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FLASH GENE
Symbol GCG contributors: mct - updated : 23-09-2020
HGNC name glucagon
HGNC id 4191
Location 2q24.2      Physical location : 162.999.385 - 163.008.914
Synonym name
  • glucagon-like peptide 1
  • glucagon-like peptide 2
  • glicentin-related polypeptide
  • oxyntomodulin
  • Synonym symbol(s) GLP1, GLP2, GRPP, OXY, OXM, GLP-1
    DNA
    TYPE functioning gene
    STRUCTURE 9.53 kb     6 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure FOXA (hepatocyte nuclear factor-3) site in the promoter, binding preferentially FOXA1 in nuclear extracts of a glucagon-producing pancreatic islet alpha-cell line
    MAPPING cloned Y linked Y status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 - 1298 - 180 - 2005 15828872
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  moderately Homo sapiens
    Endocrinepancreas   specific
    Nervousbrain     Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    Epithelialsecretoryglandularexocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    digestivestomach
    Endocrineislet cell (alpha,beta...)
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a 20 aa signal peptide (2.3 kda)
  • a C-terminal structures affecting its blood glucose lowering-function
  • secondary structure adopts an alpha-helical conformation similar to that of secretin family of hormones
    isoforms Precursor a preproprotein cleaved into at least four distinct mature peptides : glicentin (21-89 aa), glicentin-related polypeptide (21-50 aa, 3.4 kda), oxyntomodulin (53-89 aa), glucagon (53-81 aa, 3.5 kda), glucagon-like peptide 1 (98-127 aa, 3.3 kda) and glucagon-like peptide 2 (146-178 aa, 3.8 kda)
    HOMOLOGY
    interspecies homolog to rattus Gcg (91.1 pc)
    homolog to murine Gcg (90 pc)
    Homologene
    FAMILY
  • glucagon family
  • CATEGORY signaling hormone
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,lumen
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic,granule
    text
  • secreted from gut endocrine cells (glucagon-like peptide 1 and glucagon-like peptide 2)
  • intestinal hormone, also localized in the nucleus tractus solitarius (NTS) of the brain stem
  • basic FUNCTION
  • released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility
  • counteracting the glucose-lowering action of insulin by stimulating glycogenolysis and gluconeogenesis (glucagon)
  • raising the blood sugar level (glucagon)
  • playing an important role in initiating and maintaining hyperglycemic conditions in diabetes (glucagon)
  • being a ligand for a specific G-protein linked receptor whose signaling pathway controls cell proliferation (glucagon)
  • acting as a potent stimulator of glucose-dependent insulin release (GLP1)
  • playing important roles on gastric motility and the suppression of plasma glucagon levels (GLP1)
  • may be involved in the suppression of satiety and stimulation of glucose disposal in peripheral tissues, independent of the actions of insulin (GLP1)
  • having growth-promoting activities on intestinal epithelium (GLP1)
  • may also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin, and vasopressin secretion (GLP1)
  • increasing islet mass through stimulation of islet neogenesis and pancreatic beta cell proliferation and inhibiting beta cell apoptosis (GLP1)
  • acting as a potent insulin secretagogue (GLP1)
  • stimulating intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis (GLP2)
  • playing a key role in nutrient homeostasis, enhancing nutrient assimilation through enhanced gastrointestinal function, as well as increasing nutrient disposal (GLP2)
  • e, blood p. incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart ratressure and myocardial contractility)
  • significantly reducing food intake by inhibiting gastric emptying (oxyntomodulin)
  • may modulate gastric acid secretion and the gastro-pyloro-duodenal activity (glicentin)
  • may play an important role in intestinal mucosal growth in the early period of life (glicentin)
  • involved in the activation of PAX4 (Brun 2008)
  • GCG- activation of the SOCS-3 pathway, which antagonizes the IL6-mediated increase in STAT-3 signaling, is involved in the reduction of inflammation-induced proliferation
  • secreted in a dose-dependent manner to reduce intestinal motility and enhance proximal fat absorption
  • protects mesenteric endothelium from injury during inflammation
  • directs human embryonic stem cell differentiation into insulin-producing cells via hedgehog, cyclic adenosine monophosphate, and phosphatidylinositol-3-kinase pathways
  • incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility)
  • glucose-stimulated secretion of GCG and PYY is reduced by a sweet taste antagonist, suggesting the functional involvement of gut-expressed sweet taste receptors in glucose-stimulated secretion of both peptides in humans
  • CDX2 and NKX6-2, are involved in the regulation of GCG expression and the genesis of GCG-producing cells
  • GCG is a key component of glucose homeostasis by counteracting the effect of insulin
  • hormone secreted postprandially from the L-cells of the small intestine and regulating glucose homeostasis
  • suppresses the development of atherosclerosis by inhibiting macrophage function
  • induces macrophage polarization toward the M2 phenotype, which may contribute to the protective effects of GCG against diabetes and cardiovascular diseases
  • suggested to be involved in macrophage activation and polarization
  • controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways
  • promotes angiogenesis in human endothelial cells in a dose-dependent manner, through the AKT1, SRC and PKC pathways
  • is a potent glucoincretin hormone
  • alters in an integrated manner protein networks in cytokine-exposed human pancreatic islets while protecting them against cytokine-mediated cell death and dysfunction
  • though its primary function is to serve as an incretin, GCG reduces gastrointestinal motility
  • increases ER-mitochondria communication in VSMC, resulting in higher mitochondrial activity
  • endogenous GCG acts on paraventricular nucleus to suppress feeding
  • plasma levels of GCG are significantly associated with both systolic and diastolic blood pressure levels
  • GCG plays a pivotal role in glucose homeostasis through its receptor GCGR
  • GCG peptide-expressing neurons can alter feeding, metabolic rate, and glucose production independent of their effects on hypothalamic pituitary-adrenal (HPA) axis activation, aversive conditioning, or insulin secretion
  • is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel
  • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS behavioral
    text
  • feeding behavior
  • control of cell proliferation
  • PATHWAY
    metabolism carbohydrate
    signaling hormonal
  • glucose metabolism and homeostasis
  • GCG, GCGR signaling correlates with STAT3 activation and macrophage polarization
  • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • DUSP14 is a negative regulator of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, rapidly and strongly activated by GCG
  • post-translational activation of GCK is an important mechanism for mediating the insulinotropic effects of GCG
  • CDX2 recruits NKX6-2 in exerting its effect in stimulating GCG expression
  • activation of GCGR by GCG leads to increased glucose production by the liver
  • induces STAT3 activation in human macrophages
  • MYRIP functionally links insulin vesicle transport and GCG signaling
  • UCP2 may contribute to the regulation of hypoglycemia-induced GCG secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived human islets
  • BTG2 is a crucial regulator in GCG-induced insulin gene expression and insulin secretion via upregulation of pancreatic duodenal homeobox-1 (PDX1) in pancreatic beta-cells
  • Gln stimulates the co-release of endogenous GCG and PYY from mucosal L-cells resulting in paracrine GCG and Y1 receptor-mediated electrogenic epithelial responses
  • GCGR is expressed in the human colon and, once activated by exogenous GCG, mediates an inhibitory effect on large intestine motility through NO neural release
  • endogenous glucagon is essential for adaptive thermogenesis and it regulates brown adipose tissue (BAT) function, most likely by increasing hepatic FGF21 production
  • intestine-selective reduction of GCG expression reveals the importance of the distal gut for GCG secretion
  • cell & other
    REGULATION
    induced by hypoglycemia (glucagon release)
    nutrient ingestion (GLP1 and GLP2)
    inhibited by hyperglycemia, insulin, and somatostatin (glucagon release)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in metabolic syndrome with high-risk for cardiovascular disease, independent with the presence of diabetes
    constitutional       loss of function
    in T2D patients, deficiency in the intestinal incretin hormone GCG, which has been shown to exert neuroprotective and anti-inflammatory properties in the brain
    tumoral     --low  
    associated with unfavorable prognosis in Colorectal cancer
    Susceptibility NIDDM (minor contributor)
    Variant & Polymorphism
    Candidate gene
    Marker
  • CEACAM7, SLC4A4, GCG and CLCA1 may be prognostic markers or therapeutic targets of Colorectal cancer
  • Therapy target
  • potential of GCG as a therapeutic agent is limited by its high aggregation propensity
  • SystemTypeDisorderPubmed
    diabete  
    attractive therapeutic target for the treatment of type 2 diabetes
    obesity  
    Sweeteners and secretagogues that increase plasma concentrations of endogenous GCG may provide such an alternative means to promote GCG receptor activity as a treatment for type 2 diabetes and obesity
    diabete  
    GCG based therapy is a novel and now well established therapy of type 2 diabetes, with a particular value in combination with metformin in patients who are inadequately controlled by metformin alone
    ANIMAL & CELL MODELS
  • Glp-1 receptor (Glp-1r) null mice had reduced neural and behavioral responses specifically to sweet compounds compared to wild-type (WT) mice