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Insulin stimulation index Insulin stimulation index Olle Korsgren Korsgren, MD, PhD , MD, PhD Olle Uppsala University Hospital Uppsala University Hospital Uppsala, Sweden Uppsala, Sweden the fate of an islet Inflammation

SLIDE 1

Insulin stimulation index Insulin stimulation index

Olle Olle Korsgren Korsgren, MD, PhD , MD, PhD Uppsala University Hospital Uppsala University Hospital Uppsala, Sweden Uppsala, Sweden

SLIDE 2

“the fate of an islet”

Rejection
i.s. drugs
Inflammation

IBMIR

Donor related

factors

Preservation
Isolation

Hours

Hypoxia
Glucotoxicity
Revasculariz-

ation

Insulin

5 10 15 20 25 30 35 40

Days Weeks

SLIDE 3

Expression of inflammation-related genes in human islets

I n t e r l e u k i n

p r e c u r s

( I L

) M

y t e c h e m

a c t i c p r

e i n 1 p r e c u r s

e l l

p e c i f i c r a n t e s p r

e i n p r e c u r s

T h y m

i n b e t a

( T M S B 1 ; T H Y B 1 ) I n t e r l e u k i n

1 ( I L

1 ) I n t e r l e u k i n

p r e c u r s

( I L

) I n t e r l e u k i n

r e c e p t

a l p h a s u b u n i t p r e c u r s

( M a c r

h a g e m i g r a t i

i n h i b i t

y f a c t

( M I F ) I n s u l i n

i k e g r

t h f a c t

b i n d i n g p r

e i n 2 ( I G F B P 2 N

a m ; f i b r

l a s t g r

t h f a c t

r e c e p t

1 p r e c u r s

( F G F R 1 ) P r

i b i t i n ( P H B ) E p i t h e l i a l d i s c

d i n d

a i n r e c e p t

1 p r e c u r s

( E D D R 1 ; D D R 1 ) 50 100 150 200 250 300 350 400 450 Day 1 Day 2 Day 6 Day 7 Day 11 D e l t a

i k e p r

e i n p r e c u r s

V a s c u l a r e n d

h e l i a l g r

h f a c t

p r e c u r c

( V E G F )

U Johansson et al. BBRC, 2003, 308, 474-479

SLIDE 4

Variable

r P Age (years) 0.23 0.14 ICU length (days)

0.21

0.17 Cause of death (Traumatic/Non-traumatic) 0.21 0.18 Body mass index (kg/m

0.16 0.31 Weight of pancreas (g) 0.004 0.98 Minimal glucose (mmol/l) 0.29 0.08 Maximal ALAT (U/l)

0.25

0.11 Maximal ASAT (U/l)

0.20

0.25 Maximal amylase (U/l)

0.20

0.29 Donor-related variables Maximal ALP (U/l) 0.11 0.55 Maximal CRP (nmol/l)

0.07

0.69 Maximal Creatinine (umol/l) 0.05 0.74 Maximal r-GT (U/l)

0.005

0.98 Treatment with furosemide 0.20 0.20 Treatment with mannitol 0.12 0.45 Treatment with pitressin 0.08 0.62 Treatment with steroid

0.01

0.97 Treatment with catecholamine

0.002

0.99 TF expression in pancreas biopsy

0.48

0.005 Procurement team (center 'X'/others) 0.35 0.01 Warm ischemia time (min)

0.29

0.09 Cold ischemia time (min)

0.23

0.14 Organ perfusion volume (aorta/portal) 0.06 0.72 Procurement team (local/distant) 0.04 0.81 TNFa expression in pancreas biopsy 0.32 0.08 Organ procurement-related variables IL-8 expression in pancreas biopsy

0.23

0.21 ICAM-1 expression in pancreas biopsy

0.26

0.23 IP-10 expression in pancreas biopsy

0.24

0.28 MCP-1 expression in pancreas biopsy

0.20

0.29 RANTES expression in pancreas biopsy

0.21

0.34 TGF-b1 expression in pancreas biopsy

0.19

0.39 IL-6 expression in pancreas biopsy

0.07

0.75 IL-1b expression in pancreas biopsy 0.02 0.92 Harvest starting time (min)

0.31

0.04 Transplanted islet equivalents (IEQs) 0.19 0.23 Liberase lot (efficient/non-efficient)

0.14

0.42 Isolation method (old/new) 0.13 0.42 Isolation-related variables Harvest time (min)

0.11

0.53 Mean purity of transplanted islets (%)

0.11

0.54 Stimulation index in in vitro test 0.05 0.79 Liberase amount per g of pancreas (mg/g) 0.01 0.95 Dissection time (min) 0.03 0.87 Maximal TAT (ug/ml)

0.38

0.01 Transplantation-related variables Volume of transplanted grafts (mL) 0.20 0.25 Transplanted centers (local/distant)

0.15

0.31

C-peptide/Creatinine at 2 weeks after Tx

Donor related variables Organ procurement variables Islet isolation variables Tx related variables

SLIDE 5

“the fate of an islet”

Rejection
i.s. drugs
Inflammation

IBMIR

Donor related

factors

Preservation
Isolation

Hours

Hypoxia
Glucotoxicity
Revasculariz-

ation

Insulin

5 10 15 20 25 30 35 40

Days Weeks

SLIDE 6

SLIDE 7

1. Gassing probe 2. Test tubes 3. Peristaltic pump 4. Reaction chambers 5. Collection vials 6. Collection rack

SLIDE 8

SLIDE 9

Glucose (mM)

1 4 7 10 13 16 20 40 60 80 100 120 140

1 4 7 10 13 16 min

SLIDE 10

10 20 30 40 50 60 70 80 90

Insulin Release vs Glucose Challenge Normal Functioning Islets

36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 time (min)

SLIDE 11

Insulin Release vs Glucose Challenge

25 50 75 100 125 150 175 200 225 250 275 300 325 350 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min)

Reproducible results after day 1 & 2 in culture

SLIDE 12

20 40 60 80 100 120 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min)

Damaged Islets Phase One Insulin Release Missing

SLIDE 13

36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min) 50 100 150 200 250 300 350 400

Damaged Islets Second Phase Insulin Release Missing

SLIDE 14

5 10 15 20 25 30 35

36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min)

Damaged Islets Poor Insulin Release

SLIDE 15

20 40 60 80 100 120 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min)

Non-responsive Islets Insulin Dump

SLIDE 16

J Clin Invest 1995, 96: 721-726

SLIDE 17

Diabetes 2005, 54: 100-106

SLIDE 18

JDRF & NIH The Nordic Network for Clinical Islet Transplantation

SLIDE 19

The presence of Tissue Factor in islet cells

Lisa Moberg 2002

SLIDE 20

IBMIR IN CLINICAL ISLET TRANSPLANTATION No patients with both high C-peptide and TAT levels

Nordic network Edmonton

0,9 0,6 0,3 1,2 1,5

Nordic network Edmonton

SLIDE 21