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Oxidative Stress and Inflammation Are Associated With Age-Related Endothelial Dysfunction in Men With Low Testosterone.
Babcock, MC, DuBose, LE, Witten, TL, Stauffer, BL, Hildreth, KL, Schwartz, RS, Kohrt, WM, Moreau, KL
The Journal of clinical endocrinology and metabolism. 2022;107(2):e500-e514
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Serum testosterone declines gradually with age at a rate of ~1% per year after the third decade. Vascular aging, featuring endothelial dysfunction mediated by oxidative stress and inflammation, is a major risk factor for the development of age-associated cardiovascular disease (CVD). The aim of this study was to examine the effects of low testosterone on cardiovascular aging in men. This study is a cross-sectional study which recruited 58 healthy men of all races/ethnic backgrounds aged 50-75 years (middle-aged/older) and 18-40 years (young). Results show that middle-aged/older men with lower testosterone have evidence of “accelerated” vascular aging, as indicated by a greater age-associated endothelial dysfunction of large arteries compared with their age-matched peers. The greater macrovascular endothelial dysfunction in middle-aged/older men with chronically low testosterone was independent of CVD risk factors or symptoms of androgen deficiency. Furthermore, increased systemic oxidative stress and inflammation are mechanistically linked to the greater age-associated endothelial dysfunction in middle-aged/older men with lower testosterone. Authors conclude that normal physiological levels of testosterone may be beneficial to cardiovascular health by attenuating the age-related decline in endothelial function.
Abstract
CONTEXT Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk. OBJECTIVE We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. METHODS This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. RESULTS During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = -0.41; P = 0.002), and CRP (r = -0.28; P = 0.041). CONCLUSION Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.
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Fructose metabolism and metabolic disease.
Hannou, SA, Haslam, DE, McKeown, NM, Herman, MA
The Journal of clinical investigation. 2018;128(2):545-555
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Sugar consumption is thought to be a contributing factor in the increase in diabetes and obesity and the associated risk of cardiovascular disease worldwide. Sucrose (table sugar) and high fructose corn syrup contain almost equal amounts of fructose and glucose and are commonly added to processed foods. Whilst long-term studies are lacking, some short-term intervention studies show that fructose can impair lipid metabolism and insulin sensitivity in humans. This article reviews the biochemistry and molecular genetics of fructose metabolism as well as potential mechanisms by which excessive fructose consumption contributes to cardiometabolic disease. Fructose absorption in the human intestine is saturable, and there is a large range in capacity to absorb fructose between individuals, and unabsorbed fructose may contribute to gastrointestinal symptoms including pain and bloating. Fructose concentrations in the blood can increase 10-fold after consumption, but are rapidly cleared, mostly by the liver, where it provides substrate for metabolic processes, but may also be involved in signalling functions. Fructose may enhance glucose uptake by the liver and storage as glycogen and lipids. It may also increase production of uric acid which is implicated with gout. Excessive fructose consumption affects lipid metabolism and may contribute to fat accumulation in the liver and increase circulating triglycerides, a risk factor for heart disease. In animal models it also induces increased insulin levels. Fructose is one of the sweetest sugars which may affect appetite and overeating. It may also induce addiction-like behaviours such as binging and dependence in part by stimulating dopaminergic pathways. It also appears to induce leptin resistance which further increases food intake and obesity.
Abstract
Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.
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Glucotypes reveal new patterns of glucose dysregulation.
Hall, H, Perelman, D, Breschi, A, Limcaoco, P, Kellogg, R, McLaughlin, T, Snyder, M
PLoS biology. 2018;16(7):e2005143
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One in 10 individuals is affected by diabetes, a condition involving abnormal regulation of blood glucose. Currently, diabetes is assessed using single-time or average measurements of blood glucose, without consideration for how blood glucose fluctuates over time. This study used continuous glucose monitoring (CGM) technology to evaluate how blood glucose fluctuates in individuals over time. The authors found that many individuals considered nondiabetic by standard measures experienced frequent elevations in blood glucose levels into the pre-diabetic or diabetic range (15% and 2% of the time, respectively). The authors developed a model for determining the “glucotype” (low, moderate or severe variability) of an individual, a more comprehensive measure of glucose patterns than the standard tests currently used. The authors argue that CGM should become an important tool in early identification of those at risk for type 2 diabetes.
Abstract
Diabetes is an increasing problem worldwide; almost 30 million people, nearly 10% of the population, in the United States are diagnosed with diabetes. Another 84 million are prediabetic, and without intervention, up to 70% of these individuals may progress to type 2 diabetes. Current methods for quantifying blood glucose dysregulation in diabetes and prediabetes are limited by reliance on single-time-point measurements or on average measures of overall glycemia and neglect glucose dynamics. We have used continuous glucose monitoring (CGM) to evaluate the frequency with which individuals demonstrate elevations in postprandial glucose, the types of patterns, and how patterns vary between individuals given an identical nutrient challenge. Measurement of insulin resistance and secretion highlights the fact that the physiology underlying dysglycemia is highly variable between individuals. We developed an analytical framework that can group individuals according to specific patterns of glycemic responses called "glucotypes" that reveal heterogeneity, or subphenotypes, within traditional diagnostic categories of glucose regulation. Importantly, we found that even individuals considered normoglycemic by standard measures exhibit high glucose variability using CGM, with glucose levels reaching prediabetic and diabetic ranges 15% and 2% of the time, respectively. We thus show that glucose dysregulation, as characterized by CGM, is more prevalent and heterogeneous than previously thought and can affect individuals considered normoglycemic by standard measures, and specific patterns of glycemic responses reflect variable underlying physiology. The interindividual variability in glycemic responses to standardized meals also highlights the personal nature of glucose regulation. Through extensive phenotyping, we developed a model for identifying potential mechanisms of personal glucose dysregulation and built a webtool for visualizing a user-uploaded CGM profile and classifying individualized glucose patterns into glucotypes.
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Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans.
Johnston, JD, Ordovás, JM, Scheer, FA, Turek, FW
Advances in nutrition (Bethesda, Md.). 2016;7(2):399-406
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Chrononutrition is an emerging field that links the body’s metabolism to its endogenous circadian rhythm. It is now recognised that numerous circadian clocks are found within all major tissues and most cells of the body. This complex network of clocks influences a wide range of biological processes including neuronal, endocrine, metabolic and behavioural function. When there is a disruption in a single circadian clock, whole-organism homeostasis can be impacted, potentially resulting in the development of disease. This review explains the potential mechanisms by which circadian clocks influence biological processes through transgenic animal studies, and how they are being translated to human genetics and metabolomics. The principles of chrononutrition are clinically significant factors that should be considered when managing and treating metabolic disease, as well as maintaining health in the general population.
Abstract
Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population.
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Excessive Sugar Consumption May Be a Difficult Habit to Break: A View From the Brain and Body.
Tryon, MS, Stanhope, KL, Epel, ES, Mason, AE, Brown, R, Medici, V, Havel, PJ, Laugero, KD
The Journal of clinical endocrinology and metabolism. 2015;100(6):2239-47
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It is widely known that people eat to relieve stress. Rodent studies have shown that sugar consumption switches off activity in the networks that mediate the stress induced hypothalamic-pituitary-adrenal (HPA) autonomic nervous system. This study aimed to compare the effects of consuming drinks, sweetened with either sucrose or aspartame, on cortisol responses induced by stress. The researchers found that sucrose consumption was associated reduced stress induced cortisol, and a trend towards lower cortisol. Aspartame did not have the same effect. The Montreal Imaging Stress Task (MIST) was used to map areas of the brain associated with stress. It was found that sugar consumption caused a diminished response to MIST after two weeks of sucrose consumption, and cortisol was elevated after two weeks of aspartame. The study concluded that brain negative feedback pathways are affected by sugar, and consequently may make stressed individuals more reliant or addicted to sugar. In turn, this increases the likelihood of obesity and its associated chronic diseases.
Abstract
CONTEXT Sugar overconsumption and chronic stress are growing health concerns because they both may increase the risk for obesity and its related diseases. Rodent studies suggest that sugar consumption may activate a glucocorticoid-metabolic-brain-negative feedback pathway, which may turn off the stress response and thereby reinforce habitual sugar overconsumption. OBJECTIVE The objective of the study was to test our hypothesized glucocorticoid-metabolic-brain model in women consuming beverages sweetened with either aspartame of sucrose. DESIGN This was a parallel-arm, double-masked diet intervention study. SETTING The study was conducted at the University of California, Davis, Clinical and Translational Science Center's Clinical Research Center and the University of California, Davis, Medical Center Imaging Research Center. PARTICIPANTS Nineteen women (age range 18-40 y) with a body mass index (range 20-34 kg/m(2)) who were a subgroup from a National Institutes of Health-funded investigation of 188 participants assigned to eight experimental groups. INTERVENTION The intervention consisted of sucrose- or aspartame-sweetened beverage consumption three times per day for 2 weeks. MAIN OUTCOME MEASURES Salivary cortisol and regional brain responses to the Montreal Imaging Stress Task were measured. RESULTS Compared with aspartame, sucrose consumption was associated with significantly higher activity in the left hippocampus (P = .001). Sucrose, but not aspartame, consumption associated with reduced (P = .024) stress-induced cortisol. The sucrose group also had a lower reactivity to naltrexone, significantly (P = .041) lower nausea, and a trend (P = .080) toward lower cortisol. CONCLUSION These experimental findings support a metabolic-brain-negative feedback pathway that is affected by sugar and may make some people under stress more hooked on sugar and possibly more vulnerable to obesity and its related conditions.
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Short sleep duration and dietary intake: epidemiologic evidence, mechanisms, and health implications.
Dashti, HS, Scheer, FA, Jacques, PF, Lamon-Fava, S, Ordovás, JM
Advances in nutrition (Bethesda, Md.). 2015;6(6):648-59
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Short sleep duration is associated with various cardio-metabolic parameters that contribute to chronic disease. While the underlying mechanism is multifactorial, the link may be mediated through changes in dietary intake. This review provides an overview of the relationship between chronic short sleep duration and dietary intake. This review indicates that short sleep duration is associated with higher total caloric intake, higher fat intake and diets with relatively higher fat and lower protein composition. Further epidemiological studies are required to better establish the relationship between chronic short sleep and dietary patterns, and improvements in sleep should be an added factor in weight management programmes.
Abstract
Links between short sleep duration and obesity, type 2 diabetes, hypertension, and cardiovascular disease may be mediated through changes in dietary intake. This review provides an overview of recent epidemiologic studies on the relations between habitual short sleep duration and dietary intake in adults from 16 cross-sectional studies. The studies have observed consistent associations between short sleep duration and higher total energy intake and higher total fat intake, and limited evidence for lower fruit intake, and lower quality diets. Evidence also suggests that short sleepers may have irregular eating behavior deviating from the traditional 3 meals/d to fewer main meals and more frequent, smaller, energy-dense, and highly palatable snacks at night. Although the impact of short sleep duration on dietary intake tends to be small, if chronic, it may contribute to an increased risk of obesity and related chronic disease. Mechanisms mediating the associations between sleep duration and dietary intake are likely to be multifactorial and include differences in the appetite-related hormones leptin and ghrelin, hedonic pathways, extended hours for intake, and altered time of intake. Taking into account these epidemiologic relations and the evidence for causal relations between sleep loss and metabolism and cardiovascular function, health promotion strategies should emphasize improved sleep as an additional factor in health and weight management. Moreover, future sleep interventions in controlled studies and sleep extension trials in chronic short sleepers are imperative for establishing whether there is a causal relation between short sleep duration and changes in dietary intake.
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Timing of food intake predicts weight loss effectiveness.
Garaulet, M, Gómez-Abellán, P, Alburquerque-Béjar, JJ, Lee, YC, Ordovás, JM, Scheer, FA
International journal of obesity (2005). 2013;37(4):604-11
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As obesity is a multifactorial disease, dietary interventions must take into account a range of physiological and psychological variables. There is emerging evidence linking energy regulation to the circadian clock, emphasizing that the timing of eating may play a role in weight regulation. The aim of this study was to evaluate the role of food timing in weight loss effectiveness among 420 overweight or obese participants during a 20-week weight loss treatment. Participants were grouped as either early or late eaters for consuming their main meal, and their energy intake, expenditure, appetite hormones, CLOCK genotype, sleep duration and chronotype were studied. In this study, those who ate their main meal late lost significantly less weight than early eaters. The findings of this study indicate that timing of food intake relates to long-term weight loss effectiveness in humans. These findings may help in developing therapeutic strategies for weight loss that incorporates the timing of food consumption with the traditional energy balance and macronutrient composition.
Abstract
BACKGROUND There is emerging literature demonstrating a relationship between the timing of feeding and weight regulation in animals. However, whether the timing of food intake influences the success of a weight-loss diet in humans is unknown. OBJECTIVE To evaluate the role of food timing in weight-loss effectiveness in a sample of 420 individuals who followed a 20-week weight-loss treatment. METHODS Participants (49.5% female subjects; age (mean ± s.d.): 42 ± 11 years; BMI: 31.4 ± 5.4 kg m(-2)) were grouped in early eaters and late eaters, according to the timing of the main meal (lunch in this Mediterranean population). 51% of the subjects were early eaters and 49% were late eaters (lunch time before and after 1500 hours, respectively), energy intake and expenditure, appetite hormones, CLOCK genotype, sleep duration and chronotype were studied. RESULTS Late lunch eaters lost less weight and displayed a slower weight-loss rate during the 20 weeks of treatment than early eaters (P=0.002). Surprisingly, energy intake, dietary composition, estimated energy expenditure, appetite hormones and sleep duration was similar between both groups. Nevertheless, late eaters were more evening types, had less energetic breakfasts and skipped breakfast more frequently that early eaters (all; P<0.05). CLOCK rs4580704 single nucleotide polymorphism (SNP) associated with the timing of the main meal (P=0.015) with a higher frequency of minor allele (C) carriers among the late eaters (P=0.041). Neither sleep duration, nor CLOCK SNPs or morning/evening chronotype was independently associated with weight loss (all; P>0.05). CONCLUSIONS Eating late may influence the success of weight-loss therapy. Novel therapeutic strategies should incorporate not only the caloric intake and macronutrient distribution - as is classically done - but also the timing of food.
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Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
Wing, RR, Bolin, P, Brancati, FL, Bray, GA, Clark, JM, Coday, M, Crow, RS, Curtis, JM, Egan, CM, Espeland, MA, et al
The New England journal of medicine. 2013;369(2):145-54
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Weight loss is recommended for overweight or obese patients with type 2 diabetes as it increases glycaemic control, reduces risk factors of cardiovascular disease and improves overall quality of life. These benefits, however, are based on short-term studies and the long-term effects of weight loss in this population have not been examined. The aim of this randomised trial was to elucidate whether an intensive lifestyle intervention of weight loss and increased physical activity would decrease cardiovascular morbidity and mortality in overweight or obese adults with type 2 diabetes. Participants were either assigned to an intervention group receiving diet and exercise counselling, or a control group receiving diabetes support and education. A total of 5145 patients were enrolled in the study and the median follow-up was nearly 10 years. The findings of this study showed that an intensive lifestyle intervention did not reduce the risk of cardiovascular morbidity and mortality, as compared with a control programme of diabetes support and education, among overweight and obese patients. While this primary outcome was not reduced, participants in the intervention group experienced various clinically beneficial outcomes throughout the follow-up period.
Abstract
BACKGROUND Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. METHODS In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. RESULTS The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.).
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Three 15-min bouts of moderate postmeal walking significantly improves 24-h glycemic control in older people at risk for impaired glucose tolerance.
DiPietro, L, Gribok, A, Stevens, MS, Hamm, LF, Rumpler, W
Diabetes care. 2013;36(10):3262-8
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The insulin response is known to decline with age, which puts older people at risk of hyperglycaemia after eating. Insulin and exercise stimulate the uptake of glucose into skeletal muscle so exercise could aid insulin in age-related impaired glucose tolerance (IGT). This small randomised controlled trial (RCT) used a multiple crossover design to compare the effect of exercise timing and frequency on glycaemia control in older people. The ten trial subjects were at risk of impaired glucose tolerance (IGT), but were otherwise healthy with an average age of sixty-nine years old. Subjects were housed in whole room calorimeters, fed three standardised meals a day and glucose levels were monitored. Subjects were randomly assigned to walk on a treadmill for either fifteen minutes after each of the three meals, or walk for forty-five minutes either at mid-morning or mid-afternoon. It was found that that both the morning walk and the post-meal walking decreased 24 hour glucose concentration, whilst the afternoon walk had little impact. Post-meal walking was effective at lowering glucose levels after each meal including dinner, where the other exercise protocols were not. The author concluded that the timing of the exercise may be as important, if not more, than volume. Short (15 minute) bouts of post-meal walking could be manageable for older people and appears to be an effective way of controlling post eating hyperglycaemia.
Abstract
OBJECTIVE The purpose of this study was to compare the effectiveness of three 15-min bouts of postmeal walking with 45 min of sustained walking on 24-h glycemic control in older persons at risk for glucose intolerance. RESEARCH DESIGN AND METHODS Inactive older (≥60 years of age) participants (N=10) were recruited from the community and were nonsmoking, with a BMI<35 kg/m2 and a fasting blood glucose concentration between 105 and 125 mg dL(-1). Participants completed three randomly ordered exercise protocols spaced 4 weeks apart. Each protocol comprised a 48-h stay in a whole-room calorimeter, with the first day serving as the control day. On the second day, participants engaged in either 1) postmeal walking for 15 min or 45 min of sustained walking performed at 2) 10:30 a.m. or 3) 4:30 p.m. All walking was on a treadmill at an absolute intensity of 3 METs. Interstitial glucose concentrations were determined over 48 h with a continuous glucose monitor. Substrate utilization was measured continuously by respiratory exchange (VCO2/VO2). RESULTS Both sustained morning walking (127±23 vs. 118±14 mg dL(-1)) and postmeal walking (129±24 vs. 116±13 mg dL(-1)) significantly improved 24-h glycemic control relative to the control day (P<0.05). Moreover, postmeal walking was significantly (P<0.01) more effective than 45 min of sustained morning or afternoon walking in lowering 3-h postdinner glucose between the control and experimental day. CONCLUSIONS Short, intermittent bouts of postmeal walking appear to be an effective way to control postprandial hyperglycemia in older people.
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Physiologic and behavioral indicators of energy deficiency in female adolescent runners with elevated bone turnover.
Barrack, MT, Van Loan, MD, Rauh, MJ, Nichols, JF
The American journal of clinical nutrition. 2010;92(3):652-9
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Young female runners are more likely to have a low bone mass for their age. It is thought that this might be partly due to them using more energy (calories) than they consume. This study looked at the relationship between nutrition intake and biomarkers of bone turnover in young female runners. Participants were competitive cross-country runners, aged 14-17. The girls ate their usual diet and kept a food diary for a week, to allow the researchers to analyse their nutritional intakes. Runners that had an elevated bone turnover consumed significantly less calories and calcium than the runners with a normal bone turnover. They were also more likely to have a lower body mass, fewer menstrual cycles, lower oestrogen and vitamin D levels, lower BMI and lower bone mass. The authors concluded that nutritional support to increase energy and calcium intake, and vitamin D levels may improve bone growth in young female runners.
Abstract
BACKGROUND Female adolescent runners have an elevated prevalence of low bone mass for agemdashan outcome that may be partially due to inadequate energy intake. OBJECTIVE The objective was to evaluate diet, menstrual history, serum hormone concentrations, and bone mass in female adolescent runners with normal or abnormal bone turnover. DESIGN Thirty-nine cross-country runners (age: 15.7 plusmn 0.2 y) participated in the study, which included a 7-d dietary assessment with the use of a food record and daily 24-h dietary recalls; serum measures of insulin-like growth factor I, estradiol, leptin, parathyroid hormone, progesterone, triiodothyronine, 25-hydroxycholecalciferol, bone-specific alkaline phosphatase (BAP), and cross-linked C-telopeptides of type I collagen (CTX); an evaluation of height, weight, bone mass, and body composition with the use of dual-energy X-ray absorptiometry; and a questionnaire to assess menses and sports participation. Age- and sex-specific BAP and CTX concentrations of at least the 97th percentile and no greater than the third percentile, respectively, were considered abnormal. RESULTS All abnormal BAP and CTX concentrations fell within the elevated ( ge 97%) range. Runners with an elevated bone turnover (EBT) (n = 13) had a lower body mass, fewer menstrual cycles in the past year, lower estradiol and 25-hydroxycholecalciferol concentrations, and a higher prevalence of body mass index lt 10% for age, vitamin D insufficiency, amenorrhea, and low bone mass. Girls with EBT consumed less than the recommended amounts of energy and had a higher prevalence of consuming lt 1300 mg Ca than did those with normal bone turnover. CONCLUSIONS Runners with EBT had a profile consistent with energy deficiency. Nutritional support to increase energy, calcium intake, and 25-hydroxycholecalciferol concentrations may improve bone mineral accrual in young runners with EBT. This trial was registered at clinicaltrials.gov as NCT01059968.