RESUMO
AIM: Previous studies with the novel once daily glucagon-like peptide-1 (GLP-1) analogue liraglutide and the GLP-1 receptor agonist exenatide have revealed profound insulinotrophic and antidiabetic effects, but also potent effects on gastric emptying (GE) and long-term and lasting reductions in body weight. In this study, we examined the acute and chronic effects of two different GLP-1 analogues with different pharmacokinetic profiles on GE, food intake and body weight. METHODS: On the basis of a series of dose-finding studies, the doses of exenatide and liraglutide with similar acute anorectic effects were identified. GE was assessed using a standard acetaminophen release assay. After the acute test, rats were dosed bi-daily for 14 days in which period food intake and body weight was monitored. On day 14, the GE rate was reassessed. RESULTS: While both compounds exerted robust acute reductions in GE, the effect was markedly diminished following 14 days of dosing with liraglutide. In contrast, exenatide-treated rats still displayed a profound reduction in GE at the 14-day time-point. Both compounds exerted similar effects on body weight. CONCLUSION: The data suggest that the 'gastric inhibitory' GLP-1 receptors in rats are subject to desensitization/tachyphylaxis but that this effect is dependent on full 24-h exposure as obtained by liraglutide. The body weight-lowering effects of GLP-1 receptor stimulation are not subject to desensitization. These data indicate that regulation of appetite signals in the brain, and not GE, is the main mechanism for liraglutide-induced weight loss.
Assuntos
Regulação do Apetite/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipocampo/efeitos dos fármacos , Obesidade/tratamento farmacológico , Redução de Peso/efeitos dos fármacos , Animais , Ingestão de Alimentos/efeitos dos fármacos , Exenatida , Peptídeo 1 Semelhante ao Glucagon/farmacocinética , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Injeções Intravenosas , Liraglutida , Masculino , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Peçonhas/farmacologiaRESUMO
The neuropeptide Y (NPY)/peptide YY (PYY) system has been implicated in the physiology of obesity for several decades. More recently ignited enormous interest in PYY3-36, an endogenous Y2-receptor agonist, as a promising anti-obesity compound. Despite this interest, there have been remarkably few subsequent reports reproducing or extending the initial findings, while at the same time studies finding no anti-obesity effects have surfaced. Out of 41 different rodent studies conducted (in 16 independent labs worldwide), 33 (83%) were unable to reproduce the reported effects and obtained no change or sometimes increased food intake, despite use of the same experimental conditions (i.e. adaptation protocols, routes of drug administration and doses, rodent strains, diets, drug vendors, light cycles, room temperatures). Among studies by authors in the original study, procedural caveats are reported under which positive effects may be obtained. Currently, data speak against a sustained decrease in food intake, body fat, or body weight gain following PYY3-36 administration and make the previously suggested role of the hypothalamic melanocortin system unlikely as is the existence of PYY deficiency in human obesity. We review the studies that are in the public domain which support or challenge PYY3-36 as a potential anti-obesity target.
Assuntos
Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Peptídeo YY/farmacologia , Animais , Comportamento Animal , Interpretação Estatística de Dados , Dipeptidil Peptidase 4/metabolismo , Humanos , Fragmentos de Peptídeos , Peptídeo YY/administração & dosagem , Receptores de Neuropeptídeo Y/agonistas , Resposta de Saciedade/efeitos dos fármacos , Especificidade da Espécie , Estresse Fisiológico/fisiopatologiaRESUMO
Pharmacokinetics for one growth hormone secretogogue (NNC 26-0722), but not for another (NN703), differ between dogs in estrus or anestrus. We examined if the differences could be mimicked by administering estradiol during anestrus and if there was a relationship with rates of small intestine absorption. Pharmacokinetics for oral doses of NN703 (1.0-1.6 mg kg(-1)) did not differ among dogs in estrus, anestrus, or anestrus and given estradiol for 1 week (days 1, 3, and 6; 40 micro g kg(-1)), whereas plasma concentrations of NNC 26-0722 increased from undetectable in untreated, anestrus dogs to several hundred nanograms per milliliter in dogs given estradiol, with maximal concentrations measured 5 min after oral dosage. Estradiol treatment increased small intestinal absorption of NNC 26-0722 by 100% (P<0.05), but did not increase absorption of NN703, and caused a 64% increase in carrier-mediated glucose transport at 50 mmol l(-1) (P<0.05) due to increased densities of transporters. These findings indicate estrus and estradiol enhance absorptive functions of the dog proximal small intestine and can affect pharmacokinetics for some orally administered drugs.
Assuntos
Anestro/metabolismo , Dipeptídeos/farmacocinética , Estradiol/farmacologia , Glucose/farmacocinética , Absorção Intestinal/fisiologia , Intestino Delgado/metabolismo , Simportadores , Administração Oral , Animais , Proteínas de Transporte/metabolismo , Cães , Feminino , Absorção Intestinal/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Transportador 1 de Peptídeos , Transportador 1 de Glucose-SódioRESUMO
Limb lengthening in the left tibia of 30 mature female Yucatan micropigs was performed using distraction osteogenesis. A treatment group of 15 animals received recombinant porcine growth hormone (r-pGH) (100 microg/kg/day) while the others served as controls. Serial serum measurements of total insulin-like growth factor I (IGF-I), free IGF-I, IGF binding proteins -1, -2, -3 and -4 (IGFBP-1 to -4) were performed. Bone-specific alkaline phosphatase (bone-ALP) and the serum carboxyl-terminal telopeptide of type I collagen (ICTP) were measured as bone turnover markers. The GH-treated animals showed a significant increase in total IGF-I, free IGF-I and IGFBP-3 after surgery (P<0.001). Similarly, the treated animals showed a significantly higher level of bone-ALP (P<0.001) throughout the experiment compared to the controls. There was a significant correlation between bone-ALP and total IGF-I (r=0.76) in the GH-treated group and an even higher correlation for free IGF-I (r=0.90). There was no difference in the ICTP serum levels between the two groups. These data indicate that the application of species-specific growth hormone results in a stimulation of bone formation in distraction osteogenesis which may be mediated by IGF-I. The stronger correlation between free IGF-I and bone-ALP indicates that the anabolic effect of IGF-I may be regulated through the IGFBPs by binding and inactivating IGF-I.