Female-predominant cardiac remodeling in type 2 diabetes mellitus and the estrogen–GPER–HIF-1α signaling pathway

Background Type 2 diabetes mellitus (T2DM) is associated with sex-specific cardiac remodeling, but the underlying clinical and molecular basis remains unclear. We investigated sex differences in left ventricular hypertrophy (LVH) and diastolic function and examined the role of estrogen–GPER and HIF-1α signaling in diabetic cardiac remodeling. Methods This retrospective cross-sectional study included 2,638 patients with T2DM (1,537 men and 1,101 women) evaluated between June 2023 and May 2024. LVH was defined using sex-specific left ventricular mass index thresholds, and sex differences were assessed using multivariable logistic regression. Cardiac remodeling was further evaluated in male and female db/db mice. Female db/db mice received 17β-estradiol (E2), the GPER antagonist G15, or the GPER agonist G1. High-glucose-treated H9c2 cardiomyoblasts were used for complementary pharmacological and HIF-1α reactivation experiments. Echocardiography, histology, molecular assays, transcriptomic profiling, and ubiquitination analysis were performed. Results LVH was more prevalent in women than in men with T2DM (27.8% vs. 9.5%, P<0.001), and women had a higher E/e′ ratio (median 10.99 vs. 9.86, P<0.001), whereas left ventricular ejection fraction was comparable. After adjustment for age, HbA1c, body mass index, and estimated glomerular filtration rate, female sex remained associated with LVH (odds ratio 3.71, 95% confidence interval 2.91–4.73, P<0.001). The sex-by-age-group interaction was not significant (P for interaction=0.405). Female db/db mice showed greater cardiac mass, wall thickening, fibrosis, cardiomyocyte hypertrophy, and diastolic impairment than male db/db mice. E2 and G1 attenuated these abnormalities, whereas G15 blunted the protective effects of E2. G1 reduced HIF-1α, ANGPT2, and VEGFA expression and increased HIF-1α ubiquitination. Pharmacological HIF-1α reactivation partially reversed the molecular and cellular effects of G1 in high-glucose-treated cardiomyoblasts. Conclusions Women with T2DM had a higher prevalence of LVH and greater diastolic dysfunction than men. The findings support a role for impaired estrogen–GPER signaling in female-predominant diabetic cardiac remodeling. GPER activation was associated with suppression of the HIF-1α/ANGPT2/VEGFA axis and may represent a potential therapeutic strategy.