Context: Data from large clinical trials of postmenopausal women suggest incidence of diabetes is reduced in women randomized to estrogen-based hormone therapy when compared with placebo. Whether this is due to an effect of estrogen on insulin or glucose metabolism remains unclear.

Objective: To test the hypothesis that estradiol (E₂) increases insulin secretion and clearance.

Design: Serum insulin and C-peptide responses to hyperglycemia (250 mg/dL) plus intravenous L-arginine were measured on 2 separate days, with (EST) and without (CON) subacute (24 h) transdermal E₂ administration.

Study Participants: Eleven postmenopausal women (mean±SD; 55±4 y).

Main Outcomes: Insulin secretion and clearance were estimated from the C-peptide AUC and the molar ratio of C-peptide-to-insulin AUC, respectively. Mean glucose disposal rate (GDR) was estimated from the rate of glucose infusion during the final 30 min of the hyperglycemic clamp.

Results: There were no differences in insulin secretion or clearance between the EST day and CON day. Fasting glucose was lower on the EST day compared with the CON day (93±6 vs. 98±8 mg/dL), but mean GDR was not different. However, when one outlier was excluded from analysis GDR was increased after EST compared with CON. Further, a strong inverse association was observed between years since menopause and E₂-mediated changes in GDR (r=-0.794, p=0.004).

Conclusions: Contrary to our hypothesis, 24 hours of transdermal E₂ administration did not alter insulin secretion or clearance in postmenopausal women. However, a longer time since menopause was associated with a reduced effect of E₂ to increase glucose uptake.