glucagon-like-peptide-1 and Psychotic-Disorders

Diabetes and psychotic disorders are occasionally comorbid. Possible pathophysiologies linking these disorders include inflammation and oxidative stress. Glucagon like peptide-1 (GLP-1) agonists modulate glucose metabolism and may exert neuroprotective effects via central GLP-1 receptors.. To explore the effects of GLP-1 agonist, liraglutide, on ketamine-induced hyper-locomotion and cognitive dysfunction and the associated inflammation and oxidative stress in normoglycemic and diabetic rats.. Rats were divided into: Chow fed (non-diabetic) and high fat diet fed/STZ (diabetic) groups: I. non-diabetic/control, non-diabetic/liraglutide, non-diabetic/ketamine, non-diabetic/ketamine/liraglutide groups. II. diabetic/control, diabetic/liraglutide, diabetic/ketamine and diabetic/ketamine/liraglutide groups. Hyperlocomotion and cognitive dysfunction were assessed using open field and water maze tests. Biochemical parameters were measured in serum and hippocampus.. Ketamine induced hyperlocomotion and cognitive dysfunction, with hippocampal histopathological changes. Increase in tumour necrosis factor (TNF)-alpha and oxidative stress and reduction in brain-derived neurotrophic factor (BDNF) were noted. These changes were augmented in diabetic compared to non-diabetic rats. Liraglutide significantly improved hyperlocomotion, and cognitive dysfunction and hippocampal histopathological changes in non-diabetic and diabetic rats. Improvement in glucose homeostasis, reduction in TNF alpha and malondialdehyde, and increase in glutathione and BDNF were observed in serum and hippocampus.. Beneficial effects of liraglutide on ketamine-induced hyperlocomotion and cognitive dysfunction are associated with reduction in TNF alpha and oxidative stress. Since effects of liraglutide occurred in diabetic and non-diabetic rats, glycemic and non-glycemic effects (via central GLP-1 receptors) might be involved. Targeting oxidative stress and inflammation by GLP-1 agonists, may be a promising approach in psychotic patients with diabetes.

Topics: Animals; Behavior, Animal; Blood Glucose; Brain-Derived Neurotrophic Factor; Cognition Disorders; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Hippocampus; Hypoglycemic Agents; Inflammation; Insulin; Ketamine; Learning; Liraglutide; Male; Maze Learning; Movement; Oxidative Stress; Psychotic Disorders; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma.

Topics: Adult; Adverse Childhood Experiences; Antipsychotic Agents; Biomarkers; C-Peptide; Female; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Plasminogen Activator Inhibitor 1; Psychotic Disorders; Resistin

The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups. In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project. The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (p < 0.01 for all markers except for PAI-1 p < 0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups. These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets.

Topics: Adult; Antipsychotic Agents; Biomarkers; Chemokine CCL4; Chemokines; Cytokines; Female; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Interleukin-17; Interleukin-6; Leptin; Male; Plasminogen Activator Inhibitor 1; Psychotic Disorders; Vascular Endothelial Growth Factor A; Young Adult

Recent studies indicate a high comorbidity between type-2 diabetes mellitus (T2DM) and neurological disorders. Many are associated with abnormalities in dopamine neurotransmission such as schizophrenia. Because most of the antipsychotic drugs aggravate pre-existing insulin resistance in type-2 diabetics, there is a need to search for alternative antipsychotics. Glucagon like peptide-1 (GLP-1) is a gut hormone primarily involved in glucose homeostasis. GLP-1 agonist (liraglutide) and dipeptidyl peptidase-IV (DPP-IV) inhibitor (sitagliptin) are the US-FDA approved medications for the management of T2DM. However, little is known about their role in dopamine mediated neurological disorders like schizophrenia. To address this, we used apomorphine-induced cage climbing behavior as a murine model for psychosis and examined for potential antipsychotic-like effect of liraglutide and sitagliptin. While acute liraglutide treatment (50 μg/kg; i.p.) significantly attenuated apomorphine (3 mg/kg, s.c.) induced cage climbing, sitagliptin (50mg/kg; i.p.) failed to elicit such effect. This is the first preclinical evidence for antipsychotic-like effect of GLP-1 receptor agonist. These results open an opportunity to explore GLP-1 analogs for their potential to modulate spectrum of dopamine-mediated neurological disorders.

Topics: Animals; Antipsychotic Agents; Apomorphine; Disease Models, Animal; Dopamine Agonists; Glucagon-Like Peptide 1; Liraglutide; Male; Mice; Psychotic Disorders; Pyrazines; Sitagliptin Phosphate; Statistics, Nonparametric; Triazoles