Il Diabete di Tipo 2 Emanuele Bosi Università Vita-Salute San Raffaele

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1 Il Diabete di Tipo 2 Emanuele Bosi Università Vita-Salute San Raffaele
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 Worldwide prevalence of diabetes in 2000
Number of persons < 5,000 5,000–74,000 75,000–349,000 350,000–1,499,000 1,500,000–4,999,000 > 5,000,000 No data available Total cases 150 million adults Adapted from WHO Diabetes Programme Facts and Figures: Accessed 1 August, 2006.

6 Worldwide prevalence of diabetes in 2030 (projected)
Number of persons < 5,000 5,000–74,000 75,000–349,000 350,000–1,499,000 1,500,000–4,999,000 > 5,000,000 No data available Total cases > 300 million adults 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 2 IGT Anni % % > >45 anni - noto - non-noto 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 Abnormal islet function The development of impaired glucose homeostasis predisposing to T2DM is prompted by the occurrence of insulin resistance but then dependent on the loss of normal activity at the pancreatic islet. In healthy individuals, reductions in insulin sensitivity (insulin resistance) are offset by adaptations of insulin secretion from the -cell, resulting in normal glucose processing. Progression to impaired glucose tolerance and T2DM, on the other hand, results from a failure of this adaptive mechanism, leading to abnormal -cell function—inadequate or decreased insulin secretion causing impaired glucose uptake.1 Furthermore, due to the diminished ability of muscle to store or oxidize glucose in patients with impaired glucose tolerance, lactate is released into the circulation, and inadequate insulin action in adipose tissue leads to increased glycerol and free fatty acid release. Free fatty acids provide energy for gluconeogenesis, and lactate and glycerol are gluconeogenic substrates. Thus, insulin resistance in the context of progressive islet dysfunction leads to increasingly excessive fasting and postprandial hepatic glucose production and, accordingly, hyperglycemia. Reference 1. Ahren B, Pacini G. Islet adaptation to insulin resistance: mechanisms and implications for intervention. Diabetes Obes Metab. 2005;7(1):2–8. NGT IGT / T2DM 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 Prediabetes (IFG/IGT)
Natural history of type 2 diabetes: progressive deterioration of Islet Cell Function in the Setting of Insulin Resistance Prediabetes (IFG/IGT) Diagnosis Insulin Resistance Islet Dysfunction NGT Diabetes Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, MN:International Diabetes Center; 2000.

11 Insulino resistenza Definizione: Ridotto effetto biologico dell’insulina 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 is a common feature of many human diseases
Cardiovascular disease Hypertension Dyslipidemia INSULIN RESISTANCE Liver, muscle, adipocyte endothelium Polycystic ovary syndrome (PCOS) Obesity Type 2 diabetes

13 - + - + Esempi di insulino-resistenza: Effetti dell’Insulina
sulla Captazione del 2-Deossi-Glucosio nel Muscolo Scheletrico Umano 2 4 6 8 10 * nmol/mg per min Insulina - + - + Controlli Obesi Goodyear, Giorgino et al, J Clin Invest, 1995

14 Esempi di insulino-resistenza: Stimolazione dell’Attività di
PI 3-Chinasi Associata a IRS-1 nel Muscolo Umano 4000 Controlli 3000 Obesi Unità Arbitrarie 2000 * * 1000 2 15 30 minuti di stimolazione con insulina 100 nM Goodyear, Giorgino et al, J Clin Invest, 1995

15 Obesità come fattore di rischio per diabete di tipo 2
24 20 16 Rischio Relativo 12 8 4 <71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 96.4 Circonferenza addominale (cm) Carey et al., Am J Epidemiol, 1997

16 b-Cell Function Insulin Sensitivity
b-Cell Function Declines While Insulin Sensitivity Remains Stable in Type 2 Diabetes 80 60 b-Cell Function Insulin Sensitivity 60 40 HOMA (%) 40 HOMA (%) 20 20 2 4 6 2 4 6 Years from diagnosis Years from diagnosis 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;15:290–296.

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

18 -cell function (%, HOMA)
UKPDS: Loss of b-cell function is the major determinant of disease progression in T2DM Sulphonylurea At start of UKPDS, -cell function was already compromised -cell function deteriorates over time (~4%/year) Metformin 100 Diet 80 60 -cell function (%, HOMA) Disease progression in type 2 diabetes As UKPDS demonstrated, even with intensive therapy, target glycaemic levels are not maintained long-term. One of the main reasons for this is that type 2 diabetes is a progressive disease characterised by continued, worsening -cell failure. Indeed, at the time of diagnosis, -cell function is already markedly compromised (by approximately 50%), and, as the above slide shows, function continues to worsen, even in patients receiving pharmacological treatment. Furthermore, as the extrapolation on this slide demonstrates, -cell function may have been suboptimal for 10 years prior to diagnosis. As insulin secretagogues, the efficacy of sulphonylureas may be particularly affected by continued -cell failure because of their reliance on residual -cell function. The ideal long-term treatment for diabetes should therefore address continued -cell deterioration. References UKPDS 16. Diabetes 1995;44:1249–1258 40 20 Extrapolation of -cell function prior to UKPDS –10 –8 –6 –4 –2 2 4 6 UKPDS Years from diagnosis Adapted from: UKPDS 16. Diabetes 1995;44:1249–1258. HOMA: homeostasis model assessment. n=4209

19 Il volume b-cellulare è ridotto del 40% già in presenza di IFG
Lo studio dei pancreas autoptici ha dimostrato che il volume relativo b-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 b-cell function and mass
Glucotoxicity Lipotoxicity Secretory defects Inflammation Islet amyloid deposition Incretin failure alpha-cell dysfunction

21 Determinants of progressive loss of b-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 b-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
Controllo Diabete di Tipo 2 120 100 80 60 40 20 20 g glucosio 120 100 80 60 40 20 20 g glucosio IRI plasmatica (µU/ml) IRI plasmatica (µU/ml) – – Tempo (minuti) Tempo (minuti) Ward WK, et al. Diabetes Care 1984;7:491–502.

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

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

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

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

28 Diffuse islet amyloidosis

29 Diffuse islet amyloidosis

30 Human islet amyloid polypeptide (IAPP)
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 b-cell function and mass
Glucotoxicity Lipotoxicity Secretory defects Inflammation Islet amyloid deposition Incretin failure Incretins: GIP, GLP-1 alpha-cell dysfunction

32 The Glucoregulatory Role of GLP-1
Promotes satiety and reduces appetite DISCUSSION By decreasing β-cell workload and improving β-cell response, GLP-1 is an important regulator of glucose homeostasis. Upon food ingestion, GLP-1 is secreted into the circulation. GLP-1 increases β-cell response by enhancing glucose-dependent insulin secretion. BACKGROUND GLP-1 is secreted from L cells of the small intestine. GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake Effect on Beta cell: Drucker DJ. Diabetes. 1998;47: Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160: Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160: Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39: Effects on CNS: Flint A, et al. J Clin Invest. 1998;101: Alpha cells: ↓ Postprandial glucagon secretion Liver: ↓ Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying 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:

33 GLP-1 stimulates b-cell regeneration and mass in animal models
Key Red arrows indicate effect of GLP-1 b-cell neogenesis b-cell GLP-1 stimulates -cell regeneration and mass Studies have demonstrated that GLP-1 plays an important role in maintaining -cells. In animal studies, GLP-1 increases -cell mass through the stimulation of -cell neogenesis, growth and proliferation. Proliferation results from differentiation and division of existing -cells, while neogenesis occurs through differentiation of insulin-secreting cells from precursor cells in the pancreatic ductal epithelium (Bulotta et al. 2002). Additionally, a recent study using freshly isolated human islets reported a reduction in the number of apoptotic -cells following 5 days of in vitro treatment with GLP-1 (Farilla et al. 2003). These observations of increased -cell mass and decreased apoptosis are of particular interest in the treatment of type 2 diabetes as progressive -cell dysfunction is one of the main pathophysiologies of the disease. References Bulotta et al. J Mol Endocrinol 2002;29:347–360 Farilla et al. Endocrinology 2003;144:5149–5158 b-cell proliferation b-cell apoptosis b-cell hypertrophy b-cell regeneration and increased mass Farilla et al. Endocrinology 2003;144:5149–5158. Bulotta et al. J Mol Endocrinol 2002;29:347–360.

34 Reduced GLP-1 secretion in type 2 diabetes
20 GLP-1 (pM) * * * * * * * 15 Normal 10 IGT T2D patients Mixed Meal 5 60 120 180 240 Time (min) Source: Adapted from Toft-Nielsen et al. ( 2001): J Clin Endocrinol Metab 86:

35 The burden of Type 2 Diabetes

36 Type 2 diabetes is NOT a mild disease
Stroke Diabetic retinopathy 1.2- to 1.8-fold increase in stroke3 Leading cause of blindness in working-age adults1 Cardiovascular disease 75% diabetic patients die from CV events4 Diabetic nephropathy Diabetic neuropathy Leading cause of end-stage renal disease2 Leading cause of non-traumatic lower extremity amputations5 1Fong DS, et al. Diabetes Care 2003;26 (Suppl. 1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003;26 (Suppl. 1):S94–S98. 3Kannel WB, et al. Am Heart J 1990;120:672–676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997. 5Mayfield JA, et al. Diabetes Care 2003;26 (Suppl. 1):S78–S79.

37 Serious complications of type 2 diabetes are present at diagnosis
Retinopathy 21 Abnormal ECG 18 Absent foot pulses ( 2) and/or ischaemic feet 14 Impaired reflexes and/or decreased vibration sense 7 Angina 3 Intermittent claudication 3 Myocardial infarction 2 Stroke/transient ischaemic attack Prevalence (%)* *Some patients had more than one complication at time of diagnosis Adapted from UKPDS VIII. Diabetologia 1991;34:877–890.

38 Type 2 diabetes increases the risk of CVD
Males with diabetes Females with diabetes Any CV event Stroke Intermittent claudication † Cardiac failure † CHD † ‡ MI ‡ Angina pectoris Sudden death * N/A Coronary mortality † † 1 2 3 4 5 6 Age-adjusted risk ratio (1 = risk for individuals without diabetes) *P < 0.1; †P < 0.05; ‡P < 0.01; §P < 0.001 Adapted from Kannel WB, et al. Am Heart J 1990;120:672–676.

39 Relative cost of diabetes
120 $104 100 $92 80 $65 Direct and indirect costs (US$ billion) 60 $44 40 $30 20 Stroke Depression Arthritis Diabetes Cancer US data from 1990–1993 Adapted from Accessed 1 August, 2006.

40 Aggressive Glycemic Control in T2DM Reduces Risk of Complications
Risk Reduction With 1% Decline in Updated HbA1c P <.0001 P =.035 P =.021 P <.0001 P <.0001 14% 12% 16% 19% 21% 15 37% 43% 30 UKPDS 35: Risk Reduction in Diabetes-Related Complications (Updated HbA1c) [Note: be sure to include brief discussion linking this study with clinical data from UKPDS 33 (Lancet 1998; see p.409, 2nd column)] In the UKPDS, each 1% decrease in updated* HbA1c reduced the risk** of microvascular complications by 37%, peripheral vascular disease (PVD) by 43%, MI by 14%, stroke by 12%, heart failure by 16%, and cataract extraction by 19%, as shown on the slide. The investigators did not identify a cutoff point for HbA1c associated with the onset of risk for complications. Thus, a target value for HbA1c was not suggested, although the authors noted that HbA1c levels nearer to normal are obviously preferable. These data indicate that there is a quantitative relation between the risk of complications of diabetes and glycemia over time. The risk was shown to be lowest in patients with HbA1c concentrations <6%. *Updated = HbA1c measured over time as an updated mean of annual measurements. **As assessed by Cox regression models. Potential confounding risk factors included in all Cox models were sex, age, ethnic group, smoking (current/ever/never) at time of diagnosis of diabetes, and baseline HDL-C and LDL-C, triglyceride, presence of albuminuria ( > 50 mg/L measured in a single morning urine sample) measured after 3 months‘dietary treatment, and systolic blood pressure represented by the mean of measures at 2 and 9 months after diagnosis. Stratton IM et al. BMJ. 2000;321: 45 Micro-vascular disease PVD* MI Stroke Heart failure Cataract extraction Death related to diabetes 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
Mean reduction in diabetes-related costs for improved vs. unimproved type 2 diabetes patients 1994 1995 1996 1997 –100 –200 –300 –400 –500 Cost per patient per year ($US) –600 –700 –$685 –800 –$772 –$821 –900 –1000 –$950 Patients whose HbA1c 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) Adapted from Wagner EH, et al. JAMA 2001;285:182–189.

42 Therapeutic Goals in Type 2 Diabetes

43 < 6.0%* (individual goal)
Current Treatment Goals for Glycemic Control: Towards Reducing Risk of Complications ADA ACE IDF HbA1c < 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) 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) 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): 5-11.

44 Two Thirds of People with Type 2 Diabetes are Not at Goal1
HbA1c Level % Patients <7.0% 37.0 7.0%–8.0% 25.8 >8.0% 37.2 >9.0% 20.2 >10.0% 12.4 1NHANES 1999–2000 Data T2DM represents ~90%–95% of cases Adapted from Adapted from Saydah SH, et al. JAMA. 2004;291:

45 6.2% – upper limit of normal range
UKPDS: type 2 diabetes is progressively worsening independently on current therapies 9 Conventional* Glibenclamide Chlorpropamide Metformin 8 Insulin Median HbA1c (%) UKPDS clearly showed the need for new diabetes treatments In UKPDS, the yearly median HbA1c in patients receiving conventional treatment increased steadily throughout the trial. Indeed, within 2 years of diagnosis, this group had a median HbA1c above the recommended target level of < 7.0%. In contrast, median HbA1c fell during the first year in patients receiving intensive treatment (glibenclamide, chloropropamide, metformin or insulin) but gradually increased subsequently and only remained within the recommended treatment target for the first 3–6 years of treatment (depending on assigned treatment). During the remaining years of follow-up, median HbA1c continued to rise steadily above treatment targets. This failure of existing treatments, even when used intensively in highly motivated patients highlights the need for new treatments in the management of type 2 diabetes. UKPDS methodology UKPDS recruited 5102 patients with newly diagnosed type 2 diabetes. Conventional therapy aimed to maintain fasting plasma glucose (FPG) at < 15 mmol/l (270 mg/dl) using diet alone initially. However, sulphonylureas, insulin or metformin could be added if target FPG was not met. Patients assigned to intensive therapy had a target FPG < 6 mmol/l (108 mg/dl) and, in insulin-treated patients, a pre-meal FPG of 4–7 mmol/l (72–126 mg/dl). Non-overweight patients were randomised to insulin or sulphonylurea monotherapy initially. Overweight patients receiving intensive treatment could also be randomised to metformin. These agents could be combined if necessary to maintain target FPG during the trial. The data in this figure are from overweight patients (UKPDS 34). The HbA1c findings in non-overweight patients were similar; regardless of treatment, median HbA1c exceeded the recommended treatment targets within 8 years of therapy (UKPDS 33). References UKPDS 34. Lancet 1998;352:854–865 UKPDS 33. Lancet 1998;352:837–853 7 Recommended treatment target ≤ 7.0† 6 6.2% – upper limit of normal range 2 4 6 8 10 Years from randomisation 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=5102

46 Determinants of type 2 diabetes and anti-diabetic agents
Insulin resistance Metformin, TZDs, insulin Loss of b-cell function Glucotoxicity Any anti-diabetic Lipotoxicity Any anti-diabetic Secretory defects Sulfonylureas, Glinides, insulin Inflammation TZDs (mild), anti-IL1b (exp) Islet amyloid deposition None (?TZDs) Incretin failure Incretin mimetics, analogues, DPP-4 inhibitors alpha-cell dysfunction Idem, insulin

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

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

49 Historical Algorithm of Therapy for Type 2 Diabetes
Inadequate nonpharmacologic therapy Oral agent 2 Oral agents 3 Oral agents It has been common practice to reserve insulin therapy until relatively late in the treatment plan for patients with type 2 diabetes. Typically, it is introduced after patients have failed to achieve glycaemic control with diet and with combination therapy using 2 or 3 oral hypoglycaemic agents of escalating dosages1,2 Based on the time associated with various oral agent alterations (eg, titration and combination therapy), patients are often out of control for lengthy periods and thus increase the risk of complications related to chronic hyperglycaemia1 Add insulin Adapted from Mudaliar S et al. In: Ellenberg and Rifkin’s Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 2003: 1. Mudaliar S, Henry R. The oral antidiabetic agents. In: Porte D, Jr, Sherwin RS, Baron A. Ellenberg and Rifkin’s Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 2003: 2. Riddle MC. Tactics for type II diabetes. Endocrinol Metab Clin North Am. 1997;26:

50 Possible Alternative Algorithm of Therapy for Type 2 Diabetes
Inadequate nonpharmacologic therapy Severe symptoms Severe hyperglycaemia Ketosis Pregnancy Oral agent 2 Oral agents 3 Oral agents Clinicians may consider this proposed algorithm for the treatment of patients with type 2 diabetes. In this algorithm, insulin can be integrated into a patient’s regimen at various stages of the disease Add Insulin Earlier in the Algorithm

51 Beta-cell function (%) Approximate time (years)
The Number of Medications Taken Usually Increases With Duration of Disease Diabetes diagnosed Monotherapy failure Requiring insulin 100 80 Monotherapy Dual-drug regimens Multidrug combo insulin Insulin- based regimens 60 Beta-cell function (%) 40 IGT 20 10 15–25 Approximate time (years) 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 Management of Hyperglycemia in Type 2 Diabetes: ADA/EASD Consensus Algorithm for the Initiation and Adjustment of Therapy Diagnosis Step 1 Lifestyle Intervention + Metformin No Yes* A1C≥7% Add Basal Insulin# (most effective) Add Sulfonylurea (least expensive) Add Glitazone (no hypoglycemia) Step 2 No Yes* A1C≥7% Intensify Insulin# Add Glitazone Add Basal Insulin# Add Sulfonylurea Step 3 Add Basal or Intensify Insulin# Intensive Insulin + Metformin ± Glitazone No Yes* A1C≥7% Nathan DM et al, Diabetes Care, 2006; Diabetologia 2006

54 Nel DMT2 sono elevati sia i livelli di glicemia a digiuno sia i post-prandiali
Diabete non controllato (HbA1c ~8%) 300 Iperglicemia post-prandiale: HbA1c ~+1% 200 Iperglicemia a Digiuno: HbA1c ~+2% Glicemia plasmatica (mg/dl) 100 HbA1c normale~5% Nei soggetti con DMT2 sia i livelli di glicemia a digiuno che post-prandiali sono significativamente più elevati rispetto ai soggetti sani. In un soggetto con HbA1c di 8%, circa il 2% è determinato dall’ipeglicemia a digiuno (basale) e un ulteriore 1% e determinato dall’iperglicemia post-prandiale L’iperglicemia a digiuno è determinata da un’eccessiva produzione epatica di glucosio Riddle M. Diabetes Care 1990;13:676–86. DeFronzo R. Diabetes 1988;37:667–87.  C  P  C 06.00 12.00 18.00 24.00 06.00 Momenti della giornata (ore) C=colazione; P=pranzo; C=cena. Adapted from Riddle M. Diabetes Care 1990;13:67686.