Interactions between energy surplus and short-term exercise on glucose and insulin responses in healthy people with induced, mild insulin insensitivity

Short-term exercise can enhance insulin action, but the effect may be negated by the opposing action of energy surplus. The purpose of this investigation was to test the hypothesis that a single exercise bout would increase insulin action, even when opposed by a concurrent energy surplus. After 2 days in energy balance without exercise, baseline glucose and insulin areas under the curve and the insulin sensitivity index (C-ISI) were measured during an oral glucose tolerance test in 9 healthy, habitually active subjects (6 males, 3 females). A state of relative insulin insensitivity was then induced by systematic overfeeding (OF) to generate a daily energy surplus of 768 +/- 203 kcal/d for 3 days, and the oral glucose tolerance test was repeated. In the following 24 hours, the OF was increased approximately 2-fold (+6284 +/- 1669 kJ/d) and subjects performed a single bout of exercise (expenditure = 3063 +/- 803 kJ) to maintain the same energy surplus (+3125 +/- 933 kJ/d; OF and exercise) as OF. After OF, fasting insulin tended to be higher (+36%, P = .099), insulin AUC rose by 38% (P = .002), and C-ISI declined from 6.6 +/- 3.1 to 4.6 +/- 1.8 (P = .007) compared with baseline. After OF and exercise, fasting insulin remained elevated (+43% compared with baseline; P = .043) and C-ISI rose only slightly (4.6 +/- 1.8 to 5.2 +/- 2.3; P = .058), but insulin AUC declined by 20% (P = .048) compared with OF. A single exercise bout, opposed by a concurrent energy surplus, decreased the insulin response to a glucose challenge, but only partially restored the insulin AUC to baseline and had no impact on C-ISI or fasting insulin concentrations.     

Regulation of average 24h human plasma leptin level; the influence of exercise and physiological changes in energy balance

OBJECTIVE: The effects of short-term moderate physiological changes in energy flux and energy balance, by exercise and over- or underfeeding, on a 24h plasma leptin profile, were investigated. DESIGN: Subjects were studied over 24h in four randomized conditions: no exercise/energy balance (energy intake (EI)=energy expenditure (EE)=11.8+/-0.8 MJ); exercise/energy balance (EI=EE=15.1+/-0.6 MJ); exercise/negative energy balance (EI=11.8+/-0.8 MJ, EE=15.1+/-0.8 MJ); exercise/positive energy balance (El=18.6+/-0.7 MJ, EE=15.1+/-0.6 MJ). SUBJECTS: Eight healthy, lean men (age: 23.5+/-7.0y, body fat 14.1+/-5.4%, body mass index (BMI): 21.4+/-2.3 kg/m2). MEASUREMENTS: Blood was sampled every hour during the daytime (09.00-23.00h) and every two hours during the night (01.00-09.00h) for analysis of plasma leptin, insulin, glucose, FFA and catecholamines. RESULTS: Plasma leptin levels were highest around 01.00h (mean+/-s.e.m. 4.9+/-2.0 ng/ml) and lowest around 11.00 h. (2.3+/-0.7 ng/ml). An increased 24h EE, induced by exercise under conditions of energy balance, significantly decreased the peak and average 24h plasma leptin concentration. A positive energy balance, by overfeeding, resulted in a significantly higher amplitude of the 24h plasma leptin curve, compared to a condition of energy balance. CONCLUSION: Exercise decreases peak and average 24h plasma leptin concentration and a moderately positive energy balance increases the amplitude of the 24h plasma leptin profile. These effects are not acute, but are manifest within 24h. The variations of average 24h FFA and average 24h glucose concentrations almost fully explained the variation in average 24h leptin concentration across trials.     

Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis

OBJECTIVE: The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects. DESIGN: Seven GH-deficient patients (aged 37 +/- 4 years (mean +/- s.e.)) were studied on four occasions in a 2 x 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp. RESULTS: Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 +/- 120 (-GH - Aci), 711 +/- 130 (-GH + Aci), 806 +/- 130 (+GH - Aci), 574 +/- 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (microg/l): 11.2 +/- 4.4 (-GH - Aci), 11.7 +/- 4.4 (-GH + Aci), 11.5 +/- 4.4 (+GH - Aci), 13.9 +/- 4.2 (+GH + Aci), P = 0.005. CONCLUSION: Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.     

The effect of increased lipid intake on hormonal responses during aerobic exercise in endurance-trained men

In view of the growing health problem associated with obesity, clarification of the regulation of energy homeostasis is important. Peripheral signals, such as ghrelin and leptin, have been shown to influence energy homeostasis. Nutrients and physical exercise, in turn, influence hormone levels. Data on the hormonal response to physical exercise (standardized negative energy balance) after high-fat (HF) or low-fat (LF) diet with identical carbohydrate intake are currently not available. The aim of the study was to investigate whether a short-term dietary intervention with HF and LF affects ghrelin and leptin levels and their modulators, GH, insulin and cortisol, before and during aerobic exercise. Eleven healthy, endurance-trained male athletes (W(max) 365 +/- 29 W) were investigated twice in a randomized crossover design following two types of diet: 1. LF - 0.5 g fat/kg body weight (BW) per day for 2.5 days; 2. HF - 0.5 g fat/kg BW per day for 1 day followed by 3.5 g fat/kg BW per day for 1.5 days. After a standardized carbohydrate snack in the morning, metabolites and hormones (GH, ghrelin, leptin, insulin and cortisol) were measured before and at regular intervals throughout a 3-h aerobic exercise test on a cycloergometer at 50% of W(max). Diet did not significantly affect GH and cortisol concentrations during exercise but resulted in a significant increase in ghrelin and decrease in leptin concentrations after LF compared with HF diet (area under the curve (AUC) ghrelin LF vs HF: P < 0.03; AUC leptin LF vs HF: P < 0.02, Wilcoxon rank test). These data suggest that acute negative energy balance induced by exercise elicits a hormonal response with opposite changes of ghrelin and leptin. In addition, the hormonal response is modulated by the preceding intake of fat.     

Plasma acylation-stimulating protein,adiponectin, leptin,and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects

We examined fasting plasma insulin, acylation-stimulating protein (ASP), leptin, adiponectin, ghrelin, and metabolic/cardiovascular risk profile before and 15 +/- 6 months after isolated Roux-en-Y gastric bypass surgery in 50 morbidly obese subjects. Average preoperative plasma lipids were mostly normal, whereas ASP, insulin, and leptin were elevated, and adiponectin and ghrelin were decreased. Postoperatively, body weight decreased significantly (-36.4 +/- 9.6%) and was best predicted by preoperative adiponectin concentration in weight-stable subjects (r = -0.59; P = 0.02). Plasma lipids and insulin resistance improved, leptin and ASP decreased (-76.3 +/- 14.6% and -35.9 +/- 52.2%; P < 0.001), and adiponectin increased (50.1 +/- 47.0%; P < 0.001). The decrease in apolipoprotein B was best predicted by the decrease in ASP (r = 0.55; P = 0.009), whereas the improved postoperative insulin sensitivity was best predicted by the increase in adiponectin (r = 0.70; P = 0.01). Despite bypassing 95% of the stomach and isolating the fundus from contact with ingested nutrients, circulating ghrelin did not decrease after surgery. In fact, plasma ghrelin increased postoperatively in the subset of subjects undergoing active weight loss (+60.5 +/- 23.2%; P < 0.001); ghrelin, however, remained unchanged in weight-stable subjects. In summary, 1) preoperative adiponectin concentrations may be predictive of the extent of weight loss; 2) changes in ASP and adiponectin are predictive of decreased apolipoprotein B and improved insulin action, respectively; and 3) plasma ghrelin increases after gastric bypass surgery in patients experiencing active weight loss.     

Ghrelin secretion in severely obese subjects before and after a 3-week integrated body mass reduction program

Ghrelin, the endogenous ligand of GH-secretagogue receptors, has been implicated in the regulation of feeding behavior and energy balance. Aim of the study was to investigate ghrelin levels in fasting conditions and after a standard meal test in obese subjects before and after a 3-week integrated body weight reduction (BWR) program (consisting of energy-restricted diet, exercise training, psychological counselling and nutritional education). Weight, height, fat mass, fat free mass (by impedentiometry), circulating ghrelin, insulin and leptin levels were evaluated in 10 obese subjects (3 male, 7 female; mean age: 35 +/- 9.3 yr; body mass index BMI: 45.2 +/- 10.6 kg/m2) before and after weight reduction. At baseline, obese subjects showed significantly lower ghrelin levels than controls, which were negatively correlated with BMI, weight, insulin and leptin levels. Fasting ghrelin levels were not modified by standard meal test in obese subjects (from 110.8 +/- 69.7 to 91.8 +/- 70.2 pmol/l p=ns), while a significant reduction was observed in controls (from 352.4 +/- 176.7 to 199.0 +/- 105.2 pmol/l; p<0.01). After a 3-week integrated BWR program obese subjects significantly reduced weight, BMI and leptin levels, while no significant changes were found both in fasting ghrelin and in ghrelin response after the meal. In conclusion, 5% weight loss obtained after a short-term period of integrated BWR program is not sufficient to normalize fasting ghrelin levels nor to restore the normal ghrelin suppression after a meal in severely obese subjects.     

Plasma ghrelin concentration and energy balance: overfeeding and negative energy balance studies in twins

Central (intracerebral ventral) and peripheral (subcutaneous and intraperitoneal) administration of ghrelin causes obesity in rodents by increasing food intake and decreasing fat oxidation. Recent studies in humans have shown that plasma ghrelin concentration was inversely related to body fat and was lower in Pima Indians, a population susceptible to obesity. Whether ghrelin plays a role in the etiology of obesity in humans is unknown. We, therefore, measured plasma ghrelin concentration before and after two interventions in monozygotic twins previously studied at Laval University, Quebec City. Twelve pairs of monozygotic twins were overfed by 84,000 kcal over a 100-day period, whereas another seven pairs of monozygotic twins were submitted to a 53,000 kcal negative energy balance induced by exercise over a 93-day period. At baseline, for all the subjects, plasma ghrelin concentration was negatively correlated with body mass and body fatness (r varying from 0.36 to 0.45). The intraclass coefficient for the twin resemblance (r(I) = 0.75; p = 0.006) indicated that plasma ghrelin concentration is a familial trait. In response to the 100-day intervention, plasma ghrelin exhibited a non-significant decrease of 61 +/- 30 fmol/l (p = 0.18) with overfeeding and a non-significant increase of 58 +/- 34 fmol/l (p = 0.17) with negative energy balance. However, there was no relationship between baseline plasma ghrelin concentration and the magnitude of body weight change in both interventions. These first experimental data under "clamped energy balance conditions" do not provide evidence that plasma ghrelin is involved in the etiology of human obesity. However, studies in free-living individuals are needed to clarify this question.     

Effects of short-term carbohydrate or fat overfeeding on energy expenditure and plasma leptin concentrations in healthy female subjects

OBJECTIVE: To determine the effects of excess carbohydrate or fat intake on plasma leptin concentrations and energy expenditure. DESIGN: Ten healthy lean females were studied: (a) during a 3 day isoenergetic diet (ISO); (b) during 3 day carbohydrate overfeeding (CHO OF); and (c) during 3 day fat overfeeding (FAT OF). During each test, basal metabolic rate, the energy expended during mild physical activity and recovery, and 24 h energy expenditure (24 h EE) were measured with indirect calorimetry. The concentrations of glucose and lactate were monitored in subcutaneous interstitial fluid over a 24 h period using microdialysis. Plasma hormone and substrate concentrations were measured in a blood sample collected in the morning of the fourth day. RESULTS: CHO OF increased plasma leptin concentrations by 28%, and 24 h EE by 7%. Basal metabolic rate and the energy expended during physical activity were not affected. FAT OF did not significantly change plasma leptin concentrations or energy expenditure. There was no relationship between changes in leptin concentrations and changes in energy expenditure, suggesting that leptin is not involved in the stimulation of energy metabolism during overfeeding. Interstitial subcutaneous glucose and lactate concentrations were not altered by CHO OF and FAT OF. CONCLUSIONS: CHO OF, but not FAT OF, increases energy expenditure and leptin concentration.     

Beta-2 adrenergic receptor variants are associated with subcutaneous fat accumulation in response to long-term overfeeding.

OBJECTIVE: The effects of alpha-2A (A2A)-, beta-2 (B2)- and beta-3 (B3)-adrenergic receptor (ADR) gene polymorphisms on adiposity, fat distribution and plasma insulin and leptin changes in response to long-term overfeeding were explored. METHODS: Twenty four men (mean (+/-s.d.) age 21+/-2 y) who constituted 12 pairs of identical twins ate a 4.2 MJ/day energy surplus, 6 days a week, for a period of 100 days. Total body fat was assessed by hydrodensitometry and total subcutaneous fat by the sum of eight skinfolds. Abdominal fat areas were measured by computerized tomography (CT). Plasma glucose and insulin during fasting and in response to an oral glucose tolerance test (OGTT) were assayed. The insulin and glucose areas were computed using the trapezoidal method. Plasma leptin was measured with an enzyme-linked immunosorbent assay. The ADR polymorphisms were identified by PCR or Southern blot technique. RESULTS: The ADRB2 Gln27Gln genotype (n=10) was associated with a larger gain (percentage change) in weight (P<0.001) and total subcutaneous (P<0.005) fat than the Glu27Glu/Gln27Glu genotype (n=14). In addition, overfeeding induced greater increases in the insulin areas under the curve during the OGTT and the fasting plasma level of leptin (P<0.01 and <0.03, respectively) among Gln27Gln than in the Glu27Glu/Gln27Glu subjects. The body composition and metabolic changes among the ADRB2 BanI 3.7/3.4 kb subjects (n=10) were similar to those of Gln27Gln subjects. ADRA2A DraI (n=4) 6.3/6.3 kb subjects experienced a decrease (-8%) while 6.7/6.3 kb subjects (n=20) registered an increase (+10%; P=0.017) of OGTT glucose area after the 100-day caloric surplus. The four carriers of the ADRB3 variant (Trp64Arg) experienced the same magnitude of changes as the 20 homozygotes for the Trp allele. In general, comparisons based on the 24 subjects considered as unrelated men and the mean values for each of the 12 pairs yielded similar results. CONCLUSION: The ADRB2 Gln27Gln subjects gained more weight and total subcutaneous fatness and also experienced a greater increase in insulin resistance than Glu27Glu/Gln27Glu subjects with exposure to long-term overfeeding. Similar differences were observed between carriers and non-carriers of the ADRB2 3.7/3.4 kb BanI variant. Genetic variation at the ADRB2 locus could thus be one of the factors responsible for the large inter-individual differences observed in the response to long-term alterations in energy balance and should be further investigated.     

Is ghrelin a signal of decreased fat-free mass in elderly subjects?

OBJECTIVE: Aging is associated with appetite decline, weight loss, reduced fat-free mass (FFM), and increased fat mass (FM). Ghrelin and leptin are short- and long-term determinants of energy balance respectively, whose dysregulation could alter food intake. We evaluate the relationship of circulating ghrelin and leptin responses to standardized oral mixed nutrient load (SOMNL) with body composition, daily food intake, and insulin sensitivity in healthy elderly subjects (ES). DESIGN AND METHODS: Twenty-six ES (12/14 M/F, 69+/-4 years) and ten young healthy controls (LY) (5/5 M/F, 27+/-3 years) were studied at the International Center for the Assessment of Nutritional Status (Milan, Italy) with air plethysmography, dual energy X-ray absorptiometry, indirect calorimetry, and dietary intake assessment. Basal and postprandial ghrelin, leptin, testosterone, glucose, insulin and C-peptide concentrations, and insulin resistance (homeostasis model assessment (HOMA-R)) and sensitivity (quantitative insulin-sensitivity check index (QUICKI)) were evaluated. RESULTS: Basal ghrelin levels were similar in ES and LY, whereas leptin was higher in ES than LY, in agreement with the higher amount of FM. Basal and percentage change in ghrelin were inversely related to FFM, appendicular skeletal muscle mass (SMM), and QUICKI, but not to FM. Basal and percentage change in leptin were directly related to FM and not to FFM indexes. Ghrelin basal concentration was negatively correlated with energy and protein intake and with QUICKI. Percentage change in Ghrelin after SOMNL correlated negatively with protein intake, but positively with resting energy expenditure and energy intake, and glucose, insulin, C-peptide basal concentrations, and HOMA-R. CONCLUSION: In ES, basal and postprandial ghrelin increases with FFM, specifically SMM, reduction, whereas leptin increases with relative FM increases.     

Circulating and cerebrospinal fluid ghrelin and leptin: potential role in altered body weight in Huntington's disease

OBJECTIVE: In addition to neurological impairment, weight loss is a prominent characteristic of Huntington's disease (HD). Neuropathologically, the disease affects the caudate nucleus and the cerebral cortex, and also the hypothalamus. The recently discovered orexigenic hormone of gastric origin, ghrelin and the adipocyte hormone leptin, are two peripherally produced hormones exerting opposite effects on specific populations of hypothalamic neurons that play a key role in regulating energy intake and energy output. The aim of this study was to investigate the possible involvement of cerebrospinal fluid (CSF) and circulating ghrelin and leptin in the regulation of energy balance in patients with HD. METHODS: Twenty healthy normal-weight subjects undergoing orthopedic surgery, and fifteen patients with genetically verified HD, were enrolled in this study. The unified Huntington's disease rating scale (UHDRS) was used to assess clinical course of the disease. Blood samples for hormonal measurements were obtained by venipuncture and in-parallel CSF samples for leptin/ghrelin determination were obtained by lumbar puncture. RESULTS: Patients with HD had increased concentrations of ghrelin in plasma compared with healthy subjects (4523.7+/-563.9 vs 2781.1+/-306.2 pg/ml, P<0.01). On the other hand, patients with HD had decreased concentrations of leptin in plasma compared with healthy subjects (4.8+/-1.6 vs 10.9+/-2.4 ng/ml, P<0.01). The concentrations of CSF ghrelin and CSF leptin were equivalent to values in healthy subjects. No correlation was found between disease duration--and other clinical features of HD--and plasma or CSF leptin/ghrelin levels. In patients with HD, baseline levels of GH, IGF-I, insulin and glucose did not differ from those in healthy subjects. CONCLUSION: High circulating ghrelin and low leptin levels in patients with HD suggest a state of negative energy balance. Early nutritional support of patients with HD is advocated since patients with HD and higher body mass index at presentation have slower progression of the disease.     

Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake

Leptin plays a vital role in the regulation of energy balance in rodent models of obesity. However, less information is available about its homeostatic role in humans. The aim of this study was to determine whether leptin serves as an indicator of short-term energy balance by measuring acute effects of small manipulations in energy intake on leptin levels in normal individuals. The 12-day study was composed of four consecutive dietary-treatment periods of 3 days each. Baseline (BASE) [100% total energy expenditure (TEE)] feeding, followed by random crossover periods of overfeeding (130% TEE) or underfeeding (70% TEE) separated by a eucaloric (100% TEE) washout (WASH) period. The study participants were six healthy, nonobese subjects. Leptin levels serially measured throughout the study period allowed a daily profile for each treatment period to be constructed and a 24-h average to be calculated; ad libitum intake during breakfast "buffet" following each treatment period was also measured. Average changes in mesor leptin levels during WASH, which were sensitive to energy balance effected during the prior period, were observed. After underfeeding, leptin levels during WASH were 88 +/- 16% of those during BASE compared with 135 +/- 22% following overfeeding (P = 0.03). Leptin levels did not return to BASE during WASH when intake returned to 100% TEE, but instead were restored (104 +/- 21% and 106 +/- 16%; not significant) only after subjects crossed-over to complementary dietary treatment that restored cumulative energy balance. Changes in ad libitum intake from BASE correlated with changes in leptin levels (r2 = 0.40; P = 0.01). Leptin levels are acutely responsive to modest changes in energy balance. Because leptin levels returned to BASE only after completion of a complementary feeding period and restoration of cumulative energy balance, leptin levels reflect short-term cumulative energy balance. Leptin seems to maintain cumulative energy balance by modulating energy intake.     

Plasma ghrelin in obesity before and after weight loss after laparoscopical adjustable gastric banding

Weight reduction after gastric bypass surgery has been attributed to a decrease of the orexigenic peptide ghrelin, which may be regulated by insulin and leptin. This study examined effects of long-term weight loss after laparoscopical adjustable gastric banding on plasma ghrelin and leptin concentrations and their relationship with insulin action. Severely obese patients (15 women, three men, 36 +/- 12 yr) underwent clinical examinations every 3 months and modified oral glucose tolerance tests to assess parameters of insulin sensitivity and secretion every 6 months. After surgery, body mass index fell from 45.3 +/- 5.3 to 37.2 +/- 5.3 and 33.6 +/- 5.5 kg/m(2) at 6 and 12 months, respectively (P < 0.0001). This was associated with lower (P < 0.0001) plasma glucose, insulin, insulin resistance, waist circumference, and blood pressure. Plasma leptin decreased from 27.6 +/- 9.5 to 17.7 +/- 9.8 (P = 0.0005) and 12.7 +/- 5.1 ng/ml (P < 0.0001). Plasma ghrelin was comparable before and at 6 months (234 +/- 53; 232 +/- 53 pmol/liter) but increased at 12 months (261 +/- 72 pmol/liter; P = 0.05 vs. 6 months). At 6 and 12 months, ghrelin levels correlated negatively with fasting plasma insulin levels and hepatic insulin extraction but not with body mass or insulin action.In conclusion, prolonged weight loss results in a rise of fasting ghrelin concentrations that correlates with fasting insulin concentrations but not improvement of insulin sensitivity.     

Predictors of postabsorptive ghrelin secretion after intake of different macronutrients

CONTEXT: Release of ghrelin, a gastrointestinal hormone regulating feeding and energy balance, is blunted in obesity, a condition associated with insulin resistance. OBJECTIVE: The objective was to identify anthropometric and metabolic predictors of postabsorptive ghrelin secretion. DESIGN: We evaluated ghrelin, insulin, glucose, and leptin secretion overnight and after intake of different macronutrients. SUBJECTS: Ten obese subjects (age, 31.8 +/- 2.5 yr; body mass index, 43.4 +/- 0.8 kg/m(2)) and six lean subjects (age, 33.5 +/- 2.4 yr; body mass index, 21.8 +/- 1.4 kg/m(2)) participated in the study. MAIN OUTCOME MEASURES: The main outcome measures were resting energy expenditure (REE); fat mass; nighttime approximate entropy (ApEn) and synchronicity (cross-ApEn) of ghrelin, insulin, and leptin; insulin sensitivity by homeostatic model approach insulin-sensitivity (HOMA-S%); postabsorptive area under the curve (AUC); and Delta of ghrelin, insulin, glucose, and leptin after carbohydrate-, lipid-, and protein-rich test meals. RESULTS: Nighttime ApEn scores were higher in obese than lean subjects (P < 0.01). Cross-ApEn revealed a synchronicity between ghrelin-insulin, ghrelin-leptin, and insulin-leptin in both groups. Compared with baseline, ghrelin decreased significantly (P < 0.01) in lean and obese subjects after carbohydrates (42.2 vs. 28.5%; P < 0.05), lipids (40.2 vs. 26.2%; P < 0.01), and proteins (42.2 vs. 26.3%; P < 0.01) devoid of between-meal ghrelin differences. Significant associations occurred between nocturnal ghrelin ApEn and insulin (r = 0.53; P < 0.05), postmeal ghrelin AUCs and REE (r = -0.57; P < 0.05), and HOMA-S% (r = 0.52; P < 0.05), postmeal ghrelin Delta and HOMA-S% (r = 0.60; P < 0.05). REE (beta = -0.57; P = 0.02) and ghrelin ApEn (beta = -0.62; P = 0.01) were predictors of postmeal ghrelin AUC and Delta, respectively. CONCLUSIONS: Obesity determined a decreased orderliness of ghrelin secretion and a relative loss of ghrelin-insulin synchrony. Postabsorptive ghrelin secretion decreased significantly both in obese and lean subjects, was related to insulin sensitivity, and was predicted by energy expenditure and hormone pulsatility.     

Effect of exercise training combined with phytoestrogens on adipokines and C-reactive protein in postmenopausal women: a randomized trial

Phytoestrogens and training could be effective to reduce cardiovascular and type 2 diabetes mellitus risk factors in postmenopausal women. Nevertheless, the impact of their combination on adipokines and systemic inflammation was never investigated. The objective was to verify if 6 months of mixed training combined with phytoestrogens could have an additional effect on adipokine levels and systemic inflammation in obese postmenopausal women. Fifty-two obese women aged between 50 and 70 years were randomly assigned to (1) exercise with placebo (EX + PL; n = 25) or (2) exercise with phytoestrogens (EX + PHY; n = 27). Body weight, waist circumference, fat mass, and lean body mass (dual-energy x-ray absorptiometry) were assessed. Fasting plasma glucose and insulin, adiponectin, leptin, and C-reactive protein (CRP) levels were obtained after a 12-hour overnight fast. Total energy intake was measured with a 3-day dietary record. All measurements were performed before and after the 6-month intervention. Although energy intake remained unchanged, body composition was improved in all women (all Ps < .02). Plasma CRP and leptin levels decreased in both groups similarly (all Ps < .03), whereas plasma adiponectin and insulin did not change with exercise combined with placebo or phytoestrogens. Correlation analyses showed that homeostasis model assessment of insulin resistance (r = -0.58, P = .02) and fasting insulin levels (r = -0.42, P = .02) at baseline were both correlated with changes in leptin levels. Baseline fasting glucose (r = -0.36, P = .03) and adiponectin (r = 0.45, P = .005) levels were associated with changes in CRP concentrations. Although mixed exercise program combined with phytoestrogens does not seem to provide any additional effect, mixed training improves systemic inflammation and leptin concentrations in obese postmenopausal women.     

Variability of appetite control mechanisms in response to 9 weeks of progressive overfeeding in humans

BACKGROUND: The current epidemic of obesity demonstrates that mechanisms for maintaining human energy balance are readily subverted by adverse environmental conditions. The critical elements of this dysregulation are poorly understood. Most previous research into what regulates the intake side of the energy balance equation has been handicapped by the use of short-term within-day experimental tests. OBJECTIVE: We enrolled six non-obese men to a 17-week protocol involving three 21 days periods of progressive overfeeding (+20, +40 and +60%) separated by free diet periods to test for compensatory satiety. RESULTS: Responses to overfeeding differed markedly with evidence of 'compensators' and 'non-compensators', but on average, subsequent food intake was stimulated rather than suppressed after overfeeding in spite of markedly elevated body fat (+13%) and fasting leptin (+116%). DISCUSSION: The inefficient response of in-built appetite control mechanisms emphasizes the need to adopt intentional cognitive restraint in the modern environment when food is plentiful.     

Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women

Previous studies indicate that leptin secretion is regulated by insulin-mediated glucose metabolism. Because fructose, unlike glucose, does not stimulate insulin secretion, we hypothesized that meals high in fructose would result in lower leptin concentrations than meals containing the same amount of glucose. Blood samples were collected every 30-60 min for 24 h from 12 normal-weight women on 2 randomized days during which the subjects consumed three meals containing 55, 30, and 15% of total kilocalories as carbohydrate, fat, and protein, respectively, with 30% of kilocalories as either a fructose-sweetened [high fructose (HFr)] or glucose-sweetened [high glucose (HGl)] beverage. Meals were isocaloric in the two treatments. Postprandial glycemic excursions were reduced by 66 +/- 12%, and insulin responses were 65 +/- 5% lower (both P < 0.001) during HFr consumption. The area under the curve for leptin during the first 12 h (-33 +/- 7%; P < 0.005), the entire 24 h (-21 +/- 8%; P < 0.02), and the diurnal amplitude (peak - nadir) (24 +/- 6%; P < 0.0025) were reduced on the HFr day compared with the HGl day. In addition, circulating levels of the orexigenic gastroenteric hormone, ghrelin, were suppressed by approximately 30% 1-2 h after ingestion of each HGl meal (P < 0.01), but postprandial suppression of ghrelin was significantly less pronounced after HFr meals (P < 0.05 vs. HGl). Consumption of HFr meals produced a rapid and prolonged elevation of plasma triglycerides compared with the HGl day (P < 0.005). Because insulin and leptin, and possibly ghrelin, function as key signals to the central nervous system in the long-term regulation of energy balance, decreases of circulating insulin and leptin and increased ghrelin concentrations, as demonstrated in this study, could lead to increased caloric intake and ultimately contribute to weight gain and obesity during chronic consumption of diets high in fructose.     

Effect of a sulfonylurea and insulin on energy expenditure in type II diabetes mellitus

Previous studies demonstrated that administration of insulin and oral hypoglycemic agents tends to produce weight gain in type II diabetic patients. The goal of this study was to determine the potential contribution of changes in metabolic rate and urinary glucose excretion to changes in energy balance associated with treatment with glyburide and insulin. Six obese type II diabetic patients (52-61 yr old; 123-214% of ideal weight) were fed a weight-maintaining diet of fixed composition and caloric content in a Clinical Research Center. The mean fasting plasma glucose concentrations were 10.7 +/- 1.3 (+/- SE) mmol/L before treatment, 7.9 +/- 1.4 mmol/L at the end of 2 weeks of glyburide treatment, and 5.2 +/- 0.3 mmol/L at the end of 2 weeks of insulin treatment. Urinary glucose excretion decreased from 48 +/- 19 g/day before treatment to 20 +/- 9 g/day at the end of glyburide treatment and 2 +/- 1 g/day at the end of insulin treatment. Neither treatment affected mean postabsorptive resting metabolic rate (untreated 4.86 +/- 0.50 kJ/min; glyburide-treated, 4.63 +/- 0.45 kJ/min; insulin-treated, 4.70 +/- 0.46 kJ/min) or postprandial resting metabolic rate (untreated, 5.71 +/- 0.55 kJ/min; glyburide-treated, 5.60 +/- 0.39 kJ/min; insulin-treated, 5.70 +/- 0.51 kJ/min). However, the two patients with the largest decreases in urinary glucose excretion also had decreases in energy expenditure. These data indicate that many obese type II diabetic patients could have significant weight gain from reduced energy losses alone.     

Leptin increases circulating glucose, insulin and glucagon via sympathetic neural activation in fasted mice.

OBJECTIVE: A number of recent studies suggest that leptin has effects on glucose metabolism and pancreatic hormone secretion. Therefore, the effect of leptin administration on circulating glucose, insulin and glucagon in fed and fasted mice was investigated. The potential contribution of the sympathetic nervous system to the effects of leptin was also examined. DESIGN: Recombinant human or murine leptin was administered intraperitoneally (300 microg/mouse per 12 h over 24 h) to fed or fasted, normal or chemically sympathectomized NMRI mice. Blood samples were collected at baseline and after 24 h. MEASUREMENTS: Plasma concentrations of glucose, insulin and glucagon. RESULTS: In the fed state (n = 24), leptin administration did not affect glucose, insulin or glucagon concentrations after 24 h. Fasting (n = 24) reduced body weight by 2.2+/-0.4 g, plasma glucose by 3.7+/-0.4 mmol/l, plasma insulin by 138+/-35 pmol/l, and plasma glucagon by 32+/-7 pg/ml. In fasted mice, human leptin (n = 24) increased plasma glucose by 1.5+/-0.2 mmol/l (P = 0.041), plasma insulin by 95+/-22 pmol/l (P = 0.018), and plasma glucagon by 16+/-3 pg/ml (P = 0.025), relative to saline-injected control animals. Murine leptin exerted similar stimulating effects on circulating glucose (+1.0+/-0.2 mmol/l, P = 0.046), insulin (+58+/-17 pmol/l, P = 0.038) and glucagon (+24+/-9 pg/ml, P = 0.018) as human leptin in fasted mice (n = 12) with no significant effect in fed mice (n = 12). Human leptin did not affect circulating glucose, insulin or glucagon in fasted mice after chemical sympathectomy with 6-hydroxydopamine (40 mg/kg iv 48 h prior to fasting; n = 12). CONCLUSION: Leptin increases circulating glucose, insulin and glucagon in 24 h fasted mice by a mechanism requiring intact sympathetic nerves.     

Circulating ghrelin levels in basal conditions and during glucose tolerance test in acromegalic patients

BACKGROUND: Ghrelin exerts a wide range of metabolic functions. In contrast to the body of information accumulated on the role of ghrelin on energy balance, the possible relevance of the peptide on GH secretion in physiological and pathological conditions has so far been poorly investigated. AIM: The aim of the present study was to evaluate circulating ghrelin levels in acromegalic patients in basal conditions and in response to oral glucose tolerance test (OGTT). PATIENTS: Serum ghrelin, insulin and leptin levels were measured in 31 healthy normal weight subjects as controls, 25 patients with simple obesity and 17 non-diabetic acromegalic patients. Ghrelin and insulin response to OGTT was evaluated in six controls, four obese and six acromegalic patients. RESULTS: The acromegalic patients showed ghrelin levels lower than those observed in normal weight subjects (201+/-20 vs 329+/-32 pmol/l, P<0.05) and similar to those found in obese subjects (165+/-14 pmol/l, P=not significant). Both obese and acromegalic patients had insulin levels significantly higher than controls, while high levels of leptin were detected only in obese subjects. Serum ghrelin levels showed a significant negative correlation with insulin, leptin and body mass index (P<0.05) in normal and obese subjects. No correlation was observed in acromegalic patients, although those with severe insulin resistance showed the lowest ghrelin values (161+/-20 pmol/l). In controls and obese subjects, ghrelin levels showed a significant decrease (25-40%) during OGTT, while no effect was detectable in acromegalic patients. CONCLUSIONS: This study reports that patients with active acromegaly show low levels of circulating ghrelin that are not further reduced by OGTT, this pattern of secretion probably depending on both GH-induced insulin resistance and the putative GH/IGF-I negative feedback control on ghrelin secretion.