Estrogen Blunts Neuroendocrine and Metabolic Responses to Hypoglycemia

Abstract

This study tested the hypothesis that estrogen is the mechanism responsible for the sexual dimorphism present in the neuroendocrine and metabolic responses to hypoglycemia. Postmenopausal women receiving (E2; n = 8) or not receiving (NO E2; n = 9) estrogen replacement were compared with age- and BMI-matched male subjects (n = 8) during a single-step 2-h hyperinsulinemic-hypoglycemic clamp. Plasma insulin (599 ± 28 pmol/l) and glucose (2.9 ± 0.03 mmol/l) levels were similar among all groups during the glucose clamp. In response to hypoglycemia, epinephrine (2.8 ± 0.6 vs. 5.8 ± 0.8 and 4.4 ± 0.5 nmol/l), glucagon (57 ± 8 vs. 77 ± 8 and 126 ± 18 ng/l), and endogenous glucose production (2 ± 2 vs. 10 ± 2 and 6 ± 3 μmol · kg⁻¹ · min⁻¹) were significantly lower in E2 vs. both NO E2 and male subjects (P < 0.05). These reduced counterregulatory responses resulted in significantly greater glucose infusion rates (16 ± 2 vs. 6 ± 2 and 6 ± 3 μmol · kg⁻¹ · min⁻¹; P < 0.01) in E2 vs. both NO E2 and male subjects. Pancreatic polypeptide was significantly lower (P < 0.05) in both the E2 and NO E2 groups compared with the male subjects (136 ± 20 and 136 ± 23 vs. 194 ± 16 pmol/l). Last, glycerol (36 ± 3 vs. 47 ± 5 μmol/l; P < 0.05), lactate (1.4 ± 0.1 vs. 1.8 ± 0.2 mmol/l; P < 0.05), and muscle sympathetic nerve activity (19 ± 4 to 27 ± 4 vs. 27 ± 5 to 42 ± 6 bursts/min; P < 0.05) responses to hypoglycemia were all significantly lower in E2 vs. NO E2 subjects. We conclude that estrogen appears to play a major role in the sexual dimorphism present in counterregulatory responses to hypoglycemia in healthy humans.