Glucagon-like peptide-1 agonists combating clozapine-associated obesity and diabetes

Abstract Obesity and diabetes are both risk factors and consequences of psychiatric disorders. Glucagon like peptide 1 (GLP-1) receptor agonists such as liraglutide are widely used in the treatment of diabetes and obesity. There are considerable amounts of preclinical studies showing the effects of liraglutide on promotion of neurogenesis, while preventing apoptosis and oxidation. Preliminary clinical evidence has suggested that liraglutide could decrease weight gain, improve cognition and prevent cognitive decline. Accordingly, liraglutide has been regarded as a potential candidate for the management of psychiatric disorders. Herein, we will discuss the association between obesity/diabetes and psychiatric disorders, and the emerging use of liraglutide in psychiatry.

Download Full-text

Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1

Journal of Clinical Pathology ◽

10.1136/jcp.2006.043232 ◽

2008 ◽

Vol 61 (4) ◽

pp. 401-409 ◽

Cited By ~ 44

Author(s):

L R Ranganath

Keyword(s):

B Cell ◽

Cell Mass ◽

Therapeutic Agents ◽

Glycosidase Inhibitors ◽

Therapeutic Implications ◽

Obesity And Diabetes ◽

Control Of Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

High Doses

Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are intestinal postprandial hormones that stimulate insulin release from the pancreas as long as circulating glucose concentrations are raised. In addition to their effect on insulin secretion and consequent glucose lowering, GIP and GLP-1, especially the latter, have a number of physiological effects such as inhibition of glucagon release, gastric emptying and food intake, as well as a tropic action on pancreatic B-cell mass. There is currently a pandemic of obesity and diabetes, and existing treatments are largely inadequate both in regard to efficacy as well as their ability to tackle important factors in the pathogenesis of type 2 diabetes (T2D). There is increasing evidence that current treatments do not address the issue of progressive B-cell failure in T2D. Since obesity is the engine that is driving the epidemic of diabetes, it is disappointing that most treatments that succeed in lowering plasma glucose are also associated with weight gain. It is now well established that intensively treated T2D has a better outcome than standard treatment. Consequently, achieving better control of diabetes with lower HbA1c is the goal of optimal treatment. Despite the use of usual therapeutic agents in T2D, often in high doses and as combinations, such as metformin, sulphonylurea, α-glycosidase inhibitors, thiazolidinediones and a number of animal and human insulin preparations, optimal control of glycaemia is not achieved. The use of incretins as therapeutic agents offers a new approach to the treatment of T2D.

Download Full-text

Distinct Identity of GLP-1R, GLP-2R, and GIPR Expressing Cells and Signaling Circuits Within the Gastrointestinal Tract

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.703966 ◽

2021 ◽

Vol 9 ◽

Author(s):

Nadya M. Morrow ◽

Antonio A. Hanson ◽

Erin E. Mulvihill

Keyword(s):

Cellular Localization ◽

Γδ T Cells ◽

Nutrient Content ◽

Intraepithelial Lymphocytes ◽

Metabolic Effects ◽

Current State ◽

Obesity And Diabetes ◽

Clinical Models ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Enteroendocrine cells directly integrate signals of nutrient content within the gut lumen with distant hormonal responses and nutrient disposal via the production and secretion of peptides, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). Given their direct and indirect control of post-prandial nutrient uptake and demonstrated translational relevance for the treatment of type 2 diabetes, malabsorption and cardiometabolic disease, there is significant interest in the locally engaged circuits mediating these metabolic effects. Although several specific populations of cells in the intestine have been identified to express endocrine receptors, including intraepithelial lymphocytes (IELs) and αβ and γδ T-cells (Glp1r+) and smooth muscle cells (Glp2r+), the definitive cellular localization and co-expression, particularly in regards to the Gipr remain elusive. Here we review the current state of the literature and evaluate the identity of Glp1r, Glp2r, and Gipr expressing cells within preclinical and clinical models. Further elaboration of our understanding of the initiating G-protein coupled receptor (GPCR) circuits engaged locally within the intestine and how they become altered with high-fat diet feeding can offer insight into the dysregulation observed in obesity and diabetes.

Download Full-text

Diet-induced obesity enhances postprandial glucagon-like peptide-1 secretion in Wistar rats, but not in diabetic Goto-Kakizaki rats

British Journal Of Nutrition ◽

10.1017/s000711452000433x ◽

2020 ◽

pp. 1-13

Author(s):

Jukkrapong Pinyo ◽

Hiroshi Hara ◽

Tohru Hira

Keyword(s):

Wistar Rats ◽

Control Diet ◽

Postprandial Glucose ◽

Diabetic Rats ◽

Gk Rats ◽

Obesity And Diabetes ◽

Male Wistar Rats ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Insulin Responses

Abstract Glucagon-like peptide-1 (GLP-1) is postprandially secreted from enteroendocrine L-cells and enhances insulin secretion. Currently, it is still controversial whether postprandial GLP-1 responses are altered in obesity and diabetes. To address the issue and to find out possible factors related, we compared postprandial GLP-1 responses in normal rats and in diabetic rats chronically fed an obesogenic diet. Male Wistar rats and diabetic Goto-Kakizaki (GK) rats were fed either a control diet or a high-fat/high-sucrose (HFS, 30 % fat and 40 % sucrose) diet for 26 weeks. Meal tolerance tests were performed for monitoring postprandial responses after a liquid diet administration (62·76 kJ/kg body weight) every 4 or 8 weeks. Postprandial glucose, GLP-1 and insulin responses in Wistar rats fed the HFS diet (WH) were higher than Wistar rats fed the control diet (WC). Although GK rats fed the HFS diet (GH) had higher glycaemic responses than GK rats fed the control diet (GC), these groups had similar postprandial GLP-1 and insulin responses throughout the study. Jejunal and ileal GLP-1 contents were increased by the HFS diet only in Wistar rats. Furthermore, mRNA expression levels of fatty acid receptors (Ffar1) in the jejunum were mildly (P = 0·053) increased by the HFS diet in Wistar rats, but not in GK rats. These results demonstrate that postprandial GLP-1 responses are enhanced under an obesogenic status in normal rats, but not in diabetic rats. Failure of adaptive enhancement of GLP-1 response in GK rats could be partly responsible for the development of glucose intolerance.

Download Full-text

Glucagon, GLP-1 and Thermogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms20143445 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3445 ◽

Cited By ~ 6

Author(s):

Ismael González-García ◽

Edward Milbank ◽

Carlos Diéguez ◽

Miguel López ◽

Cristina Contreras

Keyword(s):

Energy Expenditure ◽

Direct Action ◽

Short Review ◽

Obesity And Diabetes ◽

Promising Target ◽

Brown Adipose ◽

Endocrine Factors ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Maintain Body Temperature

Brown adipose tissue (BAT) thermogenesis is a conserved mechanism to maintain body temperature in mammals. However, since BAT contribution to energy expenditure can represent a relevant modulator of metabolic homeostasis, many studies have focused on the nervous system and endocrine factors that control the activity of this tissue. There is long-established evidence that the counter-regulatory hormone glucagon negatively influences energy balance, enhances satiety, and increases energy expenditure. Despite compelling evidence showing that glucagon has direct action on BAT thermogenesis, recent findings are questioning this conventional attribute of glucagon action. Glucagon like peptide-1 (GLP-1) is an incretin secreted by the intestinal tract which strongly decreases feeding, and, furthermore, improves metabolic parameters associated with obesity and diabetes. Therefore, GLP-1 receptors (GLP-1-R) have emerged as a promising target in the treatment of metabolic disorders. In this short review, we will summarize the latest evidence in this regard, as well as the current therapeutic glucagon- and GLP-1-based approaches to treating obesity.

Download Full-text

Use of glucagon‐like peptide‐1 receptor agonistsfor pediatric patients with obesity and diabetes: the providers’ perspectives

Pediatric Diabetes ◽

10.1111/pedi.13234 ◽

2021 ◽

Author(s):

Evgenia Gourgari ◽

Lina Huerta‐Saenz ◽

Ksenia N. Tonyushkina ◽

Elizabeth T. Rosolowsky ◽

Ines Guttmann‐Bauman

Keyword(s):

Pediatric Patients ◽

Obesity And Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Download Full-text

Improvement of Glucose Tolerance by Food Factors Having Glucagon-Like Peptide-1 Releasing Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22126623 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6623

Author(s):

Tohru Hira ◽

Aphichat Trakooncharoenvit ◽

Hayate Taguchi ◽

Hiroshi Hara

Keyword(s):

Glucose Tolerance ◽

Animal Studies ◽

Animal Experiments ◽

Gastrointestinal Hormone ◽

Peptidase Activity ◽

Potent Effect ◽

Obesity And Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Meal Ingestion

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes.

Download Full-text

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus

World Journal of Diabetes ◽

10.4239/wjd.v9.i6.80 ◽

2018 ◽

Vol 9 (6) ◽

pp. 80-91 ◽

Cited By ~ 4

Author(s):

Vishal J Patel ◽

Amit A Joharapurkar ◽

Samadhan G Kshirsagar ◽

Brijesh K Sutariya ◽

Maulik S Patel ◽

...

Keyword(s):

Diabetes Mellitus ◽

Kidney Injury ◽

Murine Models ◽

Obesity And Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucagon Receptors

Download Full-text

Glucagon-Like Peptide 1 and Taste Perception: From Molecular Mechanisms to Potential Clinical Implications

International Journal of Molecular Sciences ◽

10.3390/ijms22020902 ◽

2021 ◽

Vol 22 (2) ◽

pp. 902

Author(s):

Mojca Jensterle ◽

Manfredi Rizzo ◽

Andrej Janez

Keyword(s):

Molecular Mechanisms ◽

Taste Perception ◽

Taste Bud ◽

Treatment Target ◽

Obesity And Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Potential Strategy ◽

New Treatment ◽

The Impact

Preclinical studies provided some important insights into the action of glucagon-like peptide 1 (GLP-1) in taste perception. This review examines the literature to uncover some molecular mechanisms and connections between GLP-1 and the gustatory coding. Local GLP-1 production in the taste bud cells, the expression of GLP-1 receptor on the adjacent nerves, a functional continuum in the perception of sweet chemicals from the gut to the tongue and an identification of GLP-1 induced signaling pathways in peripheral and central gustatory coding all strongly suggest that GLP-1 is involved in the taste perception, especially sweet. However, the impact of GLP-1 based therapies on gustatory coding in humans remains largely unaddressed. Based on the molecular background we encourage further exploration of the tongue as a new treatment target for GLP-1 receptor agonists in clinical studies. Given that pharmacological manipulation of gustatory coding may represent a new potential strategy against obesity and diabetes, the topic is of utmost clinical relevance.

Download Full-text