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Diabete Mellito


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Diabete Mellito

  1. 1. Diabete Mellito Liberamente tratto dall’Harrison 17th ed.
  2. 2. • Malattia endocrino metabolica • L’ iperglicemia è l’attore protagonista • Dialogo sbagliato sbagliato fra glucosio e insulina
  3. 3. Iperglicemia • ridotta secrezione di insulina • ridotto utilizzo di glucosio • aumento nella produzione di glucosio
  4. 4. Alterazioni patofisiologiche • Le alterazioni metaboliche associate a DM sono la principale causa di: • Grave nefropatia (end-stage renal disease ESRD) • amputazione degli arti inferiore non ascrivibile a trauma • cecità in età adulta
  5. 5. Classificazione DM • classificato in base in base al processo patogenetico che determina l’iperglicemia
  6. 6. • Tipo I (5-10%): completa o quasi totale deficienza di insulina, distruzione β-cells. • Tipo II (~90-95%): gruppo eterogeneo di disordini con vario grado di ridotta secrezione di insulina, resistenza all’insulina e aumentata produzione di glucosio
  7. 7. • Altri tipi di DM: difetti genetici o problemi metabolici che coinvolgono azione e sintesi dell’insulina, difetti mitocondriali, malattia pankreas esocrino con distruzione isole, eccesso di ormoni contrinsulari come in acromegalia e sindrome Cushing. • DM Gestazionale: intolleranza al glucosio che si manifesta in ~4% delle gravidanze
  8. 8. Epidemiologia • La prevalenza di DM di tipo II aumenta con lo sviluppo industriale dei paesi essendo legato a sedentarietà e obesità • in USA il 7% della popolazione ha DM
  9. 9. Criteri di diagnosi di DM Diagnosis and Classification Table 2—Criteria for the diagnosis of diabetes Tab 1. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at (A1 least 8 h.* reco OR 2. Symptoms of hyperglycemia and a casual plasma glucose 200 mg/dl (11.1 Dia mmol/l). Casual is defined as any time of day without regard to time since last The meal. The classic symptoms of hyperglycemia include polyuria, polydipsia, and anc unexplained weight loss. and OR the 3. 2-h plasma glucose 200 mg/dl (11.1 mmol/l) during an OGTT. The test Fo should be performed as described by the World Health Organization, using a Con glucose load containing the equivalent of 75 g anhydrous glucose dissolved in litu water.* of t teri *In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day. agn are Tes
  10. 10. Screening test per DM tipo II • Uso della glicemia plasmatica a digiuno (FGP) • Ogni 3 anni per soggetti >45 anni • anche prima se BMI>25kg/m2 o altri fattori di rischio
  11. 11. Fattori di rischio per DM II 2278 TABLE 338-3 RISK FACTORS FOR TYPE 2 DIABETES MELLITUS Family history of diabetes (i.e., parent or sibling with type 2 diabetes) K+ Obesity (BMI ≥25 kg/m2) ATP-sensitive Habitual physical inactivity K+ channel Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Previously identified IFG or IGT History of GDM or delivery of baby >4 kg (>9 lb) ATP Hypertension (blood pressure ≥140/90 mmHg) HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level Mitochondria >250 mg/dL (2.82 mmol/L) Polycystic ovary syndrome or acanthosis nigricans Pyruv History of vascular disease Note: BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose toler- Glucose-6-p ance; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein. G Source: Adapted from American Diabetes Association, 2007. Glucos GLUT2 (Table 338-3). In contrast to type 2 DM, a long asymptomatic period
  12. 12. Biosintesi dell’insulina • In cellule β delle isole pancreatiche • da precursore Preproinsulina (86AA) • Insulina: catene A e B legate da ponte disolfuro • Catena C secreta insieme a insulina. Ha un’emivita plasmatica maggiore rispetto a insulina, utile a discriminare se insulina è esogena o endogena in ipoglicemia
  13. 13. Secrezione dell’insulina • glucosio plasmatico è il regolatore principale della secrezione di insulina • livelli di glucosio plasmatico > 70mg/dL stimolano la sintesi di insulina • incretine (Glucagon-like peptide 1) stimolano secrezione insulina dopo i pasti e riducono quella di glucagone. Prodotte da cellule L intestino tenue. Analoghi come exan-tide usati farmacologicamente. • influenzata anche da AA, chetoni, altri nutrienti, peptidi GI
  14. 14. story of vascular disease transcription Glucose-6-phosphate factors ote: BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose toler- Glucokinase Glucosio e secrezione dell’insulina ce; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein. urce: Adapted from American Diabetes Association, 2007. Glucose Nucleus Insulin GLUT2 Secretory granules ble 338-3). In contrast to type 2 DM, a long asymptomatic period hyperglycemia is rare prior to the diagnosis of type 1 DM. A num- Glucose of immunologic markers for type 1 DM are becoming available Voltage dependent cussed below), but their routine Ca2+ is discouraged2+pending the + use channel Ca K FIGURE 338-4 Diabetes and abnormalities in glucose-stimulated ntification of clinically beneficial interventions for individuals at ATP-sensitive h risk for+developing type 1 DM.Depolarization K channel SUR insulin secretion. Glucose and other nutrients regulate insulin secre- Incretins tion by the pancreatic beta cell. Glucose is transported by the GLUT2 – Ca2+ glucose transporter; subsequent glucose metabolism by the beta cell + ULIN BIOSYNTHESIS, SECRETION, AND ACTION cAMP ATP/ADP alters ion channel activity, leading to insulin secretion. The SUR recep- SYNTHESIS Mitochondria tor is the binding site for drugs that act as insulin secretagogues. Mu- vel ulin is produced in the beta cells of the pancreatic islets. It is initial- tations in the events or proteins underlined are a cause of maturity Islet ynthesized as a single-chain 86-amino-acid precursor + Pyruvate polypeptide, onset diabetes of the young (MODY) or other forms of diabetes. SUR, transcription proinsulin. Subsequent proteolytic processing removes the amino- factors sulfonylurea receptor; ATP, adenosine triphosphate; ADP, adenosine Glucose-6-phosphate minal signal peptide, giving rise to proinsulin. Proinsulin is struc- oler- diphosphate, cAMP, cyclic adenosine monophosphate. (Adapted from Glucokinase ally related to insulin-like growth factors I and II, which bind Glucose WL Lowe, in JL Jameson (ed): Principles of Molecular Medicine. Totowa, NJ, kly to the insulin receptor. Cleavage of an internal 31-residue Insulin Nucleus frag- Humana, 1998.) GLUT2 nt from proinsulin generates the C peptideSecretory A (21 amino ac- and the granules eriod B (30 amino acids) chains of insulin, which are connected by and ry bursts occurring about every 10 min, superimposed upon greater num- Glucose ulfide bonds. The mature insulin molecule and C peptide are stored amplitude oscillations of about 80–150 min. Incretins are released from ilable ether and cosecreted from secretory granules in the beta cells. Be- neuroendocrine cells of the gastrointestinal tract following food inges- g the als the C peptide is Diabetesmoreabnormalitiesinsulin, it is a useful se at FIGURE 338-4 cleared and slowly than in glucose-stimulated tion and amplify glucose-stimulated insulin secretion and suppress glu- rker of insulin secretion. Glucose and other nutrients regulate insulin secre- insulin secretion and allows discrimination of endogenous cagon secretion. Glucagon-like peptide 1 (GLP-1), the most potent exogenousby the pancreatic beta in the evaluation of hypoglycemia tion sources of insulin cell. Glucose is transported by the GLUT2 incretin, is released from L cells in the small intestine and stimulates insu- haps. 339 and transporter; subsequent glucose cosecrete isletthe beta cell glucose 344). Pancreatic beta cells metabolism by amyloid lin secretion only when the blood glucose is above the fasting level. Incre- ypeptide (IAPP) or amylin, a leading to insulin secretion. The SUR with alters ion channel activity, 37-amino-acid peptide, along recep- tin analogues, such as exena-tide, are being used to enhance endogenous tor is the binding site for drugs that act as insulin secretagogues. Mu-
  15. 15. Azione dell’insulina • ~50% subito degradata dal fegato • agisce su recettore tirosin chinasico • Fosforilazione IRS e attivazione degli effetti metabolici e mitogeni dell’insulina. Attiva sintesi proteica, glicogeno sintesi, lipogenesi. Di solito resistenza solo per effetti metabolici. • principale controllore omesostasi glicemia aumentando uptake e consumo periferico del glucosio
  16. 16. Glucagone • glucagone secreto da cellule α isole pancreatiche • secreto quando ci sono bassi livelli plasmatici di insulina o glucosio • stimola la gluconeogenesi e la glicogenolisi nel fegato e nella midollare del rene
  17. 17. Patogenesi: DM tipo I • completa o quasi totale deficienza di insulina, distruzione β-cells • risultato di fattori genetici, ambientali e immunologici • principalmente questa distruzione è di origine autoimmune • in alcuni casi l’autoimmunità non è dimostrata e il meccanismo è sconosciuto
  18. 18. iabetes Mellitus sponse by altering the beta cell destruction and most, but not all, individuals II autoimmune binding affinity of different antigens for class Beta cell mass (% of m ates have evidence of islet-directed autoimmunity. Some individuals who ost- molecules. have the clinical phenotype of type 1 DM lack immunologic markers Patogenesi: DM tipo I on, Most individuals with type 1 DM have the HLA DR3 and/or DR4 haplo- indicative of an autoimmune process involving the beta cells. These in- 50 ne, type. Refinements inare thought to develop insulin have shown that thenon- dividuals genotyping of HLA loci deficiency by unknown, hap- The lotypes DQA1*0301,mechanisms andand DQB1*0201 are most African immune DQB1*0302, are ketosis prone; many are strongly an associated with type or DM. These haplotypes are present in 40% type 1 American 1 Asian in heritage. The temporal development of of chil- No diabetes DM is shown schematically as a function of beta cell mass in Fig. 338-6. Diabetes bly Individuals with a genetic susceptibility have normal beta cell mass at birth but begin to lose beta cells secondary to autoimmune destruc- 0 Immunologic 0 tion that occurs over months to years. This autoimmune process is (Birth) trigger Time (years) thought to be triggered by an infectious or environmental stimulus and to be sustained by a beta cell–specificabnormalities majority, Immunologic molecule. In the FIGURE 338-6 Temporal model for development of type 1 diabe- immunologic markers appear after the triggering event but before dia- tes. Individuals with a genetic predisposition are exposed to an im- betes becomes clinically overt. Beta cell mass then begins to decline, munologic trigger that initiates an autoimmune process, resulting in a Genetic and insulin secretion becomes progressively impaired, although nor- gradual decline in beta cell mass. The downward slope of the beta cell nd Progressive impairment mal predisposition is maintained. The rate of decline in beta cell glucose tolerance mass varies among individuals and may not be continuous. This pro- he 100 of insulin release mass varies widely among individuals, with some patients progressing gressive impairment in insulin release results in diabetes when ~80% om of the beta cell mass is destroyed. A “honeymoon” phase may be seen Beta cell mass (% of max) rapidly to clinical diabetes and others evolving more slowly. Features Overt diabetes als of diabetes do not become evident until a majority of beta cells are de- in the first 1 or 2 years after the onset of diabetes and is associated ho stroyed (~80%). At this point, residual functional beta cells still exist with reduced insulin requirements. [Adapted from Medical Manage- but are insufficient in number to maintain glucose tolerance. The ment of Type 1 Diabetes, 3d ed, JS Skyler (ed). American Diabetes Associa- ers events that trigger the transition from glucose intolerance to frank dia- tion, Alexandria, VA, 1998.] in- 50 on- an e1 No diabetes -6. Diabetes at uc- 0 0 is (Birth) Time (years) lus ty, FIGURE 338-6 Temporal model for development of type 1 diabe- ia- tes. Individuals with a genetic predisposition are exposed to an im-
  19. 19. Patogenesi: DM tipo I • la predisposizione al DM tipo I è multigenica, principalmente su regione HLA del cromosoma 6 • cellule α, δ e PP sono risparmiate dall’autoimmunità • la distruzione è mediata principalmente dai linfociti T • cellule β molto sensibili a effetto tossico IL-1,TNF- α, INF-γ
  20. 20. Patogenesi: DM tipo I • Oltre ad Ab contro insulina, sono presenti anche altri enzimi e proteine (ICAs - islet cells autoIg) • ICAs non sono specifici solo delle cellule β, non si sa perché le altre cellule siano risparmiate dal processo autoimmune
  21. 21. Patogenesi: DM tipo II • Resistenza insulinica o anormale secrezione d’insulina: si pensa che la resistenza preceda la l’inadeguata secrezione • alta componente genetica: se entrambi i genitori hanno DM di tipo II il rischio si avvicina al 40% • malattia poligenica e multifattoriale influenzata da obesità, alimentazione e attività fisica
  22. 22. Patogenesi: DM tipo II • caratteristiche DM tipo 2: • ridotta secrezione di insulina • resistenza all’insulina • eccessiva produzione di glucosio a livello epatico per resistenza insulinica • alterato metabolismo lipidico (↑LDL, ↑TGL, ↓HDL) • obesità centrale
  23. 23. Patogenesi: DM tipo II secrezione ⇔ resistenza A-B) resistenza insulinica oxyge transd compensata da aumentata contro 1000 protei secrezione (iperinsulinemia) the in Insulin secretion (pmol per min) betes- Th • IGT, iperglicemia postprandiale B viscer increa NGT fatty a • iperglicemia a digiuno 500 D C IGT A cytes acids, tin). I Type 2 DM • le cellule β vanno incontro a 0 0 50 100 pendi produ resista esaurimento Insulin sensitivity M value (µmol/min per kg) pair g tion b FIGURE 338-7 Metabolic changes during the development of produ type 2 diabetes mellitus (DM). Insulin secretion and insulin sensitiv- tide, i ity are related, and as an individual becomes more insulin resistant (by resista moving from point A to point B), insulin secretion increases. A failure flamm
  24. 24. Anomalie metaboliche: DM tipo II • resistenza dovuta a minor numero recettori e a difetti nella trasduzione del segnale • si accumulano lipidi in fibrocellule muscolari con formazione di perossidi • l’effetto mitogeno dell’insulina non è soggetto a resistenza con ↑ rischio aterosclerotico
  25. 25. Anomalie metaboliche: DM tipo II • ↑ t. adiposo ⇒↑ di acidi grassi liberi in plasma e ↑ prodotto adipociti (retinol binding protein 4, leptina, TNF-α ecc..) • Adipochine regolano a loro volta la resistenza insulinica alcune producono uno stato infiammatorio che spiega marker infiammatori spesso alti in DM 2 (↑IL-6, ↑PCR) • acidi grassi diminuiscono utilizzo glucosio nei muscoli e aumentano produzione di glucosio epatica
  26. 26. Prevenzione DM tipo II • DM tipo 2 è preceduto da un periodo di intolleranza al glucosio (IGT) • cambiamenti dello stile di vita e farmaci ne ritardano la comparsa • dieta • esercizio fisico 30min/die, 5 gg a settimana • in casi particolari, seguendo le linee guida, la metformina può essere somministrata.
  27. 27. Compicazioni acute del DM • Acute • Chetoacidosi • Stato iperglicemico iperosmolare
  28. 28. Acute: chetoacidosi diabetica • deficit di insulina relativo o assoluto con aumento degli ormoni contrinsulari (glucacone, catecolammine, cortisolo, GH) • necessari sia deficit insulina che eccesso glucagone • aumento del rilascio di acidi grassi da adipociti e formazione di corpi chetonici nel fegato • chetoni neutralizzati da bicarbonato • sviluppo di acidosi metabolica
  29. 29. In chetoacidosi β-idrossibutirrato:acetoacetato=3:1
  30. 30. TABLE 338-5 MANIFESTATIONS OF DIABETIC KETOACIDOSIS wh ol Symptoms Physical findings bi Nausea/vomiting Tachycardia Thirst/polyuria Dehydration/hypotension su Abdominal pain Tachypnea/Kussmaul respirations/ Th Shortness of breath respiratory distress VL Precipitating events Abdominal tenderness (may tiv Inadequate insulin administration resemble acute pancreatitis or de Infection (pneumonia/UTI/ surgical abdomen) gastroenteritis/sepsis) Lethargy/obtundation/cerebral Infarction (cerebral, coronary, edema/possibly coma M mesenteric, peripheral) m Alito acetonemico Drugs (cocaine) (odore frutta marcia) in Pregnancy om Note: UTI, urinary tract infection. ize in sin
  31. 31. Laboratoio: chetoacidosi diabetica • iperglicemia • chetosi • acidosi metabolica (↑ gap anionico), spesso Bicarbonato <10mmol/L, pH 6.8-7.3 • kaliemia leggermente elevata per acidosi • ↓ Total body K, Na, Mg e Fosfati per disidratazione
  32. 32. Management di chetoacidosi diabetica • reidratazione • terapia con insulina short-acting • curo l’evento che ha fatto precipitare la situazione • valuto glicemia e parametri vitali • a seconda dei dati di lab somministro potassio
  33. 33. Stato iperglicemico iperosmolare • di solito soggetto anziano con DM tipo II • con storia di poliuria, perdita peso ridotta idratazione • Si presenta con iperosmolarità iponatriemica, ipotensione, tachicardia, status mentale alterato
  34. 34. Stato iperglicemico iperosmolare • Sono assenti sintomi di nausea, vomito, dolore addominale e il segno del respiro di Kussmaul • L’evento precipitante può essere un infarto o un ictus ma anche polmonite, sepsi e altre infezioni
  35. 35. Stato iperglicemico iperosmolare • causato da deficit relativo di insulina e ridotta assunzione di H2O • iperglicemia responsabile della diuresi osmotica • dati di laboratorio: • iperglicemia, può essere >1000mg/dL • iperosmolarità, >350mosm/L • azotemia prerenale
  36. 36. Stato iperglicemico iperosmolare • Management simile a quello per la chetoacidosi
  37. 37. Complicazioni croniche del DM • coinvolgono molti organi • associate ad alta morbidità e mortalità • il rischio di microangiopatia (oftalmoparie, neurpopatie, nefropatie) aumenta in funzione della durata dell’iperglicemia • anche la malattia coronarica correla con iperglicemia • dislipidemia e ipertensione giocano un ruolo importante nelle macroangiopatie • fattori genetici ne influenzano la comparsa
  38. 38. the development of macrovascular complications is less conclusive. s of both HHS eral elements patient’s fluid TABLE 338-7 CHRONIC COMPLICATIONS OF DIABETES MELLITUS Underlying or Microvascular eated. In HHS, Eye disease than in DKA Retinopathy (nonproliferative/proliferative) HHS is usually Macular edema kely to have a Neuropathy comorbidities. Sensory and motor (mono- and polyneuropathy) mortality than Autonomic Nephropathy Macrovascular amic status of Coronary artery disease . Because the Peripheral arterial disease weeks, the ra- Cerebrovascular disease need for free Other worsen neuro- Gastrointestinal (gastroparesis, diarrhea) /L), 0.45% sa- Genitourinary (uropathy/sexual dysfunction) d, the IV fluid Dermatologic sing hypoton- Infectious W). The calcu- Cataracts Glaucoma reversed over Periodontal disease onic solution).
  39. 39. Meccanismi esistono 4 ipotesi per spiegare la correlazione fra iperglicemia e complicazioni croniche (non sono mutualmente escusive) 1. glicosilazione non enzimatica di proteine. Si ha un’aumentata aterosclerosi, disfunzione endoteliale e di NOS, alterazione della matrice extracellulare e riduzione della funzione glomerualare 2. produzione di sorbitolo che genera ROS 3. attivazione PKC con attivazione espressione geni per fibronectina, collagene IV tipo, matrice extracellulare in neuroni e cellule endoteliali 4. alterazione NOS, e aumentata espressione TGF-β
  40. 40. Meccanismi • Grow factors sembrano giocare un ruolo importante in tutti questi meccanismi proposti • L’iperglicemia è comunque il fattore scatenante per le complicazioni diabetiche • il gruppo di pz. con uno stretto controllo della glicemia sviluppa meno complicazioni rispetto a quello con terapia standard • A1C mantenuta al 7% e il controllo della pressione arteriosa prevengono molte complicazioni
  41. 41. Tra le ipotesi patogenetiche delle complicanze del diabete un ruolo fondamentale ricoprono gli effetti di elevate concentrazioni di glucosio e conseguente formazione di Prodotti tardivi della glicosilazione non enzimatica (Advanced Glycation Endproducts o AGE) a livello delle proteine circolanti e strutturali. Il legame degli AGE a tali macromolecole ne determina dapprima alterazioni funzionali e in fasi successive anche modificazioni a livello dei tessuti di appartenenza. I fenomeni riscontrati in corso di diabete mellito sono sovrapponibili a quelli che si verificano nell'invecchiamento tanto che quest'ultimo fenomeno appare determinato dall'esposizione dei tessuti a normali concentrazioni di glucosio per un periodo di tempo prolungato. Un intervento terapeutico atto ad ridurre la formazione degli AGE a livello tessutale potrebbe prevenire sia il danno strutturale indotto dal diabete mellito sia le modificazioni tipiche dell’invecchiamento.
  42. 42. Complicazioni oftamologiche del DM • causa principale di cecità nell’adulto negli usa • cecità dovuta a retinopatia diabetica ed edema maculare
  43. 43. Retinopatia • classificata in 2 stages: • non proliferativa (nei primi 10-15 anni) • microaneurismi della vascolatura retinica • microemorragie • «macchie di cotone» • aumento calibro vasi venosi • perdita periciti retinici, aumento permeabilità e alterazioni del flusso portano a ischemia della retina (angiografia con fluorescina)
  44. 44. of intensive glycemic control and risk factor treatment on the develop- 228 ment of diabetic complications. Newly diagnosed individuals with type 2 DM were randomized to (1) intensive management using vari- ous combinations of insulin, a sulfonylurea, or metformin; or (2) con- ventional therapy using dietary modification and pharmacotherapy with the goal of symptom prevention. In addition, individuals were randomly assigned to different antihypertensive regimens. Individuals in the intensive treatment arm achieved an A1C of 7.0%, compared to a 7.9% A1C in the standard treatment group. The UKPDS demon- strated that each percentage point reduction in A1C was associated with a 35% reduction in microvascular complications. As in the DCCT, there was a continuous relationship between glycemic control and development of complications. Improved glycemic control did not conclusively reduce (nor worsen) cardiovascular mortality but was associated with improvement with lipoprotein risk profiles, such as re- duced triglycerides and increased HDL. FIGURE 338-9 Diabetic retinopathy results in scattered hemor- One of the major findings of the UKPDS was that strict blood pres- rhages, yellow exudates, and neovascularization. This patient sure control significantly reduced both macro- and microvascular has neovascular vessels proliferating from the optic disc, requiring ur- complications. In fact, the beneficial effects of blood pressure control gent pan retinal laser photocoagulation. were greater than the beneficial effects of glycemic control. Lowering blood pressure to moderate goals (144/82 mmHg) reduced the risk of CHAPTER DM-related death, stroke, microvascular end points, retinopathy, and Duration of DM and degree of glycemic control are the best predic- heart failure (risk reductions between 32 and 56%). tors of the development of retinopathy; hypertension is also a risk fac- Similar reductions in the risks of retinopathy and nephropathy were tor. Nonproliferative retinopathy is found in almost all individuals
  45. 45. Retinopatia • proliferativa, neovascolarizzazione in risposta a ipossia • i vasi neoformati (vicino a nervo ottico e/o macula) sono molto delicati • si rompono facilmente portando a emorragia in corpo vitreo, fibrosi che evolvono in distacco della retina per retrazione della ciccatrice • la pressione alta è un fattore di rischio e precipitante di retinopatia • trammento con controllo glicemia, pressione, fotocoagulazione, limitare esercizi con manovre di Valsava ripetute
  46. 46. Nefropatia diabetica • causa principale di end stage renal disease in USA • microalbinuria e macroalbinuria in pz. con DM associate a maggior rischio di malattia cardiovascolare • microalbuminuria più comune in DM 2 per esordio lento malattia oppure perché conseguenza di ipertensione • controllo glicemia, pressione, trattamento con ACE inibitori o bloccanti per recettore AgII (ARBs), controllo dislipidemia
  47. 47. Una delle manifestazioni precoci della nefropatia diabetica è rappresentata dall' alterazione della permselettività a livello della membrana basale glomerulare. In condizioni normali, cariche elettrostatiche negative costituite da eparansolfato ed acido sialico, presenti a livello glomerulare si oppongono all' aumento della filtrazione delle proteine circolanti. Nelle fasi precoci della nefropatia è stata dimostrata una diminuzione di tali cariche negative per cui maggiori quantità di proteine elettronegative (proteinuria selettiva per carica) viene eliminata con le urine. Il rilievo di tale proteinuria in pazienti diabetici può rappresentare un segno precoce di nefropatia. In base a tale riscontro è possibile iniziare, in pazienti selezionati, interventi terapeutici atti a ritardare la progressione di tale complicanza.
  48. 48. Storia naturale della nefropatia diabetica Anni dopo Fase Alterazione GFR diagnosi A. Ipertrofia funzionale alterazioni emodinamiche ↑ 1 B. Incipiente iniziale perdita selettività di carica 5-10 C. Incipiente terminale microalbuminoria (30-300mg/die) normale perdita selettività di volume D. Conclamata o clinica ↓ 15-20 macroalbuminuria (3g/die) perdita selettività di volume E. Insufficienza renale ↓↓ 22-30 riduzione proteinuria (200mg/24h) coma uremico o iperazotemico F. Nefrosi e uremia chiusura glocerulare 0 riduzione proteinuria
  49. 49. Neuropatia diabetica • Complicazione di ~50% DM (lunga durata) • polineuropatia • mononeuropatia • autonomopatia • rischio aumentato da fumo e BMI alto • diagnosi per esclusione di altre neuropatie • importante lo screening periodico dei pz. con DM
  50. 50. Polineuropatia/mononeuropatia • più comune forma è la polineuropatia distale simmetrica. Vi è perdita sensibilità • tuttavia anche iperestesia, parestesia o disestesia possono presentarsi da sole o combinate • è comune il dolore a riposo agli arti inferiori che con l’avanzare della neuropatia scompare lasciando spazio all’insensibilità •
  51. 51. Polineuropatia/mononeuropatia • poliradiculopatia: dolore disabilitante che coinvolge una o più radici posteriori, può essere accompagnata da debolezza muscolare, autolimitanti • mononeuropatia la più comune coinvolge III n. cranico (oculomotore), si manifesta con diplopia. A volte coinvolge altri n. cranici IV, VI, VII (paralisi di Bell)
  52. 52. Autonomopatia • coinvolge sistemi colinergici, adrenergici e peptidergici (peptide pancreatico, sostanza P) • cardiovascolare - tachicardia a riposo (vagolisi) ipotensione ortostatica - morte improvvisa. • genitourinario - ileo paralitico e difetti minzione • sudomotore - iperidrosi estremita superiori e anidrosi delle inferiori (favorisce rottura cute e ulcera, piede diabetico)
  53. 53. Autonomopatia • difetti nel sentire l’ipoglicemia
  54. 54. Complicazioni agli arti inferiori • prima causa di aumputazione non ascrivibile a trauma • ulcere e infezioni sono la prima fonte di morbidità in pz. con DM • neuropatia con conseguente alterata biomeccanica del piede • arteriopatia periferica • scarsa guarigione delle ferite
  55. 55. Complicazioni agli arti inferiori • problemi nella propiocezioni alterano da distribuzione del peso sul piede • aumentata soglia del dolore rende microtraumi non coscienti • anidrosi e fissurazione cute • ampi calli spesso precedono ulcera
  56. 56. Infezioni in DM • aumentata frequenza e gravità delle infezioni • ↓immunità cellulo-mediata e fagocitosi con iperglicemia • ridotta vascolarizzazione • iperglicemia favorisce crescita microrganismi • otite esterna da P. Aeruginosa • polmoniti, UTIs, celluliti
  57. 57. Rischio cardiovascolare • in DM maggior prevalenza di malattie cardiovascolari • spesso c’è assenza di dolore ischemico in DM per neuropatia •
  58. 58. Manifestazioni dermatologiche • allungamento tempo guarigione ferite e ulcere • papule pretibiali pigmentate (in seguito a piccoli traumi)
  59. 59. Esame fisico • BMI • esame del fundus • pressione ortostatica • ispezione dei piedi • polsi periferici • ispezione aree di iniezione di insulina • sensibilità periferica
  60. 60. TABLE 338-8 TREATMENT GOALS FOR ADULTS WITH DIABETES a Nutrition Medic Index Goal to describe the op of diabetes therap Glycemic controlb recommendations A1C <7.0c sures of MNT are Preprandial capillary plasma 5.0–7.2 mmol/L (90–130 mg/dL) DM in high-risk i glucose Peak postprandial capillary plasma <10.0 mmol/L (<180 mg/dL)d weight reduction. glucose and is discussed i Blood pressure <130/80e are directed at pre Lipidsf diabetic individua Low-density lipoprotein <2.6 mmol/L (<100 mg/dL) measures of MNT High-density lipoprotein >1.1 mmol/L (>40 mg/dL)g tions (cardiovascu Triglycerides <1.7 mmol/L (<150 mg/dL) example, in indiv aAs recommended by the ADA; Goals should be developed for each patient (see text). tein intake should Goals may be different for certain patient populations. patients with diab bA1C is primary goal. cWhile the ADA recommends an A1C < 7.0% in general, in the individual patient it rec- etary principles u ommends an “. . . A1C as close to normal (<6.0%) as possible without significant hy- ease. While the re poglycemia. . . .” Normal range for A1C—4.0–6.0 (DCCT-based assay). this chapter emph dOne-two hours after beginning of a meal. macologic approa eIn patients with reduced GFR and macroalbuminuria, the goal is <125/75. should be conside fIn decreasing order of priority. As for the gene gFor women, some suggest a goal that is 0.25 mmol/L (10 mg/dL) higher. fiber-containing f Source: Adapted from American Diabetes Association, 2007. of DM therapy, M
  61. 61. TABLE 338-9 NUTRITIONAL RECOMMENDATIONS FOR ADULTS Exercise Exercise WITH DIABETES a cular risk reductio mass, reduction in Fat 1 or type 2 DM, 20–35% of total caloric intake (during and follow Saturated fat < 7% of total calories <200 mg/day of dietary cholesterol patients with diabe Two or more servings of fish/week provide -3 polyunsaturated fatty ed over at least 3 d acids 2 DM, the exercise Minimal trans fat consumption Despite its bene Carbohydrate DM because they 45–65% of total caloric intake (low-carbohydrate diets are not mally, insulin falls recommended) Amount and type of carbohydrate importantb is a major site for m Sucrose-containing foods may be consumed with adjustments in insulin the increased musc dose increases fuel requ Protein either hyperglycem 10–35% of total caloric intake (high-protein diets are not recommended) the preexercise pla Other components level of exercise-in Fiber-containing foods may reduce postprandial glucose excursions Nonnutrient sweeteners the rise in catechol promote ketone b aSeetext for differences for patients with type 1 or type 2 diabetes. As for the general Conversely, if the c population, a healthy diet includes fruits, vegetables, and fiber-containing foods. bAmount of carbohydrate determined by estimating grams of carbohydrate in diet; gly- perinsulinemia m cemic index reflects how consumption of a particular food affects the blood glucose. glycogenolysis, dec Source: Adapted from American Diabetes Association, 2007. into muscle, leadin To avoid exercis
  62. 62. 98 Morning Afternoon Evening Night Insulin Insulin Insulin Morning Afternoon Evening Night Morning Afternoon Evening Night ana- ana- ana- Insulin Insulin Insulin effect Insulin effect Insulin effect logue* logue* logue* analogue* analogue* Bolus Bolus Bolus Regular Regular Basal Infusion NPH^ Glargine^ NPH^ B L S HS B B L S HS B B L S HS B Meals Meals Meals A B C FIGURE 338-13 Representative insulin regimens for the treat- meal. B. The injection of two shots of long-acting insulin (^, NPH or ment of diabetes. For each panel, the y-axis shows the amount of in- detemir) and short-acting insulin [glulisine, lispro, insulin aspart (solid sulin effect and the x-axis shows the time of day. B, breakfast; L, lunch; red line), or regular (green dashed line)]. Only one formulation of S, supper; HS, bedtime; CSII, continuous subcutaneous insulin infusion. short-acting insulin is used. C. Insulin administration by insulin infu- *Lispro, glulisine, or insulin aspart can be used. The time of insulin in- sion device is shown with the basal insulin and a bolus injection at jection is shown with a vertical arrow. The type of insulin is noted each meal. The basal insulin rate is decreased during the evening and above each insulin curve. A. A multiple-component insulin regimen increased slightly prior to the patient awakening in the morning. consisting of long-acting insulin (^, one shot of glargine or two shots Glulisine, lispro, or insulin aspart is used in the insulin pump. [Adapted of detemir) to provide basal insulin coverage and three shots of from H Lebovitz (ed): Therapy for Diabetes Mellitus. American Diabetes As- glulisine, lispro, or insulin aspart to provide glycemic coverage for each sociation, Alexandria, VA, 2004.] ma glucose measurements. In general, individuals with type 1 DM require mal regimen for the patient with type 1 DM, but is sometimes used for 0.5–1.0 U/kg per day of insulin divided into multiple doses, with ~50% of patients with type 2 diabetes. the insulin given as basal insulin. Continuous subcutaneous insulin infusion (CSII) is a very effective insulin Multiple-component insulin regimens refer to the combination of basal regimen for the patient with type 1 diabetes (Fig. 338-13C). To the basal in-
  63. 63. Diabetes Mellitus TABLE 383-11 GLUCOSE-LOWERING THERAPIES FOR TYPE 2 DIABETES A1C Contraindications/ Mechanism Reduction Agent-Specific Agent-Specific Relative of Action Examples (%)a Advantages Disadvantages Contraindications Oral Biguanides Hepatic glucose Metformin 1–2 Weight loss Lactic acidosis, diarrhea, Serum creatinine >1.5 production, nausea mg/dL (men) >1.4 weight loss, glu- mg/dL (women), CHF, cose, utilization, radiographic contrast insulin resistance studies, seriously ill patients, acidosis –Glucosidase Glucose Acarbose, 0.5–0.8 Reduce postpran- GI flatulence, liver Renal/liver disease inhibitors absorption Miglitol dial glycemia function tests Dipeptidyl Prolong endoge- Sitagliptin 0.5–1.0 Does not cause Reduce dose with renal peptidase IV nous GLP-1 action hypoglycemia disease inhibitors Insulin secreta- Insulin secretion Table 338-12 1–2 Lower fasting Hypoglycemia, weight Renal/liver disease gogues— blood glucose gain sulfonylureas Insulin secreta- Insulin secretion Table 338-12 1–2 Short onset of ac- Hypoglycemia Renal/liver disease gogues—non- tion, lowers post- sulfonylureas prandial glucose Thiazolidinedi- Insulin resistance, Rosiglitazone, 0.5–1.4 Lower insulin Peripheral edema, CHF, Congestive heart fail- ones glucose Pioglitazone requirements weight gain, fractures, ure, liver disease utilization macular edema; rosiglitazone may increase risk of MI Parenteral Insulin Glucose utiliza- Table 323-11 No limit Known safety Injection, weight gain, tion and other profile hypoglycemia anabolic actions GLP-1 agonist Insulin, Gluca- Exenatide 0.5–1.0 Weight loss Injection, nausea, risk Renal disease, agents gon, slow gastric of hypoglycemia with that also slow GI emptying insulin secretagogues motility Amylin agonistb Slow gastric empty- Pramlintide 0.25–0.5 Reduce postpran- Injection, nausea, risk Agents that also slow ing, Glucagon dial glycemia, of hypoglycemia with GI motility weight loss insulin Medical nutrition Insulin, resistance, Low-calorie, 1–2 Other health Compliance difficult, therapy and insulin secretion low-fat diet, benefits long-term success low physical activity exercise aA1C reduction depends partly on starting A1C. bAmylin agonist is approved for use in type 1 and type 2 diabetes.
  64. 64. TABLE 339-1 CAUSES OF HYPOGLYCEMIA 23 339 Ipoglicemia Hypoglycemia Philip E. Cryer Fasting (Postabsorptive) Hypoglycemia Drugs Especially insulin, sulfonylureas, ethanol Hypoglycemia is most commonly caused by drugs used to treat diabe- Sometimes quinine, pentamidine Rarely salicylates, sulfonamides, others tes mellitus or by exposure to other drugs, including alcohol. However, Critical illnesses a number of other disorders, including insulinoma, critical organ fail- Hepatic, renal, or cardiac failure ure, sepsis and inanition, hormone deficiencies, non-β-cell tumors, in- • la causa più comune più herited metabolic disorders, and prior gastric surgery, may cause Sepsis Inanition iatrogena hypoglycemia (Table 339-1). Hypoglycemia is most convincingly docu- Hormone deficiencies Cortisol, growth hormone, or both mented by Whipple’s triad: (1) symptoms consistent with hypoglyce- Glucagon and epinephrine (in insulin-deficient diabetes) mia, (2) a low plasma glucose concentration measured with a precise • con neuropatia autonomica method (not a glucose monitor), and (3) relief of those symptoms after Non-β-cell tumors Endogenous hyperinsulinism the plasma glucose level is raised. The lower limit of the fasting plasma minor sensibilità a sintomi glucose concentration is normally approximately 70 mg/dL (3.9 mmol/L), Insulinoma Other β cell disorders Insulin secretagogue (sulfonylurea, other) ipoglicemia but substantially lower venous glucose levels occur normally, late after a Autoimmune (autoantibodies to insulin or the insulin receptor) meal. Glucose levels <55 mg/dL (3.0 mmol/L) with symptoms that are Ectopic insulin secretion relieved promptly after the glucose level is raised document hypoglyce- mia. • triade di Whipplemorbidity; if severe and pro- Disorders of infancy or childhood Hypoglycemia can cause serious Transient intolerance of fasting longed, it can be fatal. It should be considered in any patient with Congenital hyperinsulinism episodes• confusion, an altered level of consciousness, or a seizure. of sintomi Inherited enzyme deficiencies Reactive (Postprandial) Hypoglycemia SYSTEMIC GLUCOSE BALANCE AND •COUNTERREGULATION basso glucosio plasmatico Alimentary (postgastrectomy) GLUCOSE Noninsulinoma pancreatogenous hypoglycemia syndrome Glucose is an obligate metabolic fuel for the brain under physiologic In the absence of prior surgery • scomparsa dei sintomi con conditions. The brain cannot synthesize glucose or store more than a Following Roux-en-Y-gastric bypass Other causes of endogenous hyperinsulinism few minutes’somministrazione di glucosio supply as glycogen and therefore requires a continuous Hereditary fructose intolerance, galactosemia supply of glucose from the arterial circulation. As the arterial plasma Idiopathic glucose concentration falls below the physiologic range, blood-to-
  65. 65. Sintomi e segni ipoglicemia • confusione mentale • faticabilità • perdità di conoscenza • si può arrivare a morte
  66. 66. Sintomi e segni ipoglicemia • sintomi mediati da sistema simpatico (e da adrenalina rilasciata dalla midollare del surrene) • palpitazione, tremore e agitazione • sintomi mediato da sistema parasimpatico • sudure, fame e parestesia • diaforesi e pallore • aumento freq. cardiaca e pressione
  67. 67. e. Between meals sma glucose lev- Arterial Glucose endogenous glu- Liver c glycogenolysis, Pancreas gluconeogenesis Insulin hepatic glycogen Brain ient to maintain Glucagon Kidneys Glucose or approximately production can be shorter if eased by exercise e depleted by ill- Sympathoadrenal outflow Arterial Pituitary glucose quires a coordi- Muscle Fat ors from muscle Adrenal he liver (and kid- medullae lactate, pyruvate, Gluconeogenic other amino ac- Growth Epinephrine precursor (lactate, dipose tissue are hormone amino acids, glycerol) acids and glycer- (ACTH) Sympathetic postganglionic Glucose ogenic precursor. clearance neurons lternative oxida- Adrenal (Ingestion) Norepinephrine r than the brain cortex Symptoms ). Acetylcholine alance—mainte- Cortisol plasma glucose omplished by a FIGURE 339-1 Physiology of glucose counterregulation—the mechanisms that normally pre- , neural signals, vent or rapidly correct hypoglycemia. In insulin-deficient diabetes, the key counterregulatory re- hat regulate en- sponses—suppression of insulin and increases of glucagon—are lost, and the stimulation of duction and glu- sympathoadrenal outflow is attenuated.
  68. 68. 2306 TABLE 339-2 PHYSIOLOGIC RESPONSES TO DECREASING PLASMA GLUCOSE CONCENTRATIONS C diap Glycemic Role in the Prevention or ic b Threshold, Physiologic Correction of Hypoglycemia thes Response mmol/L (mg/dL) Effects (Glucose Counterregulation) rogl ↓ Insulin 4.4–4.7 (80–85) ↑ Ra (↓Rd) Primary glucose regulatory factor/first serv defense against hypoglycemia occu ↑ Glucagon 3.6–3.9 (65–70) ↑ Ra Primary glucose counterregulatory defi factor/second defense against hypoglycemia ETIO ↑ Epinephrine 3.6–3.9 (65–70) ↑ Ra, ↓ Rc Third defense against hypoglycemia, Hyp critical when glucagon is deficient ↑ Cortisol and 3.6–3.9 (65–70) ↑ Ra, ↓ R c Involved in defense against pro- the growth hormone longed hypoglycemia, not critical fore Symptoms 2.8–3.1 (50–55) Recognition of Prompt behavioral defense against es o hypoglycemia hypoglycemia (food ingestion) ↓ Cognition <2.8 (<50) — (Compromises behavioral defense HYP against hypoglycemia) Imp Note: Ra, rate of glucose appearance, glucose production by the liver and kidneys; Rc, rate of glucose clearance, glu- limi cose utilization relative to the ambient plasma glucose concentration; Rd, rate of glucose disappearance, glucose utili- of d zation by the brain (which is unaltered by the glucoregulatory hormones) and by insulin-sensitive tissues such as bidi skeletal muscle (which is regulated by insulin, epinephrine, cortisol, and growth hormone). (T1 (T2
  69. 69. HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE Insulin deficient diabetes (Imperfect insulin replacement) (No ↓ insulin, no ↑ glucagon) Antecedent hypoglycemia • limite inferiore di glicemia plasmatica a digiuno è Sleep Reduced sympathoadrenal responses to hypoglycemia Antecedent 70mg/dL, ma nel plasma exercise venoso può essere anche Reduced sympathetic Reduced epinephrine neural responses responses più bassa Hypoglycemia Defective glucose unawareness counterregulation Recurrent hypoglycemia FIGURE 339-2 Hypoglycemia-associated autonomic failure in in- sulin-deficient diabetes. (Adapted from Cryer PE: N Engl J Med 350:2272, 2004. Copyright Massachusetts Medical Society, 2004.)
  70. 70. in hypoglycemia excluded and laboratory features with insulinoma. It 2309 ALGORITHM APPROACH TO PATIENT is most common among health care work- RE ers, patients with diabetes or their relatives, H Suspected/Documented Hypoglycemia FIGURE 339-3 Diagnostic approach to a patient with documented hypoglycemia or sus- w pected hypoglycemia based onandhistorywithsuggestive symptoms, a low plasma glucose concen- a people of a history of other factitious illnesses. However, it should be considered of tration, or both. Ab+, positive in all antibody to evaluated for hypogly- for patients being insulin; SU+, positive for sulfonylurea (or other Diabetes No diabetes sc secretagogue). cemia of obscure cause. Accidental inges- se tion of an insulin secretagogue (e.g., the result of a pharmacy error) also occurs. to Treated with Clinical clues Apparentlyconceptually attractive treatment, although controlled clinical tri- is a healthy Analytical error in the measurement of essary in patients with suspe • Insulin • Drugs als documenting its efficacy are lacking. • Sulfonylurea • Organ failure plasma glucose concentrations is rare. On drawn, whenever possible, bef • Other secretagogue • Sepsis Fasting Reactive hypoglycemia also occurs in hand, glucose monitors used to glucose the other patients with autoantibodies low documentation of a low p • Hormone deficiencies to insulin and in the noninsulinomatreatment of diabetes are not quanti- guide pancreatogenous hypoglycemia ing documentation of hypo • Non-β-cell tumor Adjust regimen • Previous gastric syndrome. Affected patients have instruments, particularly at low glu- tative symptomatic hyperinsulinemic Whipple’s triad. Thus, the ide cose levels, and these should not be used <55 mg/dL ≥55 mg/dL hypoglycemia (but negative 72-h fasts) that remits fol- surgery postprandial for the definitive diagnosis of hypoglyce- level is during a symptomati lowing partial pancreatectomy. Histologic findings include β celllow mia. Even with a quantitative method, hy- cludes hypoglycemia as the c Document improve- ment and monitor Provide adequate pertrophy with or without hyperplasia. A similar syndrome can be ar- History measured glucose concentrations following level confirms that hypoglycem glucose, treat Roux-en-Y gastric bypass surgery for obesitythe result of continued glu- tifactual, e.g., has been described. vided the latter resolve after underlying cause Strong existence of a clinically relevant idiopathic reactive elements of cose metabolism by the formed hypoglyce- The Weak cause of the hypoglycemic ep mia syndrome is debated. The issue is whether particularly in thecaused the blood ex vivo, symptoms are pres- ments, while the glucose level CHAPTER 339 Hypoglycemia ence of leukocytosis, erythrocytosis, or by hypoglycemia, an exaggerated sympathoadrenal separation of the se- Extended fast thrombocytosis, or if response to declin- clude plasma insulin, C-pepti ing glucose levels late after a rum from the formed elements is delayed meal, or some glucose-independent as levels of insulin secretagogu mechanism. In any event, caution should be exercised before labeling a Glucose (pseudohypoglycemia). When the history suggests person with a diagnosis of hypoglycemia. Frequent feedings, avoid- mechanism is not apparent, th ance of simple sugars, and high-protein diets are commonly recom- plasma glucose, insulin, and C ↑ Insulin, Whipple’s triad <55 mg/dL ≥55 mg/dL APPROACH TO THE PATIENT: mended to patients thought to have idiopathic reactive hypoglycemia. Hypoglycemia hypoglycemia would be expe The efficacy of these approaches has not been established by con- other hand, while it cannot b ↑ C-peptide ↓ C-peptide trolled clinical trials. Mixed meal In addition to recognition and docu- cose concentration measured mentation of hypoglycemia, and often symptoms raises the possibilit urgent treatment, diagnosis of the hy- Ab+ SU+ FACTITIOUS AND ARTIFACTUAL HYPOGLYCEMIA mechanism is critical for poglycemic Exogenous Whipple’s No Whipple’s DIAGNOSIS OF THE HYPOGLYCEM Factitious hypoglycemia, caused by surreptitious or even prevents, or ad- choosing a treatment that malicious Insulinoma Autoimmune Sulfonylurea insulin triad triad documented hypoglycemia, a ministration of insulin or an insulinleast minimizes, shares many clinical at secretagogue, recurrent hypogly- cemia. A diagnostic algorithm is shown Likely factitious Reactive Hypoglycemia in Fig. 339-3. hypoglycemia excluded RECOGNITION AND DOCUMENTATION Hypoglycemia is suspected in patients