Daily Endocrinology Research Analysis
Today’s top endocrinology papers span mechanistic discovery, translational omics, and practice-informing evidence. ANGPTL8 is identified as a regulator of bone marrow MSC fate during skeletal aging with antisense rescue in mice; feminizing GAHT remodels the plasma proteome toward a cis-female profile with immune and cardiometabolic signals; and observational meta-analysis suggests SGLT2 inhibitor plus GLP-1 RA combination reduces cardiorenal events versus monotherapy.
Summary
Today’s top endocrinology papers span mechanistic discovery, translational omics, and practice-informing evidence. ANGPTL8 is identified as a regulator of bone marrow MSC fate during skeletal aging with antisense rescue in mice; feminizing GAHT remodels the plasma proteome toward a cis-female profile with immune and cardiometabolic signals; and observational meta-analysis suggests SGLT2 inhibitor plus GLP-1 RA combination reduces cardiorenal events versus monotherapy.
Research Themes
- Skeletal aging and osteoblast–adipocyte lineage regulation
- Proteomic remodeling under feminizing gender-affirming hormone therapy
- Cardiorenal outcomes with combined SGLT2 inhibitor and GLP-1 RA therapy
Selected Articles
1. Angiopoietin-like 8 governs osteoblast-adipocyte lineage commitment during skeletal aging.
ANGPTL8 biases bone marrow MSCs toward adipogenesis at the expense of osteogenesis during skeletal aging by inhibiting Wnt/β-catenin signaling and engaging PPARγ. Genetic gain/loss studies and antisense oligonucleotide therapy demonstrate that targeting ANGPTL8 can reverse aging-associated bone loss and marrow adiposity in mice.
Impact: Identifies a druggable regulator of the osteoblast–adipocyte fate switch in aging bone with in vivo antisense rescue, offering a mechanistically grounded target for osteoporosis and skeletal aging.
Clinical Implications: While preclinical, ANGPTL8 inhibition (e.g., antisense oligonucleotides) could emerge as a novel approach to prevent or treat age-related bone loss by preserving osteogenesis and limiting marrow adiposity.
Key Findings
- ANGPTL8 overexpression reduces bone mass and increases bone marrow adiposity in mice.
- ANGPTL8 knockout lessens age-related bone loss and marrow fat accumulation.
- ANGPTL8 inhibits Wnt/β-catenin signaling and engages PPARγ to drive adipogenesis; partial PPARγ inhibition rescues phenotype.
- Angptl8 antisense oligonucleotide treatment improves skeletal aging phenotypes in mice.
Methodological Strengths
- Convergent in vivo genetic (overexpression and knockout) and pharmacologic (antisense) approaches
- Mechanistic dissection implicating Wnt/β-catenin and PPARγ pathways across systems
Limitations
- Preclinical mouse and cell models without human interventional validation
- Potential off-target or systemic effects of ANGPTL8 inhibition not yet characterized
Future Directions: Validate ANGPTL8 as a therapeutic target in human bone tissues and translational models; develop and safety-test clinically viable ANGPTL8 inhibitors or antisense agents.
2. Plasma proteome adaptations during feminizing gender-affirming hormone therapy.
Over 6 months of feminizing GAHT, plasma protein levels broadly decreased, especially with cyproterone, with marked reductions in spermatogenesis proteins attributable to testosterone loss and increases in leptin reflecting body composition changes. Proteomic profiles shifted toward cis-female signatures and indicated potential immune and cardiometabolic implications that differed by antiandrogen choice.
Impact: Provides the first comprehensive, longitudinal proteomic map of feminizing GAHT, linking hormonal regimens to systemic molecular changes tied to immunity and cardiometabolic risk.
Clinical Implications: Supports tailored monitoring in transgender women on estradiol therapy, including attention to immune/inflammatory profiles and cardiometabolic markers; antiandrogen selection (cyproterone vs spironolactone) may differentially modulate risk signatures.
Key Findings
- Feminizing GAHT altered levels of 245 proteins (cyproterone) and 91 (spironolactone) among 5,279 measured, with >95% decreases.
- Spermatogenesis-associated proteins decreased markedly with cyproterone, attributable to testosterone suppression.
- Leptin increased and proteomes shifted toward cis-female profiles; immune and cardiometabolic signatures changed, with cyproterone skewing away from an atherosclerosis-associated profile.
Methodological Strengths
- Prospective longitudinal design with two antiandrogen regimens and dense proteomic profiling
- External contextualization via UK Biobank sex-associated proteins and comparison to menopausal hormone therapy effects
Limitations
- Small sample size and 6-month follow-up without clinical endpoints
- Non-randomized allocation to antiandrogens and potential confounding
Future Directions: Link proteomic changes to longitudinal clinical outcomes (CVD, autoimmune events) and evaluate how antiandrogen choice modulates risk to inform personalized GAHT.
3. Effectiveness and safety of combining SGLT2 inhibitors and GLP-1 receptor agonists in individuals with type 2 diabetes: a systematic review and meta-analysis of cohort studies.
Across 18 cohort studies totaling over 1.16 million participants, SGLT2 inhibitor plus GLP-1 RA combination therapy was associated with substantially lower risks of MACE, all-cause and cardiovascular mortality, heart failure hospitalization, and kidney endpoints compared with monotherapy, without clear excess safety signals. Certainty varied (often low) due to observational design, underscoring the need for RCTs.
Impact: Provides the most comprehensive real-world synthesis to date suggesting additive cardiorenal protection with dual therapy, informing treatment strategy pending randomized trials.
Clinical Implications: For high-risk type 2 diabetes, consider early dual therapy (SGLT2i + GLP-1 RA) to maximize cardiorenal risk reduction, while individualizing by tolerance, access, and monitoring—recognizing evidence is observational.
Key Findings
- Combination therapy lowered MACE risk versus monotherapy (RR 0.56; 95% CI 0.43–0.71).
- All-cause mortality (RR 0.50) and cardiovascular mortality (RR 0.26) were reduced with combination therapy.
- Heart failure hospitalization (RR 0.67) and kidney composite endpoints (RR 0.48) were lower with dual therapy.
- No clear increase in severe hypoglycemia, DKA, genitourinary infections, or GI side effects was observed.
Methodological Strengths
- Very large aggregate sample size with multiple endpoints and consistency checks
- Transparent methods with ROBINS-I bias assessment, GRADE certainty, and PROSPERO registration
Limitations
- Observational cohorts subject to residual confounding and treatment selection bias
- Heterogeneity across studies and limited pooled safety data
Future Directions: Conduct randomized trials comparing dual therapy versus monotherapy, with standardized safety adjudication and cost-effectiveness analyses.