02_ELISAF

ΠΑΘΟΦΤ΢ΙΟΛΟΓΙΑ ΣΗ΢ ΔΙΑΒΗΣΙΚΗ΢ ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ΢ ΜΩΤ΢Η΢ ΓΛΙ΢ΑΦ, ΚΑΘΗΓΗΣΗ΢ ΠΑΘΟΛΟΓΙΑ΢ ΙΑΣΡΙΚΗ΢ ΢ΥΟΛΗ΢ ΠΑΝΓΠΙ΢ΣΗΜΙΟΤ ΙΩΑΝΝΙΝΩΝ Slide Source Lipids Online Slide Library www.lipidsonline.org

Dyslipidemia in Diabetes Increased

Decreased

 Triglycerides

 HDL

 VLDL

 Apo A-I

 LDL and small dense LDL  Apo B Slide Source LipidsOnline www.lipidsonline.org

Mean Plasma Lipids at Diagnosis of Type 2 Diabetes - UKPDS MEN Type 2

WOMEN

Control

Type 2

Control

2139

52

1574

143

TC (mg/dl)

213

205

224

217

LDL-C (mg/dl)

139

132

151*

135

43

43*

55

103

159*

95

Number of Pts

HDL-C (mg/dl) TG (mg/dl)

39** 159*

* P<0.001, ** P<0.02 comparing type 2 vs. controll UKPDS Group. Diabetes Care 1997;20:1683-1687.

Slide Source LipidsOnline www.lipidsonline.org

Abnormal Lipid Levels in Men With Type 2 Diabetes

Adapted from Garg A, Grundy SM. Diabetes Care. 1999;13:153-169.

Abnormal Lipid levels in Women With Type 2 Diabetes

Adapted from Garg A, Grundy SM. Diabetes Care. 1999;13:153-169.

Dyslipidemias in Adults with Diabetes Framingham Heart Study MEN

WOMEN

Normal

DM

Normal

DM

Increased cholesterol

14%

13%

21%

24%

Increased LDL

11%

9%

16%

15%

Decreased HDL

12%

21%

10%

25%

9%

19%

8%

17%

Increased triglycerides

Garg A et al. Diabetes Care 1990;13:153-169.

Slide Source LipidsOnline www.lipidsonline.org

ΠΑΘΟΦΤ΢ΙΟΛΟΓΙΑ ΣΗ΢ ΔΙΑΒΗΣΙΚΗ΢ ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ΢ ΚΑΙ ΑΝΣΙ΢ΣΑ΢Η ΢ΣΗ ΔΡΑ΢Η ΣΗ΢ ΙΝ΢ΟΤΛΙΝΗ΢ Slide Source LipidsOnline www.lipidsonline.org

ΑΝΣΙ΢ΣΑ΢Η ΢ΣΗΝ ΙΝ΢ΟΤΛΙΝΗ

ΔΙΑΒΗΣΙΚΗ ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ ΠΟΤ ΠΡΟΗΓΓΙΣΑΙ ΣΗ΢ ΓΜΦΑΝΙ΢Η΢ ΣΟΤ ΢ΑΚΥΑΡΩΔΗ ΔΙΑΒΗΣΗ

ΙΝ΢ΟΤΛΙΝΗ ΚΑΙ ΜΓΣΑΒΟΛΙ΢ΜΟ΢ ΣΩΝ ΛΙΠΙΔΙΩΝ

o δναζηενηόηεηαξ ηεξ εκδμθοηηάνηαξ ιηπάζεξ ημο ιηπώδμοξ ηζημύ

απειεοζένςζεξ FFA

Adipose Physiology Insulin ď&#x192;Ş FFA

Triglycerides ď&#x192;Ş Glycerol

Adipocyte FFA: free fatty acids

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

AΝΣΙ΢ΣΑ΢Η ΢ΣΗΝ ΙΝ΢ΟΤΛΙΝΗ aπειεοζένςζεξ FFA από ημ ιηπώδε ηζηό

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells

Liver

ď&#x192;ĄFFA

IR X

Insulin

Slide Source LipidsOnline www.lipidsonline.org

FORMATION AND METABOLISM OF VLDL Apo B

Microsomαl Triglyceride Transfer Protein

(εκδμπιαζμηθό δίθηομ, ER) Triglyceride – poor VLDL έθθνηζε

VLDL2

+ TRG (ζοζθεοή Golgi ή ER)

VLDL1

ΙΝ΢ΟΤΛΙΝΗ  FFA Άμεζε ακαζημιή ηεξ παναγςγήξ ( MTP)

 παναγςγήξ ηςκ VLDL1

INSULIN-RESISTANCE: PORTAL THEORY ΢πιαπκηθά ιηπμθύηηανα  εοαηζζεζία ζηε ιηπόιοζε πμο μθείιεηαη ζηηξ θαηεπμιαμίκεξ

 FFA ΗΠΑΡ

Ακηίζηαζε ζηεκ ηκζμοιίκε Am J Med 2007;120: 53-58 Lancet 2005;120: S3-S8

Free Fatty Acids (FFA) and Dyslipidemia Insulin resistance

 FFA

Liver

 Apo B100 synthesis and secretion

Adipose tissue

 VLDL-TG

TG: triglycerides

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

 HDL cholesterol

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells

Liver

FFA

IR X

 TG  Apo B  VLDL

VLDL

Insulin

Slide Source LipidsOnline www.lipidsonline.org

ΑΝΣΙ΢ΣΑ΢Η ΢ΣΗΝ ΙΝ΢ΟΤΛΙΝΗ ΚΑΙ ΠΑΡΑΓΩΓΗ ΣΩΝ VLDL

 παναγςγή FFA από ημ ιηπώδε ηζηό

 πνμζθμνά FFA ζηα επαημθύηηανα Ληπώδεξ δηήζεζε ημο ήπαημξ  παναγςγή VLDL1

De novo lipogenesis

Overproduction of VLDL is the hαllmark of the dyslipidemia in patients with type II DM  VLDL1 [ ανηζμμύ θαη όπη ημο μεγέζμοξ]

ΔΙΑΒΗΣΙΚΗ ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ

 παναγςγή VLDL1

 θαηαβμιηζμμύ VLDL, IDL θαη LDL

ΑΝΣΙ΢ΣΑ΢Η ΢ΣΗΝ ΙΝ΢ΟΤΛΙΝΗ  πνμζθμνά FFA ζηα επαημθύηηανα  ζύκζεζε θαη απμζήθεοζε TRG  έθθνηζε VLDL  LPL

 θαηαβμιηζμμύ ηςκ VLDL

TRG

Insulin Resistance and Lipoprotein Lipase •

Decreased insulin action on lipoprotein lipase leads to decreased uptake of TG -rich lipoproteins TG -rich Lipoproteins

•

Lipoprotein  lipase

Decreased insulin action on hormone sensitive lipase enhanced lipolysis leading to  FFA. In the presence of hyperinsulinaemia , FFA is used for VLDL synthesis by liver Overproduction  FFAs , glycerol adapted from: Haffner S, et al. Diabetes Care

of VLDL 1999;22:562 -568.

Increased production of TRG -rich LPs TRG Decreased catabolism of TRG-rich LPs

Relation Between Insulin Resistance and Hypertriglyceridemia Plasma TG (mg/dL)

625 500

r = 0.73 P < 0.0001

400 300 200 100 100 200 300 400 500 600 Insulin Response to Oral Glucose*

* Total area under 3-hour response curve (mean of 2 tests).

Olefsky JM et al. Am J Med. 1974;57:551-560.

Slide Source LipidsOnline www.lipidsonline.org

 VLDL1

 HDL CHOL  sd HDL

 sd LDL

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells

Liver

FFA

IR X

Insulin

 TG  Apo B  VLDL

CE VLDL (CETP) HDL

TG

(hepatic lipase)

Apo A-1 Kidney

Slide Source LipidsOnline www.lipidsonline.org

 μάδαξ ηεξ CETP μεηαβμιηθό ζύκδνμμμ

ζε

άημμα

με

Obesity 2006;14: 812-818

Association Between Hyperinsulinemia and Low HDL-C

HDL-C (mg/dL)

60 50

Hyperinsulinemic

P<0.005

Normoinsulinemic P<0.005

40 30 20 Nonobese

Reaven GM. In: LeRoith D et al., eds. Diabetes Mellitus.

Philadelphia: Lippincott-Raven,1996:509-519.

Obese Slide Source LipidsOnline www.lipidsonline.org

VLDL

IDL

APO B TRG TRG

LPL

LDL

APO B

APO B

HL

TRG

LDL (Apo B) RECEPTORS

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells

Liver

FFA

IR X

CE

 TG  Apo B  VLDL

VLDL (CETP) HDL

TG

(hepatic lipase)

Apo A-1

CE (CETP) TG

Kidney

Insulin LDL

SD LDL

(lipoprotein or hepatic lipase)

Slide Source LipidsOnline www.lipidsonline.org

Insulin Resistance of Abdominal Adipose Tissue and Atherogenic Dyslipidaemia Liver

FFA Insulin Resistant Abdominal Adipocytes

CE

 TG  Apo B

VLDL

(CETP)

(HL)

HD2

TG

CE

(CETP)

HDL3

Apo A-1

TG

Kidney LDL

( HL)

LDL

small, Dense LDL

Plasma Lipid Transport VLDL

Liver

LPL FC

CE

TG

TG

CE

FFA Adipose tissue CE: FC: FFA: LPL: TG:

cholesteryl ester free cholesterol free fatty acids lipoprotein lipase triglycerides

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

FFA Adipose and other tissues

INSULIN RESΙSTANCE & LIPOTOXICITY

Free Fatty Acids (FFA) and Pancreas Insulin resistance

 FFA

Pancreas

Adipose tissue

Short-term stimulation of insulin secretion

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

• Long-term damage to beta cells • Decreased insulin secretion

Free Fatty Acids (FFA) and Glucose Production

Insulin resistance

ď&#x201A;­ FFA

Liver

Adipose tissue ď&#x201A;­ Glucose release

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

Free Fatty Acids (FFA) and Muscle

FFA

Insulin resistance

Insulin resistance

Muscle

Adipose tissue Skeletal muscle cells

Intramuscular TG

ď&#x201A;Ż Glucose uptake TG: triglycerides

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

Free Fatty Acids (FFA) and Hypertension Insulin resistance

 FFA

Vasculature

Adipose tissue

 Constriction – greater response to alpha-adrenergic stimuli  Relaxation – decreased nitric oxide generation

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

Upper Body / Intra-abdominal (Visceral) Obesity and Insulin Resistance Muscle

Upper body / Intra-abdominal obesity

Insulin resistance

 Constriction  Relaxation

 FFA

Insulin resistance

Liver

 Glucose release

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

Vasculature

Pancreas

 Insulin secretion

΢ΠΛΑΥΝΙΚΗ ΠΑΥΤ΢ΑΡΚΙΑ

 θοηηανμθηκώκ

( ιηπώδμοξ ηζημύ)

 FFA

ΑΝΣΙ΢ΣΑ΢Η ΢ΣΗΝ ΙΝ΢ΟΤΛΙΝΗ

INFLAMMATION AND INSULIN RESISTANCE ΜΓΓΑΛΑ ΛΙΠΟΚΤΣΣΑΡΑ  ΚΤΣΣΑΡΟΚΙΝΩΝ ΠΟΤ ΓΤΟΔΩΝΟΤΝ ΣΗ ΦΛΓΓΜΟΝΗ ΑΝΣΙ΢ΣΑ΢Η ΢ΣΗΝ ΙΝ΢ΟΤΛΙΝΗ ΢ΣΟΤ΢ ΜΤ΢ ΚΑΙ ΣΟ ΗΠΑΡ ΑΛΛΑ ΚΑΙ ΣΟΠΙΚΑ ΢ΣΟ ΛΙΠΩΔΗ Ι΢ΣΟ (παναθνηκηθή δνάζε) FEBS Lett 2008;582: 97-105

ATVB 2007;27: 2276-2283 J Clin Endocrinol Metab 2007;92: 1023-1033

ΔΙΑΒΗΣΙΚΗ ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ ΚΑΙ ΑΘΗΡΩΜΑΣΩ΢Η

Patients with Elevated Triglycerides are at Increased Risk for CHD High TG associates with higher relative risk for CHD in the Framingham Heart Study

Castelli WP. Can J Cardiol. 1998;4 (suppl A):5A-10A.

Triglycerides and CVD Factor Recent Meta-Analysis of 29 Studies Groups

N = 262 525 CHD Cases

Duration of follow-up ≥10 years

CHD Risk Ratio* (95% CI)

5902

<10 years

4256

Male

7728

Female

1994

Fasting status Fasting

7484

Nonfasting

2674

Adjusted for HDL Yes

4469

Sex

No

5689

Overall CHD Risk Ratio*  TRG θαηά 100mg/dl 70%

1.72 (1.56-1.90) Decreased Risk

 θηκδύκμο θαηά

1

Increased Risk

2

Sarwar N, et al. Circulation. 2007;115:450-458.

HYPERTRIGLYCERIDEMIA AND CARDIOVASCULAR DISEASE Direct effect of the TRG-rich lipoproteins on the atherosclerotic process Hypertriglyceridemia Small dense LDL hypercoagulability

 HDL CHOL Increased postpradial lipemia

ΤΠΓΡΣΡΙΓΛΤΚΓΡΙΔΑΙΜΙΑ

ΑΤΞΗΜΓΝΗ ΜΓΣΑΓΓΤΜΑΣΙΚΗ ΛΙΠΑΙΜΙΑ

ΑΤΞΗΜΓΝΟ΢ ΚΙΝΔΤΝΟ΢ ΓΙΑ ΣΗΝ ΓΜΦΑΝΙ΢Η ΚΑΡΔΙΑΓΓΓΙΑΚΗ΢ ΝΟ΢ΟΤ

Καηάιμηπμ ποιμμηθνώκ B 48

REMNANT RECEPTOR

Καηάιμηπμ VLDL B 100

΢οκαγςκηζμόξ όζμκ αθμνά δηαμέζμο ημο ίδημο οπμδμπέα

ημκ

 θαηαιμίπςκ ηςκ ποιμμηθνώκ ΜΓΣΑΓΓΤΜΑΣΙΚΗ ΛΙΠΑΙΜΙΑ

θαηαβμιηζμό



TG Metabolism in CHD: Studies in the Postprandial State Corrected for Fasting Uncorrected

TG (mg/dL)

400

CHD Cases

300

300

TG Level*

200

CHD Cases

200 Controls 100 0

100 Controls

0

2

4

0

6 8 0 2 Hours after Test Meal

4

6

8

Error bars = SEM Patsch JR et al. Arterioscler Thromb 1992;12:1336-1345.

Slide Source LipidsOnline www.lipidsonline.org

Hypertriglyceridemia and CHD Risk: Associated Abnormalities  Accumulation of chylomicron remnants  Accumulation of VLDL remnants  Generation of small, dense LDL-C  Association with low HDL-C  Increased coagulability

-  plasminogen activator inhibitor (PAI-1) -  factor VIIc - Activation of prothrombin to thrombin

Slide Source LipidsOnline www.lipidsonline.org

Factors Promoting Thromboembolic Disease in Diabetes  Increased plasma fibrinogen  Increased plasminogen activator inhibitor 1

 Increased platelet aggregability

Thompson SG et al. N Engl J Med 1995;332:635-641.

Slide Source LipidsOnline www.lipidsonline.org

PAI-1 Activity in Blood in Patients with Type 2 Diabetes PAI-1 Activity (AU/mL)

20 15

No Diabetes Diabetes

10 5 0

Lean

PAI-1 = plasminogen activator inhibitor type 1 McGill JB et al. Diabetes. 1994;43:104-109.

Obese Slide Source LipidsOnline www.lipidsonline.org

Low HDL-C Predicts CHD Risk Low HDL-C is an independent predictor of CHD risk even when LDL-C is low

Castelli WP. Can J Cardiol. 1998;4 (suppl A):5A-10A.

Anti-atherogenic Properties of HDL HDL and reverse cholesterol transport

Anti-atherogenic Properties of HDL

 Mechanisms other than reverse cholesterol transport by

which HDL may be anti-atherogenic  Anti-oxidant effects  Inhibition of adhesion molecule expression  Inhibition of platelet activation  Prostacyclin stabilisation  Promotion of NO production

LDL Size and CHD risk

LDL size : divergent findings on CHD risk

Small, Dense, LDL Particles were an Independent Risk Factor for CAD in Quebec Cardiovascular Study

St Pierre, et al. Circulation. 2001:104:2295.

Joint Evaluation of TG and LDL Size As Predictors of First MI: TG not LDL size is an independent predictor US Physicians Health Study

Sacks F, Campos H. J Clin Endocrin Metab. Oct. 2003.

Large LDL Size is an Independent Predictor of CHD Death and MI in the Placebo but not Pravastatin Group: The CARE trial, 416 cases

Campos H, et al. JAMA 2001;286:1468-1474.

Atherogenicity of small dense LDL

Small Dense LDL and CHD: Potential Atherogenic Mechanisms  Increased susceptibility to oxidation  Increased vascular permeability

 Conformational change in apo B  Decreased affinity for LDL receptor

 Association with insulin resistance syndrome  Association with high TG and low HDL Austin MA et al. Curr Opin Lipidol 1996;7:167-171.

Slide Source LipidsOnline www.lipidsonline.org

SURROGATE MARKERS OF THE PRESENCE OF SMALL DENSE LDL AND HDL PARTICLES  TRG/HDL-C  HDL-C/Apo A1

small dense LDL small dense HDL Clin Biochem 2001;34: 583-588 Am J Cardiol 2004;93: 159-164

Oxidized LDL and thrombogenesis

ΔΙΑΒΗΣΙΚΗ ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ (1)

 non HDL CHOL ( ζογθέκηνςζε αζενςγόκςκ ιηπμπνςηεσκώκ πμο πενηέπμοκ Apo B) Non HDL CHOL = T CHOL – HDL CHOL Ο θαιύηενμξ πνμγκςζηηθόξ δείθηεξ ζε άημμα με  TRG

ΔΙΑΒΗΣΙΚΗ ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ (2)  Apo B Ο θαιύηενμξ πνμγκςζηηθόξ δείθηεξ;

ΑΝΣΙΜΓΣΩΠΙ΢Η ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ΢ ΢Γ ΑΣΟΜΑ ΜΓ ΚΑΡΔΙΟΜΓΣΑΒΟΛΙΚΟ ΚΙΝΔΤΝΟ: ADA ΚΑΙ ACCF ΢ηόπμη mg/dl

Άημμα ορειμύ θηκδύκμο με γκςζηή αγγεηαθή κόζμ ή δηαβήηε (+>1 πανάγμκηα θηκδύκμο)

Άημμα ορειμύ θηκδύκμο: α. πςνίξ δηαβήηε ή αγγεηαθή κόζμ αιιά με > 2 επηπνόζζεημοξ πανάγμκηεξ θηκδύκμο* β. με δηαβήηε πςνίξ άιιμοξ πανάγμκηεξ θηκδύκμο

LDL CHOL

non HDL CHOL

ApoB

<70

<100

<80

<100

<130

<90

* θάπκηζμα/οπένηαζε/ζεηηθό μηθμγεκεηαθό ηζημνηθό JACC 2008;151:1512-1524

The Atherogenic Metabolic Triad Hyperinsulinemia

The Atherogenic Triad

Small, dense LDL particles

Elevated apo B concentrations

Beyond LDL cholesterol, blood pressure, type 2 diabetesâ&#x20AC;Ś LDL: low-density lipoprotein

Slide Source Lipids Online Slide Library www.lipidsonline.org

LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study 6

6.2

5

(p<0.001)

4 3 2.0

2 1 0

1.0 >25.64

Apo B 1.0

<25.64 LDL Peak Particle Diameter (nm) Lamarche B et al. Circulation 1997;95:69-75.

>120 mg/dl <120 mg/dl

Plasma Insulin and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study 12.0

9.7

p<0.001

10.0

Odds Ratio

11.0

P<0.001

8.0 6.0

Apolipoprotein B

4.0 2.0 0.0

1.5 1.0 <12

3.0

3.2

p=0.04

p=0.04

12-15 >15 F-Insulin (ď ­U/ml)

Despres JP et al. N Engl J Med 1996;334:952-957.

>119 mg/dl <119 mg/dl

Odds Ratio

Plasma Insulin and Triglycerides Predict Ischemic Heart Disease: Quebec Cardiovascular Study 6.7

8.0

5.4

6.0

P=0.002

p=0.005

4.0 1.5

2.0 0.0

4.6

P<0.001

p=0.001

5.3

1.0 <12

Triglycerides >150 mg/dl <150 mg/dl

12-15 F-Insulin (ď ­U/ml)

Despres JP et al. N Engl J Med 1996;334:952-957.

>15

VISCERAL OBESITY

Metabolic abnormalities: Apo B, insulin,  small dense LDL

 risk for CHD (by 20 times) in asymptomatic middle aged men, 5 years of follow- up JAMA, 1998

The Atherogenic Triad of New Metabolic Risk Factors

Importance of Waist and Fasting Triglycerides as Screening Tools Insulin

Apo B

Small LDL

Waist

Triglycerides

> 90 cm (> 40 yrs)

> 2.0 mmol/L

Lemieux I, et al. Circulation. 2000;102:179-184.

Slide Source Lipids Online Slide Library www.lipidsonline.org

Hypertriglyceridemic waist phenotype: άκδνεξ: ΠΜ > 90cm, TRG > 180mg/dl γοκαίθεξ: ΠΜ > 88cm, TRG > 150mg/dl Δείθηεξ πανμοζίαξ πμιιώκ θανδημμεηαβμιηθώκ παναγόκηςκ θηκδύκμο Δείθηεξ πανμοζίαξ αολεμέκςκ ζογθεκηνώζεςκ μηθνώκ ποθκώκ LDL

Ι. Gazi et al: Lipids 2006;41:647-654

ΔΙΑΒΗΣΙΚΗ ΔΤ΢ΛΙΠΙΔΑΙΜΙΑ (3) Apo B: δείθηεξ ηεξ ζογθέκηνςζεξ ηςκ αζενςγόκςκ ιηπμπνςηεσκώκ Apo A1: δείθηεξ ηεξ ζογθέκηνςζεξ ακηηαζενςγόκςκ ιηπμπνςηεσκώκ

ηςκ

΢ε δηαβεηηθμύξ αζζεκείξ  Apo B  Apo A1  Apo B/Apo A1: o θαιύηενμξ αζενςμαηηθόξ δείθηεξ

ApoB/ApoA1:

Ο θαιύηενμξ αζενςμαηηθόξ δείθηεξ Ο θαιύηενμξ δείθηεξ πανμοζίαξ μηθνώκ ποθκώκ LDL

V. Tsimihodimos et al: Lipids 2007;42:403-409

Diabetes and atherosclerosis

Β΄ ΠΑΝΓΠΙ΢ΣΗΜΙΑΚΗ ΠΑΘΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΙΑΣΡΙΚΗ΢ ΢ΥΟΛΗ΢ ΠΑΝΓΠΙ΢ΣΗΜΙΟΤ ΙΩΑΝΝΙΝΩΝ

www.bpath.gr