Plasma glucagon-like peptide-1 (GLP-1) responses to duodenal fat and glucose infusions in lean and obese men

It has been suggested that obesity is associated with a reduced glucagon-like peptide-1 (GLP-1) response to oral carbohydrate, but not fat. The latter may, however, be attributable to changes in gastric emptying. We have assessed plasma GLP-1 levels in response to these infusions in lean and obese subjects. Seven healthy lean (body mass index (BMI), 19.1-24.6 kg/m(2)) and seven obese (BMI, 31.3-40.8 kg/m(2)) young men received an intraduodenal infusion of glucose and fat for 120 min (2.86 kcal/min) on two separate days. Blood samples for plasma GLP-1 were obtained at baseline and every 20 min during the infusion. Plasma GLP-1 increased during infusion of glucose and fat (P = 0.001), but there were no differences between lean and obese subjects, nor the two nutrients. We conclude that GLP-1 secretion in response to duodenal infusion of glucose and fat is not altered in obese subjects.     

Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice

Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285kcal), and 2) a mixed meal (0.285kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P=0.02), the peak intact GLP-1 levels (P=0.006) and the estimated β-cell function (P=0.005) were higher. Furthermore, the peak insulin (P=0.004) and intact GLP-1 (P=0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1.     

Beta adrenoceptor blockade and responses of serum lipids to a meal and to exercise.

During a randomised placebo controlled trial of the effects of nadolol in hypertensive patients serum lipid profiles were obtained while the patients were fasting and during and after a meal and an exercise test. Treatment with nadolol was associated with a significant reduction in high density lipoprotein cholesterol at all time points. Serum triglyceride concentrations during treatment with nadolol were higher in the fasting state, though not significantly so, increased further postprandially, and were significantly higher during and after exercise. The changes in high density lipoprotein cholesterol and triglyceride concentrations during beta adrenoceptor blockade may be secondary to a reduction in lipoprotein lipase activity.     

Substrate usage during prolonged exercise following a preexercise meal

The effect of a high-carbohydrate meal 4 h before 105 min of exercise at 70% of maximal O2 uptake was determined in seven endurance-trained cyclists and compared with exercise following a 16-h fast. The preexercise meal produced a transient elevation of plasma insulin and blood glucose, which returned to fasting basal levels prior to the initiation of exercise. The meal also resulted in a 42% elevation (P less than 0.05) of glycogen within the vastus lateralis at the beginning of exercise. The 1st h of exercise when subjects were fed was characterized by a 13-25% decline (P less than 0.05) in blood glucose concentration, a suppression of the normal increase in plasma free fatty acids and blood glycerol, and a 45% (P less than 0.05) greater rate of carbohydrate oxidation compared with exercise when subjects were fasted. After 105 min of exercise, there were no significant differences when subjects were fed or fasted regarding blood glucose levels, rate of carbohydrate oxidation, or muscle glycogen concentration. The greater muscle glycogen utilization (97 +/- 18 vs. 64 +/- 8 mmol glucosyl units X kg-1; P less than 0.05) and carbohydrate oxidation when subjects were fed appeared to be derived from the glycogen synthesized following the meal. These results indicate that preexercise feedings alter substrate availability despite a return of plasma insulin to fasting levels prior to exercise and that these effects persist until the 2nd h of exercise.     

Metabolic and hormonal responses to prolonged physical exercise in dogs after a single fat-enriched meal

Metabolic and hormonal responses to prolonged treadmill exercise in dogs fed a fat-enriched meal 4 h prior to the exercise were compared to those measured 4 h after a mixed meal or in the postabsorptive state. Ingestion of the fat-enriched meal caused significant elevations in the resting values of plasma triglyceride (TG), free fatty acid (FFA), and glycerol concentrations. A reduction of the plasma TG concentration (from 1.6 +/- 0.2 to 1.1 +/- 0.10 mmol X l-1, P less than 0.005) occurred only in dogs exercising after the fat-enriched meal. No significant changes in this variable were noted in dogs fed a mixed meal, whilst in the postabsorptive state exercise caused an increase in the plasma TG level (from 0.42 +/- 0.03 to 0.99 +/- 0.11 mmol X l-1, P less than 0.01). The exercise-induced elevations in plasma FFA and glycerol concentrations were the highest in the dogs given the fat-enriched meal. Plasma glycerol during exercise correlated with the initial values of circulating TG (r = 0.73). The plasma FFA-glycerol ratio, at the end of exercise was lowest in the dogs taking the fat-enriched meal (1.39 +/- 0.19), suggesting an increased utilization of FFA in comparison with that in the postabsorptive state (3.27 +/- 0.37) or after a mixed meal (2.88 +/- 0.55). Basal serum insulin (IRI) concentrations were similarly enhanced in dogs fed fat-enriched and mixed meals, and they were reduced to control values within 60 min of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction between GLP-1 and CCK-33 in inhibiting food intake and appetite in men

Glucagon-like peptide-1 (GLP-1) and CCK-33 were intravenously infused alone or in combination into normal weight men for 60 min before they were served a lunch of ham sandwiches, chocolate mousse, and orange juice. Infusion of GLP-1 (dose: 0.9 pmol x kg(-1) x min(-1)) or CCK-33 (dose: 0.2 pmol x kg(-1) x min(-1)) each reduced calorie intake of the test meal. However, simultaneous infusion of these peptide doses reduced calorie intake less than the sum of the peptides' individual effects. Infusions of the same doses of GLP-1 plus CCK-33 had neither individual nor interactive effects on meal size or calorie consumption. The combination of GLP-1 plus CCK-33 induced, however, a significant reduction in hunger feelings in the premeal period (P = 0.036 vs. all other treatments). In summary, intravenous infusion of near physiological doses of CCK-33 and GLP-1 produced specific inhibitions of hunger feeling in men; the simultaneous infusion resulted in an infra-additive reduction in calorie consumption, rejecting thereby the hypothesis that the two peptides exert a positive synergistic effect on food intake compared with the effects observed with infusion of individual peptides. In conclusion, CCK and GLP-1 are meal-related satiety signals that are released from the gastrointestinal tract during food intake.     

GLP-1 regulates exercise endurance and skeletal muscle remodeling via GLP-1R/AMPK pathway

Exercise-induced physical endurance enhancement and skeletal muscle remodeling can prevent and delay the development of multiple diseases, especially metabolic syndrome. Herein, the study explored the association between glucagon-like peptide-1 (GLP-1) secretion and exercise, and its effect on skeletal muscle remodeling to enhance endurance capacity. We found both acute exercise and short-term endurance training significantly increased the secretion of GLP-1 in mice. Recombinant adeno-associated virus (AAV) encoding Gcg (proglucagon) was used to induce the overexpression of GLP-1 in skeletal muscle of mice. Overexpression of GLP-1 in skeletal muscle enhanced endurance capacity. Meanwhile, glycogen synthesis, glucose uptake, type I fibers proportion, and mitochondrial biogenesis were augmented in GLP-1-AAV skeletal muscle. Furthermore, the in vitro experiment showed that exendin-4 (a GLP-1 receptor agonist) treatment remarkably promoted glucose uptake, type I fibers formation, and mitochondrial respiration. Mechanistically, the knockdown of AMPK could reverse the effects imposed by GLP-1R activation in vitro. Taken together, these results verify that GLP-1 regulates skeletal muscle remodeling to enhance exercise endurance possibly via GLP-1R signaling-mediated phosphorylation of AMPK.     

Effects of oral fructose and glucose on plasma GLP-1 and appetite in normal subjects.

Oral glucose is a potent stimulant of glucagon-like peptide-1 (GLP-1) secretion. The effect of oral fructose on GLP-1 secretion in humans is unknown. The aims of this study were to determine (i) whether oral fructose stimulates GLP-1 secretion and (ii) the comparative effects of oral glucose and fructose on appetite. On 3 separate days, 8 fasting healthy males received, in single-blind randomized order (i) 75 g glucose, (ii) 75 fructose, or (iii) 75 g glucose followed by 75 g fructose I h later. Venous glucose, insulin and GLP-1 were measured. Appetite was assessed by visual analog questionnaires and intake of a buffet meal. Whereas glucose and fructose both increased plasma glucose, insulin and GLP-1 (P < 0.000)] for all), the response to glucose was much greater (P < 0.005 for all). There was no increase in plasma GLP-1 when fructose was given after glucose. There was no difference in food intake after oral glucose or fructose. We conclude that oral fructose (75 g) stimulates GLP-1 (and insulin) secretion, but the response is less than that to 75 g glucose. These observations suggest that neither GLP-1 nor insulin play a major role in the regulation of satiation.     

Aerobic exercise training conserves insulin sensitivity for 1 yr following weight loss in overweight women

The objectives of this study were to 1) identify the independent effects of exercise (aerobic or resistance training) and weight loss on whole body insulin sensitivity and 2) determine if aerobic or resistance training would be more successful for maintaining improved whole body insulin sensitivity 1 yr following weight loss. Subjects were 97 healthy, premenopausal women, body mass index (BMI) 27-30 kg/m(2). Following randomized assignment to one of three groups, diet only, diet + aerobic, or diet + resistance training until a BMI <25 kg/m(2) was achieved, body composition, fat distribution, and whole body insulin sensitivity were determined at baseline, in the weight reduced state, and at 1-yr follow up. The whole body insulin sensitivity index (S(I)) was determined using a frequently sampled intravenous glucose tolerance test. Results of repeated-measures ANOVA indicated a significant improvement in S(I) following weight loss. However, there were no group or group×time interactions. At 1-yr follow up, there were no significant time or group interactions for S(I;) however, there was a significant group×time interaction for S(I). Post hoc analysis revealed that women in the aerobic training group showed a significant increased S(I) from weight reduced to 1-yr follow up (P < 0.05), which was independent of intra-abdominal adipose tissue and %fat. No significant differences in S(I) from weight reduced to 1-yr follow up were observed for diet only or diet + resistance groups. Additionally, multiple linear regression analysis revealed that change in whole body insulin sensitivity from baseline to 1-yr follow up was independently associated with the change in Vo(2max) from baseline to 1-yr follow up (P < 0.05). These results suggest that long-term aerobic exercise training may conserve improvements in S(I) following weight loss and that maintaining cardiovascular fitness following weight loss may be important for maintaining improvements in S(I).     

Leptin in a lean population of Filipino adolescents

To clarify the role of leptin as a signal of energy status in humans, this study investigated the relationship of leptin to measures of body composition, maturity, and lifestyle factors in a lean sample of 293 male and 303 female Filipino adolescents (age 14-16 years). Participants were selected from the Cebu Longitudinal Health and Nutrition Survey, a representative birth cohort study begun in 1983. Using IOTF criteria, the prevalence of overweight (2.2%) and obesity (0.3%) were extremely low, and leptin levels were among the lowest reported in any healthy population (mean: 0.78 and 3.57 ng/dl in males and females). As expected, adiposity was the strongest predictor of leptin, with triceps skinfold explaining 40.2 and 30.6% of leptin variance in males and females. In females, subscapular skinfold was a significant predictor of leptin independent of triceps, while no anthropometric measure predicted leptin independent of triceps in males. There were few relationships between lifestyle factors and leptin independent of adiposity. In males, leptin levels varied little across most of the triceps distribution, suggesting that the leptin-adipose regulatory system is sensitive to very small changes in leptin in lean populations, at least among males. These findings add to the small but growing list of studies documenting differences in leptin biology among chronically lean populations.     

Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution

We aimed to investigate how assimilation of nutrients affects the postprandial responses of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and to evaluate the effect of pancreatic enzyme substitution (PES) on insulin secretion in patients with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI). Eight male patients with CP and PEI were studied. Blood was sampled frequently on two separate days after ingestion of a liquid meal with and without PES, respectively. Eight healthy male subjects served as a control group. beta-Cell responsiveness was estimated as changes in insulin secretion rates in response to changes in postprandial plasma glucose (PG). There was no difference in the PG incremental area under curve (AUC) for patients with and without PES [406 +/- 100 vs. 425 +/- 80 mM.4 h (mean +/- SE), P = 0.8]. The response of total GLP-1 was higher after PES (AUC: 7.8 +/- 1.2 vs. 5.3 +/- 0.6 nM.4 h, P = 0.01), as was the response of total GIP (AUC: 32.7 +/- 7.5 vs. 21.1 +/- 8.3 nM.4 h, P = 0.01). Concurrently, both plasma insulin, plasma C-peptide, and total insulin secretion increased after PES (AUC: 17.7 +/- 4.2 vs. 13.6 +/- 2.9 nM.4 h, P = 0.02; 237 +/- 31.4 vs. 200 +/- 27.4 nM.4 h, P = 0.005; and 595 +/- 82 vs. 497 +/- 80 pmol.kg(-1).4 h, P = 0.01, respectively). beta-Cell responsiveness to glucose was not significantly different on the two study days for patients with CP. These results suggest that the secretion of GLP-1 and GIP is under influence of the digestion and absorption of nutrients in the small intestine and that PES increases insulin secretion.     

Headaches in overweight children and adolescents referred to a tertiary-care center in Israel

Objective: To assess the association between obesity and primary headaches in children and adolescents. Methods and Procedures: In a prospective study, the short‐questionnaire version based on existing International Headache Society diagnostic criteria was administered. Two hundred and seventy‐three children and adolescents (61% females) aged 9–17 years were assessed. One hundred and sixteen (42.5%) subjects were of normal weight, 45 (16.5%) were at risk for overweight (BMI >85th and <95th percentile for age and gender) and 112 (41%) were overweight (BMI ≥95th percentile). The outcome measures were prevalence of headaches, type of headaches, association between headaches and elevated blood pressure in overweight subjects. Results: Headache was reported in 39 (14.3%) subjects, with a similar rate in females (14.5%) and males (14%). Among 39 subjects with headaches, 20 (17.9%) were overweight, 7 (15.6%) were at risk for overweight and 12 (10.3%) were normal‐weight children. Among females, 7.7% of normal‐weight group suffered from headaches, compared with 14.8% of the at risk for overweight group and 20.3% of the overweight group (P for trend 0.04). Among males, the occurrence of headaches was similar in all three weight groups (P = 0.96). The occurrence of headaches increased from 10.6% among children aged 9–11 years to 21.8% in the 15–18 years age group (P < 0.05). In multivariate analysis, a significant independent risk for headaches was present in overweight females (odds ratio (OR) = 3.93, 95% confidence interval (CI) 1.28–12.1) and in adolescents aged 15–18 years (OR = 2.62, 95% CI 1.07–6.45). Elevated blood pressure was not independently associated with headaches. Of the 15 children with migraine, 12 were either at risk for overweight or overweight. Discussion: Overweight females had an almost fourfold excess risk of headaches when compared with normal‐weight girls.     

Splenic immune responses following treadmill exercise in mice

The in vitro proliferation response to lipopolysaccharide and pokeweek mitogen by splenic lymphocytes and the effect on the total splenic lymphocyte number were examined in C57BL/6J mice following an 8-week treadmill training program (30 m/min, 8 degrees slope, 30 min/day, 5 times/week) and after a single bout of exhaustive exercise (50% stepwise increases in final running speed for 10-min intervals). Plasma corticosterone levels were also measured to evaluate whether changes in adrenocortical activation were associated with exercise-induced immunomodulation. In comparison to sedentary controls, trained mice had an increase of 35% in succinate dehydrogenase activity per unit of protein in the quadriceps femoris muscle. Trained mice showed an increase in splenic lymphocyte proliferation to both mitogens which was evident 72 h after completion of the final training session, relative to sedentary controls. Immediately following exercise, however, lymphocyte proliferative responses were depressed compared with the training and the control values. The exercise regimen resulted in a reduction in total number of mononuclear cells per spleen. Changes in plasma corticosterone levels after exercise were not clearly associated with immunodepression or immunoenhancement of splenic lymphocyte mitogenesis. Taken together, the data suggest that moderate endurance training augments splenic B lymphocyte mitogenesis and further, that the immediate effects of exercise on splenic immune function vary with the duration and intensity of the work.     

Short-term fatty acid intervention elicits differential gene expression responses in adipose tissue from lean and overweight men

The goal of this study was to investigate the effect of a short-term nutritional intervention on gene expression in adipose tissue from lean and overweight subjects. Gene expression profiles were measured after consumption of an intervention spread (increased levels of polyunsaturated fatty acids, conjugated linoleic acid and medium chain triglycerides) and a control spread (40 g of fat daily) for 9 days. Adipose tissue gene expression profiles of lean and overweight subjects were distinctly different, mainly with respect to defense response and metabolism. The intervention resulted in lower expression of genes related to energy metabolism in lean subjects, whereas expression of inflammatory genes was down-regulated and expression of lipid metabolism genes was up-regulated in the majority of overweight subjects. Individual responses in overweight subjects were variable and these correlated better to waist–hip ratio and fat percentage than BMI.     

Adipocyte triglyceride turnover and lipolysis in lean and overweight subjects

Human obesity is associated with decreased triglyceride turnover and impaired lipolysis in adipocytes. We determined whether such defects also occur in subjects with only moderate increase in fat mass. Human abdominal subcutaneous adipose tissue was investigated in healthy, nonobese subjects [body mass index (BMI) > 17 kg/m² and BMI < 30 kg/m²]. Triglyceride age, reflecting lipid turnover, was examined in 41 subjects by assessing the incorporation of atmospheric ¹⁴C into adipose lipids. Adipocyte lipolysis was examined as the ability of lipolytic agents to stimulate glycerol release in 333 subjects. Adipocyte triglyceride age was markedly increased in overweight (BMI ≥ 25 kg/m²) compared with lean subjects (P = 0.017) with triglyceride T_1/2 of 14 and 9 months, respectively (P = 0.04). Triglyceride age correlated positively with BMI (P = 0.002) but not with adipocyte volume (P = 0.2). Noradrenaline-, isoprenaline- or dibutyryl cyclic AMP-induced lipolysis was inversely correlated with triglyceride age (P < 0.01) and BMI (P < 0.0001) independently of basal lipolysis, gender, and nicotine use. Current, but not the highest or lowest BMI in adult life, correlated significantly (inversely) with lipolysis. In conclusion, adipocyte triglyceride turnover and lipolytic activity are decreased in overweight subjects and reflect the current BMI status. These changes may confer an increased risk for early development and/or maintenance of excess body fat.