5 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.
7 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.
10 Tipo 1Tipo 2Insulino-resistenza; incapacità delle cellule β di compensare la ridotta sensibilitàDistruzione delle cellule β pancreaticheEziologiaTipicamente più elevati della normaZeroLivelli di insulinaRidottaZeroAzione dell’insulinaSìNon necessariamenteInsulino-resistenzaTipicamente > 40 anniTipicamente < 30 anniEtà di esordioIperglicemiaComaChetoacidosiDeperimentoComplicanze acuteIdemNeuropatiaRetinopatiaNefropatiaPatologie vascolariCoronaropatieComplicanze cronicheDiversi farmaci, tra cuiinsulinaInsulinaInterventi farmacologici
11 Intracellular signalling pathways of insulin action.
21 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.
22 Insulin resistance and antidiabetic drugs, Biochemical Pharmacology, Volume 58, Issue 10, 15 November 1999, Pages Clifford J. Bailey
31 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.
36 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.
37 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.
50 NUOVE TERAPIE FARMACOLOGICHE PER IL DIABETE DI TIPO 2 Analoghi delle incretineInibitori della dipeptidil peptidasi IVInibitori del co-trasportatore sodio-glucosio (SGLT2)Inibitori della 11-β-idrossisteroide deidrogenasi 1
53 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.