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The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents.

ABSTRACT: The incretin hormone, glucagon-like peptide 1 (GLP-1), regulates gastric emptying, glucose-dependent stimulation of insulin secretion and glucagon release, and GLP-1 analogs are therefore approved for treatment of type II diabetes. GLP-1 receptors are expressed in reward-related areas such as the ventral tegmental area and nucleus accumbens, and GLP-1 was recently shown to regulate several alcohol-mediated behaviors as well as amphetamine-induced, cocaine-induced and nicotine-induced reward. The present series of experiments were undertaken to investigate the effect of the GLP-1 receptor agonist, liraglutide, on several alcohol-related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well-documented effects of alcohol on the mesolimbic dopamine system, namely alcohol-induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self-administration of alcohol in selectively bred Sardinian alcohol-preferring rats. Collectively, these data suggest that GLP-1 receptor agonists could be tested for treatment of alcohol dependence in humans.

SUBMITTER: Vallof D

PROVIDER: S-EPMC5049632 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents.

Vallöf Daniel D Maccioni Paola P Colombo Giancarlo G Mandrapa Minja M Jörnulf Julia Winsa JW Egecioglu Emil E Engel Jörgen A JA Jerlhag Elisabet E

Addiction biology 20150825 2

The incretin hormone, glucagon-like peptide 1 (GLP-1), regulates gastric emptying, glucose-dependent stimulation of insulin secretion and glucagon release, and GLP-1 analogs are therefore approved for treatment of type II diabetes. GLP-1 receptors are expressed in reward-related areas such as the ventral tegmental area and nucleus accumbens, and GLP-1 was recently shown to regulate several alcohol-mediated behaviors as well as amphetamine-induced, cocaine-induced and nicotine-induced reward. The ...[more]

PMID: 26303264

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Project description:BackgroundThe glucagon-like peptide-1 receptor (GLP1R) agonist liraglutide improves glycemic control and reduces body weight of adult type 2 diabetic patients. However, efficacy and safety of liraglutide in adolescents has not been systematically investigated. Furthermore, possible pro-proliferative effects of GLP1R agonists on the endocrine and exocrine pancreas need to be further evaluated. We studied effects of liraglutide in adolescent pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) in the beta-cells, leading to a pre-diabetic condition including disturbed glucose tolerance, reduced insulin secretion and progressive reduction of functional beta-cell mass.MethodsTwo-month-old GIPR(dn) transgenic pigs were treated daily with liraglutide (0.6-1.2 mg per day) or placebo for 90 days. Glucose homeostasis was evaluated prior to and at the end of the treatment period by performing mixed meal and intravenous glucose tolerance tests (MMGTT and IVGTT). Finally animals were subjected to necropsy and quantitative-stereological analyses were performed for evaluation of alpha- and beta-cell mass, beta-cell proliferation as well as acinus-cell proliferation.ResultsMMGTT at the end of the study revealed 23% smaller area under the curve (AUC) for glucose, a 36% smaller AUC insulin, and improved insulin sensitivity, while IVGTT showed a 15% smaller AUC glucose but unchanged AUC insulin in liraglutide- vs. placebo-treated animals. Liraglutide led to marked reductions in body weight gain (-31%) and food intake (-30%) compared to placebo treatment, associated with reduced phosphorylation of insulin receptor beta (INSRB)/insulin-like growth factor-1 receptor beta (IGF1RB) and protein kinase B (AKT) in skeletal muscle. Absolute alpha- and beta-cell mass was reduced in liraglutide-treated animals, but alpha- and beta-cell mass-to-body weight ratios were unchanged. Liraglutide neither stimulated beta-cell proliferation in the endocrine pancreas nor acinus-cell proliferation in the exocrine pancreas, excluding both beneficial and detrimental effects on the pig pancreas.ConclusionsAlthough plasma liraglutide levels of adolescent transgenic pigs treated in our study were higher compared to human trials, pro-proliferative effects on the endocrine or exocrine pancreas or other liraglutide-related side-effects were not observed.

Project description:BACKGROUND:Dulaglutide is a new, long-acting glucagon-like peptide analogue in the treatment of type 2 diabetes. It is available in two doses, 0.75 and 1.5 mg, given by injection once weekly. This systematic review reports the effectiveness and safety of dulaglutide in type 2 diabetes in dual and triple therapy. METHODS:MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, and conference abstracts were searched from 2005 to August 2014, and updated in January 2015. Company websites and references of included studies were checked for potentially relevant studies. European Medicines Agency and US Food and Drug Administration websites were searched. RESULTS:Four trials were included. All were manufacturer-funded randomized controlled trials from the Assessment of Weekly Administration of Dulaglutide in Diabetes (AWARD) program. AWARD-1 compared dulaglutide 1.5 mg against exenatide 10 µg twice daily and placebo, AWARD-2 compared dulaglutide 0.75 and 1.5 mg against insulin glargine, AWARD-5 compared dulaglutide 0.75 and 1.5 mg against sitagliptin 100 mg and placebo, and AWARD-6 compared dulaglutide 1.5 mg against liraglutide 1.8 mg. The duration of follow-up in the trials ranged from 26 to 104 weeks. The primary outcome of all the included trials was change in HbA1c. At 26 weeks, greater HbA1c reductions were seen with dulaglutide than with twice daily exenatide (dulaglutide 1.5/0.75 mg: -1.5%/-1.3%; exe: 0.99%) and sitagliptin (1.5/0.75 mg -1.22%/-1.01%; sitagliptin: -0.6%). HbA1c change was greater with dulaglutide 1.5 mg (-1.08%) than with glargine (-0.63%), but not with dulaglutide 0.75 mg (-0.76%). Dulaglutide 1.5 mg was found to be noninferior to liraglutide 1.8 mg. More patients treated with dulaglutide achieved HbA1c targets of <7% and ≤6.5%. Reduction in weight was greater with dulaglutide than with sitagliptin and exenatide. Hypoglycemia was infrequent. The main adverse events were nausea, diarrhea, and vomiting. CONCLUSION:Dulaglutide is effective in the treatment of patients with type 2 diabetes but we need long follow-up data for safety concerns.

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The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents.

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The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents.

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