Insulin stimulation index Insulin stimulation index Olle Korsgren - PowerPoint PPT Presentation

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 •Donor related IBMIR factors •Preservation •Isolation Hours Insulin 40 35 30 •Hypoxia •Rejection 25 •Glucotoxicity 20 •i.s. drugs •Revasculariz- 15 10 ation 5 Days Weeks

I n t e Expression of inflammation-related genes in human islets r l e u k M i n o n - 6 o c p y r I t e V n e t c a e u c s h r r c l s u e e o l m u a r k r o ( i n I t e a L - n T c 8 - h d t 6 y i o c p ) m r t h p e o e T r c s o u l - i i a c t r n e e s l i o b l g l n r e - r s 1 o t ( a p t I p h - e L I 1 c r - n e 8 f 0 i t a f i c ) e c ( c u r t T r l o r e M a s u r o n S k p r t B i r e n e 1 s - c 0 2 p u ; r r r o e c T o H t c e e r I Y i p n B n ( t t V 1 p o e 0 r r E r l ) e G a e c l u F u p k ) r h s i a n o - r s 1 u 1 D b ( e u I l n L t a i - M t 1 - a l p 1 i c k r ) r e e o c p p u r r h o s a t o g e r e i n ( m p i r g e r c a u t i r o s n o N r i - n s h a i m b i ; t o f r i b y r f o a b c l t a o s r t ( g M r I o I n F w s ) u t h l i n f - a l c i k t e o r g r r e E o c w p e i t p t h h t e o f r l a i 1 c a l t p o d r r e i s b c c u i P o n r r i d o s d i o h i n n r g i b d ( i p t F o i G r n m o F t a ( R e P i n i H 1 n ) r B 2 e ) c ( e I p G t F o B r P 1 2 p r e c u r s o r ( E D BBRC, 2003, 308, 474-479 U Johansson et al. D R 1 ; D D Day 11 Day 7 Day 6 Day 2 Day 1 R 1 ) 0 50 100 150 200 250 300 350 400 450

C-peptide/Creatinine at 2 weeks after Tx Variable r P 0.23 0.14 Age (years) ICU length (days) -0.21 0.17 Cause of death (Traumatic/Non-traumatic) 0.21 0.18 2 ) 0.16 0.31 Body mass index (kg/m 0.004 0.98 Weight of pancreas (g) Minimal glucose (mmol/l) 0.29 0.08 Maximal ALAT (U/l) -0.25 0.11 -0.20 0.25 Maximal ASAT (U/l) -0.20 0.29 Maximal amylase (U/l) Donor related variables Donor-related variables Maximal ALP (U/l) 0.11 0.55 Maximal CRP (nmol/l) -0.07 0.69 0.05 0.74 Maximal Creatinine (umol/l) -0.005 0.98 Maximal r-GT (U/l) 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 -0.48 0.005 TF expression in pancreas biopsy Procurement team (center 'X'/others) 0.35 0.01 -0.29 0.09 Warm ischemia time (min) Cold ischemia time (min) -0.23 0.14 0.06 0.72 Organ perfusion volume (aorta/portal) Procurement team (local/distant) 0.04 0.81 0.32 0.08 TNFa expression in pancreas biopsy Organ procurement variables Organ procurement-related variables IL-8 expression in pancreas biopsy -0.23 0.21 -0.26 0.23 ICAM-1 expression in pancreas biopsy -0.24 0.28 IP-10 expression in pancreas biopsy -0.20 0.29 MCP-1 expression in pancreas biopsy RANTES expression in pancreas biopsy -0.21 0.34 -0.19 0.39 TGF-b1 expression in pancreas biopsy -0.07 0.75 IL-6 expression in pancreas biopsy 0.02 0.92 IL-1b expression in pancreas biopsy Harvest starting time (min) -0.31 0.04 0.19 0.23 Transplanted islet equivalents (IEQs) -0.14 0.42 Liberase lot (efficient/non-efficient) Isolation method (old/new) 0.13 0.42 Islet isolation variables Isolation-related variables Harvest time (min) -0.11 0.53 -0.11 0.54 Mean purity of transplanted islets (%) 0.05 0.79 Stimulation index in in vitro test Liberase amount per g of pancreas (mg/g) 0.01 0.95 Dissection time (min) 0.03 0.87 -0.38 0.01 Maximal TAT (ug/ml) Tx related variables Transplantation-related variables 0.20 0.25 Volume of transplanted grafts (mL) Transplanted centers (local/distant) -0.15 0.31

“the fate of an islet” •Inflammation •Donor related IBMIR factors •Preservation •Isolation Hours Insulin 40 35 •Hypoxia 30 •Rejection 25 •Glucotoxicity 20 •i.s. drugs •Revasculariz- 15 ation 10 5 Days Weeks

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

16 13 10 -2 7 4 1 140 120 100 Glucose (mM) 80 min 60 40 20 0 0 1 16 13 10 7 4

Insulin Release vs Glucose Challenge Normal Functioning Islets 90 80 70 60 50 40 30 20 10 0 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 time (min)

Insulin Release vs Glucose Challenge Reproducible results after day 1 & 2 in culture 350 325 300 275 250 225 200 175 150 125 100 75 50 25 0 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 120 100 80 60 40 20 0 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min)

Damaged Islets Second Phase Insulin Release Missing 400 350 300 250 200 150 100 50 0 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min)

Damaged Islets Poor Insulin Release 35 30 25 20 15 10 5 0 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min)

Non-responsive Islets Insulin Dump 120 100 80 60 40 20 0 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 Time (min)

J Clin Invest 1995, 96: 721-726

Diabetes 2005, 54: 100-106

The Nordic Network for Clinical Islet Transplantation JDRF & NIH

The presence of Tissue Factor in islet cells T Lisa Moberg 2002

IBMIR IN CLINICAL ISLET TRANSPLANTATION No patients with both high C-peptide and TAT levels Nordic network Edmonton 1,5 Nordic network Edmonton 1,2 0,9 0,6 0,3