Daily Endocrinology Research Analysis
Analyzed 73 papers and selected 3 impactful papers.
Summary
Analyzed 73 papers and selected 3 impactful articles.
Selected Articles
1. Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.
Cryo-EM structures demonstrate that bivalent ligands S961 and Ins-AC-S2 antagonize the insulin receptor by stabilizing an inactive conformation, whereas reversing the site order (as in S597) yields agonism. Distinct interactions involving αCT and FnIII-2/insert domains differentiate S961 from Ins-AC-S2. These insights guide rational design of insulin receptor antagonists for congenital hyperinsulinism.
Impact: Provides first high-resolution structural rationale distinguishing antagonist versus agonist behavior in bivalent insulin receptor ligands, a key step toward targeted therapies for congenital hyperinsulinism.
Clinical Implications: Enables structure-guided development of safer, more selective insulin receptor antagonists that could offer medical therapy for congenital hyperinsulinism and experimental tools to modulate insulin signaling.
Key Findings
- S961 and Ins-AC-S2 bind and stabilize an inactive insulin receptor conformation, explaining their antagonism.
- Module order (site 1 vs site 2) in bivalent ligands determines agonist (S597) versus antagonist (S961/Ins-AC-S2) activity.
- Distinct receptor interactions (αCT displacement/engagement; FnIII-2/insert contacts) differentiate S961 and Ins-AC-S2.
Methodological Strengths
- High-resolution cryo-EM structures capturing ligand-receptor complexes in defined conformations
- Comparative structural analysis across antagonist and agonist bivalent ligands to infer mechanism
Limitations
- Preclinical structural work without in vivo pharmacodynamic/efficacy data
- Potential differences between engineered receptor constructs and native cellular contexts
Future Directions: Translate structural principles into optimized antagonists with favorable PK/PD; validate efficacy and safety in preclinical models of congenital hyperinsulinism and early-phase clinical studies.
Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which comprise segments for binding each of the two insulin-binding sites (site 1 and site 2) on the receptor. Notably, S597 - containing the same receptor binding segments as S961 but in the opposite order (site 2-site 1) - is an insulin receptor agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of the receptor, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is influenced by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we show subtle differences between the receptor-binding mechanisms of S961 and Ins-AC-S2, which include displacement or engagement of αCT, and a binding interface between the Ins-AC-S2 insulin and the receptor FnIII-2/insert domains. These structural insights may inform development of next generation insulin receptor antagonists for treatment of congenital hyperinsulinism.
2. The Mineralocorticoid Receptor and Its Antagonist Finerenone Regulate Hepatic Lipid Accumulation via the AMPK/SREBP1/FASN Signaling.
In db/db mice and FFA-treated hepatocytes, finerenone reduced hepatic steatosis by inhibiting mineralocorticoid receptor signaling, activating AMPK, and downregulating SREBP1/FASN, thereby suppressing de novo lipogenesis. Genetic and pharmacologic perturbations confirm AMPK dependence and MR specificity. These data position hepatic MR as a modifiable node in MASLD and support therapeutic repurposing of finerenone.
Impact: Identifies a mechanistic MR–AMPK–SREBP1/FASN axis driving steatosis and demonstrates that finerenone modulates this pathway to reduce hepatic lipid accumulation, suggesting repurposing in MASLD.
Clinical Implications: Supports evaluation of finerenone as a metabolic-hepatic therapy in MASLD, particularly among patients with diabetes and steatosis; motivates biomarker-guided trials assessing hepatic endpoints.
Key Findings
- Finerenone decreased hepatic lipid accumulation in db/db mice and FFA-treated hepatocytes.
- Mechanistically, finerenone inhibited MR signaling, activated AMPK, and downregulated SREBP1/FASN to suppress de novo lipogenesis.
- AMPKα knockdown/inhibition abrogated effects; NR3C2 knockdown phenocopied finerenone; aldosterone reversed finerenone’s lipid-lowering actions.
Methodological Strengths
- Convergent in vivo (db/db mice) and in vitro (FFA-treated hepatocytes) models
- Mechanistic validation using genetic knockdown and pathway perturbation
Limitations
- Preclinical models without human clinical validation
- Potential sex- or species-specific effects not fully addressed
Future Directions: Conduct early-phase trials of finerenone in MASLD with imaging/biopsy endpoints; test MR–AMPK pathway biomarkers for patient selection; explore combination with lifestyle or metabolic therapies.
Metabolic dysfunction-associated steatotic liver disease (MASLD), closely linked to obesity and diabetes, remains poorly understood, with limited therapeutic options. The mineralocorticoid receptor (MR) has been implicated in metabolic dysregulation, yet its role in hepatic lipid metabolism remains incompletely defined. Finerenone, a non-steroidal MR antagonist, has demonstrated renal and cardiovascular benefits in diabetes , yet its effects on hepatic metabolism have not been fully explored. This study aimed to evaluate the hepatoprotective effects of finerenone in MASLD and elucidate the underlying mechanisms. MASLD models were established using db/db mice and free fatty acid-treated hepatocytes. Treatment with finerenone significantly reduced hepatic lipid accumulation in both in vitro and in vivo models. Mechanistically, MASLD was characterized by overactivation of hepatic MR signaling, evidenced by increased NR3C2 expression and upregulation of canonical MR target genes. Finerenone inhibits and antagonizes excessive MR activation, enhanced AMP-activated protein kinase (AMPK) phosphorylation, and downregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), thereby inhibiting de novo lipogenesis. The lipid-lowering effects of finerenone were abrogated by AMPKα knockdown or inhibition, while NR3C2 knockdown mimicked the metabolic effects of finerenone without additive benefit, supporting an MR-dependent mechanism. Conversely, aldosterone reversed the lipid-lowering effects of finerenone through the AMPK/SREBP1/FASN pathway. In conclusion, finerenone alleviates hepatic lipid accumulation in MASLD, at least in part, by inhibiting MR signaling and modulating the AMPK/SREBP1/FASN pathway. These findings highlight a previously underrecognized role of MR in hepatic lipid metabolism and support finerenone as a potential therapeutic strategy for MASLD.
3. Predictors of treatment response to mineralocorticoid receptor antagonists in primary aldosteronism: insights from the SPAIN-ALDO registry.
In 402 primary aldosteronism patients on MRA therapy (median follow-up 38 months), complete clinical success occurred in 16% and complete biochemical response in 50%. Female sex, lower BMI, fewer antihypertensives, and higher potassium predicted clinical success; lower aldosterone, higher renin, spironolactone use, and higher MRA dose predicted biochemical normalization.
Impact: Provides pragmatic predictors to personalize MRA therapy in primary aldosteronism, informing agent selection and dose titration to maximize response.
Clinical Implications: Baseline renin-aldosterone status, sex, BMI, and early potassium trends can guide counseling and titration; spironolactone and adequate dosing may improve biochemical control.
Key Findings
- Complete clinical success occurred in 16.2% and partial response in 65.5% after MRA therapy (median 38 months).
- Predictors of clinical success: female sex, lower BMI, fewer antihypertensive agents, higher potassium.
- Predictors of complete biochemical response: lower baseline aldosterone, higher baseline renin, spironolactone (vs eplerenone), and higher MRA dose.
Methodological Strengths
- Large real-world registry with extended follow-up
- Evaluation of both clinical and biochemical endpoints with multivariable analysis
Limitations
- Retrospective observational design with potential confounding and selection bias
- Heterogeneity in MRA titration strategies and agent choice across centers
Future Directions: Prospective validation and integration into risk scores/algorithms; randomized trials testing dose-targeted strategies and agent selection informed by baseline renin-aldosterone profile.
BACKGROUND: Data on factors predicting favorable response to medical therapy in primary aldosteronism, based on Primary Aldosteronism Medical treatment Outcome (PAMO) criteria, remain limited. AIM: This study aimed to identify baseline parameters independently associated with clinical and biochemical responses to mineralocorticoid receptor antagonist (MRA) therapy after at least 6 months of treatment. METHODS: Primary aldosteronism patients from the SPAIN-ALDO registry, treated medically with MRA (or amiloride) and with available clinical and/or biochemical follow-up data after at least 6 months of therapy were included. RESULTS: A total of 402 patients (38.3% women; mean age 57 ± 11.8 years) were analyzed. Median follow-up duration was 38 months [interquartile range (IQR) 20-76]. At last visit, 55% of patients were receiving spironolactone, 44% eplerenone, and 1.2% amiloride. Among 389 patients with clinical follow-up data, 16.2% achieved complete clinical success, 65.5% partial response, and 18.3% showed no response. Complete clinical response was more likely in women, in patients with lower BMI, fewer antihypertensive medications, and higher potassium levels. Among 261 patients with biochemical follow-up data, 50.1% had complete biochemical response, 21.5% partial, and 28.4% absent. Predictors of complete biochemical response included lower baseline aldosterone concentration, higher baseline renin levels, use of spironolactone rather than eplerenone, and higher MRA doses. CONCLUSION: Early identification of primary aldosteronism and optimized titration of MRA therapy, especially with eplerenone, are crucial for improving clinical and biochemical outcomes.