Gender-Related Differences in Counterregulatory Responses to Antecedent Hypoglycemia in Normal Humans1

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·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.

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Sympathetic and cardiovascular responses to glossopharyngeal insufflation in trained apnea divers

Journal of Applied Physiology ◽

10.1152/japplphysiol.00522.2010 ◽

2010 ◽

Vol 109 (6) ◽

pp. 1728-1735 ◽

Cited By ~ 12

Author(s):

Karsten Heusser ◽

Gordan Dzamonja ◽

Toni Breskovic ◽

Craig D. Steinback ◽

André Diedrich ◽

...

Keyword(s):

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Peripheral Resistance ◽

Intrathoracic Pressure ◽

Cardiovascular Responses ◽

The Other ◽

Nerve Activity ◽

Future Studies ◽

Men 2 ◽

Lung Packing

Glossopharyngeal insufflation (lung packing) is a common maneuver among experienced apnea divers by which additional air is pumped into the lungs. It has been shown that packing may compromise cardiovascular homeostasis. We tested the hypothesis that the packing-mediated increase in intrathoracic pressure enhances the baroreflex-mediated increase in muscle sympathetic nerve activity (MSNA) in response to an exaggerated drop in cardiac output (CO). We compared changes in hemodynamics and MSNA (peroneal microneurography) during maximal breath-holds without and with prior moderate packing (0.79 ± 0.40 liters) in 14 trained divers (12 men, 2 women, 26.7 ± 4.5 yr, body mass index 24.8 ± 2.4 kg/m2). Packing did not change apnea time (3.8 ± 1.0 vs. 3.8 ± 1.2 min), hemoglobin oxygen desaturation (−17.6 ± 12.3 vs. −18.7 ± 12.8%), or the reduction in CO (1 min: −3.65 ± 1.83 vs. −3.39 ± 1.96 l/min; end of apnea: −2.44 ± 1.33 vs. −2.16 ± 1.44 l/min). On the other hand, packing dampened the early, i.e., 1-min increase in mean arterial pressure (MAP, 1 min: 9.2 ± 8.3 vs. 2.4 ± 11.0 mmHg, P < 0.01) and in total peripheral resistance (relative TPR, 1 min: 2.1 ± 0.5 vs. 1.9 ± 0.5, P < 0.05) but it augmented the concomitant rise in MSNA (1 min: 28.0 ± 11.7 vs. 39.4 ± 12.7 bursts/min, P < 0.001; 32.8 ± 16.4 vs. 43.9 ± 14.8 bursts/100 heart beats, P < 0.01; 3.3 ± 2.1 vs. 4.8 ± 3.2 au/min, P < 0.05). We conclude that the early sympathoactivation 1 min into apnea after moderate packing is due to mechanisms other than excessive reduction in CO. We speculate that lower MAP despite increased MSNA after packing might be explained by vasodilator substances released by the lungs. This idea should be addressed in future studies.

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Tissue factor and Toll-like receptor (TLR)4 in hyperglycaemia-hyperinsulinaemia

Thrombosis and Haemostasis ◽

10.1160/th14-10-0884 ◽

2015 ◽

Vol 113 (04) ◽

pp. 750-758 ◽

Cited By ~ 10

Author(s):

Anamika Singh ◽

Guenther Boden ◽

A. Koneti Rao

Keyword(s):

Tissue Factor ◽

Healthy Subjects ◽

Toll Like Receptor ◽

Elevated Plasma ◽

Type 2 Dm ◽

Type 1 Dm

SummaryDiabetes mellitus (DM) patients have an increased incidence of cardiovascular events. Blood tissue factor-procoagulant activity (TF-PCA), the initiating mechanism for blood coagulation, is elevated in DM. We have shown that hyperglycaemia (HG), hyperinsulinaemia (HI) and combined HG+HI (induced using 24-hour infusion clamps) increases TF-PCA in healthy and type 2 DM (T2DM) subjects, but not in type 1 DM (T1DM) subjects. The mechanisms for this are unknown. DM patients have elevated plasma lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. We postulated that TLR4 plays a role in modulating TF levels. We studied the effect of HG+HI on TLR4 and TF-PCA in vivo during 24-hour HG+HI infusion clamps in healthy subjects, and T1DM and T2DM subjects, and in vitro in blood. In vivo, in healthy subjects, 24-hour HG + HI infusion increased TLR4 six-fold, which correlated with TF-PCA (r=0.91, p<0.0001). T2DM patients showed smaller increases in both. In T1DM subjects, TLR4 declined (50%, p<0.05) and correlated with TF-PCA (r=0.55; p<0.05). In vitro, HG (200 mg/dl added glucose) and HI (1-100 nM added insulin) increased TF-PCA in healthy subjects (˜2-fold, 2-4 hours). Insulin inhibited by ~30% LPSinduced increase in TF-PCA and high glucose reversed it. TLR4 levels paralleled TF-PCA (r=0.71, p<0.0001); HG and HI increased TLR4 and insulin inhibited LPS-induced TLR4 increase. This is first evidence that even in healthy subjects, HG of short duration increases TLR4 and TFPCA, key players in inflammation and thrombosis. TLR4-TF interplay is strikingly different in non-diabetic, T1DM and T2DM subjects.

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Dissociation of muscle sympathetic nerve activity and leg vascular resistance in humans

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.3.h1215 ◽

2000 ◽

Vol 279 (3) ◽

pp. H1215-H1219 ◽

Cited By ~ 34

Author(s):

J. Kevin Shoemaker ◽

Michael D. Herr ◽

Lawrence I. Sinoway

Keyword(s):

Arterial Pressure ◽

Vascular Resistance ◽

Femoral Artery ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Blood Velocity ◽

Handgrip Exercise ◽

Nerve Activity

We examined the hypothesis that the increase in inactive leg vascular resistance during forearm metaboreflex activation is dissociated from muscle sympathetic nerve activity (MSNA). MSNA (microneurography), femoral artery mean blood velocity (FAMBV, Doppler), mean arterial pressure (MAP), and heart rate (HR) were assessed during fatiguing static handgrip exercise (SHG, 2 min) followed by posthandgrip ischemia (PHI, 2 min). Whereas both MAP and MSNA increase during SHG, the transition from SHG to PHI is characterized by a transient reduction in MAP but sustained elevation in MSNA, facilitating separation of these factors in vivo. Femoral artery vascular resistance (FAVR) was calculated (MAP/MBV). MSNA increased by 59 ± 20% above baseline during SHG ( P < 0.05) and was 58 ± 18 and 78 ± 18% above baseline at 10 and 20 s of PHI, respectively ( P < 0.05 vs. baseline). Compared with baseline, FAVR increased 51 ± 22% during SHG ( P < 0.0001) but returned to baseline levels during the first 30 s of PHI, reflecting the changes in MAP ( P < 0.005) and not MSNA. It was concluded that control of leg muscle vascular resistance is sensitive to changes in arterial pressure and can be dissociated from sympathetic factors.

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