Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds

Abstract

The aims of this study were 1) to determine whether differential glycemic thresholds are the mechanism responsible for the sexual dimorphism present in neuroendocrine responses during hypoglycemia and 2) to define the differences in counterregulatory physiological responses that occur over a range of mild to moderate hypoglycemia in healthy men and women. Fifteen (8 male, 7 female) lean healthy adults underwent four separate randomized 2-h hyperinsulinemic (1.5 mU. kg(-1).min(-1)) glucose clamp studies at euglycemia (90 mg/dl) or hypoglycemia of 70, 60, or 50 mg/dl. Plasma insulin levels were similar during euglycemic and hypoglycemic studies (91-96 +/- 8 microU/ml) in men and women. Hypoglycemia of 70, 60, and 50 mg/dl all resulted in significant increases (P < 0.05, P < 0.01) in epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels compared with euglycemic studies in men and women. Plasma norepinephrine levels were increased (P < 0.05) only relative to euglycemic studies at a hypoglycemia of 50 mg/dl. Muscle sympathetic nerve activity (MSNA) increased significantly during hyperinsulinemic-euglycemic control studies. Further elevations of MSNA did not occur until hypoglycemia of 60 mg/dl in both men and women. Plasma epinephrine, glucagon, growth hormone, and pancreatic polypeptide were significantly increased in men compared with women during hypoglycemia of 70, 60, and 50 mg/dl. MSNA, heart rate, and systolic blood pressure responses were also significantly increased in men at hypoglycemia of 60 and 50 mg/dl. In summary, these studies have demonstrated that, in healthy men and women, the glycemic thresholds for activation of epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide occur between 70 and 79 mg/dl. Thresholds for activation of MSNA occur between 60 and 69 mg/dl, whereas norepinephrine is not activated until glycemia is between 50 and 59 mg/dl. We conclude that 1) differential glycemic thresholds are not the cause of the sexual dimorphism present in counterregulatory responses to hypoglycemia; 2) reduced central nervous system efferent input appears to be the mechanism responsible for lowered neuroendocrine responses to hypoglycemia in women; and 3) physiological counterregulatory responses (neuroendocrine, cardiovascular, and autonomic nervous system) are reduced across a broad range of hypoglycemia in healthy women compared with healthy men.

β2‐Adrenergic receptor regulation of human neutrophil function is sexually dimorphic

“…However, the number of receptors expressed on the membrane does not necessarily reflect the level of receptor signaling activity (Lombardi et al, 1999) and therefore, we cannot exclude other mechanisms contributing to the observed sexual dimorphism. While plasma levels of endogenous catecholamines, such as adrenaline and noradrenaline, are relevant to b 2 -adrenergic receptor activity, we found no gender difference in the levels of catecholamines, in agreement with the literature (Davis et al, 2000;Geelen et al, 2002). Plasma catecholamine concentrations usually range around 1 Â 10 À9 M for noradrenaline and 0.2 Â 10 À9 M for adrenaline, but increase in response to stress and anxiety (Swain, 2000), or hypoglycemia (Goldstein et al, 2003).…”

Estrogen Blunts Neuroendocrine and Metabolic Responses to Hypoglycemia

“…Finally, estrogen has been suggested to increase baseline growth hormone levels (39), and we did see this trend between E2 and NO E2 subjects in baseline growth hormone levels when the men were removed from the analysis (P ϭ 0.07). However, we have previously reported that women have a decreased, rather than an increased, growth hormone response to hypoglycemia (2). Because aging decreases growth hormone levels (39), the growth hormone responses to hypoglycemia in this study were significantly truncated compared with our earlier work.…”

“…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.…”

Effects of a Selective Serotonin Reuptake Inhibitor, Fluoxetine, on Counterregulatory Responses to Hypoglycemia in Healthy Individuals

“…Stratified block randomization was performed by the Vanderbilt University Investigational Pharmacy. The subjects were stratified according to sex because sex is known to affect counterregulatory responses (15). Randomization was performed within each sex, and blocks of two were used to ensure an equal number of male and female subjects in the placebo and fluoxetine treatment groups.…”