diabete mellito, aspetti biochimico-molecolari. am-unimi 2 diabete mellito un gruppo eterogeneo di...

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  • Diabete mellito, aspetti biochimico-molecolari
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  • AM-UniMi 2 Diabete mellito Un gruppo eterogeneo di malattie caratterizzate da un metabolismo anormale dei CARBOIDRATI, causato da un DEFICT DI INSULINA assoluto (tipo 1) o relativo (tipo 2), che provoca IPERGLICEMIA
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  • AM-UniMi 3 Rischi associati al diabete mellito malattiarischio rispetto ai non diabetici Cecit20 volte Insufficienza renale25 volte Amputazione40 volte Infarto miocardico2 5 volte Ictus2 3 volte Nathan, N Engl J Med 1993
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  • AM-UniMi 4 14.2 17.5 23 % 15.6 22.5 44 % 26.5 32.9 24 % 84.5 132.3 57 % 9.4 14.1 50 % 1.0 1.3 33 % 2000: 151 milioni 2010: 221 milioni Incremento 46 % Prevalenza e incremento dei diabetici nel mondo
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  • AM-UniMi 5 Epidemiologia Prevalenza in Italia:circa 2 milioni (3,5 %) Tipo 1: circa 5 % Tipo 2: circa 90 % IncidenzaNord-Italia: 5-6/100.000 nuovi casi/anno Prevalenza nel mondo 2001: circa 140.000.000 2025: circa 300.000.000
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  • AM-UniMi 6 Frequenza del diabete e dellintolleranza al glucosio in funzione dellet etdiabete diagnosticato diabete non diagnosticato intolleranza al glucosio 45 543,81,34,4 55 649,51,86,4 65 7410,05,010,0 oltre i 7511,35,019,4 Garancini et al, 1995
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  • AM-UniMi 7 t.adiposo fegato t.adiposo muscolo GLUCOSIO
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  • AM-UniMi 8 Euglicemia: Glucosio 3,5-6,0 mmol/L
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  • AM-UniMi 9 Segni, sintomi e conseguenze dellipoglicemia Morte Danni cerebrali permanenti Convulsioni Coma Letargia Sintomi da neuroglicopenia Controregolazione Sfumata sintomatologia neurologica
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  • AM-UniMi 10 Diabete tipo 1, sviluppo Markers - antigeni HLA classe II DR3, DR4 (DR2: protettivo) - anticorpi anticellule - anticorpi antiinsulina induzione attivazione e "homing" sulle cellule distruzione
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  • AM-UniMi 12 LOSS OF FIRST PHASE INSULIN RESPONSE TIME Stages in Development of Type 1 Diabetes BETA CELL MASS DIABETES PRE- DIABETES GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY NEWLY DIAGNOSED DIABETES MULTIPLE ANTIBODY POSITIVE GENETICALLY AT RISK
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  • AM-UniMi 13 Portatori di alleli HLA DR3-DR4: rischio 6-7 % Parente di I grado (senza conoscere genotipo): rischio 3-6 % Parente di I grado (con assetto genetico noto):rischio 6-16 % Diabete di tipo 1
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  • AM-UniMi 14 Possibile patogenesi del Diabete di tipo 2 Ambiente
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  • AM-UniMi 16 Caratteristiche cliniche del LADA (Latent Autoimmune Diabetes of the Adult) Prevalenza: circa il 10 % del diabete delladulto Et desordio generalmente superiore ai 35 anni Quadro desordio lento od attenuato Sviluppo graduale di insulino-dipendenza Frequente presenza di anticorpi antiGAD
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  • AM-UniMi 17 Prevalenza: oltre 5 % delle gravidanze Definizione: Intolleranza ai CHO di vario grado e severit, con inizio o primo riscontro durante la gravidanza Screening: OGCT (50g) Diagnosi: OGTT (100 o 75g) Classificazione dopo il parto: NGT, IFG, IGT, Diabete Diabete Gestazionale Lapolla, 2001
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  • AM-UniMi 18 Altre condizioni patologiche a rischio di evoluzione a diabete mellito Ridotta tolleranza al glucosio (IGT: impaired glucose tolerance) Alterata glicemia a digiuno (IFG: impaired fasting glucose)
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  • AM-UniMi 20 Glicemia - variazioni giornaliere M. Luzzana, 1999
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  • AM-UniMi 23 Sticking to membranes. Hexokinases associate with various cellular membranes, and this association affects their activity. These enzymes are not only involved in glucose sensing and metabolism but also in signal transduction. This duality is achieved by switching between a bound and unbound form that interacts with different proteins, such as regulatory DNA-protein complexes in the nucleus. Receptors for hexokinases (purple) must be present to enable differential targeting of these enzymes to different subcellular locations. Hexokinases associate with membranes of subcellular compartments, such as the endoplasmic reticulum (ER) and mitochondria. Frommer et al, Science 2003
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  • AM-UniMi 30 Purpose of review Glucose homeostasis must be finely regulated. Changes in glucose levels elicit a complex neuroendocrine response that prevents or rapidly corrects hyper- or hypoglycemia. It is well established that different parts of the brain, particularly the hypothalamus and the brain stem, are important centres involved in the monitoring of glucose status and the regulation of feeding. The pioneering work of Mayer, including his proposal of the glucostatic theory, has recently received experimental support from the molecular, electro-physiological and physiological fields. Recent findings Making the analogy with the cell of the islet of Langerhans, it has been proposed that glucose sensing could be assured in some cells of the brain by proteins such as glucose transporter 2, glucokinase and the ATP-dependent potassium channel. Furthermore, some pathological conditions such as diabetes and obesity have been shown to alter this glucose sensing system. Summary These findings could lead to a better understanding of metabolic disorders, with hypoglycemia possibly being the most deleterious.Brain glucose sensing mechanism and glucose homeostasis. Brain glucose sensing mechanism and glucose homeostasis Luc Pnicaud, Corinne Leloup, Anne Lorsignol, Thierry Alquier and Elise Guillod Current Opinion in Clinical Nutrition and Metabolic Care 2002, 5:539543
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  • AM-UniMi 31 trasportatori del glucosio GLUT1: RBC/epatociti492 aa1p35-31.3 GLUT2: -cell/fegato524 aa3q26 GLUT3: cervello496 aa12p13 GLUT4: insulin-resp.509 aa17p13 GLUT5: intestino501 aa1p31 GLUT6: pseudogene GLUT7: reticolo endoplasmico epatociti
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  • AM-UniMi 33 Sci. STKE, Vol. 2003, Issue 169, pp. pe5, 11 February 2003 A Long Search for Glut4 Activation Konstantin V. Kandror * Boston University School of Medicine, Boston, MA 02118, USA. Summary: Insulin stimulates glucose transport in its target cells by translocation of the glucose transporter isoform 4 (Glut4) from an intracellular storage pool to the plasma membrane. A large body of evidence indicates that activity of Glut4 at the plasma membrane may vary. Recent findings suggest that p38 MAPK may be involved in regulation of the intrinsic activity of the transporter.
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  • AM-UniMi 39 Figure 1 (A) Schematic representation of human PG. Tissue-specific post-translational processing of PG in the pancreas (B) and small intestine (C). The numbers indicate positions of amino acid residues and cleavage sites. Relative presence of glucagon and GLP-1 derived from the post-translational processing of preproglucagon molecule in the pancreas (D) and small intestine (E). In the pancreas, PG is cleaved to produce GRPP, glucagon, IP-1 and MPGF. All of these products are present in approximately equimolar amounts and are secreted synchronously. In addition to these predominant products, small amounts of a peptide corresponding to the GLP-1 domain are also formed. This molecule, which is probably biologically inactive, corresponds to PG(72107), but small amounts of PG(72108) are also formed. GLP-1 regulates glucose homeostasis 719 EUROPEAN JOURNAL OF ENDOCRINOLOGY (2000) 143 www.eje.org
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  • AM-UniMi 40 Figure 2 Schematic representation of GLP-1 action on target tissues. The role of GLP-1 on muscle and adipose tissues is represented with a question mark next to the proposed enhancement of insulin sensitivity based on the yet controversial findings reported.
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  • AM-UniMi 41 SEVERAL BIOLOGICAL FEATURES of glucagon-like peptide 1 (GLP-1) have led to propose this peptide hormone as an ideal candidate for the treatment of diabetes(1). GLP-1 lowers postprandial hyperglycemia via three independent mechanisms: increases insulin secretion, inhibits glucagon release, and inhibits gastrointestinal motility. Perhaps even more important is the observation that the insulin secretory action of GLP-1 is regulated by the plasma concentration of glucose, virtually preventing the possibility of developing reactive hypoglycemia while inducing the release of insulin (2). Finally, it is of significant clinical relevance the observation that GLP-1 retains its glucose lowering activity in patients with diabetes, even many years after clinical onset of the disease, when islet -cells are no longer responsive to other pharmacological insulin-secretin

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