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Il Diabete di Tipo 2 Emanuele Bosi Corso di Endocrinologia e Malattie del Ricambio Università Vita-Salute San Raffaele A.A. 2009-2010.

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Presentazione sul tema: "Il Diabete di Tipo 2 Emanuele Bosi Corso di Endocrinologia e Malattie del Ricambio Università Vita-Salute San Raffaele A.A. 2009-2010."— Transcript della presentazione:

1 Il Diabete di Tipo 2 Emanuele Bosi Corso di Endocrinologia e Malattie del Ricambio Università Vita-Salute San Raffaele A.A

2 Il Diabete Mellito di tipo 2 Forma di diabete ad esordio prevalentemente adulto, caratterizzata da insulino-resistenza ed insulino deficienza relativa. Normalmente non richiede terapia insulinica Eziologia ignota: - forte componente genetica (concordanza gemelli identici >90%) a localizzazione sconosciuta. - fattori di rischio: sovrappeso e obesità, sedentarietà, età, ipertensione arteriosa, dislipidemia Fenotipo fisiopatologico relativamente eterogeneo Non evolve mai in chetoacidosi; in casi estremi coma iperosmolare Per molti anni può decorrere in modo totalmente asintomatico Si associa ad un aumentato rischio di morbosità e mortalità cardiovascolare anche per livelli glicemici modestamente elevati

3 Quanto è diffuso il diabete di tipo 2?

4 The type 2 diabetes pandemia

5 Adapted from WHO Diabetes Programme Facts and Figures: Accessed 1 August, Worldwide prevalence of diabetes in 2000 Number of persons < 5,000 5,000–74,000 75,000–349, ,000–1,499,000 1,500,000–4,999,000 > 5,000,000 No data available Total cases 150 million adults

6 Worldwide prevalence of diabetes in 2030 (projected) Total cases > 300 million adults Number of persons < 5,000 5,000–74,000 75,000–349, ,000–1,499,000 1,500,000–4,999,000 > 5,000,000 No data available Adapted from WHO Diabetes Programme Facts and Figures: Accessed 1 August, 2006.

7 Prevalenza delle alterazioni del metabolismo dei carboidrati in Italia età come fattore di rischio Diabete di tipo 2IGT Anni % > >45 anni noto non-noto 2.9- Cremona Study

8 Pathophysiology and Natural History of Type 2 Diabetes

9 Abnormal Islet Function Determines the Development of IGT and T2DM in the Setting of Insulin Resistance Genetics, age, lifestyle, environmental factors Insulin resistance Normal islet function NGTIGT / T2DM Abnormal islet function T2DM = type 2 diabetes mellitus; NGT = normal glucose tolerance; IGT = impaired glucose tolerance Adapted from Ahren B, Pacini G. Diabetes Obes Metab. 2005;7(1):2–8.

10 Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, MN:International Diabetes Center; Prediabetes (IFG/IGT) NGT Diabetes Diagnosis Natural history of type 2 diabetes: progressive deterioration of Islet Cell Function in the Setting of Insulin Resistance Insulin Resistance Islet Dysfunction

11 Insulino resistenza Definizione: Ridotto effetto biologico dellinsulina per difetto a localizzazione post-recettoriale Eziologia: indeterminata Fattori di rischio: Genetici: elevata familiarità, geni non identificati Età Sedentarietà Alimentazione Obesità e sovrappeso

12 INSULIN RESISTANCE Liver, muscle, adipocyte endothelium Obesity Dyslipidemia Hypertension Type 2 diabetes Insulin resistance is a common feature of many human diseases Cardiovascular disease Polycystic ovary syndrome (PCOS)

13 Esempi di insulino-resistenza: Effetti dellInsulina Esempi di insulino-resistenza: Effetti dellInsulina sulla Captazione del 2-Deossi-Glucosio nel Muscolo Scheletrico Umano ControlliObesi Insulina -+-+ * nmol/mg per min Goodyear, Giorgino et al, J Clin Invest, 1995

14 Esempi di insulino-resistenza: Stimolazione dellAttività di PI 3-Chinasi Associata a IRS-1 nel Muscolo Umano minuti di stimolazione con insulina 100 nM Controlli Obesi Unità Arbitrarie * * Goodyear, Giorgino et al, J Clin Invest, 1995

15 Obesità come fattore di rischio per diabete di tipo 2 Carey et al., Am J Epidemiol, 1997 Rischio Relativo 71– <71 76–8181.1–8686.1–9191.1– Circonferenza addominale (cm)

16 Years from diagnosis -Cell Function Declines While Insulin Sensitivity Remains Stable in Type 2 Diabetes -Cell Function Declines While Insulin Sensitivity Remains Stable in Type 2 Diabetes 10-year follow-up of the Belfast Diet Study: Data from 67 newly diagnosed subjects with type 2 diabetes mellitus (N=432) who required oral antihyperglycemic therapy or insulin due to secondary failure of diet therapy at 5–7 years. HOMA=Homeostasis Model Assessment; data expressed as percentages of values in lean nondiabetic reference population. Adapted from Levy J et al. Diabet Med. 1998;15:290– HOMA (%) HOMA (%) HOMA (%) Years from diagnosis -Cell Function -Cell Function Insulin Sensitivity

17 Hypothetical Model for Postnatal Pancreatic ß-Cell Growth in Humans CJ Rhodes, Science, 2005

18 At start of UKPDS, -cell function was already compromised -cell function deteriorates over time (~4%/year) Adapted from: UKPDS 16. Diabetes 1995;44:1249–1258. HOMA: homeostasis model assessment. n=4209 Extrapolation of -cell function prior to UKPDS -cell function (%, HOMA) Years from diagnosis UKPDS –4–46–10–8–8–6–6–2– Diet Sulphonylurea Metformin UKPDS: Loss of -cell function is the major determinant of disease progression in T2DM

19 Il volume -cellulare è ridotto del 40% già in presenza di IFG Lo studio dei pancreas autoptici ha dimostrato che il volume relativo -cellulare dei soggetti obesi con IFG e dei soggetti con diabete di tipo 2 è rispettivamente ridotto del 40 e del 63% rispetto a quello dei soggetti obesi non-diabetici Butler AE, et al. Diabetes 52: , 2003

20 Determinants of progressive loss of -cell function and mass Glucotoxicity Lipotoxicity Secretory defects Inflammation Islet amyloid deposition Incretin failure alpha-cell dysfunction

21 Determinants of progressive loss of -cell function and mass Glucotoxicity reversible, tend to resolve after Lipotoxicity normalization of glucose by any mean Secretory defects Inflammation Islet amyloid deposition Incretin failure alpha-cell dysfunction

22 Determinants of progressive loss of -cell function and mass Glucotoxicity Lipotoxicity Secretory defects: early, selective for glucose Inflammation Islet amyloid deposition Incretin failure alpha-cell dysfunction

23 Perdita della Fase Precoce della Secrezione Insulinica nel Diabete Tipo 2 Ward WK, et al. Diabetes Care 1984;7:491–502. ControlloDiabete di Tipo – Tempo (minuti) – Tempo (minuti) IRI plasmatica (µU/ml) IRI plasmatica (µU/ml) 20 g glucosio 20 g glucosio

24 Glucotoxicity Lipotoxicity Secretory defects Inflammation: mediated by IL-1, IL-6, TNF- Islet amyloid deposition Incretin failure alpha-cell dysfunction Determinants of progressive loss of -cell function and mass

25 Interleukin-1–Receptor Antagonist in Type 2 Diabetes Mellitus Larsen CM et Al NEJM 356: , 2007

26 Determinants of progressive loss of -cell function and mass Glucotoxicity Lipotoxicity Secretory defects Inflammation Islet amyloid deposition: IAPP (Amylin) Incretin failure alpha-cell dysfunction

27 Rhodes C. Science 307: , 2005 Morfologia del pancreas endocrino nel normale, nellobeso non diabetico e nel diabetico di tipo 2 Nellobeso non-diabetico il numero delle isole è aumentato e le isole tendono ad essere più grandi, principalmente per un aumento delle -cellule Nel diabetico di tipo 2, il numero delle isole è diminuito, cè una riduzione marcata delle -cellule e compaiono depositi di amiloide (in viola) che occupano buona parte dellisola

28 Diffuse islet amyloidosis

29

30 Human islet amyloid polypeptide (IAPP). The amyloidogenic region of IAPP is responsible for providing a toxic conformational structure within the islets.

31 Determinants of progressive loss of -cell function and mass Glucotoxicity Lipotoxicity Secretory defects Inflammation Islet amyloid deposition Incretin failureIncretins: GIP, GLP-1 alpha-cell dysfunction

32 The Glucoregulatory Role of GLP-1 Beta cells: Enhances glucose-dependent insulin secretion Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47: Flint A, et alLarsson H, et al Nauck MA, et alDrucker DJ Liver: Glucagon reduces hepatic glucose output Alpha cells: Postprandial glucagon secretion Stomach: Helps regulate gastric emptying Promotes satiety and reduces appetite

33 GLP-1 stimulates -cell regeneration and mass in animal models Farilla et al. Endocrinology 2003;144:5149–5158. Bulotta et al. J Mol Endocrinol 2002;29:347–360. -cell neogenesis -cell proliferation -cell hypertrophy -cell apoptosis -cell regeneration and increased mass -cell Red arrows indicate effect of GLP-1 Key

34 Reduced GLP-1 secretion in type 2 diabetes T2D patients * * * * * * * Time (min) GLP-1 (pM) IGT Normal Source: Adapted from Toft-Nielsen et al. ( 2001): J Clin Endocrinol Metab 86: Mixed Meal

35 The burden of Type 2 Diabetes

36 Diabetic retinopathy Leading cause of blindness in working-age adults 1 Diabetic nephropathy Leading cause of end-stage renal disease 2 Cardiovascular disease Stroke 1.2- to 1.8-fold increase in stroke 3 Diabetic neuropathy Leading cause of non- traumatic lower extremity amputations 5 75% diabetic patients die from CV events 4 Type 2 diabetes is NOT a mild disease 1 Fong DS, et al. Diabetes Care 2003;26 (Suppl. 1):S99–S Molitch ME, et al. Diabetes Care 2003;26 (Suppl. 1):S94–S98. 3 Kannel WB, et al. Am Heart J 1990;120:672– Gray RP & Yudkin JS. In Textbook of Diabetes Mayfield JA, et al. Diabetes Care 2003;26 (Suppl. 1):S78–S79.

37 Complication Retinopathy21 Abnormal ECG18 Absent foot pulses ( 2) and/or ischaemic feet 14 Impaired reflexes and/or decreased vibration sense7 Angina3 Intermittent claudication3 Myocardial infarction2 Stroke/transient ischaemic attack 1 Prevalence (%)* *Some patients had more than one complication at time of diagnosis Adapted from UKPDS VIII. Diabetologia 1991;34:877–890. Serious complications of type 2 diabetes are present at diagnosis

38 45 Type 2 diabetes increases the risk of CVD *P < 0.1; P < 0.05; P < 0.01; § P < Coronary mortality Sudden death Angina pectoris MI CHD Cardiac failure Intermittent claudication Stroke Any CV event § * § § § § Males with diabetes Females with diabetes Age-adjusted risk ratio (1 = risk for individuals without diabetes) Adapted from Kannel WB, et al. Am Heart J 1990;120:672–676. N/A

39 Relative cost of diabetes US data from 1990–1993 Adapted from Accessed 1 August, Direct and indirect costs (US$ billion) Stroke DepressionArthritisDiabetesCancer $92 $104 $65 $44 $30

40 Aggressive Glycemic Control in T2DM Reduces Risk of Complications Risk Reduction With 1% Decline in Updated HbA 1c Micro-vascular disease PVD*MIStrokeHeart failure Cataract extraction Death related to diabetes P <.0001 P =.035P =.021P < %43% 14%12%16%19%21% 15 PVD = Peripheral Vascular Disease; MI = Myocardial Infarction *UKPDS 35: Prospective observational analysis of UKPDS patients (n = 4585, incidence analysis; n = 3642, relative risk analysis). Median 10.0 years of follow up. Adapted from Stratton IM, et al. BMJ. 2000;321:

41 Absolute cost savings associated with improved glycaemic control –$772 –$685 –$950 –$821 –1000 –900 –800 –700 –600 –500 –400 –300 –200 – Cost per patient per year ($US) Mean reduction in diabetes-related costs for improved vs. unimproved type 2 diabetes patients Adapted from Wagner EH, et al. JAMA 2001;285:182–189. Patients whose HbA 1c decreased 1% between 1992 and 1993 and sustained the decline through 1994 were considered to be improved (n = 732); all others were classified as unimproved (n = 4,012)

42 Therapeutic Goals in Type 2 Diabetes

43 ADA = American Diabetes Association; ACE = American College of Endocrinology; IDF = International Diabetes Federation *Referenced to a non-diabetic range of 4.0%–6.0% using a DCCT-based assay; Upper limit of normal = 6.0% Measurements should be made 1–2 hours after the beginning of the meal Adapted from American Diabetes Association. Diabetes Care. 2005;28(supp 1):S4-S36. International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, American Association of Clinical Endocrinologists and the American College of Endocrinology. Endocrine Practice. 2002;8(suppl 1): ADAACEIDF HbA 1c < 6.0%* (individual goal) < 7.0%* (general goal) 6.5% < 6.5%* Preprandial capillary plasma glucose 90–130 mg/dL (5.0–7.2 mmol/L) < 110 mg/dL (< 6.0 mmol/L) < 110 mg/dL (< 6.0 mmol/L) Peak postprandial capillary plasma glucose < 180 mg/dL (< 10.0 mmol/L) < 140 mg/dL (< 7.7 mmol/L) < 145 mg/dL (< 8.0 mmol/L) Current Treatment Goals for Glycemic Control: Towards Reducing Risk of Complications

44 1 NHANES 1999–2000 Data T2DM represents ~90%–95% of cases Adapted from Adapted from Saydah SH, et al. JAMA. 2004;291: Two Thirds of People with Type 2 Diabetes are Not at Goal 1 HbA 1c Level% Patients <7.0% %–8.0%25.8 >8.0%37.2 >9.0%20.2 >10.0%12.4

45 UKPDS: type 2 diabetes is progressively worsening independently on current therapies Adapted from: UKPDS 34. Lancet 1998:352:854–865. *Using diet initially then sulphonylureas, insulin and/or metformin if FPG > 15 mmol/l; ADA clinical practice recommendations. n= Median HbA 1c (%) Years from randomisation Conventional* Glibenclamide Chlorpropamide Metformin Insulin 6.2% – upper limit of normal range Recommended treatment target

46 Determinants of type 2 diabetes and anti-diabetic agents Insulin resistanceMetformin, TZDs, insulin Loss of -cell function GlucotoxicityAny anti-diabetic LipotoxicityAny anti-diabetic Secretory defectsSulfonylureas, Glinides, insulin Inflammation TZDs (mild), anti-IL1 (exp) Islet amyloid depositionNone (?TZDs) Incretin failureIncretin mimetics, analogues, DPP-4 inhibitors alpha-cell dysfunctionIdem, insulin

47 Metformin TZDs α-Glucosidase inhibitors GI effects (nausea, diarrhea), lactic acidosis (rare) GI effects (flatulence, diarrhea) Weight gain, edema, fractures, ?CHF Incretin mimetics (injection) GI effects (nausea, vomiting, diarrhea) SUs Glinides Hypoglycemia, weight gain, hyperinsulinemia* Major Adverse Events of Current Treatments for T2DM Limit Efficacy

48 Lifestyle Changes Diet and Exercise Oral Monotherapy Standard Approach to the Management of T2DM: Treatment Intensification Oral Combination + Oral + Insulin ++ Insulin

49 Adapted from Mudaliar S et al. In: Ellenberg and Rifkins Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 2003: Add insulin Oral agent 2 Oral agents Inadequate nonpharmacologic therapy 3 Oral agents Historical Algorithm of Therapy for Type 2 Diabetes

50 Possible Alternative Algorithm of Therapy for Type 2 Diabetes Oral agent 2 Oral agents 3 Oral agents Add Insulin Earlier in the Algorithm Severe symptoms Severe hyperglycaemiaSevere hyperglycaemia Ketosis Pregnancy Inadequate nonpharmacologic therapy

51 The Number of Medications Taken Usually Increases With Duration of Disease Beta-cell function (%) 01015–25 Diabetes diagnosed Insulin- based regimens Multidrug combo ± insulin Approximate time (years) Monotherapy failure Requiring insulin Dual-drug regimens Monotherapy IGT IGT=impaired glucose tolerance. UKPDS 16. Diabetes. 1995;44:1249–1258. Turner RC et al. JAMA. 1999;281:2005–2012; Warren RE. Diabetes Res Clin Pract. 2004;65:S3–S8; Lebovitz HE. Med Clin N Am. 2004;88:847–863.

52

53 Nathan DM et al, Diabetes Care, 2006; Diabetologia 2006 Diagnosis Lifestyle Intervention + Metformin No Yes* A 1C 7% Add Basal Insulin # (most effective) Add Basal Insulin # (most effective) Add Sulfonylurea (least expensive) Add Sulfonylurea (least expensive) Add Glitazone (no hypoglycemia) Add Glitazone (no hypoglycemia) No Yes* A 1C 7% No Yes* A 1C 7% No Yes* A 1C 7% Intensify Insulin # Add Glitazone Add Basal Insulin # Add Sulfonylurea Add Basal or Intensify Insulin # Intensive Insulin + Metformin ± Glitazone No Yes* No Yes* A 1C 7% Step 1 Step 2 Step 3 Management of Hyperglycemia in Type 2 Diabetes: ADA/EASD Consensus Algorithm for the Initiation and Adjustment of Therapy

54 Iperglicemia post-prandiale: HbA1c ~+1% C=colazione; P=pranzo; C=cena. Adapted from Riddle M. Diabetes Care 1990;13: Glicemia plasmatica (mg/dl) Momenti della giornata (ore) Diabete non controllato (HbA 1c ~8%) Iperglicemia a Digiuno: HbA1c ~ +2% C P C HbA 1c normale~5% Nel DMT2 sono elevati sia i livelli di glicemia a digiuno sia i post- prandiali


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