Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The GPR119 was recently shown to be activated by oleoylethanolamide (OEA), a naturally occurring bioactive lipid with hypophagic and anti-obesity effects. In this study, we have cloned and characterized its murine counterpart, Gpr119. The full-length cDNA contained an open reading frame of 1008bp encoding a 335-amino acid protein. The genomic organization of Gpr119 was unique, having a 3'-untranslated second exon that was also involved in an alternative splicing event. Gene expression analyses confirmed its specific expressions in pancreatic islets and two endocrine cell-lines, MIN6 and alphaTC1. Immunohistochemistry and double-immunofluorescence studies using a specific antibody revealed the predominant Gpr119 localization in pancreatic polypeptide (PP)-cells of islets. No definitive evidence of Gpr119-immunoreactivity in adult beta- or alpha-cells was obtained. The Gpr119 mRNA levels were elevated in islets of obese hyperglycemic db/db mice as compared to control islets, suggesting a possible involvement of this receptor in the development of obesity and diabetes.
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PMID:Expression and distribution of Gpr119 in the pancreatic islets of mice and rats: predominant localization in pancreatic polypeptide-secreting PP-cells. 1707 Jul 74

GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (beta-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G(alphas) coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic beta-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed.
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PMID:GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. 1803 23

GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.
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PMID:Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119. 1869 56

G-protein-coupled receptors (GPCRs) respond to various physiological ligands such as photons, ions, and small molecules that include amines, fatty acids, and amino acids to peptides, proteins and steroids. Therefore, this family of proteins represents an attractive target for biopharmaceutical research. The physiological role of fatty acids and other lipid molecules as important signal mediators is well studied in various metabolic pathways. Acute administration of free fatty acids (FFAs) stimulates insulin release. Conversely, chronic exposure to high levels of free fatty acids leads to impairment of beta cell function and lipotoxicity. However, the receptors through which these fatty acids and lipids act were unknown, until the identification of fatty acid binding receptors: GPR40, GPR41, GPR43, and GPR119. Based on their tissue-expression profile, and pharmacologic analysis, the fatty acid binding receptors along with lipid binding receptor GPR119 are linked to diabetes and obesity. They play a critical role in the metabolic regulation of insulin release and glucose homeostasis. In this review, the mechanism of receptor activation, pharmacology, and the physiological functions of the fatty acid binding receptors will be discussed.
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PMID:Fatty acid binding receptors and their physiological role in type 2 diabetes. 1900 45

Type 2 diabetes and obesity remain the focus of investigational drugs for metabolic disease. Only one new class of agents (Dipeptidylpeptidase 4 Inhibitors) has been approved in this field for control of blood glucose in patients with type 2 diabetes. Significant progress has been made in the elucidation of pathways of interest for new therapies in diabetes and obesity, partly through advances in human genetics that have highlighted genetic loci relevant to pancreatic beta cell dysfunction and hypothalamic control of food intake, respectively. Investigational drugs targeting these pathways are in early clinical investigation, including GPR119 agonists. Compounds targeting lipid partitioning and lipid biosynthetic enzymes also have emerged, including inhibitors of the enzymes DGAT1 and SCD1.
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PMID:Emerging therapies for metabolic diseases--the focus is on diabetes and obesity. 1948 41

Type 2 diabetes (T2D) and associated obesity have reached epidemic proportions, and there is an increasing need for orally effective agents that regulate glucose homeostasis with a concurrent reduction in body weight. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressed primarily in the human pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in the last three to five years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion and increased levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide). In rodent models, orally available GPR119-specific agonists have been shown to attenuate blood glucose levels with a simultaneous body weight loss. This review summarizes the research leading to the identification of GPR119 as a potential drug target for T2D and related metabolic disorders. In addition, an overview of the recent progress made in the discovery of orally active GPR119 agonists is provided.
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PMID:GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders. 1956 48

G-protein coupled receptors (GPCRs) are targets of approximately 30% of currently marketed drugs. Over the last few years, a number of GPCRs expressed in pancreatic beta-cells and activated by lipids have been discovered. GPR40 was shown to be activated by medium- to long-chain fatty acids (FAs). It has since been shown that GPR40 contributes to FA amplification of glucose-induced insulin secretion. Although some controversy still exists as to whether GPR40 agonists or antagonists should be designed as novel type 2 diabetes drugs, data obtained in our laboratory and others strongly suggest that GPR40 agonism might represent a valuable therapeutic approach. GPR119 is expressed in pancreatic beta-cells and enteroendocrine L-cells, and augments circulating insulin levels both through its direct insulinotropic action on beta-cells and through FA stimulation of glucagon-like peptide 1 (GLP-1) secretion. GPR120 is expressed in L-cells and was also shown to mediate FA-stimulated GLP-1 release. Finally, GPR41 and GPR43 are receptors for short-chain FAs and may indirectly regulate beta-cell function via adipokine secretion. Although the discovery of these various lipid receptors opens new and exciting avenues of research for drug development, a number of questions regarding their mechanisms of action and physiological roles remain to be answered.
Diabetes Obes Metab 2009 Nov
PMID:Lipid receptors and islet function: therapeutic implications? 1981 84

The American Chemical Society 239th National Meeting, held in San Francisco, included topics covering developments related to the chemical optimization of therapeutics. This conference report highlights selected presentations on second-generation cholesterol absorption inhibitors (CAIs), CCK2 receptor antagonists to prevent acid rebound, HIF-PH inhibitors for anemia, the neonatal Fc receptor (FcRn) as a target for autoimmune disease, and GPR119 agonists and GLP-1 receptor agonists for the treatment of diabetes. Investigational drugs discussed include LPD-608 (Lipideon Biotechnology AG), a second-generation CAI series from Merck & Co Inc, JNJ-26070109 and JNJ-42041935 (both Johnson & Johnson), SYN-1436 (Syntonix Pharmaceuticals Inc), a series of GPR119 agonists from Roche Holding AG and Schering-Plough Research Institute, and a series of GLP-1 receptor agonists from Bristol-Myers Squibb Co.
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PMID:American Chemical Society-239th national meeting--Investigating new therapeutic candidates: part 2. 21-25 March 2010, San Francisco, CA, USA. 2043 81

The American Diabetes Association 70th Scientific Sessions, held in Orlando, FL, USA, included topics covering new therapeutic developments in the field of diabetes research. This conference report highlights selected presentations on new research with novel agents. Investigational drugs discussed include the glucokinase activator SKL-19014 (Sanwa Kagaku Kenkyusho Co Ltd), the GPR119 agonist AS-1535907 (Astellas Pharma Inc), the apical sodium-dependent bile transporter (ASBT) inhibitor SC-435 (Satiogen Pharmaceuticals Inc), the VEGF-A activator SB-509 (Sangamo BioSciences Inc), and the protein tyrosine phosphatase 1b (PTP-1b) antisense inhibitor ISIS-113715 (ISIS Pharmaceuticals Inc).
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PMID:American Diabetes Association--70th scientific sessions--research on novel therapeutics: part 2. 2079 37

In the 1970s, glucose-dependent insulinotropic polypeptide (GIP, formerly gastric inhibitory polypeptide), a 42-amino acid peptide hormone, was discovered through a search for enterogastrones and subsequently identified as an incretin, or an insulinotropic hormone secreted in response to intraluminal nutrients. Independent of the discovery of GIP, the K-cell was identified in small intestine by characteristic ultrastructural features. Subsequently, it was realized that K-cells are the predominant source of circulating GIP. The density of K-cells may increase under conditions including high-fat diet and obesity, and generally correlates with plasma GIP levels. In addition to GIP, K-cells secrete xenin, a peptide with as of yet poorly understood physiological functions, and GIP is often colocalized with the other incretin hormone glucagon-like peptide-1 (GLP-1). Differential posttranslational processing of proGIP produces 30 and 42 amino acid versions of GIP. Its secretion is elicited by intraluminal nutrients, especially carbohydrate and fat, through the action of SGLT1, GPR40, GPR120, and GPR119. There is also evidence of regulation of GIP secretion via neural pathways and somatostatin. Intracellular signaling mechanisms of GIP secretion are still elusive but include activation of adenylyl cyclase, protein kinase A (PKA), and protein kinase C (PKC). GIP has extrapancreatic actions on adipogenesis, neural progenitor cell proliferation, and bone metabolism. However, the clinical or physiological relevance of these extrapancreatic actions remain to be defined in humans. The application of GIP as a glucose-lowering drug is limited due to reduced efficacy in humans with type 2 diabetes and its potential obesogenic effects demonstrated by rodent studies. There is some evidence to suggest that a reduction in GIP production or action may be a strategy to reduce obesity. The meal-dependent nature of GIP release makes K-cells a potential target for genetically engineered production of satiety factors or glucose-lowering agents, for example, insulin. Transgenic mice engineered to produce insulin from intestinal K-cells are resistant to diabetes induced by a beta-cell toxin. Collectively, K-cells and GIP play important roles in health and disease, and both may be targets for novel therapies.
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PMID:K-cells and glucose-dependent insulinotropic polypeptide in health and disease. 2109 98


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