Article

Acute hypoxia reduces exogenous glucose oxidation, glucose turnover, and metabolic clearance rate during steady-state aerobic exercise

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Abstract

Background: Exogenous carbohydrate oxidation is lower during steady-state aerobic exercise in native lowlanders sojourning at high altitude (HA) compared to sea level (SL). However, the underlying mechanism contributing to reduction in exogenous carbohydrate oxidation during steady-state aerobic exercise performed at HA have not been explored. Objective: To determine if alterations in glucose rate of appearance (Ra), disappearance (Rd) and metabolic clearance rate (MCR) at HA provide a mechanism for explaining the observation of lower exogenous carbohydrate oxidation compared to during metabolically-matched, steady-state exercise at SL. Methods: Using a randomized, crossover design, native lowlanders (n = 8 males, mean ± SD, age: 23 ± 2 yr, body mass: 87 ± 10 kg, and VO2peak: SL 4.3 ± 0.2 L/min and HA 2.9 ± 0.2 L/min) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (SL: 1.66 ± 0.14 V̇O2 L/min 329 ± 28 kcal, HA: 1.59 ± 0.10 V̇O2 L/min, 320 ± 19 kcal) treadmill exercise in SL (757 mmHg) and HA (460 mmHg) conditions after a 5-h exposure. Substrate oxidation rates (g/min) and glucose turnover (mg/kg/min) during exercise were determined using indirect calorimetry and dual tracer technique (13C-glucose oral ingestion and [6,6-2H2]-glucose primed, continuous infusion). Results: Total carbohydrate oxidation was higher (P < .05) at HA (2.15 ± 0.32) compared to SL (1.39 ± 0.14). Exogenous glucose oxidation rate was lower (P < .05) at HA (0.35 ± 0.07) than SL (0.44 ± 0.05). Muscle glycogen oxidation was higher at HA (1.67 ± 0.26) compared to SL (0.83 ± 0.13). Total glucose Ra was lower (P < .05) at HA (12.3 ± 1.5) compared to SL (13.8 ± 2.0). Exogenous glucose Ra was lower (P < .05) at HA (8.9 ± 1.3) compared to SL (10.9 ± 2.2). Glucose Rd was lower (P < .05) at HA (12.7 ± 1.7) compared to SL (14.3 ± 2.0). MCR was lower (P < .05) at HA (9.0 ± 1.8) compared to SL (12.1 ± 2.3). Circulating glucose and insulin concentrations were higher in response carbohydrate intake during exercise at HA compared to SL. Conclusion: Novel results from this investigation suggest that reductions in exogenous carbohydrate oxidation at HA may be multifactorial; however, the apparent insensitivity of peripheral tissue to glucose uptake may be a primary determinate.

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... Acute high-altitude (HA) exposure (<8 h) suppresses exogenous glucose oxidation during steady-state aerobic exercise compared with metabolically matched exercise at sea level (SL) (1)(2)(3)(4). In two separate studies (1,4), our laboratory observed that consuming exogenous glucose during metabolically matched, steady-state aerobic exercise was associated with higher concentrations of circulating glucose and insulin, and lower rates of exogenous glucose oxidation during acute HA exposure compared with SL. ...
... Acute high-altitude (HA) exposure (<8 h) suppresses exogenous glucose oxidation during steady-state aerobic exercise compared with metabolically matched exercise at sea level (SL) (1)(2)(3)(4). In two separate studies (1,4), our laboratory observed that consuming exogenous glucose during metabolically matched, steady-state aerobic exercise was associated with higher concentrations of circulating glucose and insulin, and lower rates of exogenous glucose oxidation during acute HA exposure compared with SL. Furthermore, glucose rate of disappearance (R d ) and metabolic clearance rate (MCR), kinetic measures indicative of glucose uptake and utilization (5,6), were both lower at HA compared with SL (1). ...
... In two separate studies (1,4), our laboratory observed that consuming exogenous glucose during metabolically matched, steady-state aerobic exercise was associated with higher concentrations of circulating glucose and insulin, and lower rates of exogenous glucose oxidation during acute HA exposure compared with SL. Furthermore, glucose rate of disappearance (R d ) and metabolic clearance rate (MCR), kinetic measures indicative of glucose uptake and utilization (5,6), were both lower at HA compared with SL (1). Collectively, these metabolic dysregulations suggest that acute hypoxia elicits peripheral insulin resistance in healthy exercising adults (7). ...
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Hypoxia-induced insulin resistance appears to suppress exogenous glucose oxidation during metabolically-matched aerobic exercise during acute (<8-h) high-altitude (HA) exposure. However, a better understanding of this metabolic dysregulation is needed to identify interventions to mitigate these effects. The objective of this study was to determine if differences in metabolomic profiles during exercise at sea level (SL) and HA are reflective of hypoxia-induced insulin resistance. Native lowlanders (n=8 males) consumed 145g (1.8g/min) of glucose while performing 80-min of metabolically-matched treadmill exercise at SL (757 mmHg) and HA (460 mmHg) after 5-h exposure. Exogenous glucose oxidation and glucose turnover were determined using indirect calorimetry and dual tracer technique (13C-glucose and [6,6-2H2]-glucose). Metabolite profiles were analyzed in serum as change (Δ), calculated by subtracting postprandial/exercised state SL (ΔSL) and HA (ΔHA) from fasted, rested conditions at SL. Compared to SL, exogenous glucose oxidation, glucose rate of disappearance , and glucose metabolic clearance rate (MCR) were lower (P<0.05) during exercise at HA. 118 metabolites differed between ΔSL and ΔHA (P<0.05, Q<0.10). Differences in metabolites indicated increased glycolysis, TCA cycle, amino acid catabolism, oxidative stress, and fatty acid storage, and decreased fatty acid mobilization for ΔHA. BCAA and oxidative stress metabolites, Δ3-methyl-2-oxobutyrate (r=-0.738) and Δgamma-glutamylalanine (r=-0.810), were inversely associated (P<0.05) with Δexogenous glucose oxidation. Δ3-hydroxyisobutyrate (r=-0.762) and Δ2-hydroxybutyrate/2-hydroxyisobutyrate (r=-0.738) were inversely associated (P<0.05) with glucose MCR. Coupling global metabolomics and glucose kinetic data suggest that the underlying cause for diminished exogenous glucose oxidative capacity during aerobic exercise is acute hypoxia-mediated peripheral insulin resistance.
... Our laboratories have consistently shown that unacclimatized lowlanders demonstrate a blunted ability to oxidize exogenous glucose during relative (O'Hara et al., , 2017(O'Hara et al., , , 2019 or absolute (Margolis et al., 2019;Young et al., 2018) intensity-matched aerobic exercise within hours of hypoxia exposure. Our data challenge common recommendations to increase the carbohydrate intake during exercise at high altitude (>2,500 m) to fuel exercise metabolism and augment endurance capability (Koehle, Cheng, & Sporer, 2014). ...
... Our data challenge common recommendations to increase the carbohydrate intake during exercise at high altitude (>2,500 m) to fuel exercise metabolism and augment endurance capability (Koehle, Cheng, & Sporer, 2014). As such, we read with interest the recent report by Sumi et al. (Sumi, Hayashi, Yatsutani, & Goto, 2020), as their findings, on the surface, appear to confirm our previous results (Margolis et al., 2019;O'Hara et al., 2017O'Hara et al., , 2019Young et al., 2018). Their randomized crossover study aimed to investigate the effects of acute hypoxia on exogenous glucose oxidation in nine unacclimatized lowlanders performing 30-min of absolute or relative intensity-matched aerobic exercise. ...
... In conclusion, while it appeared that results from Sumi et al. (2020) confirmed previously published findings from our laboratories (Margolis et al., 2019;O'Hara et al., 2017O'Hara et al., , 2019Young et al., 2018), careful examination of their methodological approach revealed several limitations that preclude drawing any conclusions regarding the effects of acute hypoxia exposure on exogenous glucose oxidation during aerobic exercise. However, it is clear that exogenous glucose oxidation is lower in unacclimatized lowlanders performing aerobic exercise matched for relative (O'Hara et al., 2017(O'Hara et al., , 2019 or absolute (Margolis et al., 2019;Young et al., 2018) intensities under acute hypoxic conditions compared to normoxia. ...
... our recent article (Margolis et al., 2019) that acute hypoxia blunts oxidation of exogenous carbohydrate ingested during exercise may conflict with general recommendations for increasing carbohydrate intake to support physical performance at high altitude (HA). We agree that carbohydrate is an important fuel source in lowlanders sojourning at HA, as there is an increased reliance on carbohydrate use for energy during metabolically matched steady-state exercise compared with sea level (SL) (Griffiths et al., 2019). ...
... However, the studies cited by Pesta et al. (2020) questioning the validity of our conclusions (Margolis et al., 2019) involved resting subjects, whereas our observations were made in lowlanders performing metabolically matched steady-state aerobic exercise in hypoxia and normoxia. We found that the rate of exogenous glucose oxidation during acute hypoxic exposure was reduced compared with SL. ...
... We found that the rate of exogenous glucose oxidation during acute hypoxic exposure was reduced compared with SL. Diminished exogenous glucose oxidation appeared to be the result of reduced uptake of glucose into peripheral tissue (Margolis et al., 2019). ...
... In contrast, a very recent study demonstrated reduced exogenous glucose oxidation during steady-state exercise at acute HA compared with sea level (SL) conditions (Margolis et al., 2019). Those authors conclude that their findings may conflict with current recommendations of enhanced carbohydrate intake at acute HA to support physical performance (Margolis et al., 2019). ...
... In contrast, a very recent study demonstrated reduced exogenous glucose oxidation during steady-state exercise at acute HA compared with sea level (SL) conditions (Margolis et al., 2019). Those authors conclude that their findings may conflict with current recommendations of enhanced carbohydrate intake at acute HA to support physical performance (Margolis et al., 2019). However, this conclusion may be questioned based on the mentioned studies and more recent research as well. ...
... In light of the reported elevated muscle glycogen oxidation at HA compared with SL by Margolis et al. (2019), glucose ingestion may also contribute to a faster replenishment of glycogen stores after exercise (van Hall et al., 2000) and may further benefit altitude-related suppression of immune function (Bermon et al., 2017). Moreover, carbohydrate supplementation was recently shown to enhance appetite and energy intake in hypoxic conditions (Griffiths et al., 2019). ...
... An increased reliance on, or preference for, CHO for energy provision in hypoxic environments such as moderate-to-high altitude is hypothesised [291], but CHO ingestion does not reliably augment performance at moderate-to-high altitude [292][293][294]. In fact, aerobic exercise performed during acute high altitude exposure elicited lower exogenous glucose oxidation, glucose turnover, and glucose disposal, while concomitant increases in circulating [glucose] and [insulin] suggested a reduced sensitivity of skeletal muscle to glucose uptake in hypoxia compared with exercise in normoxia [295]. Taken together, alternative fuelling strategies that attenuate declines in systemic and skeletal muscle oxygenation, exercise performance, and symptoms of mountain sickness may provide ergogenic benefit during moderate-to-high altitude exposure. ...
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The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by serving as an alternative substrate for energy provision, and by modulating inflammation, oxidative stress, catabolic processes, and gene expression. Of particular relevance to athletes are the metabolic actions of ketone bodies to alter substrate utilisation through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. There has been long-standing interest in the development of ingestible forms of ketone bodies that has recently resulted in the commercial availability of exogenous ketone supplements (EKS). These supplements in the form of ketone salts and ketone esters, in addition to ketogenic compounds such as 1,3-butanediol and medium chain triglycerides, facilitate an acute transient increase in circulating AcAc and βHB concentrations, which has been termed ‘acute nutritional ketosis’ or ‘intermittent exogenous ketosis’. Some studies have suggested beneficial effects of EKS to endurance performance, recovery, and overreaching, although many studies have failed to observe benefits of acute nutritional ketosis on performance or recovery. The present review explores the rationale and historical development of EKS, the mechanistic basis for their proposed effects, both positive and negative, and evidence to date for their effects on exercise performance and recovery outcomes before concluding with a discussion of methodological considerations and future directions in this field.
... For example, recovery in environmental extremes such as heat and cold results in reduced postexercise glycogen synthesis (42,43). In addition, unacclimatized exposure to environmental conditions, such as heat and high altitude, increase glycogenolysis and decrease the use of exogenous carbohydrate for fuel during aerobic exercise (44,45). These changes in postexercise glycogen synthesis, glycogenolysis, and exogenous glucose oxidation during and in recovery from exercise may affect postexercise recovery nutritional needs. ...
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Evidence suggests that carbohydrate and protein (CHO-PRO) ingestion after exercise enhances muscle glycogen repletion to a greater extent than carbohydrate (CHO) alone. However, there is no consensus at this point, and results across studies are mixed, which may be attributable to differences in energy content and carbohydrate intake relative to body mass consumed after exercise. The purpose of this study was determine the overall effects of CHO-PRO and the independent effects of energy and relative carbohydrate content of CHO-PRO supplementation on post-exercise muscle glycogen synthesis compared to CHO alone. Methods: Meta-analysis was conducted on crossover studies assessing the influence of CHO-PRO compared to CHO alone on post-exercise muscle glyocgen synthesis. Studies were identified in a systematic review from Pubmed and Cochrane Library databases. Data are presented as effect size [ES(95%CI)] using Hedges' g. Subgroup analyses were conducted to evaluate effects of isocaloric and non-isocaloric energy content, and dichotomized by median relative carbohydrate (high: ≥0.8g/kg/hr, low: <0.8g/kg/hr) content on glycogen synthesis. Results: 20 studies were included in the analysis. CHO-PRO had no overall effect on glycogen synthesis [0.13(-0.04,0.29)] compared to CHO. Subgroup analysis found that CHO-PRO had a positive effect [0.26(0.04,0.49)] on glycogen synthesis when the combined intervention provided more energy than CHO. Glycogen synthesis was not significant [-0.05(-0.23,0.13)] in CHO-PRO compared to CON when matched for energy content. There was no statistical difference of CHO-PRO on glycogen synthesis in high [0.07(-0.11,0.25)] or low [0.21(-0.08,0.50)] carbohydrate content compared to CHO. Conclusion: Glycogen synthesis rates are enhanced when CHO-PRO are coingested after exercise compared to CHO only when the added energy of protein is consumed in addition to, not in place of, carbohydrate.
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Purpose This study investigated the effect of carbohydrate supplementation on substrate oxidation during exercise in hypoxia after pre-exercise breakfast consumption and omission. Methods Eleven men walked in normobaric hypoxia (FiO2 ~11.7%) for 90-min at 50% of hypoxic V[Combining Dot Above]O2max. Participants were supplemented with a carbohydrate beverage (1.2g·min-1 glucose) and a placebo beverage (both enriched with U-13C6 D-glucose) after breakfast consumption and after omission. Indirect calorimetry and isotope ratio mass spectrometry were used to calculate carbohydrate (exogenous and endogenous (muscle and liver)) and fat oxidation. Results In the first 60-min of exercise, there was no significant change in relative substrate oxidation in the carbohydrate compared with placebo trial after breakfast consumption or omission (both p = 0.99). In the last 30-min of exercise, increased relative carbohydrate oxidation occurred in the carbohydrate compared with placebo trial after breakfast omission (44.0 ± 8.8 vs. 28.0 ± 12.3, p < 0.01) but not consumption (51.7 ± 12.3 vs. 44.2 ± 10.4, p = 0.38). In the same period, a reduction in relative liver (but not muscle) glucose oxidation was observed in the carbohydrate compared with placebo trials after breakfast consumption (liver: 7.7 ± 1.6% vs. 14.8 ± 2.3%, p < 0.01; muscle: 25.4 ± 9.4% vs. 29.4 ± 11.1%, p = 0.99) and omission (liver: 3.8 ± 0.8% vs. 8.7 ± 2.8%, p < 0.01; muscle: 19.4 ± 7.5% vs. 19.2 ± 12.2%, p = 0.99). No significant difference in relative exogenous carbohydrate oxidation was observed between breakfast consumption and omission trials (p = 0.14). Conclusion In acute normobaric hypoxia, carbohydrate supplementation increased relative carbohydrate oxidation during exercise (> 60 min) after breakfast omission, but not consumption.
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A recently published meta-analysis in this journal analyzed findings from studies comparing substrate use during exercise at the same relative intensity (i.e., % V̇O2max) in normoxic and hypoxic conditions. The primary conclusion was that hypoxia had no consistent effects on the contribution of carbohydrate oxidation to total energy expenditure. However, findings from studies comparing exercise at the same absolute intensity in normoxic as hypoxic conditions were not considered in the meta-analysis. Assessment of substrate oxidation using matched absolute intensity leads to different conclusions regarding hypoxic effects on fuel use during exercise, and that experimental model, (i.e., comparing responses to exercise at matched absolute intensity) has more practical application for developing nutritional recommendations for high-altitude sojourners. This commentary will discuss those differences.
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The purposes of this study were 1) to investigate the effect of carbohydrate (CHO) ingestion on endogenous glucose production (EGP) during prolonged exercise, 2) to study whether glucose appearance in the circulation could be a limiting factor for exogenous CHO oxidation, and 3) to investigate whether large CHO feedings can reduce muscle glycogen oxidation during exercise. Six well-trained subjects exercised three times for 120 min at 50% maximum workload while ingesting water (FAST), a 4% glucose solution (LO-Glc), or a 22% glucose solution (HI-Glc). A primed continuous intravenous [6, 6-2H2]glucose infusion was given, and the ingested glucose was enriched with [U-13C]glucose. Glucose ingestion significantly elevated CHO oxidation as well as the rates of appearance (Ra) and disappearance. Ra glucose equaled Ra of glucose in gut (Ra gut) during HI-Glc, whereas EGP was completely suppressed. During LO-Glc, EGP was partially suppressed, whereas Ra gut provided most of the total glucose Ra. We conclude that 1) high rates of CHO ingestion can completely block EGP, 2) Ra gut may be a limiting factor for exogenous CHO oxidation, and 3) muscle glycogen oxidation was not reduced by large glucose feedings.
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Adrenal sympathetic preganglionic neurons (ADR SPNs) regulating the chromaffin cell release of epinephrine (Epi ADR SPNs) and those controlling norepinephrine (NE ADR SPNs) secretion have been distinguished on the basis of their responses to stimulation in the rostral ventrolateral medulla, to glucopenia produced by 2-deoxyglucose, and to activation of the baroreceptor reflex. In this study, we examined the effects of arterial chemoreceptor reflex activation, produced by inhalation of 100% N(2) or intravenous injection of sodium cyanide, on these two groups of ADR SPNs, identified antidromically in urethane-anesthetized, artificially ventilated rats. The mean spontaneous discharge rates of 38 NE ADR SPNs and 51 Epi ADR SPNs were 4.4 +/- 0.4 and 5.6 +/- 0.4 spikes/s at mean arterial pressures of 98 +/- 3 and 97 +/- 3 mmHg, respectively. Ventilation with 100% N(2) for 10 s markedly excited all NE ADR SPNs (+222 +/- 23% control, n = 36). In contrast, the majority (40/48; 83%) of Epi ADR SPNs were unaffected or slightly inhibited by ventilation with 100% N(2) (population response: +6 +/- 10% control, n = 48). Similar results were obtained after injection of sodium cyanide. These observations suggest that the network controlling the spontaneous discharge of NE ADR SPNs is more sensitive to brief arterial chemoreceptor reflex activation than is that regulating the activity of Epi ADR SPNs. The differential responsiveness to activation of the arterial chemoreceptor reflex of the populations of ADR SPNs regulating epinephrine and norepinephrine secretion suggests that their primary excitatory inputs arise from separate populations of sympathetic premotor neurons and that a fall in arterial oxygen tension is not a major stimulus for reflex-mediated adrenal epinephrine secretion.
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The carotid body is currently looked at as a multipurpose sensor for blood gases, blood pH and several hormones. The matter of glucose sensing by the carotid body has been debated for several years in the literature, and nowadays there is a consensus that carotid body activity is modified by metabolic factors that contribute to glucose homeostasis. However, the sensing ability for glucose is still being pondered: are the carotid bodies low glucose sensors or, in contrast, are they overresponsive in high-glucose conditions? Herein, we debate the glucose and insulin sensing capabilities of the carotid body as the key early events in the overactivation of the carotid body that result in insulin resistance culminating in the development of metabolic diseases. Additionally, we dedicate a final section to discuss new out box therapies to decrease carotid body activity that can be applied for the treatment of metabolic diseases.
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Neurotransmitters including catecholamines and serotonin play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the “fight or flight” response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in gastrointestinal and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, gastrointestinal innate immune system, and the microbiome. Furthermore, in pathological states such as inflammatory bowel disease (IBD) and Parkinson's disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of gastrointestinal symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state-of-the-art research and literature regarding the role of neurotransmitters in regulation of normal gastrointestinal physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. This article is protected by copyright. All rights reserved
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The carotid bodies (CBs) are peripheral chemoreceptors that respond to hypoxia increasing minute ventilation and activating the sympathetic nervous system. Besides its role in ventilation we recently described that CB regulate peripheral insulin sensitivity. Knowing that the CB is functionally blocked by hyperoxia and that hyperbaric oxygen therapy (HBOT) improves fasting blood glucose in diabetes patients, we have investigated the effect of HBOT on glucose tolerance in type 2 diabetes patients. Volunteers with indication for HBOT were recruited at the Subaquatic and Hyperbaric Medicine Center of Portuguese Navy and divided into two groups: type 2 diabetes patients and controls. Groups were submitted to 20 sessions of HBOT. OGTT were done before the first and after the last HBOT session. Sixteen diabetic patients and 16 control individual were included. Fasting glycemia was143.5 ± 12.62 mg/dl in diabetic patients and 92.06 ± 2.99 mg/dl in controls. In diabetic patients glycemia post-OGTT was 280.25 ± 22.29 mg/dl before the first HBOT session. After 20 sessions, fasting and 2 h post-OGTT glycemia decreased significantly. In control group HBOT did not modify fasting glycemia and post-OGTT glycemia. Our results showed that HBOT ameliorates glucose tolerance in diabetic patients and suggest that HBOT could be used as a therapeutic intervention for type 2 diabetes.
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: Many sports incorporate training at altitude as a key component of their athlete training plan. Furthermore, many sports are required to compete at high altitude venues. Exercise at high altitude provides unique challenges to the athlete and to the sport medicine clinician working with these athletes. These challenges include altitude illness, alterations in training intensity and performance, nutritional and hydration difficulties, and challenges related to the austerity of the environment. Furthermore, many of the strategies that are typically utilized by visitors to altitude may have implications from an anti-doping point of view.This position statement was commissioned and approved by the Canadian Academy of Sport and Exercise Medicine. The purpose of this statement was to provide an evidence-based, best practices summary to assist clinicians with the preparation and management of athletes and individuals travelling to altitude for both competition and training.
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The discovery of the sensory nature of the carotid body dates back to the beginning of the 20th century. Following these seminal discoveries, research into carotid body mechanisms moved forward progressively through the 20th century, with many descriptions of the ultrastructure of the organ and stimulus-response measurements at the level of the whole organ. The later part of 20th century witnessed the first descriptions of the cellular responses and electrophysiology of isolated and cultured type I and type II cells, and there now exist a number of testable hypotheses of chemotransduction. The goal of this article is to provide a comprehensive review of current concepts on sensory transduction and transmission of the hypoxic stimulus at the carotid body with an emphasis on integrating cellular mechanisms with the whole organ responses and highlighting the gaps or discrepancies in our knowledge. It is increasingly evident that in addition to hypoxia, the carotid body responds to a wide variety of blood-borne stimuli, including reduced glucose and immune-related cytokines and we therefore also consider the evidence for a polymodal function of the carotid body and its implications. It is clear that the sensory function of the carotid body exhibits considerable plasticity in response to the chronic perturbations in environmental O2 that is associated with many physiological and pathological conditions. The mechanisms and consequences of carotid body plasticity in health and disease are discussed in the final sections of this article. © 2012 American Physiological Society. Compr Physiol 2:141-219, 2012.
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• Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia. Insulin action on glucose uptake has never been investigated during altitude hypoxia. • In eight healthy, sea level resident men (27 ± 1 years (mean ± S.E.M.); weight, 72 ± 2 kg; height, 182 ± 2 cm) hyperinsulinaemic (50 mU min−1 m−2), euglycaemic clamps were carried out at sea level, and subsequently on days 2 and 7 after a rapid passive ascent to an altitude of 4559 m. • Acute mountain sickness scores increased in the first days of altitude exposure, with a peak on day 2. Basal HGP did not change with the transition from sea level (2.2 ± 0.2 mg min− kg−1) to altitude (2.0 ± 0.1 and 2.1 ± 0.2 mg min−1 kg−1, days 2 and 7, respectively). Insulin-stimulated glucose uptake rate was halved on day two compared with sea level (4.5 ± 0.6 and 9.8 ± 1.1 mg min−1 kg−1, respectively; P −1 kg−1; P vs. day two and sea level). Concentrations of glucagon and growth hormone remained unchanged, whereas glucose, C-peptide and cortisol increased on day 2. Noradrenaline concentrations increased during the stay at altitude, while adrenaline concentrations remained unchanged. In response to insulin infusion, catecholamines increased on day 2 (noradrenaline and adrenaline) and day 7 (adrenaline), but not at sea level. • In conclusion, insulin action decreases markedly in response to two days of altitude hypoxia, but improves with more prolonged exposure. HGP is always unchanged. The changes in insulin action may in part be explained by the changes in counter-regulatory hormones.
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Acute exposure to hypoxia decreases insulin sensitivity in healthy adult humans; the mechanism is unclear, but increased activation of the sympathetic nervous system may be involved. We have investigated the hypothesis that short-term sympathetic inhibition attenuates hypoxia induced insulin resistance. Insulin sensitivity (via the hyperinsulinaemic euglycaemic clamp) was determined in 10 healthy men (age 23 ± 1 years, body mass index 24.2 ± 0.8 kg m⁻² (means ± SEM)), in a random order, during normoxia (FIO₂ =0.21), hypoxia (FIO₂ =0.11), normoxia and sympathetic inhibition (via 48 h transdermal administration of the centrally acting α2-adrenergic receptor agonist, clonidine), and hypoxia and sympathetic inhibition.Oxyhaemoglobin saturation (pulse oximetry) was decreased (P<0.001) with hypoxia (63 ± 2%) compared with normoxia (96 ± 0%), and was unaffected by sympathetic inhibition (P>0.25). The area under the noradrenaline curve (relative to the normoxia response) was increased with hypoxia (137 ± 13%; P =0.02); clonidine prevented the hypoxia induced increase (94 ± 14%; P =0.43). The glucose infusion rate (adjusted for fat free mass and circulating insulin concentration) required to maintain blood glucose concentration at 5 mmol l⁻¹ during administration of insulin was decreased in hypoxia compared with normoxia (225 ± 23 vs. 128 ± 30 nmol (kg fat free mass)⁻¹ pmol l⁻¹ min⁻¹; P =0.03), and unchanged during normoxia and sympathetic inhibition (219 ± 19; P =0.86) and hypoxia and sympathetic inhibition (169 ± 23; P =0.23). We conclude that short-term sympathetic inhibition attenuates hypoxia induced insulin resistance.
Article
Recent studies have shown that exercise training at moderate altitude or in moderate hypoxia improved glycemic parameters. From these data, it has been supposed that endurance exercise in moderate hypoxia affects substrate utilization and that exposure to moderate hypoxia in combination with exercise may be utilized as part of metabolic or diabetes prevention program. However, the influence of exercise at moderate hypoxia on circulating metabolites and hormones in terms of substrate utilization is unclear. The purpose of this study was to elucidate the influence of exercise in moderate hypoxia on substrate utilization. We determined cardiorespiratory, metabolic, and hormonal parameters during exercise and postexercise recovery at a simulated moderate altitude of 2000 m, and then we compared these variables with values obtained at sea level. Seven men participated in this study; subjects reported to the laboratory on 4 occasions. Two maximal exercise tests were performed to estimate peak oxygen uptake at the simulated 2000-m altitude and sea level on different days. Afterward, submaximal exercise tests were carried out at a simulated altitude of 2000 m or sea level, separated by 1 week. Subjects performed submaximal exercise at the same relative exercise intensity (50% peak oxygen uptake) at a simulated altitude of 2000 m and at sea level for 30 minutes. The tests were performed in random order, and subjects were blinded to the respective altitudes. Venous blood samples and expired gases were obtained before, during exercise (15 and 30 minutes), and during postexercise recovery periods (15, 30, 45, and 60 minutes). The respiratory exchange ratio during exercise and recovery at moderate altitude was greater than at sea level. The epinephrine and norepinephrine concentrations during exercise and recovery were higher (P < .05) at moderate altitude than at sea level. Free fatty acids and glycerol concentrations during recovery were lower (P < .05) at moderate altitude than at sea level. These results suggest that carbohydrate utilization is increased during exercise and postexercise recovery period in moderate hypoxia as compared with normoxia. It is also suggested that moderate hypoxia influences the changes in circulating metabolites and hormones in terms of substrate metabolism during exercise and the recovery.
In 13CO2 breath tests, based on 13C:12C ratio measurements, the appearance of 13C in exhaled CO2 was monitored after the administration of a 13C-labelled compound. Independently of the substrate used, the existence of a bicarbonate pool into which the CO2 produced enters before being exhaled, imposes a delay on the appearance of changes in the 13C:12C ratio. To estimate the nature and magnitude of this delay, we applied a two-compartment model to describe the kinetics of the body bicarbonate pool and we evaluated the 13C:12C ratio of CO2 entering that pool from the measured 13C:12C ratio in the exhaled CO2 after an oral intake of "naturally labelled" 13C-glucose. Our results demonstrated that discrepancies between total and exogenous glucose oxidation in relation to the peak occurrence time, as well as the absolute quantities, could be adequately explained by the interference of the bicarbonate stores.
Article
We hypothesized that the increased exercise arterial lactate concentration on arrival at high altitude and the subsequent decrease with acclimatization were caused by changes in blood lactate flux. Seven healthy men [age 23 +/- 2 (SE) yr, wt 72.2 +/- 1.6 kg] on a controlled diet were studied in the postabsorptive condition at sea level, on acute exposure to 4,300 m, and after 3 wk of acclimatization to 4,300 m. Subjects received a primed-continuous infusion of [6,6-2D]glucose (Brooks et al. J. Appl. Physiol. 70:919-927, 1991) and [3-13C]lactate and rested for a minimum of 90 min followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the sea level peak O2 consumption (VO2peak; 65 +/- 2% of both acute altitude and acclimatization). During rest at sea level, lactate appearance rate (Ra) was 0.52 +/- 0.03 mg.kg-1.min-1; this increased sixfold during exercise to 3.24 +/- 0.19 mg.kg-1.min-1. On acute exposure, resting lactate Ra rose from sea level values to 2.2 +/- 0.2 mg.kg-1.min-1. During exercise on acute exposure, lactate Ra rose to 18.6 +/- 2.9 mg.kg-1.min-1. Resting lactate Ra after acclimatization (1.77 +/- 0.25 mg.kg-1.min-1) was intermediate between sea level and acute exposure values. During exercise after acclimatization, lactate Ra (9.2 +/- 0.7 mg.kg-1.min-1) rose from resting values but was intermediate between sea level and acute exposure values. The increased exercise arterial lactate concentration response on arrival at high altitude and subsequent decrease with acclimatization are due to changes in blood lactate appearance.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives from the Andes than in lowlanders. In exploring how this was achieved, we found that, for a given work rate, Quechua highlanders at 4,200 m accumulated substantially less lactate than lowlanders at sea level normoxia (approximately 5-7 vs. 10-14 mM) despite hypobaric hypoxia. This phenomenon, known as the lactate paradox, was entirely refractory to normoxia-hypoxia transitions. In lowlanders, the lactate paradox is an acclimation; however, in Quechuas, the lactate paradox is an expression of metabolic organization that did not deacclimate, at least over the 6-wk period of our study. Thus it was concluded that this metabolic organization is a developmentally or genetically fixed characteristic selected because of the efficiency advantage of aerobic metabolism (high ATP yield per mol of substrate metabolized) compared with anaerobic glycolysis. Measurements of respiratory quotient indicated preferential use of carbohydrate as fuel for muscle work, which is also advantageous in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. Finally, minimizing the cost of muscle work was also reflected in energetic efficiency as classically defined (power output per metabolic power input); this was evident at all work rates but was most pronounced at submaximal work rates (efficiency approximately 1.5 times higher than in lowlander athletes). Because plots of power output vs. metabolic power input did not extrapolate to the origin, it was concluded 1) that exercise in both groups sustained a significant ATP expenditure not convertible to mechanical work but 2) that this expenditure was downregulated in Andean natives by thus far unexplained mechanisms.
There are conflicting reports in the literature which imply that the decrement in maximal aerobic power experienced by a sea-level (SL) resident sojourning at high altitude (HA) is either smaller or larger for the more aerobically "fit" person. In the present study, data collected during several investigations conducted at an altitude of 4300 m were analyzed to determine if the level of aerobic fitness influenced the decrement in maximal oxygen uptake (VO2max) at HA. The VO2max of 51 male SL residents was measured at an altitude of 50 m and again at 4300 m. The subjects' ages, heights, and weights (mean +/- SE) were 22 +/- 1 yr, 177 +/- 7 cm and 78 +/- 2 kg, respectively. The subjects' VO2max ranged from 36 to 60 ml X kg -1 X min -1 (mean +/- SE = 48 +/- 1) and the individual values were normally distributed within this range. Likewise, the decrement in VO2max at HA was normally distributed from 3 ml X kg-1 X min-1 (9% VO2max at SL) to 29 ml X kg-1 X min-1 (54% VO2max at SL), and averaged 13 +/- 1 ml X kg-1 X min-1 (27 +/- 1% VO2max at SL). The linear correlation coefficient between aerobic fitness and the magnitude of the decrement in VO2max at HA expressed in absolute terms was r = 0.56, or expressed as % VO2max at SL was r = 0.30; both were statistically significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
In 1959, Steele (Ann. N.Y. Acad. Sci. 82, 420–430) suggested a method for measuring the rates of appearance (Ra) and of disappearance (Rd) of a metabolite in an intact system under conditions when Ra and Rd were changing with time. Steele's method involved modelling the system by a one-compartment model whose effective volume was assumed. To overcome the problem of assuming an effective volume, a model consisting of two compartments rather than one has been postulated. While no distribution volume need now be assumed, a preliminary steady state experiment is required for identification of the coefficients governing exchange of material between the two compartments.In five conscious dogs 14C-hydroxymethyl inulin (tracer) was infused at a constant rate, while unlabelled inulin (tracee) was infused at varying predetermined rates and the plasma concentrations of both were measured. These were then fitted by a series of smoothly joined polynomials. When the calculated rates of appearance of unlabelled inulin were compared with the actual rates, equally good results were obtained with the one-compartment (using the best effective volume) and the two-compartment models. The calculated values of Rd and of the clearance of inulin were not validated experimentally, but their validity is likely since the equations for Rd and Ra are related, and the Ra component has been validated. The identity of unlabelled inulin and the 14C-hydroxymethyl inulin species was ascertained by gel filtration, and by the identity of their in vivo kinetics.
Article
In an attempt to determine the mechanism of decreased glucose tolerance in lean type 2 diabetics, glucose turnover in such subjects and controls was studied under basal conditions and during hyperglycemia induced by intravenous administration of glucose. The diabetics had decreased intravenous glucose tolerance and a fasting plasma glucose of 6-8 mM (108-144 mg/dl). Glucose was infused for 2 hr at 2 mg/kg per min in the controls (n = 16) and diabetics (n = 9). Furthermore, 11 healthy subjects were infused also with glucose at 4 mg/kg per min to match the glycemia of the diabetics. Glucose production, utilization, and metabolic clearance were assessed by the primed constant tracer infusion technique. In the basal state, diabetics showed normal plasma insulin, C peptide, and glucagon concentrations. Their increased basal plasma glucose levels were associated with normal rates of glucose production and utilization, but the metabolic glucose clearance was 21% lower than in the controls (P < 0.001), indicating decreased sensitivity to insulin. During infusion of glucose at 2 mg/kg per min, the hyperglycemia attained in the diabetics (170 mg/dl) was higher than that in controls (115 mg/dl) but comparable to that of the controls exposed to the higher glucose load. With the lower glucose load, metabolic clearance rate decreased more markedly in diabetics, again suggesting insulin resistance. This was further substantiated by the fact that, at the same insulin levels, glucose utilization did not increase more in the diabetics than in the controls, although the glycemia reached was considerably higher in the diabetics. With the lower glucose load, glucose production was suppressed to the same degree in the controls and diabetics, although the attained glycemia was much more marked in the latter. Because both insulin and hyperglycemia can suppress glucose production, some defect in the regulation of glucose production of the diabetics is also indicated. The insulin and C peptide levels were much higher in the controls than in the diabetics at the same levels of glycemia, demonstrating the inadequacy of insulin response to glycemia of the diabetics. Glucagon concentration was equally suppressed in all groups. In conclusion, impaired glucose tolerance of mild type 2 diabetics resulted both from inadequate insulin response and from decreased sensitivity to insulin. The insulin resistance could mainly be ascribed to inadequate glucose uptake, but a defect in glucose-induced suppression of glucose production may also have contributed.
Article
We examined the influence of plasma glucose concentration on whole-body glucose uptake and glucose clearance at two physiologic levels of hyperinsulinemia. Twelve healthy, young volunteers were divided into two groups (A and B); each subject participated in three studies. In group A, plasma insulin was raised and maintained by ∼100 μU/ml for 3 h, while plasma glucose concentration was clamped at hypoglycemic (60 ± 1 mg/dl), euglycemic (89 ± 1 mg/dl), or hyperglycemic (165 ± 3 mg/dl) levels. In group B, plasma insulin was raised by ∼50 μU/ml, while plasma glucose was clamped at 62 ± 1,86 ±2, or 143 ± 3 mg/dl for 3 h. At the higher insulin level (group A), glucose uptake rose from 5.2 ± 0.5 to 7.3 ± 0.6 to 12.2 ±1.0 mg/min· kg as plasma glucose was varied from low to high levels; glucose clearance fell slightly from 8.8 ± 1.0 to 7.8 ± 0.7 to 7.3 ± 0.6 ml/min·kg during the hypo-, eu-, and hyperglycemic clamps (P = NS). At the lower insulin level (group B), glucose uptake rose from 6.0 ± 1.2 to 8.1 ±1.7 mg/min·kg (P < 0.05) with increasing glucose levels, whereas glucose clearance fell significantly (P < 0.01) from 9.7 ± 1.8 to 5.6 ±1.1 ml/min·kg. When the data from both groups were analyzed together, insulin had a stimulatory effect on both glucose uptake and clearance. Elevation of the plasma glucose level had a similar stimulatory effect on glucose uptake (P < 0.001) but inhibited glucose clearance (P < 0.01). This inhibition, however, was modest (14% for the change from hypo- to euglycemia, and 16% for the change from eu- to hyperglycemia). We conclude that physiologic hyperglycemia exerts a modest inhibitory effect on glucose clearance, which is largely overcome at higher, yet still physiologic, plasma insulin levels (∼100 μU/ml).
Article
This investigation examined the relationship between alterations in plasma norepinephrine associated with 21 days of high-altitude exposure and muscle sympathetic activity both at rest and during exercise. Healthy sea level residents, divided into a control group (n = 5) receiving a placebo or a drug group (n = 6) receiving 240 mg/day of propranolol, were studied while at sea level, upon arrival (acute), and after 21 days of residence (chronic) at 4,300 m. Arterial norepinephrine levels and net leg uptake and release of norepinephrine were determine both at rest and during 45 min of submaximal exercise via samples collected from femoral arterial and venous catheters. Arterial norepinephrine levels increased significantly after chronic altitude exposure both at rest (84%) and during exercise (174%) compared with sea level and acute values. A net uptake of norepinephrine was found in resting legs at sea level (0.28 +/- 0.05 nmol/min) and with acute exposure (0.07 +/- 0.06 nmol/min); however, a significant switch to net leg norepinephrine release was observed with chronic altitude exposure (0.51 +/- 0.11 nmol/min). With exercise, a net release of norepinephrine by the leg occurred across all conditions with chronic exposure, again eliciting the greatest values (5.3 +/- 0.6, 8.0 +/- 1.7, and 14.4 +/- 3.1 nmol/min for sea level, acute, and chronic exposure, respectively). It was concluded that muscle sympathetic activity is significantly elevated both at rest and during submaximal exercise as a result of chronic high-altitude exposure, and muscle is a major contributor to the increase in plasma norepinephrine levels associated with prolonged altitude exposure. The presence of dense beta-blockade did not alter this adaptation to altitude.
Article
The sympathoadrenal system plays a major role in adjustments to both short- and long-term high-altitude exposure. Thus, this study investigated catecholamine responses in blood, urine, and muscle during 3 weeks' exposure to 4,300 m in control and beta-blocked subjects. Eleven healthy, sea level (SL)-resident men (aged 26 +/- 1 years) were studied under resting conditions at SL and on arrival and during 21 days at 4,300 m (Pikes Peak). Six subjects received 240 mg/d propranolol, and five were administered a placebo. Compared with SL values (38.7 +/- 4.3 v 32.4 +/- 2.8 micrograms/d for control and beta-blocked, respectively), urinary norepinephrine (NE) excretion increased significantly during altitude exposure, reaching peak values on days 6 to 7 (105.5 +/- 16.1 v 88.4 +/- 12.3 micrograms/d, respectively). Furthermore, resting arterial NE levels (increases 87%), as well as net NE release (decreases 219%) across the leg, both increased during acclimatization, indicating elevated sympathetic activity. Systemic vascular resistance and arterial pressures increased with time at altitude and correlated with NE measurements. Resting heart rates increased initially and then declined steadily after day 4 at altitude in both groups of subjects. Urinary epinephrine (EPI) excretion increased with initial exposure as compared with SL values (5.1 +/- 0.8 to 6.6 +/- 0.7 micrograms/d for control, 4.5 +/- 0.5 to 5.2 +/- 1.3 micrograms/d for beta-blocked); however, no consistent pattern was observed for the following 20 days at altitude. Arterial EPI increased upon acute exposure, but declined after 21 days' acclimatization. No changes in dopamine excretion were observed with beta-blockade or altitude exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
We determined whether increased glycolytic flux from hyperglycemia and hyperinsulinemia directly reduces fatty acid oxidation during exercise. Fatty acid oxidation rates were measured during constant-rate intravenous infusion of trace amounts of a long-chain fatty acid ([1-13C]palmitate; Pal) vs. a medium-chain fatty acid ([1-13C]octanoate; Oct). Six endurance-trained men cycled for 40 min at 50% of maximal O2 uptake 1) after an overnight fast ("fasting") and 2) after ingestion of 1.4 g/kg of glucose at 60 min and again 10 min before exercise (Glc). Glc caused hyperinsulinemia, a preexercise blood glucose of 6 mM, and a 34% reduction in total fat oxidation during exercise due to an approximately equal reduction in oxidation of plasma-free fatty acids (FFA) and intramuscular triglycerides (all P < 0.05). Oxidation of Pal was significantly reduced during Glc compared with fast (i.e., 70.0 +/- 4.1 vs. 86.0 +/- 1.9% of tracer infusion rate; P < 0.05). However, Glc had no effect on Oct oxidation, which is apparently not limited by mitochondrial transport. Furthermore, Glc reduced plasma FFA appearance 36% (P < 0.05), indicating a coordination of effects on adipose tissue and muscle. In summary, substrate oxidation during exercise can be regulated by increased glycolytic flux that is accompanied by a direct inhibition of long-chain fatty acid oxidation. These observations indicate that carbohydrate availability can directly regulate fat oxidation during exercise.
Article
1. Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia. Insulin action on glucose uptake has never been investigated during altitude hypoxia. 2. In eight healthy, sea level resident men (27 +/- 1 years (mean +/- S.E.M); weight, 72 +/- 2 kg; height, 182 +/- 2 cm) hyperinsulinaemic (50 mU min-1 m-2), euglycaemic clamps were carried out at sea level, and subsequently on days 2 and 7 after a rapid passive ascent to an altitude of 4559 m. 3. Acute mountain sickness scores increased in the first days of altitude exposure, with a peak on day 2. Basal HGP did not change with the transition from sea level (2.2 +/- 0.2 mg min-1 kg-1) to altitude (2.0 +/- 0.1 and 2.1 +/- 0.2 mg min-1 kg-1, days 2 and 7, respectively). Insulin-stimulated glucose uptake rate was halved on day two compared with sea level (4.5 +/- 0.6 and 9.8 +/- 1.1 mg min-1 kg-1, respectively; P < 0.05), and was partly restored on day 7 (7.4 +/- 1.4 mg min-1 kg-1; P < 0.05 vs. day two and sea level). Concentrations of glucagon and growth hormone remained unchanged, whereas glucose, C-peptide and cortisol increased on day 2. Noradrenaline concentrations increased during the stay at altitude, while adrenaline concentrations remained unchanged. In response to insulin infusion, catecholamines increased on day 2 (noradrenaline and adrenaline) and day 7 (adrenaline), but not at sea level. 4. In conclusion, insulin action decreases markedly in response to two days of altitude hypoxia, but improves with more prolonged exposure. HGP is always unchanged. The changes in insulin action may in part be explained by the changes in counter-regulatory hormones.
Article
Insulin-induced stimulation of muscle glucose uptake (MGU) is impaired in people with type 2 diabetes. To determine whether insulin-induced stimulation of splanchnic glucose uptake (SGU) is also impaired, we simultaneously measured leg glucose uptake (LGU) and SGU in 14 nondiabetic subjects and 16 subjects with type 2 diabetes using a combined organ catheterization-tracer infusion technique. Glucose was clamped at approximately 9.3 mmol/l, while insulin concentrations were maintained at approximately 72 pmol/l (low) and approximately 150 pmol/l (high) for 3 h each. Endogenous hormone secretion was inhibited with somatostatin. Total body glucose disappearance was lower (P < 0.01) and glucose production higher (P < 0.01) during both insulin infusions in the diabetic compared with the nondiabetic subjects, indicating insulin resistance. Splanchnic glucose production was higher (P < 0.05) in the diabetic subjects during the low but not the high insulin infusion. SGU was slightly lower in the diabetic than in the nondiabetic subjects during the low insulin infusion and 50-60% lower (P < 0.05) during the high insulin infusion. LGU (P < 0.001), but not SGU, was inversely correlated with the degree of visceral adiposity. The contribution of the indirect pathway to hepatic glycogen synthesis did not differ in the diabetic and nondiabetic subjects. In contrast, both flux through the UDP-glucose pool (P < 0.05) and the contribution of the direct pathway to glycogen synthesis (P < 0.01) were lower in the diabetic than in the nondiabetic subjects, indicating decreased uptake and/or phosphorylation of extracellular glucose. On the other hand, glycogenolysis was equally suppressed in both groups. In summary, type 2 diabetes impairs the ability of insulin to stimulate both MGU and SGU. The defect appears to reside at a proximal (e.g., glucokinase) metabolic step and is not related to the degree of visceral adiposity. These data suggest that impaired hepatic glucose uptake as well as MGU contribute to hyperglycemia in people with type 2 diabetes.
Article
MAZZEO, R.S., and J.T. REEVES. Adrenergic contribution during acclimatization to high altitude: Perspectives from Pikes Peak. Exerc. Sport Sci. Rev., Vol. 31, No. 1, pp. 13-18, 2003. We have examined the sympathoadrenal responses to both acute and chronic high-altitude exposure at the summit of Pikes Peak, CO, in both men and women. A dissociation between the adrenal medullary response (acute) with that of the sympathetic nervous system (Chronic) is observed. Both alpha- and beta-adrenergic contributions to key metabolic and physiologic adjustments to high-altitude exposure are evident.
Article
This investigation examined the influence of alpha-adrenergic blockade on plasma and urinary catecholamine responses to both exercise and high-altitude exposure. Sixteen nonsmoking, eumenorrheic women (age 23.2 +/- 1.4 years, 68.7 +/- 1.0 kg) were studied at sea level and during 12 days of high-altitude exposure (4,300 m). Subjects received either alpha-blockade (prazosin 3 mg/d) or a placebo in a double-blinded, randomized fashion. Resting plasma and 24-hour urine samples were collected periodically throughout the duration of the study. Further, subjects participated in submaximal exercise tests (50 minutes at 50% sea level maximum oxygen consumption [Vo2max]) at Sea level and on days 1 and 12 at altitude. Urinary norepinephrine (NE) excretion rates increased significantly over time at altitude, with blocked subjects having greater values compared to controls. Plasma NE levels increased significantly with chronic altitude exposure compared to sea level and acute hypoxia both at rest and during exercise. NE levels at rest were greater for blocked compared to control subjects during all conditions. Urinary and plasma epinephrine (EPI) levels increased dramatically, with acute altitude exposure returning to sea level values by day 12 of altitude exposure. EPI levels were greater for blocked compared to placebo both at rest and during exercise for all conditions studied. Changes in alpha-adrenergic activity over time at altitude were associated with select metabolic and physiologic adjustments. The presence of alpha-blockade significantly affected these responses during chronic altitude exposure. It was concluded that: (1) alpha-adrenergic blockade elicited a potentiated sympathoadrenal response to the stress of both exercise as well as high-altitude exposure, and (2) the sympathetics, via alpha-adrenergic stimulation, contribute to a number of key adaptations associated with acclimatization to high altitude.
Article
To determine whether the insulin dose-response curves for suppression of endogenous glucose production (EGP) and stimulation of splanchnic glucose uptake (SGU) differ in nondiabetic humans and are abnormal in type 2 diabetes, 14 nondiabetic and 12 diabetic subjects were studied. Glucose was clamped at similar to9.5 mmol/l and endogenous hormone secretion inhibited by somatostatin, while glucagon and growth hormone were replaced by an exogenous infusion. Insulin was progressively increased from similar to150 to similar to350 and similar to700 pmol/l by means of an exogenous insulin infusion, while EGP, SGU, and leg glucose uptake (LGU) were measured using the splanchnic and leg catheterization methods, combined with a [3-3H]glucose infusion. In nondiabetic subjects, an increase in insulin from similar to150 to similar to350 pmol/l resulted in maximal suppression of EGP, whereas SGU continued to increase (P < 0.001) when insulin was increased to similar to700 pmol/l. In contrast, EGP progressively decreased (P < 0.001) and SGU progressively increased (P < 0.001) in the diabetic subjects as insulin increased from similar to 150 to similar to 700 pmol/l. Although EGP was higher (P < 0.01) in the diabetic than nondiabetic subjects only at the lowest insulin concentration, SGU was lower (P < 0.01) in the diabetic subjects at all insulin concentrations tested. On the other hand, in contrast to LGU and overall glucose disposal, the increment in SGU in response to both increments in insulin did not differ in the diabetic and nondiabetic subjects, implying a right shifted but parallel dose-response curve. These data indicate that the dose-response curves for suppression of glucose production and stimulation of glucose uptake differ in nondiabetic subjects and are abnormal in people with type 2 diabetes. Taken together, these data also suggest that agents that enhance SGU in diabetic patients (e.g. glucokinase activators) are likely to improve glucose tolerance.