Endocrinology Research Analysis
March 2025 endocrinology research linked fundamental mechanisms to practice-changing interventions. A first-in-class small molecule that directly modulates BMAL1 opened a new path for circadian pharmacology, while a mechanistic RCT showed sucralose acutely heightens hypothalamic appetite signaling. Outcome-level clinical evidence consolidated automated insulin delivery for insulin-treated type 2 diabetes and established oral semaglutide as an oral GLP-1 with cardiovascular benefit. In liver–meta
Summary
March 2025 endocrinology research linked fundamental mechanisms to practice-changing interventions. A first-in-class small molecule that directly modulates BMAL1 opened a new path for circadian pharmacology, while a mechanistic RCT showed sucralose acutely heightens hypothalamic appetite signaling. Outcome-level clinical evidence consolidated automated insulin delivery for insulin-treated type 2 diabetes and established oral semaglutide as an oral GLP-1 with cardiovascular benefit. In liver–metabolic disease, a splicing–IDH1–ammonia axis emerged as a druggable driver of MASH fibrosis, complementing epitranscriptomic regulation of adipogenesis (NAT10–ac4C–KLF9) reported this month.
Selected Articles
1. Pharmacological targeting of BMAL1 modulates circadian and immune pathways.
A selective small molecule (CCM) binds the BMAL1 PASB domain, alters its conformation, shifts cellular circadian oscillations, and downregulates inflammatory/phagocytic programs in macrophages. Multi-modal biochemical, structural, and cellular assays demonstrate target engagement. The work provides a validated chemical probe enabling clock-directed intervention development.
Impact: Opens pharmacologic access to the core clock with direct functional consequences, catalyzing a new class of circadian therapeutics across metabolic and inflammatory diseases.
Clinical Implications: A BMAL1 modulator could treat clock-linked inflammatory and metabolic disorders pending in vivo PK/PD and safety; it may also enable stratification by circadian phenotypes.
Key Findings
- Discovery of CCM, a BMAL1 PASB-binding small molecule that remodels BMAL1 conformation.
- Dose-dependent shifts in PER2-Luc circadian oscillations and suppression of inflammatory/phagocytic programs in macrophages.
- Biochemical, structural, and cellular assays validated target engagement and functional impact.
2. Non-caloric sweetener effects on brain appetite regulation in individuals across varying body weights.
In a randomized crossover trial (n=75), acute sucralose ingestion increased hypothalamic blood flow and subjective hunger versus sucrose without raising peripheral glucose. Functional connectivity between hypothalamus and motivation/somatosensory regions was strengthened. Findings suggest common non-caloric sweeteners can acutely alter central appetite signaling across BMI strata.
Impact: Direct human mechanistic evidence challenging assumptions about ‘calorie-free’ sweeteners and appetite control; immediate relevance to dietary counseling.
Clinical Implications: Advise patients that non-caloric sweeteners may acutely enhance central hunger signals despite minimal glycemic effects; long-term metabolic consequences require further trials.
Key Findings
- Sucralose increased hypothalamic blood flow and hunger relative to sucrose.
- Strengthened functional connectivity between hypothalamus and motivation/somatosensory networks without elevating peripheral glucose.
- Effects were observed across body-weight strata in a randomized crossover design.
3. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.
In an event-driven, double-blind RCT (n=9,650; median ~49.5 months), once-daily oral semaglutide reduced MACE versus placebo (HR 0.86; 95% CI 0.77–0.96) in adults with type 2 diabetes and ASCVD and/or CKD, with similar rates of serious adverse events. Kidney composite outcomes were not significantly different.
Impact: First definitive MACE reduction with an oral GLP-1 receptor agonist, expanding access to proven cardioprotection for patients unable or unwilling to use injectables.
Clinical Implications: Consider oral semaglutide for high-risk T2D with ASCVD/CKD as an oral cardioprotective option; monitor GI tolerability and integrate with SGLT2 inhibitors as appropriate.
Key Findings
- Reduced MACE vs placebo (HR 0.86; 95% CI 0.77–0.96) over ~4 years.
- Serious adverse events were similar between groups; no significant difference in confirmatory kidney composite outcomes.
- Benefit supports broader adoption of once-daily oral GLP-1 therapy in secondary prevention settings.
4. A Randomized Trial of Automated Insulin Delivery in Type 2 Diabetes.
A 13-week multicenter RCT (n=319) showed automated insulin delivery produced greater HbA1c reduction and a 14-point increase in CGM time-in-range vs usual care in insulin-treated type 2 diabetes, with low hypoglycemia rates. Multiple CGM hyperglycemia metrics favored AID.
Impact: High-quality randomized evidence in an underrepresented population supports wider adoption of closed-loop AID beyond type 1 diabetes.
Clinical Implications: Clinicians can consider AID in insulin-treated T2D to improve HbA1c and time-in-range over 3 months, with attention to long-term durability and safety.
Key Findings
- AID lowered HbA1c by an adjusted −0.6 percentage points vs control.
- Time-in-range increased by 14 percentage points with AID vs minimal change in control.
- Hypoglycemia rates were low and comparable between groups.
5. Disrupted minor intron splicing activates reductive carboxylation-mediated lipogenesis to drive metabolic dysfunction-associated steatotic liver disease progression.
Cross-species mechanistic studies show minor intron splicing defects in MASH cause Insig1/2 intron retention, SREBP1c activation, and IDH1-dependent reductive carboxylation, fueling de novo lipogenesis and hepatic ammonia accumulation to initiate fibrosis. Interventions with IDH1 inhibition, ammonia clearance, or splicing restoration mitigated fibrosis in models.
Impact: Identifies a splicing–metabolism checkpoint with multiple actionable nodes (IDH1, ammonia handling, splicing restoration) for antifibrotic strategies in MASH.
Clinical Implications: Prioritizes translational development of IDH1 inhibitors and ammonia-lowering strategies, and motivates biomarker programs based on minor intron retention for patient stratification.
Key Findings
- Minor intron splicing is disrupted in MASH, driving Insig1/2 intron retention and SREBP1c activation.
- IDH1-driven reductive carboxylation fuels lipogenesis and ammonia accumulation, initiating fibrosis; blocking IDH1 or clearing ammonia mitigates fibrogenesis.
- Restoring the splicing factor Zrsr1 attenuated fibrosis in experimental models.