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Glucagone: ↑ glicogenolisi (fegato) ↓ glicogenosintesi (fegato

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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
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