Farmaci utilizzati nella terapia del diabete

Physiologic and pharmacologic regulation of glucose homeostasis Physiologic and pharmacologic regulation of glucose homeostasis. Dietary complex carbohudrates are broken downto simple sugars in the GI tract by the action of glucosidase; simple sugars are then absorbed by GI epithelial cells and transported into the bloodstream. Glucose in the blood is taken up by all metabolically active tissues in the body. In pancreatic β cells, glucose metabolism increases levels of cytosolic ATP. Which stimulates insulin secretion. Insulin then acts on plasma membrane insulin receptors in target tissues (muscle, adipose, liver) to increase glucose uptake and storage as glycogen or triglycerides. Glucose is also taken up by other cells and tissues to fuel metabolism. In muscle cells, insulin promotes glucose storage as glycogen: In adipose cells insulin promotes glucose conversion to triglycerides. Peroxisome proliferator-activated receptor γ (PPARγ) also promotes the conversion oof glucose to triglycerides in adipose cells. In liver cells, insulin promotes glucose storage as glycogen. Glucagon promotes bothe the conversion of glycogen back to glucose and gluconeogenesis; glucos generated from glycogen or by gluconeogenesis is transported out of the liver cell into the bloodstream. Note that glucose from dietary complex carbohydrates, and insulin secreted by pancreatic β cells, bothe enter the liver in high concentrations through the portal circulation. Pharmacologic interventions that decrease blood glucose levels include inhibiting intestinal α-glucosidase; adminisgtering exogenous insulin; using sulfonylureas or meglitinides to augment secretion of insulin by β cells; and using biguanides or thiazolidinediones to enhance the action of insulin in liveror adipose cells, respectively. Diazoxide inhibits insulin secretion from pancreatic β cells.

Physiologic and pharmacologic regulation of insulin release from pancreatic β cells. In the basal state, the plasma membrane of the β cell is hyperpolarized, and the rate of insulin secretion from the cell is low. When glucose is available, it enters the cell via GLUT2 transporters in the plasma membrane and is metabolized to generate intracellular ATP. ATP binds to and inhibits the plasma membrane K+/ATP channel. Inhibition of the K+/ATP channel decreases plasma membrane K+ conductance; the resulting depolarization of the membrane activates voltage-dependent Ca2+ channels and, thereby, stimulates an influx of Ca2+. Ca2+ mediates fusion of insulin-containing secretory vesicles with the plasma membran, leading to insulin secretion. Tha K+/ATP channel, an octamer composed of Kir6.2 and SUR1 subunits, is the target of several physiologic and pharmacologic regulators: ATP binds to and inhibits Kie6.2, while sulfonylureas and meglitinides bind to and ainhibit SUR1; all three of these agents promote insulin secretion. Mg2+-ADP and diazoxide bind to and activate SUR1, thereby inhibiting insulin secretion.

Tipo 1 Tipo 2 Insulino-resistenza; incapacità delle cellule β di compensare la ridotta sensibilità Distruzione delle cellule β pancreatiche Eziologia Tipicamente più elevati della norma Zero Livelli di insulina Ridotta Zero Azione dell’insulina Sì Non necessariamente Insulino-resistenza Tipicamente > 40 anni Tipicamente < 30 anni Età di esordio Iperglicemia Coma Chetoacidosi Deperimento Complicanze acute Idem Neuropatia Retinopatia Nefropatia Patologie vascolari Coronaropatie Complicanze croniche Diversi farmaci, tra cui insulina Insulina Interventi farmacologici

Intracellular signalling pathways of insulin action.

Forme di diabete mellito DIABETE DI TIPO I o insulino-dipendente diabete giovanile DIABETE DI TIPO II o non-insulino-dipendente insulino-resistente diabete dell’età matura

Fig. 1. Schematic of potential new drug target areas (right panel) to address the defects of insulin secretion by pancreatic B-cells and defects of insulin action (insulin resistance) (left panel) in liver, muscle and fat in type 2 diabetes mellitus. Abbreviations: , increase; , decrease; GLUT4, insulin-stimulated glucose transporter isoform 4; PEPCK, phosphoenolpyruvate carboxykinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKB, protein kinase B.

Insulin resistance and antidiabetic drugs, Biochemical Pharmacology, Volume 58, Issue 10, 15 November 1999, Pages 1511-1520 Clifford J. Bailey

There are many alternative routes for the delivery of insulin There are many alternative routes for the delivery of insulin.   a | The pulmonary route might be the first of these to be used for clinical care of insulin-requiring patients with diabetes. Other options for the delivery of insulin include b | whole-organ pancreas transplantation, or c | transplantation of isolated islet cells or genetically modified stem cells. Other routes for the delivery of insulin include nasal, oral–gastrointestinal, buccal, rectal, vaginal, uterus, ocular and dermal. *The table shows surface areas of different sites in the body.

Biguanidi

Tiazolidinedioni (o Glitazoni) Fig. 4. Structures of peroxisome proliferator activated receptor (PPAR- ) agonists. (a) Thiazolidinedione PPAR- agonists, (b) nonthiazolidinedione PPAR- agonists and (c) a putative endogenous PPAR- ligand. Abbreviation: PG, prostaglandin.

EFFETTO DEI TIAZOLIDINEDIONI

Fig. 3. Heterodimerization of peroxisome proliferator activated receptor (PPAR- ) with the retinoid X receptor (RXR) produces an active transcription complex that binds to a peroxisome-proliferator-response element (PPRE). In the absence of ligand, the heterodimer forms high-affinity complexes with nuclear co-repressor proteins, such as nuclear receptor co-repressor (N-CoR), which prevent transcriptional activation by sequestration of the receptor complex from the promoter. Dissociation of co-repressors occurs as a consequence of a ligand-induced conformational change, and the activated heterodimer can then bind to the PPRE. This results in activation or suppression of transcription of a target gene. Recently, co-activators such as PPAR- co-activator 1 (PGC-1) have been identified, which promote the assembly of an effective transcriptional complex that includes histone acetyltransferases (HATs) and steroid receptor co-activator-1 (SR-1). Abbreviation: cis-RA, cis-retinoic acid.

Fig. 2. Thiazolidinediones reduce blood glucose concentrations by stimulating the nuclear peroxisome proliferator activated receptor (PPAR- ), which, in conjuction with the retinoid X receptor (RXR), promotes transcription of certain insulin-sensitive genes. This effect occurs mainly in adipocytes, which strongly express PPAR- . Stimulation of PPAR- causes increased expression of the glucose transporter GLUT4, fatty acid transporter protein (FATP), adipocyte fatty acid binding protein (aP2), fatty acyl-CoA synthase and other enzymes involved in lipogenesis. A resulting decrease in circulating free fatty acids improves glucose utilization via the glucose¯fatty-acid cycle. Thiazolidinediones also decrease hepatic gluconeogenesis.

Sulfoniluree

Meglitinidi

EFFETTO DELLE SOLFONILUREE E DELLE MEGLITINIDI

Acarbosio

NUOVE TERAPIE FARMACOLOGICHE PER IL DIABETE DI TIPO 2 Analoghi delle incretine

GLP1 = glucagon-like peptide 1 Stimolano la liberazione di insulina Diminuzione del glucosio ematico incretins (GLP1, GIP) Inibiscono la liberazione di glucagone GLP1 = glucagon-like peptide 1 GIP = glucose-dependent insulinotropic peptide

GLP1 = glucagon-like peptide 1 Stimolano la liberazione di insulina Diminuzione del glucosio ematico incretins (GLP1, GIP) Inibiscono la liberazione di glucagone Inattivate da DPP-IV GLP1 = glucagon-like peptide 1 GIP = glucose-dependent insulinotropic peptide DPP-IV = dipeptidyl peptidase IV

NUOVE TERAPIE FARMACOLOGICHE PER IL DIABETE DI TIPO 2 Analoghi delle incretine Inibitori della dipeptidil peptidasi IV

NUOVE TERAPIE FARMACOLOGICHE PER IL DIABETE DI TIPO 2 Analoghi delle incretine Inibitori della dipeptidil peptidasi IV Inibitori del co-trasportatore sodio-glucosio (SGLT2) Inibitori della 11-β-idrossisteroide deidrogenasi 1

B-chain Processing of human insulin. Preproinsulin is synthesized and exported into the endoplasmic reticulum, where the signal peptide (not shown) is cleaved to generate proinsulin. Intramolecular disulfide bonds (Cys-Cys) aid in the proper folding of iproinsulin, Proinsulin is transported to secretory vescicles where prohormone convertases act on dipeptide cleavage sites in proinsulin (boxes) to genetae insulin and connceting © peptide. Two disulfide bonds aid in holeding the A-chain and the B-chain of insulin together. Insulin ad C-peptide are secreted together from pancreatic β cell. In Lispro, an artifical insulin designed to be absorbed more rapidly after injection, a proline and a lysine residue in the COOH-terminus of the B-chain are transposed; this minor alteration does not affect the ability of the molecule to bind the insulin receptor and to mediate insulin action: In glargine insulin, an A-chain apsaragine is replaced with glycine, and two arginines are added to the COOH-terminus of the B-chain. These modifications slow the absorption of insulin relative to regula rinsulin.

Scheme to indicate potential links between different components of the Insulin Resistance Syndrome (Syndrome X). Inherited and acquired disturbances affecting energy balance, insulin sensitivity, and pancreatic -cell function give rise to obesity, insulin resistance, defective insulin secretion, and T2DM. Insulin resistance and/or hyperinsulinaemia contribute to other key features of the syndrome, which are risk factors for coronary heart disease.