TOSSICITÀ DEGLI ACIDI GRASSI (CICLO DI RANDLE). obesità

TOSSICITÀ DEGLI ACIDI GRASSI (CICLO DI RANDLE).
obesità
 NEFA plasmatici
insulino-resistenza
danno alla cellula β
1
Randle Cycle
2
GLUT 4
+
–
PI3K
–
3
4
5
IL-1 CRP
6
α
7
Anti- and proinflammatory adipokines
8
TNF-α:
 fosforilazione
Ser IR e IRS1
insulino-resistenza
obesità
 TNF-α
 lipasi
ormone-sensibile
 NEFA plasmatici
 VLDL
9
10
11
digiuno
 TG
adiponectina
 sensibilità insulina
12
13
14
15
PPAR (peroxisome proliferator-activated receptors):
rispondono alle variazioni della composizione lipidica della dieta
16
L = thiazolidinediones
(rosiglitazone, pioglitazone)
activate PPAR-γ
increased insulin sensitivity
improved beta cell function
decreased beta cell apoptosis
17
18
19
 NEFA
PPARγ
20
21
Mechanism of action of metformin in cancer
22
23
oral hypoglycemic agents:
• sulfonylureas (tolbutamide, gliclazide, glibenclamide,
glimepiride): inhibit K+ATP channel activity in β-cells and
thereby stimulate insulin secretion;
• GLP-1 analogs, DPP-4 inhibitors: increase the
stimulation of insulin secretion;
• biguanides (metformin, meglitinide, repaglinide,
nateglinide): reduce hepatic gluconeogenesis, increase
insulin sensitivity, peripheral glucose uptake, fatty acid
oxidation, decrease absorption of glucose from the
gastrointestinal tract;
• thiazolidinediones (rosiglitazone, pioglitazone): increase
glucose uptake by peripheral tissues (insulin sensitizers),
increase fatty acids accumulation in the adipose tissue;
• α-glucosidase inhibitors (acarbose): inhibit absorption of
glucose from the gastrointestinal tract.
24
25
Side effects:
•
•
•
•
sulfonylureas: hypoglycemia;
GLP-1 analogs: pancreas and thyroid tumors;
biguanides: lactic acidosis, diarrhea, dyspepsia;
thiazolidinediones: fluid retention, weight gain, heart
failure, osteoporosis, bladder cancer;
• α-glucosidase inhibitors: flatulence, diarrhea.
26
27
Accelerator hypothesis:
costituzione
obesità
predisposizione
autoimmunità
insulino-resistenza
T2DM
apoptosi cellule β
T1DM
28

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