Etiopatogenia DZ tip 2

INSULINO REZISTENA

DEFINITIE SI RELATII GENERALE MUSCHI: Stimularea transportului glucozei

FICAT: Suprimarea productiei hepatice de glucoza TESUT ADIPOS: Inhibitia lipolizei

STAREA IN CARE NIVELE ALE INSULINEMIEI, EFICIENTE LA SUBIECTII NORMALI, NU PRODUC EFECTELE BIOLOGICE OBISNUITE.

CELULA BETA PANCREATICA: Functionalitatea si viata celulelor beta pancreatice pot fi afectate de rezistenta la insulina.

IN T2DM, REZISTENTA LA INSULINA ESTE DETERMINATA GENETIC

25% DIN POPULATIA GENERALA PREZINTA REZISTENTA LA INSULINA

RAZISTENTA LA INSULINA ESTE INFLUENTATA DE FACTORI DE MEDIU - gradul adipozitatii corporale si mai ales distributia ei - exercitiul fizic si gradul de antrenament

 25% DIN POPULATIA GENERALA PREZINTA REZISTENTA LA INSULINA REZISTENTA LA INSULINA ESTE INFLUENTATA DE FACTORI DE MEDIU: - gradul adipozitatii corporale si mai ales distributia ei - exercitiul fizic si gradul de antrenament

Metode de masurare a Rezistentei la insulina

Glucose Clamp Insulin Tolerance Test

Insulin Suppression Test

Regional Arterio-Venous Balance Frequently Samples IV Glucose Tolerance Test (FSIVGTT) Homeostatic Model Assessment (HOMA) Continuous Infusion of Glucose with Model Assessment (CIGMA) Quantitative Insulin-Sensitivity Check Index (QUICKI)
Radziuk J. J Clin Endocrinol Metab 2000;85(12):4426-4433. Matsuda M, DeFronzo RA. Diabetes Care 1999;22(9):1462-1470. Welch S, et al. J Clin Endocrinol Metab 1990;71(6):1508-1518. Katz A, et al.J Clin Endocrinol Metab 2000;85(7):2402-2410. Matthews DR, et al.Diabetologia 1985;28(7):412-419. Fukushima M, et al. Diabetes Care 2000;23(7):1038-9. Taniguchi A, et al.Diabetes Care 2000;23(9):1439-1440.

HOMA (Homeostasis Model Assessment)

Estimarile pot fi efectuate utilizand o formula matematica simpla:

Insulin resistance =

insulin* (mU/mL) glucose* (mg/dl) 405 20 insulin* (mU/mL) glucose* (mmol/L) - 3.5

b-Cell function (%) =

Intre sensibilitatea la insulina estimata prin HOMA si cea estimata prin euglycemic clamp a fost gasita o corelatie foarte stransa: - (r = - 0,820) intr-un studiu recent, pe 115 subiecti europeni obezi si neobezi, diabetici si nediabetici (Bonora E et al. Diabetes Care
2000,23:67-63

- (r = - 0,613) inainte si (r = -0,734) dupa tratament cu dieta si

Glucose clamp
Metoda se bazeaza pe mentinerea unui nivel fix (de aici si numele derivat din limba engleza : to clamp inseamna a fixa) al glicemiei in cursul unei infuzii simultane de insulina si glucoza. Nivelul glicemiei care se mentine constant pe parcursul investigatiei poate fi : 1. Nivelul bazal normal (euglycemic clamp). Aceste metode investigheaza in exclusivitate sensibilitatea tesuturilor (in principal hepatic si muscular) la actiunea insulinei. 3. Nivel crescut al glicemiei, in jur de 180 mg/dl: (hyperglycemic clamp). Hyperglycemic clamp este utilizata deobicei pentru masurarea raspunsului insulinosecretor.

Hyperinsulinemic Euglycemic clamp

1. Administrarea insulinei Nivelul insulinemiei este crescut si mentinut constant, la un nivel dinainte stabilit, prin administrarea insulinei in infuzie iv.
Rata de infuzie (mU/Kg/min) Nivelul insulinemiei (mU/ml) 364 575 102 14 18215 65362 1718850 10277577 0.4 0.5 1.0 2.0 5.0 10 30

De obicei rata infuziei de insulina este raportata la suprafata corporala. Suprafata corporala ( S ) se calculeaza dupa urmatoarea formula: S (m2) = G 0,425 (kg) x I 0,725 (cm) x 71,84 x 10-4 Rata de infuzie cel mai des folosita este de 40 mUmin-1m2 si corespunde

cu aproximatie la 1 mU/Kgcorp/min.

Hyperinsulinemic Euglycemic Clamp

2. Administrarea glucozei Pentru a mentine constant nivelul glicemiei pe durata probei, este necesara administrarea unei infuzii (variabile) de ser glucozat (deobicei ser glucozat hiperton, solutie 20%) cu ajutorul unei pompe de infuzie automata.

In cursul investigatiei se tinde la obtinerea perioadei de steady-state.

In acesta conditii, daca emisia hepatica de glucoza este complet suprimata, rata de infuzie a glucozei este egala cu rata de captare a glucozei in tesuturile periferice (in principal tesutul muscular) sub actiunea insulinei. Rata de infuzie a glucozei reprezinta astfel un indicator al sensibilitatii tesuturilor la insulina. Cu cat subiectul este mai rezistent la insulina cu atat rata de infuzie a

Euglycemic Hyperinsulinemic Clamp

Euglycemic Clamp

Ferrannini E. Atlas of Diabetes (R. Kahn editor) Current Medicine,Philadelphia, 2000: 95

Avantaje:
Posibilitatea de a asocia EC cu alte investigatii :
- calorimetria indirecta - biopsia musculara - cateterism regional (pentru a masura schimburile regionale, la nivelul unui membru sau organ). - rezonanta magnetica nucleara (NMR) - tomografia in emisie de pozitroni (PET).

Muschiul striat scheletic sediul major al rezistentei la insulina

1. In cursul Euglycemic clamp (E clamp), majoritatea glucozei este captata in tesuturile periferice:

- muschi (in principal)

- tesut adipos (1%) - splanhne (o cantitate neglijabila)

2. Glucoza captata in muschi poate fi utilizata pe una din cele doua cai:

- oxidativa : - neoxidativa:

CO2 + H2O lactat sau glicogen

de C13 din glicogenul muscular

A permis masurarea directa, in vivo (la niv m. gastrocnemian) a cantitatii de glicogen sintetizat in cursul E Clamp:
-Captarea glucozei redusa la diabetici : 30 fata de 51 mmol/Kg/min la normali

-Rata medie a metab neoxidativ al glucozei redusa la diabetici: 22 fata de 42 mmol/Kg/min la normali
-Rata medie a sintezei glicogenului redusa la diabetici: 78 fata de 183 mmol unitati glicosil/Kg/min

CONCLUZIE: Rezistenta la insulina este rezultatul unui defect al caii metabolice a sintezei glicogenului muscular
Shulman, 1990

CAILE METABOLICE ALE GLUCOZEI IN MUSCHIUL STRIAT

Metoda spectroscopiei in RMN folosind C13 si P 31

S-a masurat concentratiile intramiocelulare (6 T2DM si 7 N) in cursul Hyperglycemic Clamp (180 mg/dl) pentru:
glucoza libera glucozo 6-fosfat glicogen

Rezultate:
Nivelele sintezei glicogenului si ale glucozo 6-fosfatului reduse cu 80% la diabetici

Concluzie: Afectarea transportului glucozei joaca un rol important in producerea rezistentei la insulina

Cline et al. 1999

Actiunea insulinei asupra transportului glucozei

Cellular mechanisms in the insulin resistance associated to obesity and type 2 diabetes mellitus

Nauru seen from the air

Melanesian and Polynesian in its descent, the population had a traditional way of life till the beginning of the 20th century.

Extensive phosphate mining let the money to flow in

In 1970, Nauruans were among the richest people and this changed their way of life: become sedentary and consuming a high fat hypercaloric diet.

They sow no need to work for a living while other Pacific Islander were doing the work in the mines. The future looked bright

 in a short time, Nauru get one of the world

fattest populations. While diabetes was not known before 1950, now around 50% of Nauruans suffer from the disease and it stems from their sedentary lifestyle and fatty diet coupled with genes more suited to protect them from starvation.

The Economist 2001 20th December

Obesity is an important risk for type 2 diabetes mellitus

Insulin resistance states (such as obesity and type 2 diabetes) are characterized by lipid accumulation as triglyceride stores in non-adipose tissue: liver, skeletal and cardiac muscle, and in pancreatic -cells.

Electron micrograph of tibialis anterior muscle

IMCL

mi: mithocondria; IMCL droplets in close contact to mitochondria; mf:myofibrils Howald H et al: J Appl Physiol 2002;92:2264-2272

Electron micrograph of a longitudinal section of skeletal muscle tissue

li: lipid droplet; mc: central mitocondria; mf:myofilaments

Hoppeler H et al 2002

magnetic resonance spectroscopy can quantitate the intracellular (liver and muscle) triglyceride stores

1H

Szczepaniak LS et al. Am J Physiol Endocrinol Metab 1999;276:E977-E989

The FFA levels are an important link connecting obesity and type 2 diabetes to insulin resistance. An increased FFA level accounts for 50% ot the insulin resistance in people with obesity and/or type 2 diabetes

Boden G et al.Best Pract Res Clin Endocrinol Metab 2003;17:399-410

Relationship between IMCL-triglycerides and plasma FFA levels

Boden G et al. Diabetes 2001;50:1612-1617

Skeletal muscle glucose transport/fosforilation and glycogen

synthesis at high FFA levels ( triglyceride emulsion+heparin infusion) during hyperinsulinemic euglycemic clamp (healthy subjects)

Open symbols: TG + heparin infusion

Closed symbols: no TG/heparin infusion

Roden M et al. J Clin Invest 1966;97:2859-2865

Insulin resistance is manifest after a 4-6 hours from increase in FFA levels and is accompanied by: Increase in cellular levels of - Triglycerides - DAG (di-acyl-glycerol) - Increased PKC activity Decreased levels of I

Boden G et al. Diabetes 2001;50:1612-1617 Itani S et al. Diabetes 2002;51:2005-2011

Potential mechanisms of FFA on insulin resistance and atherogenesis in human muscle

plasma FFA
Fatty Acil- CoA DAG Ceramide

IRS1- serine/threonine

phosph.

IRS1- tirosine phosphorilation

ROS PKC NF Activation I Degradation

ROS

PI 3 Kinase/Akt-PKB

GLUT 4 translocation at cellular membrane Proinflammatory and Proatherogenic Proteins

Glucose uptake/transport

Boden G, Laakso M. Diabetes Care 2004;27:2253-2259

In the (A-ZIP/F-1) lipoatrophic mice the lack of fat is associated with insulin resistance and hyperglycemia
The phenotype of lipoatrophic mice is similar to that of human lipoatrophic diabetes : -lack of fat, insulinresistance with hyperinsulinemia , hiperphagia, hiperlipidemia, fatty liver and organomegaly. Transplantation of wild-type fat reversed completely or partially the lipoatrophic phenotype. The beneficial effects of fat transplantation were dose dependent. In this figure, lipoatrophic sham operated mice (left) and lipoatrophic mice after 3 weeks of fat (seven graft) transplantation.

Gavrilova O et al. J Clin Invest 2000;105:271-278

Liver histology 13 weeks after fat transplant in lipoatrophic mice

Large vacuolated hepatocytes (due to lipid deposition) in the sham-operated but not transplanted mice

Sham operated (left) and transplanted (right)

Gavrilova O et al. J Clin Invest 2000;105:271-278

But the fat transplanted from ob/ob mice (leptin-deficient) failed to reverse the metbolic disturbances. This highlighted the importance of LEPTIN, an adipocyte derived hormone.

Generalized Lipodystrophy
Girl aged 6 yrs, 2 mo. Height:122 cm Weight:21,5 Kg Lack of adipose tissue at face, trunk and limbs The increase in abdomen is due to hepatosplenomegaly. Echography disclosed hepatic steatosis. Visible ombilical hernia Acanthosis nigricans, gingival hipertrophy.

Basal values:
Plasma Glucose= 93 mg/dl; serum insulin= 32.3 U/ml. HOMA-R index : 7,4 Triglycerides: 193 mg/dl;T-colesterol:126 mg/dl HDL-colesterol: 21 mg/dl ALT/AST: 113/64 U/L

Acanthosis Nigricans

The increase in intracellular triglyceride stores in non-adipose tissues may be the consequence of: -Prolonged exposure to increased plasma levels of FFA -Defects in mitochondrial (oxidative activity) fatty acid oxidation
-Both

Intramyocellular lipid content is increased and muscle mitochondrial phosphorylation activity is decreased in healthy young,lean, insulin-resistant offspring of patients with Type 2 DM

Petersen KF et al. N Engl J Med 2004; 350: 664-671

Muscle Mitochondrial oxidativephosphorylation activity is reduced in lean offspring of patients with type 2 DM
80% increase in intramyocellular triglyceride content 60% reduction in insulin-stimulated glucose uptake 30% reduction in mitochondrial phosphorylation Insulin resistance in skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation.

Petersen KF et al: N engl J Med 2004;350:664-671

Morphological differences in the skeletal muscle mitochondria from volunteers:

a. Lean, healty volunteer b. Obese volunteer

c.

Type 2 diabetes volunteer

Kelley DE et al: Diabetes 2002;51:2944-2950

Relationship between mitochondrial size and insulin sensitivity

Between insulin sensitivity (euglycemic clamp) and muscle mitochondrial size there was a positive correlation. (r=0,72;n=21;p<0,01)

Kelley DE et al:Diabetes 2002;51:2944-2950

CONCLUSION
Excessive intake of nutrients and/or mitochondrial dysfunction may lead to increased intracellular content of lipid metabolites. Increased intracellular lipid metabolites can activate signal transduction pathways that induce inflammation and impair insulin signalling. Future therapeutic strategies may target the decrease in plasma FFA concentration, normalization of mitochondrial function and inhibition of inflammatory pathways in insulinresponsive tissues.

CARDIOVASCULAR RISK FACTORS DURING THE PRELIMINARY PHASES LEADING TO TYPE 2 DIABETES

The Burden of Diabetes

- From 135 million in 1995, today 177 million people suffer from diabetes.

-For 2025 it is estimated that at least 300 million people throughout the world will suffer from diabetes.
-The estimated lifetime risk to develop diabetes, for individuals born in year 2000 in USA is: 32.8% for males and 38.5% for females. -For an individual diagnosed at 40 years, men will lose 11.6 life-years and 18.6 quality-adjusted life-years and women will lose 14.3 life-years and 22.0 quality-adjusted life-years
King H et al. Diabetes Care 1998; 21: 1414-1431 Narayan KMV et al. JAMA 2003; 290: 1884-1830

MORTALITY IN PEOPLE WITH DIABETES

Causes of Death
50 40

% of Deaths

30
20 10 0 Ischemic Other Diabetes Cancer Stroke Infection Other heart heart disease disease

Geiss LS et al. In: Diabetes in America 2nd ed. 1995; chap 11

CVD Mortality Decreases in General Population and Diabetes Mortality Increases

% change in age-adjusted mortality rate since 1980 50 40 30 20 10 0 -10 -20 -30 -40 -50 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998

Diabetes Cancer All-cause CVD

Sobel et al. Circulation. 2003;107:636-642.

The vascular complications are already present at the time of diagnosis

Data from UKPDS
- 33% of newly diagnosed type 2 diabetic patients had either an abnormal ECK or retinopathy. -Arterial Hypertension, defined as systolic pressure>160 mm Hg and diastolic pressure > 90 mm Hg was present in 37% males and 52% females. -50% from newly diagnosed type 2 diabetic patients had clinical evidence of diabetic tissue damage at diagnosis. -As compared to age matched normal subjects, newly diagnosed diabetic patients were more obese, had greater plasma insulin and triglyceride levels, increased urinary albumin excretion and lower levels of HDL-cholesterol.

The vascular complications are associated predominantly with different risk factors
Data from UKPDS MACROVASCULAR Complications (Strokes, heart attacks,peripheral arterial disease) were predominantly associated with hypertension, hypertrigliceridemia, low HDL-cholesterol, smoking and increased urinary albumin excretion. MICROVASCULAR Complications: Retinopathy was predominantly associated with hyperglycemia

UK Prospective Diabetes Study 6. Diabetes Res 1990;13:1-11

THE CLOCK

FOR
CARDIOVASCULAR DISEASE START TICKING LONG BEFORE THE ONSET OF CLINICAL DIABETES
Haffner SM et al: JAMA 1990;263:2893-2898

Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes

NURSES HEALTH STUDY
111629 Female nurses 30-35 years, free of diagnosed Diabetes and CVD at baseline
RECRUITED: 1976 FOLLOWED: 20 years DURING FOLLOW-UP: - 5894 developped T2 DM - 1556 cases of MI - 1405 strokes

Hu FB et al. Diabetes Care 2002; 25: 1129 - 1134

Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes

Multivariate RR of MI or stroke before clinical diagnosis of diabetes

Hu FB et al. Diabetes Care 2002;25:1129-1134

San Antonio Heart Study:Clinical characteristics of subjects at baseline according to conversion status at follow-up
Nondiabetic (n=1539) Type 2 Diabetes (n=195) Difference (DM Non-DM) p

HDL cholesterol, mmol/L LDL cholesterol, mmol/L

1.25 0.01 3.230.02

1.140.02 3.09 0.07

-0.11 -0.14

<0.001 0.459

Triglyceride, mmol/L SBP, mm Hg DBP, mm Hg Fasting insulin, pmol/L

HOMA IR I30-I0/G30-G0 pmol/mmol

1.530.03 117.80.35 71.50.2 742

2.80.1 227 11

2.020.07 120.71.0 73.20.7 1086

3.90.2 11930

0.49 2.9 2.2 34.0

1.1 -108

<0.001
0.016 0.042 <0.001 <0.001 <0.001

Haffner SM et al.Circulation 2000;101:975-980

Insulin Resistance and the Metabolic Syndrome

IR is associated with the metabolic syndrome, a cluster of risk factors including
Hyperglycemia Low HDL High TGs Abdominal obesity HTN Older age

Data from NHANES III demonstrate presence of metabolic syndrome in 23% of the general population ATP III criteria recognize IR as a CVD risk factor

Park et al. Arch Intern Med. 2003;163:427-436.

The metabolic syndrome

WHOa
Insulin resistance &/or FPG Plus 2 or more of: Blood pressure TG, HDL-C Microalbuminuria Central obesity Central obesity

EGIRb
Insulin resistance (hyperinsulinaemia) Plus 2 or more of: Blood pressure TG, HDL-Cd

NCEPc
FPG Plus 2 or more of: Blood pressure TG HDL-C Central obesity

aWorld Health Organisation; bEuropean Group for the study of Insulin resistance; cNational Cholesterol Education Program; dand/or treatment for dyslipidaemia Eschwege E. Diabetes Metab 2003;29:6S19-27

Definition of Metabolic Syndrome from NCEP ATP III

Metabolic Syndrome
The IDF worldwide consensus definition

Prevalence of metabolic syndrome among NHANES III participants over 50 years of age categorized by glucose intolerance

Alexander CM et al. Diabetes 2003; 52:1210-1214

Prevalence of CHD among NHANES III participants over 50 years of age categorized by presence of metabolic syndrome and diabetes

Alexander CM et al. Diabetes 2003; 52:1210-1214

The risk for incidence of type 2 diabetes is greatly increased in persons with the metabolic syndrome traits
San Antonio Heart Study: more than 60% of the insulin resistant subjects developed diabetes during 7.5 year follow-up

The prevalence of metabolic syndrome increase with deterioration of glucose tolerance

Five-year conversion rates for developing diabetes by the numbers of RFs present at baseline
The Insulin Resistance Atherosclerosis Study

Five-year conversion rates for developing diabetes by the presence at baseline of one or more CVD RFs.
DAgostino RB et al. Diabetes Care 2004; 27: 2234 - 2240

The metabolic syndrome is a precursor and a significant predictor of CVD and type 2 diabetes

The connections between metabolic abnormalities

and vascular complications.

The risk for microvascular complications such as retinopathy, nephropaty, neuropathy is related to hyperglycemia.

The risk increase with the onset of elevated blood glucose levels.

The risk for macrovascular complications increase much earlier being predominantly associated to metabolic abnormalities that cluster around insulin resistance.

The best time point to start preventive interventions is different for micro and macro-vascular complications.

Is screening and early diagnosis of type 2 diabetes worthwhile?

The length of the preclinical asymptomatic phase during which glucose levels within diabetes range coexist with CVD risk factors may be as long as 12 years Between UKPDS participants, people with newly diagnosed diabetes and lower initial glycemia had a significantly reduced risk for progression of microvascular complications
Harris MI et al. Diabetes Care 1992; 14: 815-819 Colagiuri S et aliabetes Care 2002;25: 1410-1417

Targeted Screening of high-risk individuals may identify:

-Individuals with prediabetes susceptible to clinical interventions to prevent or delay the progress to clinical diabetes. - Individuals with diabetes in which multifactorial treatment of risk factors may delay or prevent complications.

Conclusions (1)
Early detecton of T2DM could offer the possibility to implement therapeutic interventions during the preclinical asymptomatic phase:
-Counseling for lifestyle optimisation. -Tight glycemic control. -Intensive use and targeted choice of antihypertensive agents.

-More aggressive use of lipid treatment and aspirin.

However, the magnitude of benefit of earlier therapeutic initiation as compared to initiation after clinical diagnosis is, at present time, not evaluated.

Conclusions (2)
It is presumed, from indirect evidence, that the impact of earlier

interventions that target macrovascular complications (treating

CVD risk factors as hypertension, dyslipidemia, prothrombotic state) may have a greater favorable effect than earlier initiation of interventions that target microvascular complications ( as tight glycemic control). Current evidence suggests that the benefits of screening for T2DM are more likely to come from modifications of CVD risk factors rather than from tight glycemic control.

ADA: Recommendations for evaluation of hig-risk individuals

Persons aged 45 years with a BMI 25 Kg/m2 (Asian Americans at BMI 23 Kg/m2 ) should be screened at 3-year intervals. Age < 45 years with BMI 25 Kg/m2 plus additional risk factors for type 2 diabetes FPG is the recommended screening test. The OGTT may be necessary when FPG is normal. Diagnostic testing should be performed in any clinical situation

in which such testing is warranted

Done as part of health care office visit
ADA: Position statement Diabetes Care 2004; 27 Suppl 1: S11-S14

ADA position statement:Risk factors for T2DM

Hypertension History of gestational diabetes or baby weighing > 4000 g Polycystic ovary syndrome High-risk ethnic group

HDL-cholesterol < 35 mg/dl

Triglycerides > 250 mg/dl First degree relative with diabetes

History of vascular disease

Habitual inactivity
ADA. Diabetes Care 2004;27 (suppl1):S11-S14