Daily Endocrinology Research Analysis
Analyzed 33 papers and selected 3 impactful papers.
Summary
A phase 3 randomized trial showed that the aldosterone synthase inhibitor baxdrostat robustly lowers ambulatory systolic blood pressure in resistant hypertension. A human pluripotent stem cell–derived adrenal organoid model recapitulated prenatal adrenocortical zonation and modeled X-linked adrenal hypoplasia congenita via NR0B1 loss. Mechanistic work in Diabetologia identified ER–mitochondria contact sites as key hubs coupling nutrient sensing to GLP-1 secretion, impaired in obesity and type 2 diabetes.
Research Themes
- Aldosterone pathway inhibition for resistant hypertension
- Adrenal organoid models of developmental zonation and disease
- Organelle contact sites (MAMs) regulating incretin (GLP-1) biology
Selected Articles
1. Effect of baxdrostat on ambulatory blood pressure in patients with resistant hypertension (Bax24): a phase 3, randomised, double-blind, placebo-controlled trial.
In resistant hypertension, baxdrostat lowered 24-h ambulatory systolic BP by a placebo-corrected 14.0 mm Hg over 12 weeks. Adverse events were somewhat more frequent with baxdrostat, with confirmed potassium >6 mmol/L in 3% of recipients.
Impact: Demonstrates robust BP lowering with aldosterone synthase inhibition in a phase 3 RCT, addressing a major unmet need in resistant hypertension.
Clinical Implications: Baxdrostat may become a valuable add-on therapy for resistant hypertension pending longer-term safety and outcomes data; monitoring for hyperkalemia is essential.
Key Findings
- Placebo-corrected change in 24-h ambulatory SBP at 12 weeks: −14.0 mm Hg (95% CI −17.2 to −10.8; p<0.0001).
- Within-group LS mean change in 24-h ambulatory SBP: −16.6 mm Hg with baxdrostat vs −2.6 mm Hg with placebo.
- Adverse events occurred in 52% (baxdrostat) vs 37% (placebo); confirmed K+ >6 mmol/L in 3% with baxdrostat.
- Effect observed on top of ≥3 background antihypertensives including a diuretic across 22 countries.
Methodological Strengths
- International phase 3 randomized, double-blind, placebo-controlled design with ABPM endpoint
- Prospective registration and prespecified primary analysis with multicenter conduct
Limitations
- Relatively short 12-week treatment period without cardiovascular outcomes
- Modest randomized sample size with substantial screen/run-in exclusions; missing ABPM data not imputed
Future Directions: Evaluate long-term efficacy, safety (especially hyperkalemia), and cardiovascular outcomes; define responder subgroups and combinations with mineralocorticoid receptor antagonists.
BACKGROUND: Aldosterone dysregulation is an important contributor in the pathogenesis of hard-to-control hypertension. We aimed to assess the effect of baxdrostat, a selective aldosterone synthase inhibitor, on ambulatory blood pressure in patients with resistant hypertension. METHODS: The Bax24 international, phase 3, randomised, double-blind, placebo-controlled trial recruited adults (aged ≥18 years) with seated systolic blood pressure (SBP) ≥140 mm Hg and <170 mm Hg, despite receiving three or more antihypertensive m
2. Modeling human prenatal adrenocortical functional zonation dynamics from pluripotent stem cells.
A human PSC-derived adrenal organoid recapitulates prenatal zonation: capsule RSPO3/WNT specifies definitive zone progenitors, which differentiate into cortisol- and androgen-producing zones under RSPO3 and ACTH. NR0B1 loss drives primordium-to-fetal zone conversion, modeling X-linked adrenal hypoplasia congenita; DZ with capsule cells reconstituted ACTH-responsive zonation in vivo.
Impact: Provides a mechanistically detailed human adrenal development platform with in vivo reconstitution and disease modeling of NR0B1-related adrenal hypoplasia.
Clinical Implications: Establishes a foundation for regenerative strategies for adrenal insufficiency and a human model to screen modulators of WNT/ACTH pathways and test gene/cell therapies.
Key Findings
- PSC-derived adrenal organoids recapitulated capsule-to-core zonation with RSPO3/WNT specifying definitive zone progenitors.
- Under RSPO3 and ACTH, progenitors differentiated into cortisol-producing transitional and androgen-producing fetal zones.
- NR0B1 loss impaired definitive zone specification and triggered primordium-to-fetal zone conversion, mirroring X-linked adrenal hypoplasia congenita.
- Co-encapsulation and implantation of DZ and capsule cells reconstituted ACTH-responsive zonation in vivo.
Methodological Strengths
- Human PSC-derived organoid system with multi-lineage differentiation and zonation fidelity
- In vivo reconstitution of ACTH-responsive tissue and genetic disease modeling (NR0B1 loss)
Limitations
- Primarily preclinical organoid and transplantation models; long-term function and safety not established
- Generalizability to adult adrenal physiology and disease heterogeneity remains to be defined
Future Directions: Leverage the platform for drug screening, gene editing for congenital adrenal disorders, and development of transplantation protocols for adrenal insufficiency.
The adrenal cortex produces essential steroid hormones through a concentric zonal architecture, established by the centripetal transdifferentiation of subcapsular progenitors within a capsule-derived niche. To capture this complexity, we establish a human pluripotent stem cell-derived adrenal organoid system that faithfully recapitulates this process. RSPO3/WNT signaling from the capsule specifies definitive zone (DZ) progenitors from the adrenal primordium, which then differentiate into a cortisol-
3. Endoplasmic reticulum-mitochondria contact sites are signalling hubs connecting nutrient sensing and GLP-1 secretion in L cells of the mouse gut: from physiology to obesity and type 2 diabetes.
Glucose and deoxycholic acid dynamically reinforced ER–mitochondria contacts in L cells, increasing ER–mitochondria Ca2+ exchange and driving GLP-1 secretion; disrupting organelle coupling blocked secretion. Obesity reinforced basal contacts but blunted MAM upregulation and GLP-1 release to glucose. Distinct SGLT1- and TGR5–cAMP–PKA-dependent mechanisms mediated the responses.
Impact: Identifies organelle contact sites (MAMs) as causal regulators of nutrient-induced GLP-1 secretion and reveals their dysregulation in obesity/T2D, highlighting a novel target for incretin modulation.
Clinical Implications: Targeting ER–mitochondria coupling may enhance endogenous GLP-1 secretion and complement GLP-1 receptor agonists, potentially improving glycaemic outcomes in obesity and type 2 diabetes.
Key Findings
- Glucose and deoxycholic acid increased ER–mitochondria interactions in STC-1 cells (1.8- and 2.1-fold), ileal organoids (1.7- and 1.3-fold), and in vivo L cells (1.3- and 1.2-fold).
- Glucose elevated ER–mitochondria Ca2+ exchange (1.2-fold) and a paracrine action of secreted GLP-1 contributed to MAM regulation.
- Pharmacologic/genetic disruption of ER–mitochondria coupling or Ca2+ handling reduced glucose-induced GLP-1 secretion (~31–52% decrements).
- Diet-induced obesity reinforced basal MAMs and abolished glucose-stimulated MAM upregulation and GLP-1 secretion in vivo.
- Mechanisms differed: SGLT1-mediated electrogenic effect for glucose; TGR5–cAMP–PKA pathway for deoxycholic acid.
Methodological Strengths
- Convergent evidence across cell line, ex vivo organoids, and in vivo enteroendocrine L cells
- Causal perturbations using pharmacologic and genetic tools with time-resolved imaging and Ca2+ assays
Limitations
- Predominantly murine systems and L-cell line; human translational validation is lacking
- Therapeutic modulation of MAMs was not tested in clinical settings
Future Directions: Validate MAM–GLP-1 coupling in human L cells/biopsies and develop small molecules or peptides to modulate ER–mitochondria contacts in metabolic disease.
AIMS/HYPOTHESIS: Postprandial glucagon-like peptide-1 (GLP-1) secretion by enteroendocrine L cells of the gut plays an important role in glucose homeostasis, thus representing a therapeutic option of ever-growing significance for type 2 diabetes. However, the precise mechanisms linking nutrient sensing and GLP-1 secretion are incompletely understood. In this study, we focused on a potential new role for endoplasmic reticulum (ER)-mitochondria contact sites, called mitochondria-associated membranes (