Effects of gender on neuroendocrine and metabolic counterregulatory responses to exercise in normal man

Significant, sexual dimorphisms exist in counterregulatory responses to commonly occurring stresses, such as hypoglycemia, fasting, and cognitive testing. The question of whether counterregulatory responses differ during exercise in healthy men and women remains controversial. The aim of this study was to determine whether a sexual dimorphism exists in neuroendocrine, metabolic, or cardiovascular responses to prolonged moderate exercise. Sixteen healthy (eight men and eight women) subjects matched for age (28+/-2 yr), body mass index (22+/-1 kg/m2), nutrient intake, and spectrum of physical fitness were studied in a randomized fashion during 90 min of exercise on a cycle ergometer at 80% of their anaerobic threshold (approximately 50% VO2 max). Respiratory quotient and oxygen consumption relative to body weight were identical in men and women. Glycemia was equated (5.3+/-0.2 mmol/L) during exercise via an exogenous glucose infusion. Gender had significant effects on counterregulatory responses during exercise. Arterialized epinephrine (1.05+/-0.2 vs. 0.45+/-0.04 nmol/L), norepinephrine (9.2+/-1.1 vs. 5.8+/-1.1 nmol/L), and pancreatic polypeptide (52+/-6 vs. 37+/-6 pmol/L) were significantly (P<0.01) increased in men compared to women, respectively. Plasma glucagon, cortisol, and GH levels responded similarly in men and women. Insulin values were higher at baseline in men and fell by a greater amount to reach similar levels during exercise compared to those in women. Endogenous glucose production, measured with [3-3H]glucose was similar in men and women. Carbohydrate oxidation was significantly increased in men relative to women (21.2+/-2 vs. 15.6+/-2 mg/kg fat free mass x min; P<0.05). Despite reduced sympathetic nervous system (SNS) drive, lipolytic responses were increased in women. Arterialized blood glycerol (215+/-30 vs. 140+/-20 micromol/L), beta-hydroxybutyrate (54+/-9 vs. 25+/-10 micromol/L), and plasma nonesterified fatty acids (720+/-56 vs. 469+/-103 micromol/L) were significantly (P<0.01) increased in women. In keeping with increased SNS activity, systolic blood pressure and mean arterial pressure were significantly increased (P<0.01) in men. In summary, this study demonstrates that a significant sexual dimorphism exists in neuroendocrine, metabolic, and cardiovascular counterregulatory responses to prolonged moderate exercise in man. We conclude that during exercise, men have increased autonomic nervous system (epinephrine, norepinephrine, pancreatic polypeptide), cardiovascular (systolic, mean arterial pressure) and certain metabolic (carbohydrate oxidation) counterregulatory responses, but that women have increased lipolytic (glycerol, nonesterified fatty acids) and ketogenic (beta-hydroxybutyrate) responses. Women may compensate for diminished SNS activity during exercise by increased lipolytic responses.     

Glucagon responses to hypoglycemia in adrenalectomized man

In order to examine the possibility that epinephrine is involved in either the mediation or modulation of the enhanced glucagon release during glucopenia, glucagon responses to insulin-induced hypoglycemia were evaluated in four men with bilateral adrenalectomy in comparison with ten normal men. In the adrenalectomized patients, the mean nadir of plasma glucose and the rate of ascent to baseline levels were indistinguishable from those observed in normal subjects. Similarly, glucagon responses in the adrenalectomized group were not different from those encountered in the normal volunteers. We conclude that epinephrine does not contribute significantly to the augmented glucagon release during abrupt glucopenia in normal man and is not necessary for normal recovery from hypoglycemia.     

Hormonal responses to insulin-induced hypoglycemia in man

Insulin-induced hypoglycemia is a potent stress stimulating ACTH release, but the factors responsible for this ACTH secretion are not known. In this study, several ACTH-stimulating factors, such as CRH, arginine vasopressin (AVP), epinephrine (E), norepinephrine (NE), and dopamine, in addition to ACTH, cortisol, and glucose, were simultaneously measured in plasma before and 15, 30, 60, 90, and 120 min after iv administration of 0.1 U/kg BW regular insulin to seven normal subjects. Insulin administration resulted in significant rises in the mean plasma ACTH level from 4.6 +/- 1.1 (+/- SEM) to 21.6 +/- 4.8 pmol/L at 30 min (P less than 0.01) and in plasma cortisol from 330 +/- 60 to 720 +/- 50 nmol/L at 60 min (P less than 0.01). These increases were preceded by a 41.0 +/- 1.9% (P less than 0.001) fall in blood glucose levels. The mean plasma CRH level rose significantly from 1.0 +/- 0.1 to 1.2 +/- 0.1 pmol/L (P less than 0.01) at 30 min and remained elevated until 120 min. In addition, concomitant and significant rises in plasma AVP levels (basal, 1.5 +/- 0.01; peak, 4.5 +/- 1.1 pmol/L at 30 min; P less than 0.01), E (basal, less than 50; peak, 640 +/- 130 pmol/L at 30 min; P less than 0.01), and NE (basal, 0.07 +/- 0.01; peak, 0.17 +/- 0.03 nmol/L at 60 min; P less than 0.05), but not dopamine, also occurred. These results suggest that multiple ACTH-releasing factors, such as CRH, AVP, E, and NE, are involved in ACTH secretion induced by insulin-induced hypoglycemia in man.     

Effects of nonselective and beta-1-selective blockade on glucose metabolism and hormone responses during insulin-induced hypoglycemia in normal man

The effects of nonselective beta-blockade (propranolol) and beta-1-selective blockade (atenolol) on glucose metabolism during insulin-induced hypoglycemia were studied in eight normal subjects during constant infusion of 3-[3H]glucose. Propranolol and to a lesser extent atenolol prolonged the hypoglycemic response to insulin. After maximal hypoglycemia a significant increase in glucose uptake rate was seen after propranolol and a corresponding trend was found in the atenolol experiments. The two beta-blockers did not influence glucose production rate after insulin administration. FFA concentration declined rapidly after insulin. Propranolol delayed the subsequent normalization of FFA whereas atenolol had no significant effect. Propranolol increased epinephrine and GH responses to hypoglycemia, whereas atenolol had no effect. Neither of the two beta-blockers influenced the concentrations of glucagon, norepinephrine, and PRL. It is concluded that nonselective beta-blockade prolongs the hypoglycemic response to insulin through an increased tissue uptake of glucose which is not counteracted by an increased glucose production. It is suggested that nonselective beta-blockade increases muscle glucose uptake by lowering FFA concentrations. beta-Blocker inhibition of the antiinsulin effect of epinephrine on glucose uptake in muscle can, however, not be excluded.     

Plasma GH responses to GHRH and insulin-induced hypoglycemia in man

Changes in plasma GH levels in response to an intravenous bolus injection of 200 micrograms GHRH-44 or 0.1 U/kg body weight regular insulin were examined in normal men who were pre-treated with 200 micrograms GHRH-44 or 0.1 U/kg body weight regular insulin 120 min in advance. The prior bolus injection of GHRH-44 inhibited the plasma GH response to the subsequent administration of GHRH-44 whereas the plasma GH response to the subsequent injection of insulin was not influenced by the prior administration of GHRH-44. The prior administration of insulin attenuated the plasma GH response to the subsequently given GHRH-44. These results suggest that desensitization of GHRH receptors in somatotrophs and/or somatostatin hypersecretion induced by increase in plasma GH levels following the prior GHRH-44 administration may be involved in the mechanism by which the prior GHRH-44 administration or insulin-induced hypoglycemia suppressed plasma GH responses to the following GHRH-44 administration. Sudden suppression of somatostatin secretion, which causes rebound of GH secretion, may occur in insulin-induced hypoglycemia.     

Effects of oral glucose on systemic glucose metabolism during hyperinsulinemic hypoglycemia in normal man

The widespread use of oral glucose in the treatment of hypoglycemia is mainly empirically based, and little is known about the time lag and subsequent magnitude of effects following its administration. To define the systemic impact and time course of effects following oral glucose during hypoglycemia, we investigated 7 healthy young men twice. On both occasions, a 6-hour hyperinsulinemic (1.5 mU/kg/min)-hypoglycemic clamp was performed to ensure similar plasma glucose profiles during a stepwise decrease toward a nadir less than 50 mg/100 mL after 3 hours. On the first occasion, subjects ingested 40 g glucose and 4 g 3-ortho-methylglucose ([3-OMG] to trace glucose absorption) dissolved in 400 mL tap water after 3.5 hours. The second examination was identical except for the omission of 40 g oral glucose, and glucose levels were clamped at hypoglycemic concentrations similar to those recorded on the first examination. Plasma glucose curves were superimposable, and all participants reached a nadir less than 50 mg/100 mL. Similar increases in growth hormone (GH) and glucagon were observed in both situations. The glucose infusion rates (GIRs) were lower after oral glucose, with the difference starting after 5 to 10 minutes, being statistically significant after 20 minutes, and reaching a maximum of 8.5 +/- 1.6 mg/kg/min after 40 minutes. Circulating 3-OMG increased after 20 minutes. In both situations, infusion of insulin resulted in insulin levels of approximately 150 microU/mL and a suppression of C-peptide levels from 2.0 to 1.1 nmol/L (P < .01). After glucose ingestion, both serum C-peptide and glucagon-like peptide-1 (GLP-1) increased (C-peptide from 1.1 +/- 0.05 to 1.4 +/- 0.05 nmol/L and GLP-1 from 3.2 +/- 0.8 to 18.1 +/- 3.3 pmol/L), in contrast to the situation without oral glucose (P < .05). Isotopically determined glucose turnover was similar. In conclusion, our data suggest that oral glucose affects systemic glucose metabolism rapidly after 5 to 10 minutes. Quantitatively, the immediate impact is relatively small, with the gross impact observed after approximately 40 minutes. Future studies aiming to identify therapeutic oral agents with prompt effect seem warranted.     

Differential effects of aging on neuroendocrine responses to physostigmine in normal men

We assessed the effects of age on cholinergic regulation of the hypothalamic-pituitary-adrenal axis and other neuroendocrine systems by measuring the plasma cortisol and beta-endorphin responses to an infusion of the centrally active cholinesterase inhibitor physostigmine (0.0125 mg/kg) in 12 healthy older men (68 +/- 1.7 yr) and 9 healthy young men (25 +/- 1.4 yr). We also measured the responses to physostigmine of plasma GH, arginine vasopressin, epinephrine, and norepinephrine (NE). As estimated by comparing calculated areas under the curve, older subjects had greater cortisol (P = 0.02) and beta-endorphin (P less than 0.01) secretory responses, but a reduced GH (P less than 0.01) secretory response. The arginine vasopressin response did not differ between groups. By analysis of variance, older subjects also had a greater epinephrine response (P = 0.01). Older subjects had higher basal NE concentrations (P less than 0.05), but NE responses to physostigmine did not differ between groups. These findings suggest age-related enhancement of the cholinergic stimulatory regulation of the hypothalamic-pituitary-adrenal axis and adrenal medulla. They also confirm previous reports of reduced GH secretory response with aging in normal men.     

Gender-related differences in counterregulatory responses to antecedent hypoglycemia in normal humans

Compared to men, inherent counterregulatory responses are reduced in healthy and type 1 diabetic women. Despite this, the prevalence of hypoglycemia in patients with type 1 diabetes (type 1 DM) is gender neutral. The aim of this study was to determine the in vivo mechanism(s) responsible for this apparent clinical paradox. The central importance of antecedent hypoglycemia in causing subsequent counterregulatory failure is now established. We, therefore, hypothesized that a gender-related difference to the blunting effects of prior hypoglycemia may exist, and this could explain why type 1 DM women do not have an increased prevalence of hypoglycemia despite reduced counterregulatory responses. Fifteen healthy male and female individuals (eight men and seven women) underwent four separate 2-day experimental protocols in a randomized fashion. Day 1 involved identical morning and afternoon 2-h hyperinsulinemic (9 pmol/kg x min) glucose clamp studies with 5.1 +/- 0.1, 3.9 +/- 0.1, 3.3 +/- 0.1, or 2.9 +/- 0.1 mmol/L. Day 2 consisted of a single 2-h hypoglycemic clamp of 2.9 +/- 0.1 mmol/L. Insulin levels were similar on both days of each protocol in men and women. After day 1 euglycemia (5.1 +/- 0.1 mmol/L), day 2 counterregulatory responses were significantly increased (P < 0.01) in men relative to women. In women, counterregulatory responses were resistant to the effects of day 1 hypoglycemia. Antecedent hypoglycemia of 3.9, 3.3, and 2.9 +/- 0.1 mmol/L produced 3 +/- 2%, 5 +/- 2%, and 25 +/- 4% aggregate reductions in day 2 neuroendocrine, muscle sympathetic nerve activity, and metabolic counterregulatory responses. In marked contrast, identical day 1 hypoglycemia of 3.9, 3.3, and 2.9 +/- 0.1 mmol/L in men produced significantly greater reductions in day 2 counterregulatory responses of 30 +/- 6%, 39 +/- 6%, and 52 +/- 6%, respectively. The net effect of the differential gender effects of antecedent hypoglycemia was to overcome the usually increased (50%) sympathetic nervous system (SNS) counterregulatory responses to hypoglycemia found in men. We conclude that 1) antecedent hypoglycemia produces less blunting of counterregulatory responses to subsequent hypoglycemia in women relative to men; 2) two episodes of antecedent hypoglycemia can overcome the greater SNS response to hypoglycemia usually found in men; and 3) the reduced susceptibility of women to the blunting effects of antecedent hypoglycemia may be the mechanism explaining why, despite inherently reduced SNS counterregulatory responses, female type 1 DM patients have a similar prevalence of hypoglycemia compared to men.     

Naloxone attenuates recovery from insulin-induced hypoglycemia in normal man

The effect of the opioid antagonist, naloxone, on recovery of serum glucose concentrations from insulin-induced (0.1 U/kg) hypoglycemia was determined in five normal adult men. Each subject was studied on 2 separate days, at least 2 weeks apart, during an infusion of either normal saline (6.5 ml/h) or naloxone (0.8 mg/h). The order of the infusions was randomized and double blinded. Although glucose recovery was complete by 120 min after insulin administration during each study, the fractional rate of glucose recovery as determined by analysis of covariance was significantly slower during the naloxone infusions (P = 0.008). Plasma glucagon, serum cortisol, and serum GH concentrations were not different during glucose recovery on either study day. These studies suggest that endogenous opioids contribute to glucose recovery from insulin-induced hypoglycemia and therefore may be important to glucose homeostasis in normal man.     

Effects of angiotensin II infusion on the early morning surge of ACTH and o-CRH-provoked ACTH secretion in normal man

The question of whether elevated plasma angiotensin II (AII) levels modulate ACTH secretion in man still awaits a definite answer. We performed two sets of experiments pertinent to that problem: Seven healthy young males each received AII (5 ng/kg/min) and sham infusions on different days in a randomized sequence from 03.00 h to 06.00 h in the morning, while plasma ACTH and cortisol were measured every 20 min. Mean blood pressure rose by about 10 mmHg during AII infusion. Mean plasma ACTH levels were slightly higher with AII than with sham infusion in every single individual (P less than 0.05). Differences in a pre- and post-infusion period were significant. Plasma cortisol levels were almost identical with or without AII infusion. Nine healthy young males received AII (5 ng/kg/min) or sham infusions on different days from 16.30 h to 20.00 h in a randomized sequence and a 100 micrograms o-CRH injection at 17.00 h. Plasma ACTH and cortisol were measured every 15 or 30 min between 16.30 h and 20.00 h. Mean blood pressure rose by about 14 mmHg during AII infusion. The rapid increment and further change in plasma ACTH and cortisol was not significantly different between the AII and sham infusion studies. Conclusions: The dose of AII infused was probably just above the threshold of ACTH stimulation, although AII plasma levels obtained were probably far above the physiological range. On the adrenal level, a vasoconstrictor effect of AII may have prevented stimulation of cortisol. This may be different in states of sodium depletion with reduced vascular effects of AII.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sodium salicylate augments the plasma adrenocorticotropin and cortisol responses to insulin hypoglycemia in man

To test the hypothesis that prostaglandins attenuate neuroendocrine responses to changes in circulating glucose levels in man, we studied the effects of sodium salicylate (SS), a prostaglandin synthesis inhibitor, on the plasma ACTH and cortisol responses to insulin hypoglycemia. Six normal men were given insulin (0.05 U/kg, iv) on 2 different days during the infusion of either SS (40 mg/min) or saline. Compared to the saline control, SS had no significant effect on either the rate of fall of plasma glucose after insulin or the glucose nadir (mean +/- SEM, 33 +/- 3 vs. 36 +/- 3 mg/dl; P = NS). Peak ACTH levels after insulin were higher during SS compared to those during saline in all six subjects (316 +/- 95 vs. 102 +/- 26 pg/ml; P less than 0.05), and SS had a clear effect to increase both the overall ACTH response (F = 21.3; P less than 0.01, by analysis of variance) and the plasma cortisol response (F = 6.72; P less than 0.05, by analysis of variance). The most striking example of this effect of SS occurred in one subject whose peak plasma ACTH was only 44 pg/ml during saline but reached 750 pg/ml during SS despite an identical fall of plasma glucose to 42 mg/dl. Augmentation of the ACTH and cortisol responses to insulin hypoglycemia may be the result of an alteration by SS of recognition of glucose levels by glucose-sensitive cells of the brain, and effect which could be due to the inhibition of prostaglandin synthesis.     

Observations on morning and afternoon glucose tolerance: Differences between sexes

Summary One hundred non-obese and non-diabetic individuals, 50 men and 50 women, were submitted to oral glucose tolerance tests performed in the morning and in the afternoon on different days. Although great individual variations were noted in both sexes, in men the mean blood sugar (BS) values did not significantly differ between the two tests; in women, however, the mean values after glucose loading were significantly higher during the afternoon test. By dividing the test population into those aged 50 and below and those over 50 it was found that only the group of younger women showed significant differences between the two tests with higher mean BS values during the afternoon test.     

Antecedent hypoglycemia, catecholamine depletion, and subsequent sympathetic neural responses

Antecedent hypoglycemia is well known to impair sympathetic responses to subsequent hypoglycemia. However, it is less clear whether this occurs through altered sympathetic neural traffic or through decreased adrenal catecholamine release per se. It is also not clear whether antecedent hypoglycemia impairs sympathetic responsiveness to subsequent nonhypoglycemic sympathetic stimuli. We exposed rats to two episodes of insulin-induced hypoglycemia or sham hypoglycemia (n = 15 per group) on d -2 and -1 before exposure to transient (10 min) hypotension on d 0. Adrenal sympathetic nerve activity (SNA) was directly recorded in the conscious state and plasma catecholamine concentrations were assessed. We also examined the effect of antecedent hypoglycemia on phosphorylated and nonphosphorylated tyrosine hydroxylase (TH) protein expression as well as the expression of phenylethanolamine N-methyltransferase. Adrenal SNA was not significantly altered by antecedent hypoglycemia either at baseline of d 0 (before hypotension) or in response to hypotension. In contrast, plasma epinephrine (EPI) responsiveness was impaired by more than 50% (P = 0.025) in rats exposed to antecedent vs. sham hypoglycemia. Antecedent hypoglycemia had no effect on norepinephrine responsiveness to hypotension. In studies of adrenal tissue from separate rats, antecedent hypoglycemia decreased adrenal EPI content but did not significantly alter the expression of TH, phosphorylated TH, or phenylethanolamine N-methyltransferase. In summary, antecedent hypoglycemia impaired EPI responsiveness to subsequent hypotension despite no reduction in adrenal SNA and in association with reduced adrenal EPI content. Thus, antecedent hypoglycemia impaired responsiveness to a subsequent nonhypoglycemic sympathetic stimulus, an effect mediated at the level of the adrenal medullae.     

The metabolic response to norepinephrine in normal versus diabetic man

Summary Norepinephrine was infused for 60 minutes in high physiological concentration (0.08 μg/ kg/min) into seven insulin dependent diabetic subjects with no demonstrable endogenous insulin secretion and into seven normal subjects. Insulin dependent diabetic subjects had a stable, free insulin concentration of 23±5 μU/ml which was unaffected by norepinephrine infusion. In the normal subjects, norepinephrine induced an initial inhibition of insulin secretion which lasted for approximately 20 minutes. Norepinephrine infusion caused a rapid increase in both ketone body and glucose concentrations but this response did not differ between the two groups. In contrast, plasma nonesterified fatty acid and triglyceride concentrations were increased significantly more in the normal than in the diabetic subjects. The increase in plasma glucagon concentrations was similar in the two groups of subjects. The cause of the differential metabolic response to norepinephrine between the normal and diabetic groups was not resolved, but may be related, at least in part, to suppression of endogenous insulin secretion in the normal subjects.     

Effect of aminophylline on ventilatory responses in normal man

The bronchodilator effects of aminophylline have been well documented but its effect on ventilatory drives has not been systematically evaluated. Accordingly, the ventilatory responses to hypoxia and to hypercapnia were measured before and after the intravenous administration of 5 mg of aminophylline per kg of body weight to 6 normal subjects. Hypoxic ventilatory response, as measured by an index of the relation between ventilation and hypoxia (parameter A) increased from a mean +/- SE control value of 146 +/- 25 to 254 +/- 35 75 min after the infusion (P less than 0.05). Significant increases in A were also noticed immediately after and 35 and 50 min after the aminophylline infusion. Oxygen consumption increased from a control value of 235 +/- 21 to 263 +/- 21 ml per min STPD (P less than 0.03), and CO2 production increased from 184 +/- 12 to 202 +/- 13 ml per min STPD (P less than 0.01) after aminophylline. Hypercapnic ventilatory response, measured as the slope of the ventilatory response to hypercapnia, was not altered after the aminophylline. Thus, in addition to bronchodilation, the augmentation of the ventilatory response to hypoxia may be a useful factor when this drug is used in acute respiratory failure secondary to airway obstruction.     

Intestinal and metabolic responses to an alpha-glucosidase inhibitor in normal volunteers

Postprandial hyperglycemia in diabetic patients can be modified by delaying the digestion and/or absorption of dietary carbohydrates. We have studied an orally active alpha-glucosidase inhibitor, Bay 1099, in normal volunteers to determine whether these inhibitors can decrease postprandial rises in serum glucose without causing gastrointestinal symptoms or significant fecal caloric wastage. Six subjects were given 25, 50, or 100 mg of Bay 1099 or placebo before meals for 1 week, each with a 1-week washout period. Fasting and postprandial concentrations of glucose, insulin, glucagon, enteroglucagon, and gastrointestinal inhibitory peptide (GIP) were measured after the first and last dose of Bay 1099, and the fecal excretions of protein, fat, fiber, and total calories were measured on the last three days of each diet. The passage of unabsorbed carbohydrate into the colon was determined by breath hydrogen analysis three times during each study week. Increasing doses of Bay 1099 were found to decrease the postprandial rise in serum glucose concentration, delay the time to peak insulin concentration, and decrease the output of GIP after the meal. No adaptation was apparent after 1 week of therapy. A dose of inhibitor (50 mg tid), which greatly improves postprandial glucose and hormone output in diabetes, was associated with minimal symptoms and no excess fecal caloric losses. Thus, glucosidase inhibitors such as Bay 1099 may be useful in the management of patients with carbohydrate intolerance.     

Dependency of arterial compliance on circulating neuroendocrine and metabolic factors in normal subjects.

Reduced arterial compliance is now recognized as a feature of hypertension. Similarly, metabolic factors such as insulin, catecholamines and lipids are also associated with hypertension. This study explores the possibility that these neuroendocrine and metabolic factors may separately influence arterial compliance. Proximal compliance (aorta and large arteries) and distal compliance (small arteries and arterioles) were measured in 57 volunteers (30 hypertensive and 27 normotensive subjects, mean age 45 years). Compliance was quantified by analysis of arterial pulse wave contours obtained intraarterially together with hemodynamic estimates. Proximal compliance correlated with plasma insulin (r = -0.49; p less than 0.001), norepinephrine (r = -0.50; p less than 0.002), triglycerides (r = -0.39; p less than 0.01), total cholesterol (r = -0.33; p = 0.02) and high-density lipoprotein cholesterol (HDL) (r = 0.37; p less than 0.02). Similarly, distal compliance correlated with insulin (r = -0.37; p less than 0.02), triglycerides (r = -0.39; p less than 0.01), total cholesterol (r = -0.38; p less than 0.01) and HDL (r = 0.51, p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)