Glucagone:  glicogenolisi (fegato)  glicogenosintesi (fegato)  gluconeogenesi (fegato)  glicolisi (fegato)  demolizione dei trigliceridi (fegato)  assunzione di aminoacidi (fegato)  ureagenesi (fegato)  sintesi insulina (pancreas) Meccanismo d’azione: aumento cAMP, aumento attività PKA emivita del glucagone: 5 min 1 catecolammine digiuno: glucagone lipolisi adipocita NEFA plasmatici epatocita acetil-CoA glucoso ossalacetato citrato ciclo del citrato corpi chetonici digiuno: 3 Insulina:  assunzione di glucoso (fegato, muscolo, adipocita)  glicolisi (fegato)  glicogenosintesi (fegato, muscolo)  glicogenolisi (fegato, muscolo)  sintesi di acidi grassi (fegato)  chetogenesi (fegato)  sintesi di trigliceridi (adipocita)  demolizione dei trigliceridi (adipocita)  sintesi di proteine, DNA, RNA  demolizione di proteine  sintesi di glucagone (pancreas) emivita dell’insulina: 5 min 4 pasto: lipolisi insulina adipocita NEFA plasmatici acetil-CoA glucoso ossalacetato citrato piruvato insulina glucoso ciclo del citrato epatocita corpi chetonici pasto: 6 digiuno: 7 8 120 glicemia (mg/100 ml) 110 100 90 80 30 60 90 120 150 min pasto 9 ouabain phlorizin cytochalasin B 10 trasportatore maggiori siti di espressione Km glucoso (mM) GLUT1 maggior parte dei tessuti (cervello, rene, colon, 1-5 eritrociti, barriere vasi-tessuti, placenta, adipociti, muscolo scheletrico, tessuti fetali, etc.) GLUT2 fegato, cellule β, rene (membrana basolaterale), 15-40 intestino tenue (membrana basolaterale) GLUT3 cervello, rene placenta e molti altri tessuti 1-2 GLUT4 muscolo scheletrico, cuore e adipociti 1-5 GLUT5 intestino tenue (fruttoso) 6 SGLT1/2 (cotrasporto Na/glucoso) intestino tenue (membrana luminale, SGLT1) rene (membrana luminale, SGLT1/2) 0,8-1,6 11 12 glucoso insulina OUT esocitosi IN GLUT-1 recettore dell'insulina GLUT-4 13 indinavir 14 endocitosi 15 75-80% of insulin-induced glucose uptake occurs in muscle (mainly red) 5-20% of insulin-induced glucose uptake occurs in adipocytes importance of physical activity in insulin sensitivity 16 17 gap junctions: 18 CRAC CRAC = Ca2+ release-activated Ca2+ current 19 Orai1 20 thapsigargin calsequestrin (SR) calreticulin (ER) parvalbumin calbindin calretinin 21 Secrezione di insulina: glucoso somatostatina acidi grassi liberi agonisti 2-adrenergici corpi chetonici aminoacidi glucagone incretine: glucagon-like peptide 1 (GLP-1) peptide inibitore gastrico (GIP) colecistochinina (CCK) sulfoniluree acetilcolina 22 23 24 KATP channel-dependent pathway 25 nifedipine CaM and CaMK inhibitors SUR = sulfonylureas receptor Kir6.2 = inwardly rectifying K+ channel 26 27 SUR inhibitors sulfanylureas tolbutamide glibenclamide gliclazide glimepiride glipizide glinides SUR activators diazoxide repaglinide nateglinide 28 KATP channel-independent pathway 29 + CICR: Ca2+-induced Ca2+ release 30 31 Structure of proglucagon and the proglucagon-derived peptides (PGDP) IP1 (PC2) (PC1) brain cells GRPP: glicentin-related pancreatic peptide GLP-1: glucagon-like peptide 1 GLP-2: glucagon-like peptide 2 IP1: intervening peptide 1 IP2: intervening peptide 2 32 low glucose hyperpolarization depolarization 33  glucose insulin Zn2+ vagus  glucose depolarization ACh β-agonists  Adenylate cyclase  VGCC  cAMP  Ca2+  PKA  secretion of glucagon 34 Effect of glucose on glucagon and insulin release 35 Dose-response relationships: glucose suppresses glucagon and stimulates insulin release 36 37 or gastric inhibitory polypeptide 38 (ileal brake) (via MAPK) (via MAPK) 39 GLP-1 GLP-1 R G prot cAMP/PKA Insulin synthesis and secretion MAPK Proliferation Anti-apoptosis GLP-2: a growth factor for intestinal epithelium, it slows the ingestion and transit of food through the GI tract; it also induces NO-mediated vasodilation ed exerts anti-inflammatory effects. 40 dipeptidyl-peptidase IV (DPP-IV) sitagliptin 41  GLP-1R agonists (exenatide, liraglutide) Unfortunately, GLP-1R agonists were shown to induce preneoplastic lesions and/or cancers in the pancreas 42 glucose, amino acids delta cells 43 44 ketone bodies GPR40 = G protein-coupled receptor 45 Why is insulin secretion biphasic? 46 Why is insulin secretion pulsatory? “calcium blindness” when calcium increases beyond a threshold, it inhibits calciuminduced calcium release and blocks insulin secretion 47 48 insulin liver Receptor-mediated endocytosis GSH-insulin transhydrogenase Chain A and B insulinase (IDE) Protein degradation 49 Recettore dell’insulina insulina     regione iuxtamembrana TyrK proteina ATP sito di fosforilazione in Ser/Thr Tyr ADP proteina Tyr autofosforilabili Tyr-P 50 51 Insulin-mediated post-receptor events PTB PH SH2 SH2 p85 p110 PH = pleckstrin homology 52 PH PH PH Ser/Thr 53 insulin wortmannin mTOR/ 54 Mechanisms of turning off the insulin signal 55 SOCS = suppressors of cytokine signaling 56 57