Daily Endocrinology Research Analysis

A distinguishing feature of older mesenchymal stem cells (MSCs) from bone marrow (BM) is the transition in their differentiation capabilities from osteoblasts to adipocytes. However, the mechanisms underlying these cellular events during the aging process remain unclear. We identified angiopoietin-like protein 8 (ANGPTL8), an adipokine implicated in lipid metabolism, that influenced the fate of MSCs in BM during skeletal aging. Our studies revealed that ANGPTL8 steered MSCs toward adipogenic differentiation, overshadowing osteoblastogenesis. Mice with overexpressed ANGPTL8 exhibited reduced bone mass and increased BM adiposity, while those with transgenic depletion of ANGPTL8 showed lowered bone loss and less accumulation of BM fat. ANGPTL8 influenced the BM niche of MSCs by inhibiting the Wnt/β-catenin signaling pathway. Partial inhibition of PPARγ rescued some aspects of the phenotype in MSCs with ANGPTL8 overexpression. Furthermore, treatment with an Angptl8 antisense oligonucleotide improved the phenotype of aging mice. Our research suggests that ANGPTL8 is a crucial regulator of senesence-related changes in the BM niche and the cell-fate switch of MSCs.

Sex differences manifest in various traits, as well as in the risk of cardiovascular, metabolic and immunological conditions. Despite the clear physical changes induced by gender-affirming hormone therapy (GAHT), little is known about how it affects underlying physiological and biochemical processes. Here we examined plasma proteome changes over 6 months of feminizing GAHT in 40 transgender individuals treated with estradiol plus one of two antiandrogens: cyproterone acetate or spironolactone. Testosterone levels dropped markedly in the cyproterone group, but less so in those receiving spironolactone. Among 5,279 total proteins measured, feminizing GAHT changed the levels of 245 and 91, in the cyproterone and spironolactone groups, respectively, with most (>95%) showing a decrease. Proteins associated with male spermatogenesis showed a marked decrease in the cyproterone group, attributable specifically to loss of testosterone. Changes in body fat percentage and breast volume following GAHT were also reflected in the plasma proteome, including an increase in leptin expression. We show that feminizing GAHT remodels the proteome toward a cis-female profile, altering 36 (cyproterone) and 22 (spironolactone) of the top 100 sex-associated proteins in UK Biobank adult data. Moreover, 43% of cyproterone-affected proteins overlapped with those altered by menopausal hormone therapy in cis women, showing the same directional changes, with notable exceptions including CXCL13 and NOS3. Feminizing GAHT skewed the protein profile toward that linked to asthma and autoimmunity, while GAHT with cyproterone specifically skewed it away from an atherosclerosis-associated profile, suggesting a protective effect. These results reveal that feminizing GAHT reshapes the plasma proteome in a hormone-dependent manner, with implications for reproductive capacity, immune regulation and long-term health outcomes.

AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiorenal risk in type 2 diabetes. However, the effect of combining these drugs remains uncertain. This systematic review aimed to evaluate the potential effectiveness and safety of combination therapy compared with monotherapy in individuals with type 2 diabetes. METHOD: We systematically searched PubMed and Embase from inception to 1 May 2025 for cohort studies comparing the effect of combination therapy with SGLT2 inhibitor or GLP-1 RA monotherapy on (cardiovascular) mortality and cardiovascular or kidney endpoints in individuals with type 2 diabetes. Studies enrolling individuals with type 1 diabetes or a maximum follow-up of less than 1 year were excluded. The primary outcome was a composite of major adverse cardiovascular events (MACE). Secondary outcomes included all-cause mortality, cardiovascular mortality, hospitalisation for heart failure, a kidney composite endpoint and serious adverse events. Risk of bias was assessed with ROBINS-I. Risk ratios (RRs) and 95% CIs were pooled in random effects meta-analyses. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included 18 cohort studies (1,164,774 participants). In cohort studies, combination therapy was associated with a lower risk of MACE (RR 0.56 [95% CI 0.43, 0.71]; low certainty of evidence) and the kidney composite endpoint (RR 0.48 [95% CI 0.32, 0.73]; very low certainty of evidence) relative to SGLT2 inhibitor or GLP-1 RA monotherapy. Combination therapy was also associated with a lower risk of all-cause mortality (RR 0.50 [95% CI 0.40, 0.63]; low certainty of evidence), cardiovascular mortality (RR 0.26 [95% CI 0.16, 0.43]; low certainty of evidence) and hospitalisation for heart failure (RR 0.67 [95% CI 0.64, 0.71]; moderate certainty of evidence). Although safety data could not be pooled due to lack of events, no differences were observed in the risk of severe hypoglycaemia, diabetic ketoacidosis, genitourinary infections and gastrointestinal side effects. No data were reported on the risk of serious adverse events or major adverse limb events. CONCLUSIONS/INTERPRETATION: Observational studies suggest that combining an SGLT2 inhibitor and a GLP-1 RA in type 2 diabetes may lower the risk of MACE, all-cause and cardiovascular mortality, hospitalisation for heart failure and kidney composite endpoints compared with monotherapy with either drug. Of course, residual confounding cannot be overcome but results support the need for future randomised trials of combined vs monotherapy. REGISTRATION: PROSPERO registration no. CRD42024532383.