Ian A. Macdonald

Integrative physiology of human adipose tissue

Adipose tissue is now recognised as a highly active metabolic and endocrine organ. Great strides have been made in uncovering the multiple functions of the adipocyte in cellular and molecular detail, but it is essential to remember that adipose tissue normally operates as a structured whole. Its functions are regulated by multiple external influences such as autonomic nervous system activity, the rate of blood flow and the delivery of a complex mix of substrates and hormones in the plasma. Attempting to understand how all these factors converge and regulate adipose tissue function is a prime example of integrative physiology. Adipose tissue metabolism is extremely dynamic, and the supply of and removal of substrates in the blood is acutely regulated according to the nutritional state. Adipose tissue possesses the ability to a very large extent to modulate its own metabolic activities, including differentiation of new adipocytes and production of blood vessels as necessary to accommodate increasing fat stores. At the same time, adipocytes signal to other tissues to regulate their energy metabolism in accordance with the bodys nutritional state. Ultimately adipocyte fat stores have to match the bodys overall surplus or deficit of energy. This implies the existence of one (or more) signal(s) to the adipose tissue that reflects the bodys energy status, and points once again to the need for an integrative view of adipose tissue function.

The Effect of Flavanol-rich Cocoa on the fMRI Response to a Cognitive Task in Healthy Young People

Flavanols are the main flavonoids found in cocoa and chocolate, and can be especially abundant in certain cocoas. Research over the past decade has identified flavanols as showing diverse beneficial physiologic and antioxidant effects, particularly in context of vascular function. The present study employed functional magnetic resonance imaging based on blood oxygenation level-dependent (BOLD) contrast to explore the effect of flavanols on the human brain. Magnetic resonance imaging was used to measure BOLD responses to a cognitive task in 16 healthy young subjects. The data presented show an increase in the BOLD signal intensity in response to a cognitive task following ingestion of flavanol-rich cocoa (5 days of 150 mg of cocoa flavanols). This may arise either as a result of altered neuronal activity, or a change in vascular responsiveness, or both—the net effect then being dependent on which of the two effects is dominant. No significant effects were evident in behavioral reaction times, switch cost, and heart rate after consumption of this moderate dose of cocoa flavanols. A pilot study evaluated the relationship between cerebral blood flow and a single acute dose (450 mg flavanols) of flavanol-rich cocoa and showed that flavanol-rich cocoa can increase the cerebral blood flow to gray matter, suggesting the potential of cocoa flavanols for treatment of vascular impairment, including dementia and strokes, and thus for maintaining cardiovascular health.

The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction.

OBJECTIVE: To assess the contribution of a thermogenic effect to weight loss induced by eight weeks treatment with sibutramine (15mg/d) vs placebo in obese subjects.DESIGN: Randomised, placebo controlled, double blind study.SUBJECTS: Thirty-two (7 male, 25 female) healthy obese body mass index (BMI) 33.9±0.5 kg/m2 subjects completed the trial.MEASUREMENTS: Energy expenditure (EE) was measured by indirect calorimetry during a 32 h stay in a respiration chamber before and after 8 weeks treatment. Visual analogue scales were completed for assessment of appetite sensation. No dietary restriction was given.RESULTS: Sibutramine caused a significant weight loss compared with placebo (−2.4 kg vs+0.3 kg, P<0.001). Despite the larger weight loss after 8 weeks, 24-h EE did not decrease more in the sibutramine than in the placebo group (−2.6% vs −2.5%, P=ns). When the changes in 24-h EE were adjusted for changes in body weight, 24-h EE decreased significantly less in the sibutramine group than in the placebo group (0.8% vs 3.8%, P<0.02). Sibutramine significantly decreased both hunger and anticipated food consumption, and increased satiety scores.CONCLUSIONS: The weight reducing effect of sibutramine in humans is caused by a dual mechanism: reduction of energy intake by increasing satiety and decreasing hunger and prevention of the decline in EE that follows weight loss.

Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men

OBJECTIVE To investigate the effect of normal aging on the protective responses against hypoglycemia, in view of the fact that type II diabetes is primarily a disease of aging, and its treatment is associated with risk of hypoglycemia with cognitive impairment. RESEARCH DESIGN AND METHODS Plasma glucose was lowered stepwise from 5 to 2.4 mmol/l and restored by manipulation of an infusion of 20% glucose during 220-min intravenous infusion of 1.5 mU · kg−1 · min−1 soluble insulin in 14 men; 7 were aged 60–70 years and the other 7 were 22–26 years. Changes in neurohumoral responses, subjective awareness, and choice reaction time were assessed. RESULTS Hormonal responses were similar in the two groups, but symptoms began earlier in the younger men (at a plasma glucose of 3.6 ± 0.1 vs. 3.0 ± 0.2 mmol/l, P = 0.02) and were more intense (P = 0.03). Four-choice reaction time, a measure of psychomotor coordination, deteriorated earlier in the older men (at a plasma glucose of 3.0 ± 0.1 vs. 2.6 ± 0.1 mmol/l, P = 0.07) and to a greater degree. The difference between the glucose level for subjective awareness of hypoglycemia and the onset of cognitive dysfunction was lost in the older men (0.0 ± 0.2 vs. 0.8 ± 0.1 mmol/l, P < 0.007). CONCLUSIONS Older men are prone to more severe cognitive impairment during hypoglycemia than younger men and are less likely to experience prior warning symptoms if blood glucose falls. This effect of normal aging may contribute to the risk of severe hypoglycemia in older diabetic patients treated with sulfonylureas and insulin.

Asthma as a Barrier to Children's Physical Activity: Implications for Body Mass Index and Mental Health

OBJECTIVES. The purpose of this work was to identify barriers to physical activity in children with asthma and to compare their customary activity levels, BMI and emotional well-being with that of children with other medical conditions. It was hypothesized that children with asthma would have higher BMI and lower levels of customary activity. PATIENTS AND METHODS. We studied children aged 7 to 14 years attending hospital outpatient clinics for either asthma (asthma group: n = 56) or for otorhinolaryngology or dermatological conditions (nonasthma group: n = 61). In this cross-sectional survey, childrens weight and height were recorded and their BMI classified according to International Obesity Task Force classification of obesity. Child mental health was assessed by the parent-rated Strengths and Difficulties Questionnaire. The child-rated Physical Activity Questionnaire assessed total sedentary and physical activities during the previous 24 hours. RESULTS. The asthma group had a higher mean BMI (20.78 vs 18.82) and higher rates of obesity (21.4% vs 6.6%). Children with asthma reported fewer physical activities than the nonasthma group (median 4 per day vs 6 per day) but comparable levels of sedentary activities. Asthma was the strongest predictor of lower activity scores, followed by younger age. The asthma group had higher levels of emotional difficulties and, within this group, more active children had better mental health. More parents in the asthma group identified the childs health as a barrier to exercise (60.7% vs 11%). The same was true of children (66.1% vs 11.5%). CONCLUSIONS. We found that children attending a hospital clinic for asthma were more likely to be obese and were significantly less active than a comparison group with other medical conditions. Asthma was identified as a barrier to exercise by parents and children. Strategies to promote exercise within pediatric asthma care are needed to protect both mental and physical health.

Regular meal frequency creates more appropriate insulin sensitivity and lipid profiles compared with irregular meal frequency in healthy lean women

Objective: To investigate the impact of irregular meal frequency on circulating lipids, insulin, glucose and uric acid concentrations which are known cardiovascular risk factors.Design: A randomised crossover dietary intervention study.Setting: Nottingham, UK—Healthy free-living women.Subjects: A total of nine lean healthy women aged 18–42 y recruited via advertisement.Intervention: A randomised crossover trial with two phases of 14 days each. In Phase 1, subjects consumed their normal diet on either 6 occasions per day (regular) or by following a variable meal frequency (3–9 meals/day, irregular). In Phase 2, subjects followed the alternative meal pattern to that followed in Phase 1, after a 2-week (wash-out) period. Subjects were asked to come to the laboratory after an overnight fast at the start and end of each phase. Blood samples were taken for measurement of circulating glucose, lipids, insulin and uric acid concentrations before and for 3 h after consumption of a high-carbohydrate test meal.Results: Fasting glucose and insulin values were not affected by meal frequency, but peak insulin and AUC of insulin responses to the test meal were higher after the irregular compared to the regular eating patterns (P<0.01). The irregular meal frequency was associated with higher fasting total (P<0.01) and LDL (P<0.05) cholesterol.Conclusion: The irregular meal frequency appears to produce a degree of insulin resistance and higher fasting lipid profiles, which may indicate a deleterious effect on these cardiovascular risk factors.Sponsorship: The Ministry of Health and Medical Education, IR Iran.

Effects of Acute Insulin-Induced Hypoglycemia on Indices of Inflammation Putative mechanism for aggravating vascular disease in diabetes

OBJECTIVE To examine the effects of acute insulin-induced hypoglycemia on inflammation, endothelial dysfunction, and platelet activation in adults with and without type 1 diabetes. RESEARCH DESIGN AND METHODS We studied 16 nondiabetic adults and 16 subjects with type 1 diabetes during euglycemia (blood glucose 4.5 mmol/l) and hypoglycemia (blood glucose 2.5 mmol/l). Markers of inflammation, thrombosis, and endothelial dysfunction (soluble P-selectin, interleukin-6, von Willebrand factor [vWF], tissue plasminogen activator [tPA], high-sensitivity C-reactive protein [hsCRP], and soluble CD40 ligand [sCD40L]) were measured; platelet-monocyte aggregation and CD40 expression on monocytes were determined using flow cytometry. RESULTS In nondiabetic participants, platelet activation occurred after hypoglycemia, with increments in platelet-monocyte aggregation and P-selectin (P ≤ 0.02). Inflammation was triggered with CD40 expression increasing maximally at 24 h (3.13 ± 2.3% vs. 2.06 ± 1.0%) after hypoglycemia (P = 0.009). Both sCD40L and hsCRP (P = 0.02) increased with a nonsignificant rise in vWF and tPA, indicating a possible endothelial effect. A reduction in sCD40L, tPA, and P-selectin occurred during euglycemia (P = 0.03, P ≤ 0.006, and P = 0.006, respectively). In type 1 diabetes, both CD40 expression (5.54 ± 4.4% vs. 3.65 ± 1.8%; P = 0.006) and plasma sCD40L concentrations increased during hypoglycemia (peak 3.41 ± 3.2 vs. 2.85 ± 2.8 ng/ml; P = 0.03). Platelet-monocyte aggregation also increased significantly at 24 h after hypoglycemia (P = 0.03). A decline in vWF and P-selectin occurred during euglycemia (P ≤ 0.04). CONCLUSIONS Acute hypoglycemia may provoke upregulation and release of vasoactive substances in adults with and without type 1 diabetes. This may be a putative mechanism for hypoglycemia-induced vascular injury.

Cardiorespiratory responses to underwater treadmill walking in healthy females.

Abstract This study compared the cardiorespiratory responses of eight healthy women (mean age 30.25 years) to submaximal exercise on land (LTm) and water treadmills (WTm) in chest-deep water (Aquaciser). In addition, the effects of two different water temperatures were examined (28 and 36°C). Each exercise test consisted of three consecutive 5-min bouts at 3.5, 4.5 and 5.5 km · h−1. Oxygen consumption (V˙O2) and heart rate (HR), measured using open-circuit spirometry and telemetry, respectively, increased linearly with increasing speed both in water and on land. At 3.5 km · h−1 V˙O2 was similar across procedures [χ = 0.6 (0.05) l · min−1]. At 4.5 and 5.5 km · h−1 V˙O2 was significantly higher in water than on land, but there was no temperature effect (WTm: 0.9 and 1.4, respectively; LTm: 0.8 and 0.9 l · min−1, respectively). HR was significantly higher in WTm at 36°C compared to WTm at 28°C at all speeds, and compared to LTm at 4.5 and 5.5 km · h−1 (P ≤ 0.003). The HR-V˙O2 relationship showed that at a V˙O2 of 0.9 l · min−1, HR was higher in water at 36°C (115 beats · min−1) than either on land (100 beats · min−1) or in water at 28°C (99 beats · min−1). The Borg scale of perceived exertion showed that walking in water at 4.5 and 5.5 km · h−1 was significantly harder than on land (WTm: 11.4 and 14, respectively; LTm: 9.9 and 11, respectively; P ≤ 0.001). These cardiorespiratory changes occurred despite a slower cadence in water (the mean difference at all speeds was 27 steps/min). Thus, walking in chest-deep water yields higher energy costs than walking at similar speeds on land. This data has implications for therapists working in hydrotherapy pools.

The association between diet and physical activity and subsequent excess weight gain and obesity assessed at 5 years of age or older: a systematic review of the epidemiological evidence

Background The geographical or natural conditions of a country affect the manner in which economic growth takes place. Overcoming natural impediments and making use of geographical and natural advantages is the duty of economic experts and researchers. In order to overcome geographical and natural hardships, investments above international norm are needed and, on the contrary, by the optimal use of natural and regional advantages of a given area, less investment is needed for economic growth. In spite of all defeats and victories, ups and downs, the inhabitants of this land have relatively always played a determining role in West Asia and have greatly influenced and being influenced by the neighboring events and nation. The Iranian territory is located inside the desert belt of the Northern Hemisphere and is geographically placed in a belt line, the same as the plains in North Africa, Tibet and Turkistan. The country of Iran is about 1648195 square kilometers. From the total 1648195 square kilometers of the Country nearly 509442 square kilometers are used in agriculture and the rest is uncultivable areas or covered by cities, villages, lakes and roads. From 31% cultivable land in Iran; the two Northern provinces on the Caspian Sea coasts with an area of 5.5% of the overall area of Iran form more than 20% of the cultivable lands. 11 Introduction Obesity arises from a complex interplay between genetic susceptibility and behaviour, primarily relating to dietary habits and physical activity (Foresight, 2007). Evidence for specific behavioural factors that promote or protect against excess weight gain have been usefully reviewed (Wareham, 2007); (Jebb, 2007), and is more limited in children compared with adults (Rennie et al., 2005). A number of behavioural risk factors have been postulated, including TV viewing, diets with a high energy density, and fast foods. Most evidence is derived from cross sectional studies which can frequently produce conflicting results. Prospective studies with accurate measure of diet and physical activity exposures, and outcomes in terms of body fatness, are deemed to provide the more robust evidence on which to base interventions to achieve long-term behavioural change and prevent excess weight gain. The question to be answered by this comprehensive systematic review of the epidemiological evidence was ‘What is the association between food, food groups, nutrition and physical activity and subsequent excess weight gain and obesity in humans?’ Relevant exposures include patterns of diet; breastfeeding; food and drink; food preparation; dietary constituents; physical activity and inactivity; energy intake; energy density of diet; energy expenditure. Outcomes in adulthood and childhood have reported separately. Outcomes of interest included markers of weight gain; overweight; obesity; markers of body composition; markers of distribution of fat. The results of this review will provide evidence of association, but not causes, of subsequent excess weight gain and obesity. There is a degree of uncertainty inherent in epidemiological evidence, given that it is impossible to determine if there are uncontrolled variables, including genetic variations. The well known association between relatively high non caloric sweetner usage and subsequent weight gain is a useful reminder that, whilst an evidence based approach is critical to the process of scientific enquiry, consideration of evidence from other types of studies (mechanistic studies, intervention studies) and understanding the context of the evidence reviewed is essential if we are to provide policy makers, industry, service providers and the public with sensible recommendations.

Chronic oral ingestion of l‐carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans

Non‐technical summary After 30 years of endeavour, this is the first study to show that muscle carnitine content can be increased in humans by dietary means and, perhaps more importantly, that carnitine plays a dual role in skeletal muscle fuel metabolism that is exercise intensity dependent. Specifically, we have shown that increasing muscle total carnitine content reduces muscle carbohydrate use during low intensity exercise, consistent with an increase in muscle lipid utilisation. However, during high intensity exercise muscle carnitine loading results in a better matching of glycolytic, pyruvate dehydrogenase complex and mitochondrial flux, thereby reducing muscle anaerobic energy generation. Collectively, these metabolic effects resulted in a reduced perception of effort and increased work output during a validated exercise performance test. These findings have significant implications for athletic performance and pathophysiological conditions where fat oxidation is impaired or anaerobic ATP production is increased during exercise.