Download - Marc Y Donath
Marc Y Donath
Targeting inflammation in the treatment of type 2 diabetes
Targeting inflammation in the treatment of type 2 diabetes
Maedler et al. J Clin Invest 2002;110:851–60
0
0.2
0.4
0.6
0.8
IL-1
(p
g/is
let)
D-glucose
L-glucose (mM)
*
5.5 5.5
27.8
33.311.1
Glucose induces IL-1β release from human islets
Islet inflammation in type 2 diabetes
Human pancreata
Type 2 diabetesControl
CD68insulin
J. Ehses et al. Diabetes 56: 2356-2370
Donath & Shoelson |
2011;11:98-107
312 patients contacted
124 screened
70 randomized
188 no response, ordisinterest, or not eligible
54 not eligible
1 randomized but did not receive study medication due to late positive Mantoux reaction (placebo)
34 assigned to anakinra 35 assigned to placebo
34 completed the study 33 completed the study
2 withdrew• 1 had an infected foot ulcer
with phlegmone• 1 unblinded himself by
analyzing study drug
NEJM 356: 1517
IL-1Ra in type 2 Diabetes
Primary endpoint: change in HbA1c at 13 weeks
PlaceboAnakinra
4
Week
13–0.6
–0.3
0.0
0.3
Gly
cate
dhem
oglo
bin
(%
)
P=0.004 P=0.03
3
Week
–2.0
–1.0
0.0
1.0
0 6 8 12Fa
stin
g p
lasm
aglu
cose
(m
M)
*P<0.01**P<0.05
* ***
**
–0.2
–0.1
0.0
0.1
–20
–10
0
20
–4
–3
–2
3
–1
–20–15–10
20
0
Change f
rom
base
line
Change f
rom
base
line
(nM
x m
in)
Change f
rom
base
line
(nM
x m
in)
Change f
rom
base
line
(nM
x m
in)
PlaceboAnakinra
P=0.005
P=0.08
2
1
0
P=0.05
10
–5
15
510
25
P=0.05
Ratio of proinsulin to insulin
AUC for C-peptide after IV glucose
AUC for C-peptide after oral glucose
AUC for C-peptide after oral and IV glucose combined
–2
–1
0
1
Change f
rom
base
line (
mg/lit
er)
PlaceboAnakinra
P<0.001
C-Reactive protein Interleukin-6
–3
–4
–5
–6
–2
–1
0
1
Change f
rom
base
line (
mg/lit
er)
–3
4
Week
13 4
Week
13
P<0.001P=0.002P=0.02
Mechanism Drug duration Main findings* Remarks/Limits Source
IL-1 receptor blockade
Anakinra(Kineret)
13 weeks HbA1c, leukocyte, CRPinsulin secretion
Dose not adapted to body weight
N Engl J Med. 356:1517-26; 2007
IL-1 receptor blockade
Anakinra(Kineret)
Follow up for 39 weeks
Sustained CRP, insulin secretion, insulin requirement
Follow up study of the one above
Diabetes Care. 32:1663-8; 2009
IL-1 receptor blockade
Anakinra(Kineret)
4 weeks insulin secretion Prediabetic patients J Clin Endocrinol Metab. 96:2119-26;
2011;
IL-1β antagonsim anti-IL-1β antibody
13 weeks HbA1c, CRPinsulin secretion
High basal HbA1c. Strong effects on
gylcaemia
Diabetes Care. 35:1654-62; 2012
IL-1β antagonsim anti-IL-1β antibody
4 weeks insulin secretionCRP Low basal HbA1c Diabetes, Obesity and Metabolism 14:
1088–1096; 2012.
IL-1β antagonsim anti-IL-1β antibody
16 weeks CRP, HbA1c insulin secretion
Underpowered for low basal HbA1c
Diabetes Metab. 2013 Dec;39(6):524-
31
IL-1β antagonsim Anti-IL-1β antibody)
12 weeks and follow up for 24
weeks
HbA1c, CRPinsulin secretion
Further improvement of HbA1c at week 24
Diabetes Care. 2013 Aug;36(8):2239-4
IL-1 receptor blockade
Anakinra(Kineret)
1 week and follow up for 4 weeks
insulin sensitivity T1D and IR EASD Meeting 2012, Abstract 560
IL-1 receptor blockade
Anakinra(Kineret)
4 weeks insulin secretion (1st phase insulin secretion improved)
Subjects with impaired glucose
tolerance
EASD Meeting 2013, Abstract 739
Clinical studies using IL-1 antagonism to treat patients with type 2 diabetes
Double-Blind, Randomized Study Evaluating the Glycemic and Anti-inflammatory Effects of Subcutaneous LY2189102, a Neutralizing IL-1β Antibody, in Patients With Type 2 Diabetes (Diabetes Care, 2013. 36:2239-46)
1. Placebo-corrected decrease in HbA1c of -0.27, -0.38 and -0.25% for 0.6, 18 and 180 mg by end of treatment (week 12)
2. Placebo-corrected decrease in HbA1c of -0.18, -0.59 and -0.43% for 0.6, 18 and 180 mg by end of follow up (weak 24; sustained effect for 12 weeks)
3. Patients achieving HbA1c < 7% 52.4, 31.3, and 26.3% for 0.6, 18, and 180 mg 4. Decreased postprandiale glucose5. Enhanced insulin secretion6. Reduction in CRP
Canakinumab (anti-IL-1β) Anti-inflammatory Thrombosis Outcomes Study (CANTOS)
Canakinumab (anti-IL-1β) Anti-inflammatory Thrombosis Outcomes Study (CANTOS)
•10,000 participants over 4 years•Primary Endpoint: cardiovascular events•Secondary Endpoints: new onset Diabetes, diabetes progression…
Donath et al. CELL Metabolism 17:860-72; 2013
The Inflacomb Study Marc Donath, Gökhan Hotamisligil, Steven Shoelson
Steven Kahn, Herbert Tilg, Stefano Del Prato, Thomas Mandrup-Poulsen, Cees Tack, Gerit-Holger Schernthaner, Thomas Stulnig, Michaela Diamant, Nicolas Paquot
Arms Comb 0 - 3 Month 3 – 6 Month 6 – 9 Month 1 Non Placebo Placebo Follow up 2 Single Anti-TNFa Anti-TNFa Follow up 3 Single Anti-IL-1b Anti-IL-1b Follow up 4 Single Salsalate Salsalate Follow up 5 Dual Salsalate + Anti-TNFa Salsalate + Anti-TNFa Follow up 6 Dual Salsalate + Anti-IL-1b Salsalate + Anti-IL-1b Follow up 7 Dual Anti-IL-1b Anti-TNFa Follow up 8 Triple Salsalate + Anti-IL-1b Salsalate + Anti-TNFa Follow up
Treatment in Immunometabolism 2013
•Diabetes & psoriasis or colitis anti-TNFα
•Diabetes & gout anti-IL-1β
•Diabetes & rheumatoid arthritis anti-TNFα or anti-IL-1β
•Diabetes & joint pain salsalate
•Diabetes & cardiovascular disease anti-IL-1β ?????
Patient with
Crohn Disease & Type 1 Diabetes
Diabetes Care 36:e90–91, 2013
Cal
pro
tect
in l
evel
(μ
g/g
)Infliximab
Normalrange
Patient with
Crohn Disease & Type 1 Diabetes
Diabetes Care 36:e90–91, 2013
C-p
epti
de
S
ecre
tio
n i
nd
ex
Infliximab
Wh
ole
bo
dy
sen
siti
vity
in
dex
Infliximab
Patient with
Crohn Disease & Type 1 Diabetes
Diabetes Care 36:e90–91, 2013
Pla
sma
glu
cose
lev
el(m
mo
l/L
)
Time (min)
Mar. 2011
Jun. 2011
Oct. 2011
Apr. 2012 Infl
ixim
ab
M. Böni-SchnetzlerS. BollerM. BorsigovaA. BrunnerE. DalmasI. DannenmannK. DembinskiE. Dror J. EhsesH. EllingsgaardM. Faulenbach C. KellerK. MaedlerD. MeierS. NussbaumerR. PrazakS. RüttiS. RüschK. RappoldN. SauterD. Schumann M. SiegfriedE. SeeligK. ThienelK. TimperC. WederE. WettesteinP. ZalaS. Xu
BostonD. Sinclair J. GromadaCambridgeF. GribbleDenmarkT. Mandrup-PoulsenA. KarlsenDenverC. DinarelloGenevaP. A. HalbanK. BouzakriSeattleS. E. Kahn TorontoD. J. DruckerZurichA. LauberD. Konrad
Hyperglycemia induced -cell production of IL-1
Control
Diabetes
IL-1Insulin
Type 2 diabetes
IL-1Insulin
Low-energy
High-energy
High-energy& phlorizin
Psammomys obesus
J Clin Invest 2002;110:851–60
OBESITYEXERCISE
IL-6
Exercise-induced GLP-1 is IL-6 dependent
Ellingsgaard et al. Nat Med 2011; 17:1481-9.
Intermittently elevated IL-6 increases GLP-1 synthesis in intestine and pancreas
PANCREAS
INTESTINE
Ellingsgaard et al. Nat Med 2011; 17:1481-9.
Proglucagon processing
Prohormoneconvertase 2 (PC2)
α cellL cellProhormoneconvertase 1/3 (PC1/3)
GRPPGRPP GlucagonGlucagon IP1IP1
GLP-1GLP-1
IP2IP2
GLP-2GLP-2
Proglucagon
GRPPGRPP GlucagonGlucagon GLP-1GLP-1IP1IP1 IP2IP2 GLP-2GLP-2
GRPPGRPP
GlucagonGlucagon
IP1IP1
GLP-1GLP-1 IP2IP2 GLP-2GLP-2
IL-6 increases GLP-1 in human α cells
Ellingsgaard et al. Nat Med 2011; 17:1481-9.
IL-6
ADIPOSE TISSUE
PANCREATIC ISLET
GLP-1
PC1/3
β cell function and survival
SKELETAL MUSCLE
αβ
αβ β
αα
β
ββα
β
α
β
β
βα β α
ββ
α
βα β
β
INTESTINE
GLP-1
SatietyEllingsgaard et al. Nat Med 2011; 17:1481-9.
• GLP-1 is a hormone Low plasma levels, short half-life Rapidly inactivated by DPP-4 in the vicinity of L-cells (<1 min)
Classical incretin concept
αβ
αβ β
αα
β
ββα
β
α
β
β
βα β α
ββ
α
βα β
βISLET
Insulin secretion
Acute GLP-1 effects on β-cells
GLP-1INTESTINE
Food
M. Y. Donath & R. Burcelin, Diabetes Care 2013 36 Suppl 2:S145-8.
IL-6
GLP-1
PC1/3
SKELETAL MUSCLE
αβ
αβ β
αα
β
ββα
β
α
β
β
βα β α
ββ
α
βα β
βISLET
Insulin production β cell survival
Chronic GLP-1 effects on β-cells
Glucagon
IL-6
ADIPOSE TISSUE
GLucose
InflammationIL-6
GLP-1
M. Y. Donath & R. Burcelin, Diabetes Care 2013 36 Suppl 2:S145-8.
• 26-year-old• Lean body mass index (21.5kg/m2)• Acute onset of hyperglycaemia• Auto-antibodies to β-cell antigens• Rapid insulin dependence
Patient with Type 1 Diabetes
Index patientCELL Metabolism 17:448–455, 2013
Patient with Type 1 Diabetes
Glucose and insulin levels during OGTT
Glucose
0 30 60 90 12002468
101214161820
Diabetes
Control
Time (min)
Glu
cose
(mM
)
insulin
0 30 60 90 1200
50100150200250300350400450500
DiabetesControl
Time (min)
Insu
lin (p
M)
CELL Metabolism 17:448–455, 2013
C CG G G C CN G C A G C CG G G C CN G C A C CG G G C C N G C A C CG G GC C T G C A G G G G C C G G G C C T G C A C CG G G C C N G C A
Affected
ControlIV.9 III.1
C CG G G C CN G C A G C CG G G C CN G C A C CG G G C C N G C A C CG G GC C T G C A G G G G C C G G G C C T G C A C CG G G C C N G C A
AffectedNon affected
IV.1 IV.2 IV.4
C CG G G C CN G C A G C CG G G C CN G C A C CG G G C C N G C A C CG G GC C T G C A G G G G C C G G G C C T G C A C CG G G C C N G C A
Affected
ControlIV.9 III.1
C CG G G C CN G C A G C CG G G C CN G C A C CG G G C C N G C A C CG G GC C T G C A G G G G C C G G G C C T G C A C CG G G C C N G C A
AffectedNon affected
IV.1 IV.2 IV.4
N CDeacetylase Domain
Regions necessary for SIRT1 activation
E1 (1-430)
c.[320T>C]
E2 (2696-2812)
E3 (4161-4402)
E4 (6681-6833)
E5 (22068-22215)
E6 (23324-23403)
E7 (24534-24719)
E8 (27751-28308)
E9 (31542-33661)
Untranslated region
p.Leu107Pro
T to C exchange in exon 1 of SIRT1SIRT1
leads to a Leucine to Proline mutation at residue 107 (L107P)
CELL Metabolism 17:448–455, 2013
Histone deacetylase Sirt1
-Regulation of lifespan / Protecting against age-related diseases
-Adaptation of metabolism to calorie intake
-Activated by Reseveratrol
Mutation of SIRT1 in Familial Type 1 Diabetes
CELL Metabolism 17:448–455, 2013
Stimulation with IL-1β Stimulation with IL-1β and INFγ
wt L107P0
2
4
6
8
NO
(fo
ld s
timu
latio
n)
Stimulation with IL-1β Stimulation with IL-1β
Stimulation with IL-1β and INFγ
Mutation of SIRT1 in Familial Type 1 Diabetes
CELL Metabolism 17:448–455, 2013
• First human mutation in SIRT1• First description of a monogenic form of type 1 diabetes• SIRT1 regulates immune and metabolic function in humans
CELL Metabolism 17:448–455, 2013
Identification of a SIRT1 Mutationin a Family with Type 1 Diabetes
MY Donath
1. Histology : <10% infiltrated islets with 15 CD45 cells 2. Clinical studies3. Genetic4. Polyglandular autoimmune syndrome
Primary defect: secretory dysfunction? Virus ?
Release of GLP-1 from islets from hyperglycaemic animals on HED.
Upregulation of α-cell GLP-1 in Psam. obesusA.M.K. Hansen et al. (Diabetologia 2011, 54:1379–1387)
Glucagon and GLP-1 secretion from non-diabetic and type 2diabetic islets
A local GLP-1 system in human pancreatic isletsP. Marchetti et al (Diabetologia 2012, 55:3262–3272)
Glucagon
Glucagon
GLP-1
GLP-1
Donath et al. CELL Metabolism 17:860-72; 2013