≥ 65% -cell defect

15
≥ 65% -cell defect Defective - cells Normal -cells Insulin Insulin Resistance Resistance Genetic Predisposition Environmental Factors Obesity TYPE 2 DIABETES Hyperinsulinemia with Normal Glucose Tolerance Impaired Glucose Tolerance Figure A1.

description

Insulin Resistance. Normal  -cells. Defective  -cells. TYPE 2 DIABETES. Genetic Predisposition. Environmental Factors. Obesity. Hyperinsulinemia with Normal Glucose Tolerance. Impaired Glucose Tolerance. ≥ 65%  -cell defect. Figure A1. Minimal Model. Glucose levels. - PowerPoint PPT Presentation

Transcript of ≥ 65% -cell defect

Page 1: ≥ 65%   -cell defect

≥ 65% -cell defect

Defective -cellsNormal -cells

Insulin ResistanceInsulin Resistance

Genetic Predisposition Environmental Factors

Obesity

TYPE 2 DIABETES

Hyperinsulinemia withNormal Glucose Tolerance

Impaired Glucose Tolerance

Figure A1.

Page 2: ≥ 65%   -cell defect

Glucose injection

Insulin injection

Minimal Model

Insulin sensitivity (SI)

Β-cell response

Glucose levels

Insulin levels

Figure A2.

Page 3: ≥ 65%   -cell defect

0

2

4

6S

I

0

2000

4000

AIR

G(0

-19)

basal 1-2 3-4 5-6 7-8 9-10 11-12

Weeks on Fat

0.00

0.25

0.50

0.75

1.00

Insu

lin C

lea

ran

ce

I II III IV

I: Basal

II: Uncompensated Resistance

III: -cell Compensation

IV: Reduced Insulin Clearance

Figure A3.

Page 4: ≥ 65%   -cell defect

0 1 2 3 4 5 6 7 80

500

1000

1500

2000

2500

Week 2Week 4Week 6

Week 0

Insulin Sensitivity

Se

cre

tio

n

Figure A4.

Page 5: ≥ 65%   -cell defect

Insulin Resistance

Increased fasting glycemia

and/or impaired glucose tolerance

Cause of Hyperinsulinemia?

Conventional wisdom:

Hyperinsulinemia(Increased secretion,Reduced clearance)

Figure A4Figure A5

Figure A5.

Page 6: ≥ 65%   -cell defect

**

* * * ** * *

* * *

*

pM

Insulin

6 WKS FAT FEEDINGBASELINE

Glucose

mg

/dL

Cortisol

GLP-1

FFA

mM

pM

GH

ng

/mL

μg

/mL

0

100

200

300

** *

**

*

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

0.2

0.4

0.6

0.8

1.0

*

75

100

125

*

0.0

3.0

6.0

9.0

0.0

2.0

4.0

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

2.0

4.0

6.0

8.0

**

Figure A6.

Page 7: ≥ 65%   -cell defect

PlasmaLymph

Insulin Levels

Rd

Glucose disposal

INSULIN IN PLASMA AND INTERSTITIAL FLUID

Hand-in-glove relationship between

interstitial insulin and glucose disposal

Glu

cose

Up

take

0

2

4

6

10

0 60 240 360Time (minutes)

120 180 300

8

Lym

ph

In

suli

n (

uU

/ml)

0

10

20

30

50

40

Figure A7.

Page 8: ≥ 65%   -cell defect

GL

UC

OS

E D

ISP

OS

AL

[mg

/kg

per

min

]

Insulin injection

Plasma

Interstitial fluid

Glucose uptake

into cells

INS

UL

IN[μ

U/m

l]IN

SU

LIN

[μU

/ml]

Figure A8.

Page 9: ≥ 65%   -cell defect

0

4

8

12

16UPTAKE

0 30 60 90 120 150 180

INSULIN

3.33 mU/min per kg

Glu

cose

Flu

x (m

g/m

in p

er

kg)

Time (minutes)

0 30 60 90 120 150 180

-1

0

1

2

3

4

Glu

cose

Flu

x (m

g/m

in p

er

kg)

Time (minutes)

LIVER OUTPUT

INSULIN

3.33 mU/min per kg

HGONHGORd

Figure A9.

Page 10: ≥ 65%   -cell defect

Figure A10.

Page 11: ≥ 65%   -cell defect

GLUCOSE PRODUCTION

FFA

Transendothelial transport barrier

adipocytes

Insulin

Figure A11.

Page 12: ≥ 65%   -cell defect

*

Week 0 Week 6

Do

g 1

Do

g 2

Do

g 3

Do

g 4

Weeks on diet

Bo

dy

Wei

gh

t (k

g)

+110%

+115%Omental

SubQ

Bo

dy

Fat

(cm

3 )

-2 0 2 4 620

25

30

35

**

* * * *

Week 0 Week 60

250

500

750

1000 *

Figure A12.

Page 13: ≥ 65%   -cell defect

Resistant LiverVisceral Fat

FFAPEPCK

G6Pase

SREBP1

FABP

TNF-IL-6

Leptin

Adiponectin

PPARSREBP-1

HSLLPL

Figure A13.

Hannah Freed
Figure A13
Page 14: ≥ 65%   -cell defect

β3-blockade

Fre

e F

atty

Aci

ds

0.1

0.2

0.3

0.4

0.1

0.2

0.3

0.4

0.1

0.2

0.3

0.4

-0.05

-0.02

0.01

0.04

0.07

0.10

-0.05

-0.02

0.01

0.04

0.07

0.10

-0.08

-0.03

0.02

0.06

0.11

0.16

-0.05

-0.02

0.01

0.04

0.07

0.10

0 10 20 30 40 50 60-0.05

-0.02

0.01

0.04

0.07

0.10

0 10 20 30 40 50 60-0.08

-0.03

0.02

0.06

0.11

0.16

11 pulses

DOG 2

DOG 3

DOG 4 DOG 10

DOG 7

DOG 5

TIME (min) TIME (min)

9 pulses

8 pulses

9 pulses10 pulses

10 pulses

Figure A14.

Hannah Freed
Figure A14
Page 15: ≥ 65%   -cell defect

“Constitutive Lipolysis”GHTSH, PTHANPGlucocorticoids“intrinsic”

“Pulsatile Lipolysis”

Figure A15.

Hannah Freed
Figure A15