Pathogenesis of the Metabolic Syndrome Prof. Richard N ...* p < 0.05, vs. week 0 p = n.s. p = n.s....

Pathogenesis

of the Metabolic Syndrome

Prof. Richard N. Bergman

The screen versions of these slides have full details of copyright and acknowledgements 1

1

Pathogenesis


Richard N. Bergman, PhD

Keck Professor of Medicine

University of Southern California

Los Angeles, California

USA 90033

2

≥ 65% ββββ -cell defect

Defective ββββ -cellsNormal ββββ -cells

Insulin resistan ce

Genetic predisposition Env ironmental factors

Metabolic syndrome and type 2 diabetes

Obesity

Type 2 diabetes

Hyperinsu lin emia

with normal glucose tolerance

Impaired glucose tolerance

“Metabolic syndrome”

3

Evolution of man

+ ====

Pathogenesis




4

22,000–28,000 BC

France

246 BC

China

Visceral adiposity is not new

5

Other possible causes of increased obesity (besides fast food and reduced exercise)

• Mean age of US mothers at first birth

• Antidepressants

• Prevalence of air conditioning

• Proportion of US adult population that is Hispanic

• Aging population

• Time spent awake

• Reduction in smoking

From Keith SW et al., Int. J. Obes., 2006

6Jee SH et al., N. Engl. J. Med., 2006, Aug. 24, 355(8): 779-87

Risk of obesity

Pathogenesis




7

Glu

co

se

dis

po

sal

rate

(m

g/k

Jo

ule

)

Effect of obesity(Lillioja and Bogardus, 1988)

Percent body fat

0 20 40 600

20

40

60

80

100

8

Female,

Age 41, BMI 49.5

W C: 118 cm

VAT volume: 559 cm3

SAT volume: 11,658 cm3

Male,

Age 40, BMI 54.4

W C: 142 cm

VAT volume: 3162 cm3

SAT volume: 9158 cm3

Courtesy of Dr Anne Sumner, NIDDK

Variability of VAT among obese subjects

Variability of VAT among obese subjects

9

Hyperinsulinemia

Insulin resistance

Hypertension

Diabetes

CVD

Colon,

breast,

prostate

cancer

Glucose

intolerance

The “metabolic syndrome”

Visceral

adiposity

Pathogenesis




10

The metabolic syndrome: time for a critical reappraisal

Kahn R., Buse J., Ferranini E. and Stern M., Diabetes Care, 28: 2289, 2005

11

“Syndrome X”“Metabolic xyndrome”

• Visceral and subcutaneous adiposity associated with:

– Hepatic insulin resistance

– Peripheral insulin resistance

– Elevated FFA

– Adipokines

– Hyperinsulinemia

“Metabolic syndrome”

12

What are the events in the pathogenesis

of the metabolic xyndrome?

Pathogenesis




13

Adiposity (visceral, subcutaneous)

Inactivity

Infection

Puberty

Pregnancy

PCOS

Insulin resistan ce

Liver and periphery

Increased insulin secretion

Reduced insulin clearance

Hyperinsu lin emia

Glucose intolerance

Mitigated!!

?

14

Animal models

Genetic

HomologyAdvantagesModel

~75% GeneticsMouse

~90%Longitudinal studies

Portal accessDog

100% The real dealHuman

~95% Primate modelMonkey

~85% Physiological measuresRat

15

Landmark (umbilicus)

Visceral and subcutaneous adiposity in the fat-fed dog model

Total trunk fat

Pathogenesis




16

“Overflow” hypothesisAnimals at basal sorted by body fat

17

Lean

Intervention

Hepatic resistan ce

Hepatic + peripheral

resistance

Visceral depot

Peripheral depot

“Overflow hypothesis”

18

* p < 0.05, vs. week 0

p = n.s.

p = n.s.

Sequelae of IIFD (isocaloric higher fat)

Adiposity

0 6 12

Weeks on diet

0

50

100

150

Fa

t v

olu

me

(c

m3)

*

*

Omental fat Subcutaneous fat

0 6 12Weeks on diet

0

10

20

30

40

We

igh

t (k

g)

Body weight

Pathogenesis




19

Adipocyte size distribution - control diet

20

Adipocyte size distribution - high fat diet

21

Isoproterenol-stimulated lipolysis - high fat diet

Pathogenesis




22

Temporal primacy of the liver in insulin resistance

Peripheral tissuesLiver

mg

/kg

/min

Euglycemic glucose clamps at 0, 6 and 12 weeks

of moderate fat feeding

Time (min)Time (min)

-30 0 30 60 90 120 150 1800

5

10

15

20

Week 0 Week 6 Week 12

23

Resistant l iverVisceral fat

FFAPEPCK

G6Pase

SREBP1

FABP

Changes in gene expression with visceral adiposity in the dog

PPARγ

SREBP-1

HSLLPL

TNF-α

IL-6

Leptin

Adiponectin

24

Superior mesenteric and celiac arteries

Portal drainage

Visceral fat

Visceral fat depot

Pathogenesis




25

Visceral lipolysis is pulsatileA-V difference across the central depot

L. Getty et al.

26

Effect of beta3-blockade (bupranolol) on bursts of FFA release:

Beta3-blockade

0 . 1

0 . 2

0 . 3

0 . 4

0 . 1

0 . 2

0 . 3

0 . 4

FF

A r

ele

as

e [

mM

/min

]

0 . 1

0 . 2

0 . 3

0 . 4

0 . 1

0 . 2

0 . 3

0 . 4

0 . 1

0 . 2

0 . 3

0 . 4

0 . 1

0 . 2

0 . 3

0 . 4

Saline control

K. Hücking et al., J. Clin. Invest. 111: 257-264 (2003)

27

“Constitutive lipolysis”GH

TSH, PTH

ANP

Glucocorticoids

“Intrinsic”

H0000 : division of labor, SNS control of oscillatory,and hormonal control of constitutive lipolysis

“Pulsatile lipolysis”

Pathogenesis




28

Oscillatory

sympathetic input?

FFA

(+TNF-α, IL-6, adiponectin?)

Visceral

fat

Flux of FFA to the liver

• Increased visceral adiposity

• Increased turnover of omental depot

• Extreme insulin resistance of central adipocytes

• Oscillatory sympathetic activation

29

-2 0 2 4 620

25

30

35

**

* * * *

Weeks on diet

Bo

dy

we

igh

t (k

g)

Week 0 Week 60

250

500

750

1000

*

*

+110%

+115%Omental

SubQ

Bo

dy

fat

(cm

3)

High fat diet

30

Liver histology

Pre-fat 6 wks HF

Pathogenesis




31

Hi fat diet: hepatic and peripheral insulin resistance

0 100 200 300 400 500

Plasma insulin (pM)

0

2

4

6

8

10

12

14

Glu

co

se u

pta

ke (

mg

/min

/kg

)

Skeletal muscle insulin resistance

Week 0:

Slope = 0.028 ± 0.006

Week 12:

Slope = 0.016 ± 0.002 (p = 0.04)

-39 ± 6% (p = 0.039)

32

Peripheral insulin resistance

Role of hemodynamics?

33

Insulin inj ection

Interstitial fluid

First-phase insulin

maximizes the rate

of increase

in interstitial insulin

and glucose disposal

Pathogenesis




34

Putative delay

in insulin action:

time to cross

the endothelial barrier

35

Setup

Insulin

Artery Venous

Lymph

Cellular

degradation

36

D

E

F

Net

fem

ora

l art

ery

in

sulin

(pm

ol/L)

Net

fem

ora

l vein

in

sulin

(pm

ol/L)

Net

lym

ph

insulin

(pm

ol/L)

Pathogenesis




37

Insulin sensitivity

Comparing whole body and local insulin sensitivity

Figure 4: 1Adapted from Ader et al., Diabetes (41), 1992; 2Adapted from Laakso et al., JCI (85): 1990;

ED50 estimated from lymph insulin using a whole body glucose clamp is 240pM,

suggesting that tissues are twice more sensitive

than previously indicated based on plasma insulin levels (480pM); Targeting skeletal muscle locally,

ED50 based on lymph measurements is 120pM, which suggests that skeletal muscle itself

is 4x as sensitive as that previously reported

from whole body techniques

Whole body

ED50

Local

ED50

Plasma 1480pM

Infused

2420pM

Infused

Lymph 1240pM

Infused

120pM

Inj ected

38

Ste

ad

y s

tate

in

su

lin

(p

M)

0

100

200

300

500

Insulin V1 V3V2

400

Dis

trib

uti

on

vo

lum

e (

ml/

kg

)

0

50

100

200

150

Ste

ad

y s

tate

in

su

lin

(p

M)

0

100

200

300

500

Insulin V1 V3V2

400

Dis

trib

uti

on

vo

lum

e (

ml/

kg

)

0

50

100

200

150

Access is reduced with fat-diet obesity,accounting for up to 50%

of insulin resistance

W ith obesity

Distribution of insulin with obesity

Muscle,adipose tissue

Blood

Liv er,GI tract

+++++

+

+++

n.s.

Fat fed

Lean

Fat fed

39

Transendothelial insulin transport (TET)

Rate limiting for glucose uptake Rate limiting for glucose uptake

by skeletal muscle by skeletal muscle in vivoin vivo

Defect in endothelial transport

of insulin may account

for as much as 50% of insulin

resistance in fat diet-induced obesity

Pathogenesis




40

I: Basal

III: ββββ -cell compensation

II: Uncompensated resistance

IV: Reduced insulin clearance

I II III IV

0

12

3

45

6

Sen

sit

ivit

y

0

1000

2000

3000

4000

Secre

tio

n

Basal 1–2 3–4 5–6 7–8 9–10 11–12

W eeks

0

Fra

cti

on

al cle

ara

nce

0.50

0.40

0.30

0.20

0.10

I: Basal

41

Increased fasting glycemia

and/or impaired

glucose tolerance

Causeof hyperinsulinemia?

Conventional wisdom:

Hyperinsulinemia

(increased secretion,

reduced clearance)

Insulin resistance

42

0

100

200 * * *

0 2 4 60

100

200

Weeks on diet

Fasting insulin

% W

ee

k 0

0

100

200

* * * *

Fasting glucose

% W

ee

k 0

Fasting FFA

% W

ee

k 0

↓↓↓↓ Insulin sensitivity

↑↑↑↑ Fasting glucose

Impaired glucosetolerance

↑↑↑↑ Fasting FFA

↑↑↑↑ Insulin secretion

Hyperinsu lin emia

Pathogenesis




43

In the normal animal, insulin resistance due to eucaloric high fat diet,

or hypercaloric high fat diet, is not associated with increases in fasting glucose or FFA

Therefore neither basal glucose nor FFA

can be a signal for compensatory hyperinsulinemia, secondary

to increased secretion/decreased clearance

What is the signal?

44Constancy of fasting glucose in the face of hyperinsulin emia

What is the signal for β-cell compensation for insulin resistance?

Possible signals:

• Fasting glucose, FFA

• 24-hour glucose, FFA

(postprandial, nocturnal)

• GLP-1 and/or other

gut peptides

• Glucocorticoid s

• Growth hormone

• Central nervous system?

45

Meal12-hour light/dark

• Dogs brought up to laboratory at 5AM

• Each animal housed within a kennel for duration

of the experiment

• Blood samples taken at 1-hr intervals starting at 6AM

from indwelling catheters exposed/secured at the neck

• Meal presented at 9AM and removed at 10AM

(uneaten food recorded, identical meal at wk 6)

24-hr plasma profiling

At week 0 & 6:

Pathogenesis




46

24-hr insulin

pM

W eek 0 W eek 6

AU

C

(mM

�hr)

6am 12pm 6pm 12am 6am0

100

200

300

400

Week 0

*

** * *

Week 6

0

1000

2000

3000 *

↑↑↑↑ 83%

Week 0 Week 6

476am 9 12pm 3 6pm 9 12am 3 6am

0

2

4

6

8

**

Week 0Week 6

6am 9 12pm 3 6pm 9 12am 3 6am0.0

2.0

4.0

6.0

8.0

Week 0Week 6

GH

Cortisol

GLP-1

6am 9 12pm 3 6pm 9 12am 3 6am0

2

4

GH

ng

/mL

GH

Effect of 6 weeks of fat-feeding on 24 hour measurements

µµ µµg

/dL

pM

48

Nocturnal measurements

of insulin, glucose

and FFA; Meal at 9 am

Chow diet

6 wk Hi fat diet

Pathogenesis




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Before fat

After fat

6am 12pm 6pm 12am 6am0.0

0.2

0.4

0.6

0.8

1.0 Week 0

**

*

** * *

* **

**

*

Week 6

FF

A (

mM

)

Following a high fat diet, overnight FFA are elevated

Kim et al., Am. J. Physiol. Endocrinol. Metab., Jun. 292(6), 2007

50

Liv er

Muscle

CNSPathogenesisof the metabolic

xyndrome

Pulse FFA

Pulse FFA

InsulinInsulin

Adipocyte

Pancreas

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Pathogenesis of the Metabolic Syndrome Prof. Richard N ...* p < 0.05, vs. week 0 p = n.s. p = n.s....

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Transcript of Pathogenesis of the Metabolic Syndrome Prof. Richard N ...* p < 0.05, vs. week 0 p = n.s. p = n.s....