Il Diabete di Tipo 2

Emanuele Bosi

Corso di Endocrinologia e Malattie del Ricambio

Università Vita-Salute San Raffaele A.A. 2009-2010

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

Quanto è diffuso

il diabete di tipo 2?

The type 2 diabetes pandemia

Adapted from WHO Diabetes Programme Facts and Figures: www.who.int/diabetes/facts/world_figures/en. Accessed 1 August, 2006.

Worldwide prevalence of diabetes in 2000

Number of persons

< 5,0005,000–74,00075,000–349,000350,000–1,499,0001,500,000–4,999,000> 5,000,000No data available

Total cases 150 million adults

Worldwide prevalence of diabetes in 2030 (projected)

Total cases > 300 million adults

Number of persons

< 5,0005,000–74,00075,000–349,000350,000–1,499,0001,500,000–4,999,000> 5,000,000No data available Adapted from WHO Diabetes Programme Facts and Figures:

www.who.int/diabetes/facts/world_figures/en. Accessed 1 August, 2006.

Prevalenza delle alterazioni del metabolismo dei carboidrati in Italia

età come fattore di rischio

Diabete di tipo 2 IGT

Anni % %45-54 5.2 4.455-64 11.3 6.665-74 15.1 10.3>75 16.6 19.4>45 anni 11.1 8.2

- noto 8.2 -- non-noto 2.9 -

Cremona Study

Pathophysiology and Natural History of Type 2 Diabetes

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

NGT IGT / 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.

Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, MN:International Diabetes Center; 2000.

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

Insulino resistenza

Definizione: Ridotto effetto biologico dell’insulina per difetto a localizzazione post-recettoriale

Eziologia: indeterminataFattori di rischio:• Genetici: elevata familiarità, geni non identificati• Età• Sedentarietà• Alimentazione• Obesità e sovrappeso

INSULIN

RESISTANCELiver, muscle, adipocyte

endothelium

Obesity

DyslipidemiaHypertension

Type 2diabetes

Insulin resistance is a common feature of many human diseases

Cardiovascular disease

Polycystic ovarysyndrome (PCOS)

Obesità come fattore di rischio per diabete di tipo 2Obesità come fattore di rischio per diabete di tipo 2

Carey et al., Carey et al., Am J Epidemiol,Am J Epidemiol, 1997 1997

Ris

chio

Rel

ativ

oR

isch

io R

elat

ivo

71–75.971–75.9

2424

2020

1616

1212

88

44

00<71<71 76–8176–81 81.1–8681.1–86 86.1–9186.1–91 91.1–96.391.1–96.3 96.496.4

Circonferenza addominale (cm)Circonferenza addominale (cm)

Years from diagnosisYears from diagnosis

-Cell Function Declines While Insulin Sensitivity Remains Stable in Type -Cell Function Declines While Insulin Sensitivity Remains Stable in Type

2 Diabetes2 Diabetes

10-year follow-up of the Belfast Diet Study: Data from 67 newly diagnosed subjects with type 2 diabetes mellitus (N=432) who 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.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 HOMA=Homeostasis Model Assessment; data expressed as percentages of values in lean nondiabetic reference population.reference population.Adapted from Levy J et al. Adapted from Levy J et al. Diabet Med.Diabet Med. 1998;15:290–296. 1998;15:290–296.

00

4040

6060

HO

MA

(%

)H

OM

A (

%)

2020

0000

4040

6060

8080

HO

MA

(H

OM

A (

%)

%)

2020

22 44 66 00 22 44 66

Years from diagnosisYears from diagnosis

-Cell Function-Cell Function Insulin SensitivityInsulin Sensitivity

Hypothetical Model for Postnatal Pancreaticß-Cell Growth in Humans

CJ Rhodes, Science, 2005

• 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

-ce

ll fu

nct

ion (

%,

HO

MA

)

Years from diagnosis

UKPDS

0

20

40

100

–4 6–10 –8 –6 –2 0 2 4

80

60

Diet

SulphonylureaMetformin

UKPDS: Loss of -cell function is the major determinant of disease progression in T2DM

Il volume -cellulare èridotto del 40% già inpresenza di IFG

Lo studio dei pancreasautoptici ha dimostrato cheil volume relativo -cellularedei soggetti obesi con IFGe dei soggetti con diabetedi tipo 2 è rispettivamenteridotto del 40 e del 63% rispetto a quello dei soggettiobesi non-diabetici

Butler AE, et al. Diabetes 52:102-110, 2003

Determinants of progressive loss of -cell function and mass

• Glucotoxicity

• Lipotoxicity

• Secretory defects

• Inflammation

• Islet amyloid deposition

• Incretin failure

• alpha-cell dysfunction

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

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

Perdita della Fase Precoce della Secrezione Insulinica nel Diabete Tipo 2

Ward WK, et al. Diabetes Care 1984;7:491–502.

Controllo Diabete di Tipo 2

120

100

80

60

40

20

0–30 0 30 60 90 120

Tempo (minuti)

–30 0 30 60 90 120

Tempo (minuti)

IRI

pla

smat

ica

(µ

U/m

l) 120

100

80

60

40

20

0IR

I p

lasm

atic

a (µ

U/m

l)

20 g glucosio20 g

glucosio

• 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

Interleukin-1–Receptor Antagonist in Type 2 Diabetes Mellitus Larsen CM et Al NEJM 356:1517 - 1526, 2007

Determinants of progressive loss of -cell function and mass

• Glucotoxicity

• Lipotoxicity

• Secretory defects

• Inflammation

• Islet amyloid deposition: IAPP (Amylin)

• Incretin failure

• alpha-cell dysfunction

Rhodes C. Science 307:380-384, 2005

Morfologia del pancreasendocrino nel normale, nell’obeso non diabetico enel diabetico di tipo 2

Nell’obeso non-diabetico ilnumero delle isole è aumentatoe le isole tendono ad esserepiù grandi, principalmente perun aumento delle -cellule

Nel diabetico di tipo 2, il numerodelle isole è diminuito, c’è unariduzione marcata delle -cellulee compaiono depositi di amiloide (in viola) che occupano buona parte dell’isola

Diffuse islet amyloidosis

Diffuse islet amyloidosis

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

Determinants of progressive loss of -cell function and mass

• Glucotoxicity

• Lipotoxicity

• Secretory defects

• Inflammation

• Islet amyloid deposition

• Incretin failure Incretins: GIP, GLP-1

• alpha-cell dysfunction

The Glucoregulatory Role of GLP-1

Beta cells:Enhances glucose-dependent

insulin secretion

Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

Liver: ↓ Glucagon reduces

hepatic glucose output

Alpha cells:↓ Postprandial

glucagon secretion

Stomach: Helps regulate

gastric emptying

GLP-1 secreted upon the ingestion of food

Promotes satiety and reduces appetite

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

Reduced GLP-1 secretion in type 2 diabetes

T2D patients

* * **

*

**

0

5

10

15

20

0 60 120 180 240

Time (min)

GLP-1 (pM)

IGT

Normal

Source: Adapted from Toft-Nielsen et al. ( 2001): J Clin Endocrinol Metab 86:3717-3723

Mixed Meal

The burden of Type 2 Diabetes

Diabeticretinopathy

Leading causeof blindnessin working-ageadults1

Diabeticnephropathy

Leading cause of end-stage renal disease2

Cardiovasculardisease

Stroke

1.2- to 1.8-fold increase in stroke3

Diabeticneuropathy

Leading cause of non-traumatic lower extremity amputations5

75% diabetic patients die from CV events4

Type 2 diabetes is NOT a mild disease

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.

Complication

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 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

4 5

Type 2 diabetes increases the risk of CVD

*P < 0.1; †P < 0.05; ‡P < 0.01; §P < 0.001

1 2 3 6

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

Relative cost of diabetes

US data from 1990–1993 Adapted from www.cdc.gov/diabetes/pubs/costs/index.htm. Accessed 1 August, 2006.

120

Dir

ect

and

in

dir

ect

cost

s(U

S$

bil

lio

n)

0

20

40

60

80

100

Stroke Depression Arthritis Diabetes Cancer

$92

$104

$65

$44

$30

Aggressive Glycemic Control in T2DM Reduces Risk of Complications

Risk Reduction With 1% Decline in Updated HbA1c

Micro-vasculardisease

PVD* MI Stroke Heartfailure

Cataractextraction

Death related to diabetes

P <.0001P <.0001 P =.035 P =.021 P <.0001

37% 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;321:405-412.

0

45

30

Therapeutic Goals in Type 2 Diabetes

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 mealAdapted 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, 2005. American Association of Clinical Endocrinologists and the American College of Endocrinology. Endocrine Practice. 2002;8(suppl 1): 5-11.

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)

< 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

1NHANES 1999–2000 DataT2DM represents ~90%–95% of casesAdapted from Adapted from Saydah SH, et al. JAMA. 2004;291:335-342.

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

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=5102

6

7

8

9

Media

n H

bA

1c

(%

)

Years from randomisation

Conventional*GlibenclamideChlorpropamideMetforminInsulin

6.2% – upper limit of normal range

Recommended treatment target ≤ 7.0†

2 4 6 8 100

Determinants of type 2 diabetes and anti-diabetic agents

Insulin resistance Metformin, TZDs, insulinLoss of -cell function• Glucotoxicity Any anti-diabetic• Lipotoxicity Any anti-diabetic• Secretory defects Sulfonylureas, Glinides, insulin• Inflammation TZDs (mild), anti-IL1 (exp)• Islet amyloid deposition None (?TZDs)• Incretin failure Incretin mimetics, analogues,

DPP-4 inhibitors• alpha-cell dysfunction Idem, insulin

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

Lifesty

le Changes

Diet and Exercise

Oral Monotherapy

Standard Approach to the Management of T2DM: Treatment Intensification

Oral Combination ++

Oral + Insulin ++ ++

Insulin

Adapted from Mudaliar S et al. In: Ellenberg and Rifkin’s Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 2003:531-557.

Add insulin

Oral agent 2 Oral agents

Inadequate nonpharmacologic

therapy

3 Oral agents

Historical Algorithm ofTherapy for Type 2 Diabetes

Possible Alternative Algorithm ofTherapy for Type 2 Diabetes

Oral agent

2 Oral agents

3 Oral agents

Add Insulin Earlier in the Algorithm

• Severe symptoms

• Severe hyperglycaemia

• Ketosis

• Pregnancy

Inadequate nonpharmacologic

therapy

The Number of Medications Taken Usually Increases With Duration of Disease

100

0

Be

ta-c

ell

fun

cti

on

(%

)

0 10 15–25

Diabetesdiagnosed

Insulin-based

regimens

Multidrugcombo

±insulin

Approximate time (years)

Monotherapyfailure

Requiring insulin

Dual-drugregimens

Monotherapy

80

60

40

20

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.

Nathan DM et al, Diabetes Care, 2006; Diabetologia 2006

DiagnosisDiagnosis

Lifestyle Intervention + MetforminLifestyle Intervention + Metformin

NoNo Yes*Yes*A1C≥7%A1C≥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)

NoNo Yes*Yes*A1C≥7%A1C≥7% NoNo Yes*Yes*A1C≥7%A1C≥7% NoNo Yes*Yes*A1C≥7%A1C≥7%

Intensify Insulin#Intensify Insulin# Add GlitazoneAdd Glitazone Add Basal Insulin#Add Basal Insulin# Add SulfonylureaAdd Sulfonylurea

Add Basal or Intensify Insulin#Add Basal or Intensify Insulin#

Intensive Insulin + Metformin ± GlitazoneIntensive Insulin + Metformin ± Glitazone

NoNo Yes*Yes* NoNo Yes*Yes*A1C≥7%A1C≥7%A1C≥7%A1C≥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

Iperglicemia post-prandiale:HbA1c ~+1%

C=colazione; P=pranzo; C=cena.Adapted from Riddle M. Diabetes Care 1990;13:67686.

Glicem

ia p

lasm

ati

ca

(mg

/dl)

300

200

100

0

Momenti della giornata (ore)

06.00 12.00 18.00 24.00 06.00

Diabete non controllato (HbA1c ~8%)

Iperglicemia aDigiuno:

HbA1c ~+2%

C

P

C

HbA1c normale~5%

Nel DMT2 sono elevati sia i livelli di glicemia a digiuno sia i post-prandiali