Introduction:Mechanisms for liraglutide-induced weight loss are poorly understood.Objective:We investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese non-diabetic individuals.Design:Participants (N=49, 18–75 years, body mass index: 30–40 kg m−2) were randomized to two of three treatments: liraglutide 1.8 mg, 3.0 mg, or placebo in a double-blind, incomplete crossover trial. After 5 weeks, 24-h energy expenditure (EE) and substrate oxidation were measured in a respiratory chamber. Gastric emptying (acetaminophen absorption method), glycemic parameters and appetite were assessed during a 5-h meal test. Ad libitum energy intake during a subsequent lunch was also assessed.Results:Five-hour gastric emptying (AUC0–300 min) was found to be equivalent for liraglutide 1.8 versus 3.0 mg (primary end point), and for both liraglutide doses versus placebo, as 90% confidence intervals for the estimated treatment ratios were contained within the prespecified interval (0.80–1.25). However, 1-h gastric emptying was 23% lower than placebo with liraglutide 3.0 mg (P=0.007), and a nonsignificant 13% lower than placebo with liraglutide 1.8 mg (P=0.14). Both liraglutide doses similarly reduced fasting glucose (0.5–0.6 mmol l−1 versus placebo, P<0.0001), glucose Cmax and 1-h AUC versus placebo; only liraglutide 3.0 mg reduced iAUC0–300 min (by ∼26% versus placebo, P=0.02). Glucagon iAUC0–300 min decreased by ∼30%, and iAUC0–60 min for insulin and C-peptide was ∼20% lower with both liraglutide doses versus placebo. Liraglutide doses similarly increased mean postprandial satiety and fullness ratings, reduced hunger and prospective food consumption and decreased ad libitum energy intake by ∼16%. Liraglutide-associated reductions in EE were partly explained by a decrease in body weight. A relative shift toward increased fat and reduced carbohydrate oxidation was observed with liraglutide. Clinicaltrials.gov ID:NCT00978393. Funding: Novo Nordisk.Conclusion:Gastric emptying AUC0–300 min was equivalent for liraglutide 1.8 and 3.0 mg, and for liraglutide versus placebo, whereas reductions in 1-h gastric emptying of 23% with liraglutide 3.0 mg and 13% with 1.8 mg versus placebo were observed. Liraglutide 3.0 mg improved postprandial glycemia to a greater extent than liraglutide 1.8 mg. Liraglutide-induced weight loss appears to be mediated by reduced appetite and energy intake rather than increased EE.
This study does not support the contention that low-fat LGI diets are more beneficial than HGI diets with regard to appetite or body-weight regulation as evaluated over 10 wk. However, it confirms previous findings of a beneficial effect of LGI diets on risk factors for ischemic heart disease.
Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A. Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. produced reduced EI, lower ratings of well-being, increases in FFA, postprandial glucose (only 0.8 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 PYY3-36) and insulin concentrations, as well as heart rate and EE (only 0.8 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 PYY3-36). PYY1-36 at 1.6 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 produced increased heart rate and postprandial insulin response. Ratings of appetite were opposite with infusions of 0.8 and 1.6 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 PYY1-36 and seemed to depend on subjects being lean or obese. PYY3-36 caused increased thermogenesis, lipolysis, postprandial insulin and glucose responses, suggestive of increased sympathoadrenal activity. PYY1-36 had no effect on EI and no clear effects on appetite but resulted in increased heart rate and postprandial insulin response. However, highest tolerable dose of PYY1-36 was probably not reached in the present study. Peptide YY; free fatty acids; insulin sensitivity; arcuate nucleus; neuropeptide Y receptors THE IMBALANCE BETWEEN energy intake (EI) and energy expenditure (EE) that produces the obese state may partly be a consequence of an inadequate appetite regulation. Hence, scientific interest in recent years has concentrated on both the secretion and function of different gastrointestinal hormones, and on the appetite regulatory centers of the brain, including the arcuate nucleus which is considered a key brain area (22).Peptide YY (PYY) is a 36-amino acid peptide released postprandially from the endocrine L cells in the distal gastrointestinal tract in proportion to the calorie and fat content of the ingested meal (1,8,18). PYY is part of the neuropeptide Y (NPY) protein family and exists in human blood in two forms: the intact PYY , in which the NH 2 -terminal Tyr-Pro dipeptide has been removed by dipeptidyl aminopeptidase IV (DPP IV) cleavage (12, 13). PYY 1-36 binds to and activates the Y1, Y2, and Y5 NPY receptor subtypes, whereas PYY 3-36 preferentially binds to the inhibitory presynaptic Y2 receptor, which is highly expressed in NPY neurons in the appetite regulatory center in the arcuate nucleus (27).Infusion of PYY 3-36 at doses producing supraphysiological plasma concentrations has been shown to result in a dosedependent decrease in subsequent food intake (8, 18). The highest suppression of food intake has been demonstrated with doses of 0.8 pmol⅐kg Ϫ1 ⅐min Ϫ1 and amounted to a decrease of between 25 and 34%, with the highest reduction in lean subjects (4,5,8,18) and a somewhat lower reduction in obese subjects (4). The differences in EI were observed either during the subsequent ad libitum meal or during the first 12 h after the infusion. In the context of appetite-suppressant effect in humans, the quantitative effect of PYY is of a magnitude not previously reported in connection with anorectic drugs (sibutramine etc.), and PYY receptors therefore constitute a very promising drug target for obesi...
The between-laboratory SD of the GI values is approximately 9. Standardized data analysis and low within-subject variation (refCV<30%) are required for accuracy. The results suggest that common misconceptions exist about which factors do and do not need to be controlled to improve precision. Controlled studies and cost-benefit analyses are needed to optimize GI methodology. The trial was registered at clinicaltrials.gov as NCT00260858.
The current study does not support the contention that the postprandial glycemic response has an important effect on short-term appetite sensations, but a low-glycemic index meal may reduce subsequent EI. In contrast, postprandial insulin seems to affect short-term appetite sensations.
Abstract:The economics profession appears to have been unaware of the long build-up to the current worldwide financial crisis and to have significantly underestimated its dimensions once it started to unfold. In our view, this lack of understanding is due to a misallocation of research efforts in economics. We trace the deeper roots of this failure to the profession's insistence on constructing models that, by design, disregard the key elements driving outcomes in real-world markets. The economics profession has failed in communicating the limitations, weaknesses, and even dangers of its preferred models to the public. This state of affairs makes clear the need for a major reorientation of focus in the research economists undertake, as well as for the establishment of an ethical code that would ask economists to understand and communicate the limitations and potential misuses of their models.
June 12, 2007; doi:10.1152/ajpendo.00153.2007 infusions have been reported to reduce energy intake (EI) in humans, whereas few studies exist on effects of PYY1-36. The aim of the present study was to examine effects of subcutaneous (sc) injections of PYY 1-36 and PYY3-36 on appetite, ad libitum EI, plasma concentrations of PYY and free fatty acids (FFA) in obese males. Twenty-four males (BMI 27-40 kg/m 2 ) were randomly assigned to two groups receiving sc injections of either PYY 1-36 or PYY3-36 in a blinded, placebo-controlled, dose-escalating, cross-over study. Subjects were studied 5 days in succession, with escalating doses of PYY [saline, 50, 100, 150, and 200 pmol PYY1-36/kg lean body mass (LBM)], or 25, 50, 75, and 100 pmol PYY 3-36/kg LBM), respectively. PYY injections resulted in dose-dependent increases in plasma PYY levels but no effect on EI in either the PYY 1-36 or the PYY3-36 group. However, increasing doses of PYY 3-36, but not PYY1-36, resulted in increased ratings of satiety and decreased ratings of hunger, thirst, and prospective food consumption. Although not dose dependently, significant elevation of plasma FFA was seen after injection of PYY 3-36, but not PYY1-36. Although sc administration of PYY was well tolerated, it remains to be determined whether high-dose PYY 3-36 is sufficient in reducing EI in long-term trials, and if so, whether the reduction in EI occurs without nausea. PYY 1-36 is unlikely to be important in regulating energy intake. The PYY 3-36 administrations caused a non-dose-dependent mobilization of FFA, likely through a direct effect. peptide YY; lipolysis; catecholamine; hunger; satiety IT IS WELL KNOWN that we are in the midst of an obesity epidemic with the associated pathological features resulting in serious consequences for human health and health-related economics. The search for potent antiobesity drug targets is therefore important and has in recent years focused on peptides altering human appetite. Peptide YY (PYY) is an endogenous 36-amino acid peptide found in endocrine cells of the gastrointestinal mucosa and in the circulation (1). It is released postprandially as PYY 1-36 and cleaved by dipeptidyl peptidase-IV to yield PYY 3-36 (9, 10). PYY 3-36 is believed to access the arcuate nucleus via systemic circulation and to act on the presynaptic inhibitory Y2 receptor of neuropeptide Y (NPY) neurons (3). PYY 1-36 has affinity for the Y1, Y2, and Y5 receptors, whereas PYY 3-36 binds more selectively to the Y2 receptor and with lower affinity to the Y5 receptor (17).Human PYY 3-36 intravenous (iv) infusion studies have demonstrated dose-dependent (4, 12) decreases in energy intake (EI) of 23-36% at subsequent meals following 90 min of infusion at a rate of 0.8 pmol⅐kg Ϫ1 ⅐min Ϫ1 (2-4, 12). The quantity of this suppression of food intake and the fact that the effect has been shown to last for 12 h (2, 3), makes PYY 3-36 a promising antiobesity drug target. However, side effects in the form of nausea, vomiting, abdominal discomfort, fullness, and sweating have a...
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