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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