Diabetes and Thyroid Center Div. of Endocrinology and Metabolism Konyang University, School of Medicine Byung-Joon Kim M.D., Ph.D.
Background Incretin effect and GLP 1 Receptor in L cells TGR5 receptor GPR120 receptor Taste receptor in tongue Taste receptor in gut (enteroendocrine cells) GLP 1 secretion through Taste receptor via sweet receptor via bitter receptor Summary and Conclusion
Venous Plasma Glucose (mg/dl) 200 20 2.0 Oral Glucose IV Glucose /L) e (nmol 100 1.0 C peptid * 15 1.5 * Incretin Effect 0 00 0.0 0 1 Glucose 0 2 60(or food) 120stimulated 180 Insulinotropic 0 1 0 2 60 hormones 120 180 Time (min) Time (min) 0.5 from enteroendocrine cells. * * * * * Same blood glucose level by oral or IV route Two candidate hormones are GLP 1 and GIP. Different insulin response Mean ± SE; N=6; *p.05; 0 1 0 2 =glucose infusion time. Nauck MA. et al. J Clin Endocrinol Metab. 63:492 498. 1986
Stimulates insulin Secretion Potentiates glucose induced insulin secretion Enhanced all steps of insulin secretion Up regulation of insulin gene expression Up regulation of genes essential for the beta cell function Increases Islet mass Beta cells proliferation Promotes differentiation of ductal progenitor cells Inhibits apoptosis Stimulated somatostatin secretion Inhibits glucagon secretion Extrapancreatic effects p Inhibits gastrointestinal secretion and motility Inhibits appetite and food intake Cardiovascular effects
Modification of GLP 1 peptide GLP 1 Analog Exendin 4 liraglutide GLP 1 Good for T2DM Limitation: Short half life Block the Enzyme activity DPPIV inhibitor Sitagliptin Vildagliptin Saxagliptin Stimulation of GLP 1 secretion GLP 1 Secretagogues
1 2 1) directly monitored nutrients via the receptors/transporters in cell surface 2) via gastroenteric nervous system and/or extrinsic nervous system 3) via paracrine manner Buchan AM. et al. Am J Physiol, 277: G1103 7, 1999
TGR5 receptor G protein coupled receptor (GPCR) responds to bile acids expressed in monocytes/macrophages intestinal cell lines, NCI H716 and STC 1 Lithocholic acid (LCA) Deoxycholic acid (DCA) Northern blot Analysis Internalization of TGR5 receptor After treatment of LCA (TGR5/GFP CHO cells) T. Maruyama et al. Biochem. Biophys. Res. Commun. 298 :714 719, 2002 K. Susumu et al. Biochem. Biophys. Res. Commun. 329:386 390, 2005
GPR120 receptor An orphan G protein coupled receptor Responced to fatty acid Expression in intestinal tract in mouse and human α-linolenic (α-la) In situ hybridization for GPR120 (ISH) immunohistochemistry with antibody to GLP 1 (IHC) A. Hirasawa et al. Nat Med. 11: 90 4, 2005
Taste Sencing Signal pathway for taste receptor
Umami sense Bitter sense Sour sense Salty sense Sweet sense
Sweet sugar sweetner Bitter denatoneum PTU Taste signals Taste receptor Gα gustducin Gβ3 Gγ13 PLCβ2 TRPM 5
Taste receptor Alpha gustducin TRMP5 calcium channel PLC β2
GLP 1 α gustducin Merge α gustducin GFP transgenic mice Duodenum Jejunum Ileum α gustducin is co expressed with GLP 1 in the small intestine L cells.
Element GLP-1 Merge Element GLP-1 Merge
Sweet receptor Heterodimeric i receptor T1R2 + T1R3
Glucose gavage 10% glucose loading in Isolated duodenal villi Blunted GLP 1secretion in a gustducin null mice after glucose gavage (5 g/kg) and ex vivo glucose loading. Jang HJ, Kim BJ, Egan JM. Proc Natl Acad Sci U S A 104:15069 15074, 2007
Blunted insulin secretion and higher glucose levels in a gustducin null mice after glucose gavage (2 g/kg). Jang HJ, Kim BJ, Egan JM. Proc Natl Acad Sci U S A 104:15069 15074, 2007
Coupling of taste receptors to G protein α subunits with [ 32 P] GTP azidoanilide NCI H716 cells Jang HJ, Kim BJ, Egan JM. Proc Natl Acad Sci U S A 104:15069 15074, 2007
NCI H716 cells Intracellular calcium is increased by external calcium loading
NCI H716 cells Lactisole: sweet receptor inhibitor Jang HJ, Kim BJ, Egan JM. Proc Natl Acad Sci U S A 104:15069 15074, 2007
A: antrum C: colon F: fundus L: liver D: duodenum H: heart I: ileum; K: kidney J: jejunum T: tongue Individual id ltrace of f[ca 2 ]i from a single STC 1 cell exposed to 10mM denatonium benzoate (DB). Wu SV, et al. Proc Natl Acad Sci U S A 99:2392 2397, 2002
Kim BJ unpublished data
Sweet ttaste t receptor and dits signal element existed din the GLP 1 producing L cells in intestine. After treatment of glucose, alpha gustducin is activated and intracellular calcium increased via sweet receptor. Glucose and sweetner can be increased GLP 1 secretion through sweet receptor. Bitter taste receptor also expressed in GLP 1 secreting L cells. Bitter compound can increase GLP 1 secretion.
Gut, L cells, can sense the sweet and bitter taste through its receptor. GLP 1 secretion was stimulated through sweet and bitter taste receptor.
Work with NIA/NIH Mount Sinai i School of Medicine i Hyeung Jin Jang Zaza Kokrashvili Michael J. Theodorakis Bedrich Mosinger Olga D. Carlson Robert F. Margolskee Jie Zhou Hyeon Ho Kim Xiangru Xu Sic L. Chan, Magdalena Juhaszova Michel Bernier Josephine M. Egan