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 mol ⅐ kg ؊1 ⅐ 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 mol ⅐ kg ؊1 ⅐ 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 mol/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. Diabetes 52:1749 -1755, 2003 M en and women respond differently to an acute bout of hypoglycemia. We have previously shown that healthy and type 1 diabetic women, compared with men, have lower catecholamine, glucagon, cortisol, growth hormone, endogenous glucose production (EGP), and lactate responses, and they have increased glycerol responses to hypoglycemia (1,2). This sexual dimorphism also appears to be present in a wide variety of physiological stresses. For example, women have been found to have reduced neuroendocrine and increased lipolytic responses to exercise (3-5) and reduced sympathetic nervous system responses to cognitive stress (6).The physiological mechanism(s) responsible for sexually dimorphic responses to stress in humans remains unknown, although it seems likely that one or more of the reproductive hormones may be responsible. Animal studies suggest that estrogen may play an important role. Estrogen administration has been shown to independently reduce catecholamine levels, either by increasing norepinephrine degradation in the brain (and thereby reducing sympathetic system drive) (7) or by decreasing secretion from the adrenal medulla (8,9). Metabolically, estrogen has been found to increase lipolysis (10), glycogen deposition (11), and glucose uptake during exercise in rats (10). Recent studies in mice even suggest that estrogen, specifically estrone sulfate, may have a direct effect on reduc...

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