6190) to higher circulating cholesterol and increased atherosclerosis through hepatic upregulation of PCSK9 and BHLHE40. Mechanistic validation used SNP‑genocopy mice, liver knockdowns of Pcsk9/Bhlhe40, sex‑hormone modulation experiments, and CRISPR‑edited human iPSC‑derived hepatocyte models to demonstrate conserved effects and sex specificity.
Impact: Bridges population genetics and mechanistic biology to reveal a genotype‑driven, druggable hepatic pathway (PCSK9/BHLHE40) that elevates atherogenic lipids with sex‑dependent modulation — immediately relevant to lipid‑lowering strategies.
Clinical Implications: Consider genotype‑informed risk assessment and aggressive lipid management (including PCSK9 inhibition) in carriers with elevated risk, and account for sex‑hormone interactions when personalizing therapy.
Key Findings
- rs6190 associates with higher cholesterol in large cohorts (UK Biobank, All of Us) particularly in women.
- SNP‑genocopy mice show hepatic GR activation of Pcsk9 and Bhlhe40, elevating lipoprotein cholesterol and atherosclerosis; liver knockdown of Pcsk9/Bhlhe40 blocks the phenotype.
- CRISPR‑edited human hepatocyte‑like cells recapitulate the mutant GR program; sex hormones modulate the effect (protective in males with corticosterone/testosterone; additive with estrogen loss in females).
2. Complete loss of PAX4 causes transient neonatal diabetes in humans.
First human cases of homozygous PAX4 loss‑of‑function were identified in transient neonatal diabetes with remission in infancy and relapse in early childhood. Functional work in CRISPR‑edited iPSC‑derived pancreatic endoderm and CUT&RUN/CUT&RUN‑RNA integration defined PAX4 target genes involved in islet development and glucose‑stimulated insulin secretion.
Impact: Establishes PAX4 complete loss as a novel genetic cause of neonatal diabetes and provides mechanistic human cell validation, refining diagnostic gene panels and informing precision counseling and future β‑cell repair strategies.
Clinical Implications: In neonatal diabetes evaluations—especially in consanguineous families—include PAX4 sequencing. Counseling should reflect possible remission and relapse; findings guide surveillance and research into PAX4‑targeted β‑cell therapies.
Key Findings
- Two individuals with homozygous PAX4 loss‑of‑function variants presented transient neonatal diabetes with relapse at 2.4 and 6.7 years.
- CRISPR‑edited iPSC pancreatic endoderm showed nonsense‑mediated decay for the stop‑gain variant, confirming functional loss.
- CUT&RUN and RNA‑seq integration identified PAX4‑regulated genes critical for islet development and glucose‑stimulated insulin secretion.
3. Association of gestational thyroid function and thyroid autoimmunity with gestational diabetes: a systematic review and individual participant meta-analysis.
An IPD meta‑analysis of 25 prospective cohorts (n=63,548) found that isolated hypothyroxinaemia (low FT4 with normal TSH) in pregnancy is associated with higher gestational diabetes risk (adjusted OR 1.52). The study supports adding FT4 assessment to antenatal screening to better identify high‑risk pregnancies.
Impact: Large IPD synthesis quantifies a clinically actionable antenatal risk factor (low FT4) for GDM across diverse cohorts, potentially altering screening practice and prevention strategies in pregnancy.
Clinical Implications: Consider measuring FT4 (not only TSH) in early pregnancy to stratify GDM risk and tailor monitoring or preventive interventions for FT4‑low women; prospective trials should test whether correcting low FT4 reduces GDM incidence.
Key Findings
- IPD meta‑analysis across 25 cohorts (n=63,548) showed isolated hypothyroxinaemia prevalence ~2.2% and association with increased GDM risk (adjusted OR 1.52).
- Lower maternal FT4 levels during pregnancy were linked with higher gestational diabetes risk after adjustment for covariates.