Obesità, Diabete e Metabolismo...

Focus su sicurezza d’uso e nutrizionale degli alimentiRoma 21-22 Novembre 2005

Obesità, Diabete e Metabolismo Lipidico

Angela A. RivelleseDipartimento di Medicina Clinica e Sperimentale,Università Federico II, Napoli

Source: Mokdad AH, et al. JAMA1999;282:16.

No Data <10% 10%-14% 15-19% ≥ 20%

Obesity* Trends Among U.S. AdultsBRFSS, 1991

(*BMI ≥ 30, or ~ 30 lbs overweight for 5’4” person)

Source: Mokdad AH, et al. JAMA1999;282:16.

No Data <10% 10%-14% 15-19% ≥ 20%





No Data <10% 10%-14% 15-19% ≥ 20%

Source: BRFSS, CDC.



Source: Mokdad A H, et al. JAMA2001;286:10

No Data <10% 10%-14% 15-19% ≥ 20%

Type 2 Diabetes Prevalence Is Projected to Reach 300 Million by 2025

USA

2000: 15M

2025: 21.9M

JAPAN

2000: 6.9M

2025: 8.5M

EUROPE

2000: 30.8M

2025: 38.5M

AMERICAS(Ex-US)

2000: 20M

2025: 42M

AFRICA

2000: 9.2M

2025: 21.5M

ASIA

2000: 71.8M

2025: 165.7M

OCEANIA

2000: 0.8M

2025: 1.5M

• About 155 million adults worldwide diagnosed with diabetes in 2000– 83 million women and 72 million men

• Between 1995 and 2025, the prevalence of diabetes in adults willincrease by 35% and the number of people with diabetes will increase by 122%

Adapted from King H et al Diabetes Care 1998;21:1414-1431.

Deficitβ-cellulare

Obesità DiabeteInsulino-

resistenza

Alterazioni lipidiche

Dislipidemia in condizioni di insulinoresistenza

TG plasmatici e VLDL Lipemia postprandiale

LDL piccole e dense COL - HDLHDL piccole e dense

VLDL particle sizeEffect of insulin sensitivity and

type 2 diabetes

40

45

50

55

nm

Insulin Insulin Type 2sensitive resistant diabetes

****p<0.05

**p<0.01vs insulin sensitive

T. Garvey et al, Diabetes 2003

Remnants

FFA

CETG

apo B

MTP

Insulina (-)

INSULINO-RESISTENZA E VLDL

VLDL1

VLDL2

LPL (±)

*Mancata soppressione della produzione di VLDL1 da parte dell’insulina con accumulo di queste particelle

Mod. da Taskinen, Diabetologia 2003

LDL particle sizeEffect of insulin sensitivity and

type 2 diabetes

19.5

20

20.5

21

21.5

nm


**

*p<0.05**p<0.01vs insulin sensitive


*

INSULINO-RESISTENZA ELDL PICCOLE E DENSE

VLDL

Chilomicroni

TRLelevate

LDLricchein TG

LE

CETGCETP

CE

Profilo delle LDL

al GGE

TGPattern A

LDLpiccolee dense

Pattern B

Lahdenperä S, Tesi PhD, 1996

HDL particle sizeEffect of insulin sensitivity and

type 2 diabetes

8

8.25

8.5

8.75

9

9.25

nm


**

*p<0.01vs insulin sensitive


INSULINO-RESISTENZA E HDL PICCOLE E DENSE

HDL piccolee dense

FegatoVLDL

LP ricchein TG

CE

LE

(mod. da Sivänne e Taskinen, Lancet, 1997)

B 48

Tg

B 48

TgCol

TgCol

TgCol

B 48

B 48

C

E

LE

LPL

Intestino

Ulteriore lipolisi TgScambi lipidi con HDLCaptazione recettoriale

Modulazione dei “remnants”Captazione recettoriale

Ulteriore captazione recettoriale

METABOLISMO DI CHILOMICRONI E VLDL(A. A. Rivellese, L. Patti. Modificato da Karpe et al, J Clin Invest, 1993)

CHILOMICRONISf

Lipolisi dei Tg mediata dalla LPLApolipoproteine C ed E da HDL

400

B 100

B 100

VLDL1

Fegato

60

20

12

0

B 100

B 100

VLDL2

IDL

LDL

Atherogenesis: a Postprandial Phenomenon

D. B. ZilversmitCirculation 60, 1979

Quesiti1 Entità delle alterazioni della lipemia postprandiale

nel diabete tipo 22 Presenza di alterazioni anche in diabetici con buon

controllo glicemico e normotrigliceridemici?Se si, quali particelle interessate?

3 Ruolo indipendente dell’insulino-resistenza nel determinismo di tali alterazioni

4 Possibilità di modulare la lipemia postprandiale

Dieta Interventi farmacologici

Plasma triglyceride daily profile in type 2 diabetic patients and controls (4 days , mean±SEM)

diabetics n=145 controls n=30

250

*

**

** **°

*° *° *° *° *°

200

mg/

dl

150

*p<0.0001 vs fasting°p<0.0001vs non diabetics

100

Fasting Before lunch

2 hrs after

3 hrs after

2 hrsafter

3 hrsafter

Beforedinner

Iovine et al. , Diabetologia, 2004

Postprandial triglycerides (3 hours after lunch) byfasting triglyceride levels

after

lunc

h

<1.69

>1.69

100

% p

artic

ipan

ts

0

20

40

60

80

TG 3h

TG Fasting

mmol/l<1.69>1.69

Iovine et al. , Diabetologia, 2004







Incremental AUC of large VLDL after a standard meal

0

400

800

1200

1600

2000

2400

* p<0.05 vs. control

0

200

400

600

800

1000

diabetescontrol

0

2

4

6

8

10

0

20

40

60

80

100

* *

*

mg/

l ⋅hµm

ol/l ⋅

h

µmol

/l ⋅h

mg/

l ⋅h

Triglycerides

Apo B-100Apo B-48

Cholesterol

*

Rivellese et al. JCEM 2004







Glucose infusion rate

0

2

4

6

8

10

12

14

16

18

0 1 2 3 4 5 6

controls diabetes

Glu

cose

infu

sion

rate

(mg

/ kg

b.w

. / m

in)

mealhours

p<0.01 at all time points

Incremental AUC of large VLDL after a standard meal eaten during a hyperinsulinemic glycemic clamp

0

400

800

1200

1600

2000

2400

0

200

400

600

800

1000

diabetescontrol

0

2

4

6

8

0

20

40

60

80

* *

*

mg/

l⋅6h

µmol

/l⋅6h

µmol

/l⋅6h

mg/

l⋅6h

Triglycerides

Apo B-100Apo B-48

Cholesterol

Annuzzi et al. ATVB 2004* p<0.05 vs. control

INSULINO-RESISTENZA E LIPEMIA POST-PRANDIALE

Chilomicroni

Chilomicroni remnants

VLDL 1

LPLLipoproteinericche in TG

FEGATO

INTESTINO

Deficitβ-cellulare

Obesità DiabeteInsulino-

resistenza

Alterazioni lipidiche

Metabolismo dei lipidi esogeni

Intestino

Remnants chilomicroni

RecettoreRemnant

Fegato

Tessuto adiposo

Muscolo

IDL

VLDL grandi

VLDL piccole

RecettoreLDL

LDLLDL

LPLLPLLipasiLipasiepaticaepatica

LPL

Trigliceridi e colesterolo alimentari

ateromaChilomicroni

FFA

Metabolismo dei lipidi endogeni

Aims of the studyTo study postprandial dyslipidemia in type 2 diabetes

evaluating

1. the role of insulin resistance (comparing obese subjects with and without type 2 diabetes vs. non-diabetic normal-weight controls)

2. the additional effect of diabetes per se (comparing obese diabetic vs. only obese)

3. the role of adipose tissue LPL

Characteristics of the subjects

48 ±943 ±1133 ±4HDL cholesterol (mg/dl)

75 ±27100 ±37104 ±26Plasma triglycerides (mg/dl)

5.2 ±0.25.2 ±0.56.5 ±1.5HbA1c (%)

162 ±25186 ±36170 ±22Plasma cholesterol (mg/dl)

90 ±988 ±15130 ±36Blood glucose (mg/dl)

83 ±4113 ±7112 ±8Waist circumference (cm)

24 ±134 ±333 ±2Body mass index (kg/m2)

38 ±846 ±948 ±8Age (years)

10109Male, n.

ControlsObeseDiabetic obese

M ± SD; *p<0.05 ANOVA

*

*

*

*

*

*

Experimental procedures

• Test meal(potato gateau: 944 kcal, 57% fat, 31% CHO, 12% protein)0-6 hrs serial plasma samples

• Abdominal subcutaneous adipose tissue needle biopsySix hrs after meal and, on a different day, in the fasting condition.

• Hyperinsulinaemic euglycaemic clamp2 hrs insulin infusion: 1.5 mU / kg b.w. / min

Insulin sensitivity evaluated by euglycaemichyperinsulinaemic clamp

0123456789

10

mg/

kg p

.c./m

in

M±SEM; *p<0.001 (ANOVA)

M value *

Diabetic Obese ControlsObese

0

2

4

6

8

10

12M / I *


Plasma glucose

0

20

40

60

80

100

120

140

160

0 2 4 6hours

mg/

dl

Plasma insulin

meal

0

10

20

30

40

50

60

70

0 2

mU

/lmeal

*

4 6hours


*Incremental AUC p<0.05 (ANOVA)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

0 2 4 6 hours

Cholesterol §

meal

mg/

dl


*

Chylomicrons (Sf >400)

0

5

10

15

20

25

30

35

0 2 4 6

Triglycerides §

meal

mg/

dl

*

0

0.1

0.2

0.3

0 2 4 6

Apo B-48

mg/

L

meal

*

0

0.5

1

1.5

0 2 4 6

mg/

L

hours

Apo B-100

meal

§ Incremental AUC p<0.05 (ANOVA); *p<0.05 vs. Obese

0

20

40

60

80

100

0 2 4 6

Triglycerides §

meal

mg/

dl

*

0

3

6

9

12

15

0 2 4 6 hoursmeal

mg/

dl

Cholesterol §ControlsObeseDiabetic obese

*

Large VLDL (Sf 60-400)

0

0.5

1

1.5

2

2.5

0 2 4 6

Apo B-48

mg/

L

meal

0

10

20

30

40

0 2 4 6 hours

Apo B-100 §

meal

mg/

L *

§ Incremental AUC p<0.05 (ANOVA); *p<0.05

Adipose tissue LPL heparin-released activity

0

50

100

150

200

250

300

nmol

FA/g

a.t.

/h

Fasting*

Diabetic Obese Controlsobese

Postprandial*


0

50

100

150

200

250

300


Adipose tissue LPL mRNA

0

0.2

0.4

0.6

0.8

1

Arb

itrar

yU

nits

Fasting *


Postprandial


0

0.2

0.4

0.6

0.8

1


Espressione della lipasi ormone sensibile (HSL) nel tessuto adiposo

Controlli

Obesi

Obesi-diabetici

---

0

0,2

0,4

0,6

0,8

1

1,2

post-prandiale

0

0,2

0,4

0,6

0,8

1

1,2

digiuno

HS

L /g

apdh

HS

L / g

apdh

M±SEM

P= 0.06

mRNA

Conclusions

• In the postprandial phase large VLDL are increased in the insulin resistant conditions of obesity with and without diabetes. This increase is therefore likely related to insulin resistance.

• Diabetes per se, independently of obesity and insulin resistance, also shows an increased postprandial chylomicron response.

• The increased postprandial chylomicrons could be the consequence of the reduced adipose tissue LPL activity observed in the diabetic patients.

Alterazioni lipoproteiche nell’obesità e nel diabete tipo 2

↓ insulina postprandiale → ↓ LPL t. adiposo

SiNo↑ Chilomicroni

IR → aumento secrezione

SiSi↑ VLDL postprandiali

IR → aumento CETP e HL

SiSi↑ LDL e HDL piccole e dense

IR → aumento secrezione

SiSi↑ VLDL a digiuno

Possibile meccanismoDiabeteObesità

Alterazione

LIDO Study Investigators

• Naples UnitA.A. RivelleseG. RiccardiG. Annuzzi R. GiaccoC. De Natale

• LabL. PattiL. Di MarinoP. Cipriano

• Roma UnitR. MasellaC. SantangeloC. GiovanniniM. D’Avanzo

• Subject recruitmentS. TurcoG. Saldalamacchia

• ImmunologyM. Viora

• ResidentsV. MinervaL. BozzettoMR Galeotalanza

• ImagingM. ManciniG. ClementeFisica

Relation between insulin sensitivity and postprandial large VLDL triglyceride

R2 = 0.2554

1

100

0.1 1 10 100

M/I ratio

Incr

emen

t al A

UC

TG

Relation between adipose tissue LPL activity andpostprandial chylomicron triglycerides

R2 = 0.261

0.5

1

1.5

2

2.5

3

100 100000

Heparin releasable LPL (µmol FA/kg fat mass/h)

Incr

emen

t al A

UC

TG

Potential “confounders” in the assessment ofpostprandial lipemia in diabetic patients

• Fasting triglyceridemia

• Blood glucose control

• Overweight / insulin resistance

• Type of meal challenge

• Type of postprandial lipid evaluation

Main characteristics of the subjects participating in the study

Type 2 diabetes Controls

(n=7) (n=5)

Age (years) 49 ±7 48 ±4

Body mass index (kg/m2) 28 ±4 25 ±4

Plasma cholesterol (mg/dL) 183 ±32 190 ±15

Plasma triglycerides (mg/dL) 92 ±31 78 ±9

HDL-cholesterol (mg/dL) 44 ±12 55 ±10

HbA1c (%) 6.2 ±0.2 -(M±SD)

Rivellese et al. JCEM, 2004

0

10

20

Plas

ma

Insu

linµU

/mL

30

40

0 2meal

4 6

0 20

40

80

mg/

dLB

lood

120

160G

luco

se

4 6

diabetes control

hours

Rivellese et al., JCEM , 2004

Factors potentially responsible of postprandial dyslipidemia in type 2 diabetes

• Hyperglycemia• Hyperinsulinemia• Insulin resistance

Plas

ma

insu

lin(p

icom

ol/l)

meal

controls diabetes

Blo

odgl

ucos

e(m

mol

/l)

0

200

400

600

800

1000

-2

*

* p<0.05 vs. control

10

8

6

4

2

06 hours-2 -1 0 1 2 3 4 5

hours-1 0 1 2 3 4 5 6

Annuzzi et al. ATVB 2004

Possible mechanisms of postprandial TRL abnormalities in type 2 diabetes

• Slower lipolysis for the competition betweenchylomicrons and hepatic VLDL (↓ insulinsuppression of VLDL secretion and/or ↑chylomicron secretion)

• ↓ LPL activity

• ↓ hepatic clearance of remnants

Lipoprotein lipase plasma activity

0

5

10

15

20

25

-2 0 2 4 6

LPL

activ

ity(n

anoM

FA

/ml/m

in)

control diabetesmeal

p<0.05

hours0

20

40

60

80

100

Post-heparin LPL(6 h after meal)

nMFA

/ml/ m

in

Pre-heparin LPL


Background

• Postprandial lipoprotein abnormalities are more frequent in type 2 diabetes

• In type 2 diabetes these abnormalities are- observed in the presence of normal fasting

triglyceridemia,- concern lipoproteins of both exogenous and endogenous origin,

- associated with insulin resistance. • It is not clear

- if diabetes per se independently of insulin resistance induces postprandial lipid abnormalities

- the role of adipose tissue, particularly of LPL


hours

Cho

lest

erol

meal

0

5

10

15

20

25

30

35

0 2 4 6

Trig

lyce

rides

mg/dl

0

2

4

6

8

mg/

dl•6

h

Incremental AUC

mg/

dl•6

hIncremental AUC

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

0 2 4 6

0

30

60

90

120

150

*

*


M±SEM; * p<0.05 vs. Obese

hours

Apo

B-1

00

meal

0

0.1

0.2

0.3

0.4

0 2 4 6

Apo

B-4

8

mg/L

0

1

2

3

mg/

dl•6

h

Incremental AUC

mg/

dl•6

hIncremental AUC

0

0.5

1

1.5

2

0 2 4 6

0

0.5

1



hours

Cho

lest

erol

meal

0

20

40

60

80

100

0 2 4 6

Trig

lyce

rides

mg/dl

0

5

10

15

20

25

30

mg/

dl•6

h

Incremental AUC

mg/

dl•6

hIncremental AUC

0

3

6

9

12

15

0 2 4 6

0

50

100

150

200

ANOVA p<0.05

ANOVA p<0.05




hours

Apo

B-1

00

meal

0

0.5

1

1.5

2

2.5

3

0 2 4 6

Apo

B-4

8

mg/L

0

20

40

60

80

100

mg/

dl•6

h

Incremental AUC

mg/

dl•6

hIncremental AUC

0

10

20

30

40

0 2 4 6

0

2

4

6

8

10


Relation between insulin sensitivity and postprandial large VLDL triglyceride

R2 = 0.1763

0

0.5

1

1.5

2

2.5

3

3.5

4

0 1 2 3

Ln M/I ratio

LnIA

UC

TG

lar

g e V

LDL

Small VLDL (Sf 20-60)

hours

Cho

lest

erol

meal

02468

101214161820

0 2 4 6

Trig

lyce

rides

mg/dl

-12

-9

-6

-3

0

3

mg/

dl•6

h

Incremental AUC

mg/

dl•6

hIncremental AUC

0

2

4

6

8

10

0 2 4 6

-20

-15

-10

-5

0

5

10

ANOVA p<0.05

ANOVA p<0.05


hours

Apo

B-1

00

meal

0

0.2

0.4

0.6

0.8

1

0 2 4 6

Apo

B-4

8

mg/L

-20

-10

0

10

20

30

mg/

dl•6

h

Incremental AUC

mg/

dl•6

hIncremental AUC

0

10

20

30

40

0 2 4 6

-0.5

0

0.5

1

1.5



Adipose tissue LPL heparin-released activity

0

50

100

150

200

250

300

nmol

FA/g

a.t.

/h

Fasting*


Postprandial*


0

50

100

150

200

250

300


Relation between heparin releasable LPL activity andpostprandial chylomicron triglycerides

R2 = 0.2632

0

0.5

1

1.5

2

2.5

3

0 2000 4000 6000 8000 10000 12000

Heparin releasable LPL (nmol FA/fat mass/h)

LnIA

UC

TG

chy

lom

icro

n s

Adipose tissue LPL total activity

0

1000

2000

3000

4000

5000

6000

nmol

FA/g

a.t.

/h

Fasting


Postprandial *


0

1000

2000

3000

4000

5000

6000


Adipose tissue LPL mRNA

0

0.2

0.4

0.6

0.8

1

Arb

itrar

yU

nits

Fasting *


Postprandial


0

0.2

0.4

0.6

0.8

1


Conclusions

• A similar postprandial increase of large VLDL is observed in the insulin resistant conditions of obesity with and without diabetes and is therefore likely related to insulin resistance.

• Diabetes per se, independently of obesity and insulin resistance, also shows an increased postprandial chylomicron response.

• The increased postprandial chylomicrons could be the consequence of the reduced adipose tissue LPL activity observed in the diabetic patients.

0

100

200

300

400

500

600

700

-2 -1 0 1 2 3 4 5 6

controls diabetes

hoursmeal

†

Pl٭٭٭as

ma

FFA

(µm

ol/l)

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

0 100 200 300 400 5006 hrs Plasma FFA (µmol/l)

L arg

eV L

DL

trig

l yce

rides

(mm

ol/ l)

r=0.88p<0.001

* p<0.05, † p<0.001 controls. Annuzzi et al. ATVB 2004

Plasma FFA

0

10

20

30

40

50

60

70

0 2 4 6hours

mic

roM

/l

*-150

-100

-50

0

50

meal

Incremental AUC

* p<0.05 ANOVA

Substrates oxidation

hoursmeal

0

1

2

3

4

5

6

0 2 3 5 6

CH

O

-5

-2.5

0

2.5

5

7.5

10

g/kg

FFM

l•6h

Incremental AUC0

0.5

1

1.5

2

2.5

0 2 3 5 6

-5

-2.5

0

2.5

5

7.5

10 p=0.046

p=0.003

g/kg

FFM

•6h

p=0.02g/kg FFM/die

Lipi

ds

Adiponectin mRNA in adipose tissue

0

0.5

1

1.5

2

2.5

3Fasting Postprandial

Diabetic Obese Obese

A.U

.

Diabetic Obese Obese

M ± SEM

Adiponectin mRNA in adipose tissue before and after the meal

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

fasting postprandial

p=0.028

A.U

.

Lipoprotein lipase and hepatic lipase activities in post-heparinplasma 6 hours after a standard meal consumed during a

hyperinsulinemic glycemic clamp.

0

20

40

60

80

100

controldiabetes

Lipoproteinlipase

nMFA

/ml/ m

i n

0

50

100

150

200

250

300

Hepaticlipase

nMFA

/ml/ m

i n

p<0.05


Post-prandial Triglycerides, apo-B48, apo-B100 of total Triglyceride rich lipoproteins.

Waist < 90 cm; TG < 2.00 mmol/l

Waist > 90 cm; TG < 2.00 mmol/l

Waist > 90 cm; TG > 2.00 mmol/l

(P. Blackburn, Atherosclerosis 2003)

Incremental AUC of plasma chylomicrons after a standard fat-rich meal

0

50

100

150

200

0

2

4

6

8

10

diabetescontrol

0

0.1

0.2

0.3

0.4

0.5

0

0.2

0.4

0.6

0.8

1

mg/

l ⋅6h

µmol

/l ⋅6h

µmol

/l ⋅6h

mg/

l ⋅6h

Triglycerides

Apo B-100Apo B-48

Cholesterol

Rivellese et al. JCEM, 2004

Incremental AUC of plasma chylomicrons after a standard meal eatenduring a hyperinsulinemic glycemic clamp

0

500

1000

1500

2000

2500

3000

050

100150200250300350400

diabetescontrol

0

1

2

3

4

5

-0.2

-0.1

0

0.1

0.2

mg/

l ⋅hµm

ol/l ⋅

h

µmol

/l ⋅h

mg/

l ⋅h

Triglycerides

Apo B-100Apo B-48

Cholesterol


Plasma Chylomicrons (Sf>400)

0

0.2

0.4

0.6

0.8

1

-2 0 2 4 6

Triglycerides

mm

ol/l

*

mealhours

0

0.02

0.04

0.06

0.08

-2 0 2 4 6

Cholesterol

mealhours

* **

0

0.1

0.2

0.3

-2 0 2 4 6

controls diabetes

0

0.05

0.1

-2 0 2 4 6

mg/

l

Apo B48 Apo B100

hours hours

meal meal



0

0.2

0.4

0.6

0.8

1

-2 0 2 4 60

0.04

0.08

0.12

0.16

-2 0 2 4 6

Triglycerides Cholesterol

meal

mm

ol/l

meal

*

**

*

*

**

* *

hours hours

0

1

2

3

-2 0 2 4 6

controls diabetes

0

5

10

15

20

25

30

-2 0 2 4 6hours hours

mg/

l

Apo B48 Apo B100

meal meal

**

*

* p<0.05 vs controls Annuzzi et al. ATVB 2004

Plasma C-peptide

0

2

4

6

8

10

-2 -1 0 1 2 3 4 5 6

Plas

ma

C-p

eptid

e(n

mol

/l)

***

hours

meal

controls diabetes

* p<0.05 vs. controlsAnnuzzi et al. ATVB 2004

Adipose tissue HSL mRNA

0

0.2

0.4

0.6

0.8

1

1.2

Arb

itrar

yU

nits

Fasting Postprandial



0

0.2

0.4

0.6

0.8

1

1.2

Aims of the study

To evaluate postprandial lipemia and the role of adipose tissue LPL in obese subjects with type 2 diabetes

compared with

- non diabetic subjects similar for degree of obesity and normal fasting triglyceride levels, and

- non diabetic normal weight controls.

41st EASD Annual Meeting, Athens

Abnormal postprandial chylomicron response and decreased adipose tissue lipoprotein lipase activity in type 2 diabetes are independent of

insulin resistance

G. Annuzzi, R. Giacco, L. Patti, L. Di Marino, C. Santangelo, C. De Natale, V. Minerva, R. Masella, G. Riccardi, A.A. Rivellese

Dept of Clinical and Experimental Medicine, Federico II University, Naples, Italy

• Postprandial lipoprotein abnormalities are more frequent in type 2 diabetes

• In type 2 diabetes these abnormalities- are observed in the presence of normal fastingtriglyceridemia,- concern lipoproteins of both exogenous andendogenous origin,- are associated with insulin resistance.

• It is not clear - if diabetes per se independently of insulin resistance

induces postprandial lipid abnormalities- the role of adipose tissue, particularly of LPL

Characteristics of the subjects

48 ±943 ±1133 ±4HDL cholesterol (mg/dl)

75 ±27100 ±37104 ±26Plasma triglycerides (mg/dl)

5.2 ±0.25.2 ±0.56.5 ±1.5HbA1c (%)

162 ±25186 ±36170 ±22Plasma cholesterol (mg/dl)

90 ±988 ±15130 ±36Blood glucose (mg/dl)

83 ±4113 ±7112 ±8Waist circumference (cm)

24 ±134 ±333 ±2Body mass index (kg/m2)

38 ±846 ±948 ±8Age (years)

10119Male, n.


M ± SD; *p<0.05 ANOVA

*

*

*

*

*

*

Experimental procedures

• Test meal(potato gateau: 944 kcal, 57% fat, 31% CHO, 12% protein)0-6 hrs serial plasma samples for cholesterol, triglyceride, apo B48,apo B100 in lipoproteins (chylomicrons, VLDL Sf 60-400, VLDL SF 20-60, IDL, LDL, HDL)

• Abdominal subcutaneous adipose tissue needle biopsySix hrs after meal and, on a different day, in the fasting condition.

• Hyperinsulinaemic euglycaemic clamp2 hrs insulin infusion: 1.5 mU / kg b.w. / min

Insulin sensitivity evaluated by euglycaemichyperinsulinaemic clamp

0123456789

10

mg/

kg p

.c./m

in


M value *


0123456789

10M / I *



Plasma glucose

0

20

40

60

80

100

120

140

160

0 2 4 6hours

mg/

dl

Plasma insulin

meal

0

10

20

30

40

50

60

70

0 2

mU

/l

meal

*

4 6hours

*Incremental AUC p<0.05 (ANOVA)

0

5

10

15

20

25

0 2 4 6

Triglycerides §

meal

mg/

dl

* *

0

3

6

9

12

0 2 4 6 hoursmeal

mg/

dl

Cholesterol §


* * * *


0

0.3

0.6

0.9

1.2

0 2 4 6

Apo B-48

mg/

L

meal

*

0

10

20

30

40

50

0 2 4 6 hours

Apo B-100

meal

mg/

L* * * *

§ IAUC p<0.05 (ANOVA); *p<0.05

mg/

dl•6

h

0

30

60

90

120

150 *

Trig

lyce

rides

0

2

4

6

8

mg/

dl•6

hC

hole

ster

ol

mg/

L•6h

0

0.2

0.4

0.6

0.8

Apo

B-4

8

0

1

2

3

mg/

L•6h

Apo

B-1

00

M±SEM; * p<0.05 vs. Obese

*

ControlsObeseDiabetic obeseIncremental AUC of Chylomicrons

after a standard meal

0

50

100

150

200

0

5

10

15

20

25

30

0

2

4

6

8

0

20

40

60

80

100

mg/

dl•6

h

mg/

dl•6

h

mg/

L•6h

mg/

L•6h

M±SEM; * p<0. 05 (ANOVA)


Trig

lyce

rides

Cho

lest

erol

Apo

B-4

8

Apo

B-1

00

* *

Incremental AUC of Large VLDL after a standard meal

ControlsObeseDiabetic obeseIncremental AUC of Small VLDL

after a standard meal

-20

-15

-10

-5

0

5

10

-10

-5

0

5

0

1

2

3

4

-10

0

10

20

30

40

50

mg/

dl•6

h

mg/

dl•6

h

mg/

L•6h

mg/

L•6h

M±SEM; * p<0. 05 (ANOVA)

Trig

lyce

rides

Cho

lest

erol

Apo

B-4

8

Apo

B-1

00

Plasma basal LPL activity

0

5

10

15

20

25

0 2 4 6

mg/

dl•6

h

Incremental AUC-10

0

10

20

30


meal

nano

MFA

/ml/m

in

Plasma FFAControlsObeseDiabetic obese

0

10

20

30

40

50

60

70

0 2 4 6

µmol

/L

µmol

/L•6

h

Incremental AUC-120

-100

-80

-60

-40

-20

0

meal

Adipose tissue LPL total activity

0

1000

2000

3000

4000

5000

6000

nmol

FA/g

a.t.

/h

Fasting


Postprandial *


0

1000

2000

3000

4000

5000

6000


Aims of the study

To evaluate postprandial lipemia and the role of adipose tissue LPL in obese subjects with type 2 diabetes

compared with

- non diabetic subjects similar for degree of obesity and normal fasting triglyceride levels, and

- non diabetic normal weight controls.

Postprandial dyslipidemia in diabetes

Clinical entity

DIABETE TIPO 2 E LIPEMIA POST-PRANDIALE

Chilomicroni

Chilomicroni remnants

VLDL grandi

LPL(riduz. rel.)

INTESTINO

FEGATO

Lipoproteinericche in TG

A. A. Rivellese, L. Patti

Date post:	11-Nov-2018
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