Targeting inflammation in the treatment of
type 2 diabetes
Marc Y Donath
Glucose induces IL-1β release from human
0.8
islets
IL-1 (pg/islet)
*
0.6
0.4
0.2
0
D-glucose
5.5
L-glucose (mM)
11.1
33.3
5.5
27.8
Maedler et al. J Clin Invest 2002;110:851–60
Islet inflammation in type 2 diabetes
Human pancreata
Control
Type 2 diabetes
insulin
CD68
J. Ehses et al. Diabetes 56: 2356-2370
Donath & Shoelson |
2011;11:98-107
IL-1Ra in type 2 Diabetes
312 patients contacted
188 no response, or
disinterest, or not eligible
124 screened
54 not eligible
70 randomized
1 randomized but did not receive study
medication due to late positive
Mantoux reaction (placebo)
34 assigned to anakinra
34 completed the study
35 assigned to placebo
33 completed the study
2 withdrew
• 1 had an infected foot ulcer
with phlegmone
• 1 unblinded himself by
analyzing study drug
NEJM 356: 1517
Primary endpoint:
change in HbA1c at 13 weeks
0.3
1.0
0.0
–0.3
–0.6
P=0.004
P=0.03
4
13
Week
Fasting plasma
glucose (mM)
Glycated
hemoglobin (%)
Placebo
Anakinra
0.0
–1.0
* *
*P<0.01
**P<0.05
**
**
–2.0
0
3
6
Week
8
12
0.0
P=0.005
–0.1
–0.2
AUC for C-peptide
after IV glucose
3
2
1
0
–1
–2
–3
–4
P=0.08
Change from baseline
(nM x min)
0.1
AUC for C-peptide
after oral glucose
Change from baseline
(nM x min)
Change from baseline
(nM x min)
Change from baseline
Ratio of proinsulin
to insulin
20
Placebo
Anakinra
P=0.05
10
0
–10
–20
AUC for C-peptide after oral
and IV glucose combined
25
20
15
10
5
0
–5
–10
–15
–20
P=0.05
C-Reactive protein
P=0.02
Interleukin-6
1
P=0.002
Change from baseline (mg/liter)
Change from baseline (mg/liter)
1
0
–1
–2
–3
–4
–5
–6
Placebo
Anakinra
P<0.001
P<0.001
4
13
0
–1
–2
–3
4
13
Week
Week
Clinical studies using IL-1 antagonism to treat patients with type 2 diabetes
Mechanism
Drug
duration
Main findings*
IL-1 receptor
blockade
Anakinra
(Kineret)
13 weeks
HbA1c, leukocyte, CRP
insulin secretion
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, CRP
insulin secretion
High basal HbA1c.
Strong effects on
gylcaemia
Diabetes Care.
35:1654-62; 2012
IL-1β antagonsim
anti-IL-1β
antibody
4 weeks
insulin secretionCRP
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):52431
IL-1β antagonsim
Anti-IL-1β
antibody)
HbA1c, CRP
insulin secretion
Further improvement
of HbA1c at week 24
Diabetes Care. 2013
Aug;36(8):2239-4
IL-1 receptor
blockade
Anakinra
(Kineret)
12 weeks and
follow up for 24
weeks
1 week and follow
up for 4 weeks
insulin sensitivity
T1D and IR
EASD Meeting
2012, Abstract 560
IL-1 receptor
blockade
Anakinra
(Kineret)
insulin secretion (1st phase
insulin secretion improved)
Subjects with impaired
glucose tolerance
EASD Meeting
2013, Abstract 739
4 weeks
Remarks/Limits
Dose not adapted to
body weight
Source
N Engl J Med.
356:1517-26; 2007
Double-Blind, Randomized Study Evaluating the Glycemic and Antiinflammatory 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
2.
3.
4.
5.
6.
and 180 mg by end of treatment (week 12)
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)
Patients achieving HbA1c < 7% 52.4, 31.3, and 26.3% for 0.6, 18, and 180 mg
Decreased postprandiale glucose
Enhanced insulin secretion
Reduction in CRP
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
1
2
3
4
5
6
7
8
Comb
Non
Single
Single
Single
Dual
Dual
Dual
Triple
0 - 3 Month
Placebo
Anti-TNFa
Anti-IL-1b
Salsalate
Salsalate + Anti-TNFa
Salsalate + Anti-IL-1b
Anti-IL-1b
Salsalate + Anti-IL-1b
3 – 6 Month
Placebo
Anti-TNFa
Anti-IL-1b
Salsalate
Salsalate + Anti-TNFa
Salsalate + Anti-IL-1b
Anti-TNFa
Salsalate + Anti-TNFa
6 – 9 Month
Follow up
Follow up
Follow up
Follow up
Follow up
Follow up
Follow up
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
Calprotectin level
(μg/g)
Infliximab
Normal
range
Diabetes Care 36:e90–91, 2013
Patient with
Crohn Disease & Type 1 Diabetes
Infliximab
Whole body
sensitivity index
C-peptide
Secretion index
Infliximab
Diabetes Care 36:e90–91, 2013
Patient with
Plasma glucose level
(mmol/L)
Crohn Disease & Type 1 Diabetes
Jun. 2011
Oct. 2011
Apr. 2012
Infliximab
Mar. 2011
Time (min)
Diabetes Care 36:e90–91, 2013
M. Böni-Schnetzler
S. Boller
M. Borsigova
A. Brunner
E. Dalmas
I. Dannenmann
K. Dembinski
E. Dror
J. Ehses
H. Ellingsgaard
M. Faulenbach
C. Keller
K. Maedler
D. Meier
S. Nussbaumer
R. Prazak
S. Rütti
S. Rüsch
K. Rappold
N. Sauter
D. Schumann
M. Siegfried
E. Seelig
K. Thienel
K. Timper
C. Weder
E. Wettestein
P. Zala
S. Xu
Boston
D. Sinclair
J. Gromada
Cambridge
F. Gribble
Denmark
T. Mandrup-Poulsen
A. Karlsen
Denver
C. Dinarello
Geneva
P. A. Halban
K. Bouzakri
Seattle
S. E. Kahn
Toronto
D. J. Drucker
Zurich
A. Lauber
D. Konrad
Hyperglycemia induced -cell production of IL-1
Type 2 diabetes
Insulin
Psammomys obesus
IL-1
Insulin
Control
Lowenergy
Diabetes
Highenergy
IL-1
High-energy
& phlorizin
J Clin Invest 2002;110:851–60
EXERCISE
OBESITY
IL-6
Exercise-induced GLP-1 is IL-6 dependent
IL-6 (pg/ml)
Active GLP-1 (pmol/l)
Resting
Running
150
100
50
0
12
10
Resting
Running
8
6
4
2
0 30 60 90 120 150
0 30 60 90 120 150
Time (min)
Time (min)
15
Exercise
WT
IL-6 KO
10
5
0
0
90
Time (min)
Active GLP-1 (pmol/l)
Active GLP-1 (pmol/l)
Exercise
12
Isotype
IL-6 AB
8
4
0
0
90
Time (min)
Ellingsgaard et al. Nat Med 2011; 17:1481-9.
Intermittently elevated IL-6 increases
GLP-1 synthesis in intestine and pancreas
INTESTINE
PANCREAS
Ellingsgaard et al. Nat Med 2011; 17:1481-9.
Proglucagon processing
Proglucagon
GRPP
Glucagon
Prohormoneconvertase 1/3 (PC1/3)
Glucagon
GLP-1
IP2
GLP-2
α cell
L cell
GRPP
IP1
Prohormoneconvertase 2 (PC2)
GRPP
IP1
GLP-1
Glucagon
IP2
IP1
GLP-2
GLP-1
IP2
GLP-2
IL-6 increases GLP-1 in human α cells
Ellingsgaard et al. Nat Med 2011; 17:1481-9.
SKELETAL MUSCLE
ADIPOSE TISSUE
IL-6
INTESTINE
PANCREATIC ISLET
PC1/3
β
GLP-1 α α α ββ α
αβ
α
β ββ β
α
α
α α β
β
β
β β β
GLP-1
β cell function and survival
Satiety
Ellingsgaard et al. Nat Med 2011; 17:1481-9.
Classical incretin concept
• GLP-1 is a hormone
 Low plasma levels, short half-life
 Rapidly inactivated by DPP-4 in the vicinity of L-cells (<1 min)
Acute GLP-1 effects on β-cells
Food
INTESTINE
GLP-1
α β β
α α β α
α αββ ββ β
α αISLET
α α β
β
β
β β β
Insulin secretion
M. Y. Donath & R. Burcelin, Diabetes Care 2013 36 Suppl 2:S145-8.
Chronic GLP-1 effects on β-cells
ADIPOSE TISSUE
IL-6
GLucose
SKELETAL MUSCLE
IL-6
IL-6
Inflammation
PC1/3
GLP-1
α β β
GLP-1 α α β α
α αββ ββ β
α αISLET
α α β
β
β
β β β
Glucagon
Insulin production
β cell survival
M. Y. Donath & R. Burcelin, Diabetes Care 2013 36 Suppl 2:S145-8.
Patient with Type 1 Diabetes
•
•
•
•
•
26-year-old
Lean body mass index (21.5kg/m2)
Acute onset of hyperglycaemia
Auto-antibodies to β-cell antigens
Rapid insulin dependence
Index patient
CELL Metabolism 17:448–455, 2013
Patient with Type 1 Diabetes
Glucose and insulin levels during OGTT
insulin
20
18
16
14
12
10
8
6
4
2
0
Diabetes
Control
Insulin (pM)
Glucose (mM)
Glucose
0
30
60
90
Time (min)
120
500
450
400
350
300
250
200
150
100
50
0
Diabetes
Control
0
30
60
90
120
Time (min)
CELL Metabolism 17:448–455, 2013
T to C exchange in exon 1 of SIRT1
leads to a Leucine to Proline mutation at residue 107 (L107P)
Affected
IV.1
IV.2
C CG G G C C N G C A G
E1 (1-430)
c.[320T>C]
N
C CG G G C C N G C A
C CG G G C C N G C A
III.1
Non affected
IV.4
Control
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 CT G C A
E5 (22068-22215) E7 (24534-24719)
E3 (4161-4402)
E2 (2696-2812)
IV.9
E4 (6681-6833)
E9 (31542-33661)
E6 (23324-23403) E8 (27751-28308)
Untranslated region
p.Leu107Pro
Deacetylase Domain
C
Regions necessary for SIRT1 activation
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
Mutation of SIRT1 in Familial Type 1 Diabetes
Stimulation
with
IL-1β
iNOS: IL1b
stimulation
iNOS mRNA
1.5
1.0
0.5
wt
0.8
0.6
0.4
0.2
0.0
L107P
wt
6
4
2
0
wt
L107P

1.0
KC mRNA
1.0
TNF mRNA

Stimulation with IL-1β

0.8
0.6
wt
8
L107P
Stimulation with IL-1β
0.4
Stimulation with IL-1β and INFγ
NO (fold stimulation)
1.0

2.0
iNOS mRNA
Stimulation with IL-1β and INFγ
L107P
0.8
0.6
0.4
wt
L107P
CELL Metabolism 17:448–455, 2013
Identification of a SIRT1 Mutation
in a Family with Type 1 Diabetes
• 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
MY Donath
1. Histology : <10% infiltrated islets with 15 CD45 cells
2. Clinical studies
3. Genetic
4. Polyglandular autoimmune syndrome
 Primary defect: secretory dysfunction? Virus ?
Upregulation of α-cell GLP-1 in Psam. obesus
A.M.K. Hansen et al. (Diabetologia 2011, 54:1379–1387)
Release of GLP-1 from islets from hyperglycaemic animals on HED.
A local GLP-1 system in human pancreatic islets
P. Marchetti et al (Diabetologia 2012, 55:3262–3272)
Glucagon and GLP-1 secretion from
non-diabetic and type 2diabetic islets
Glucagon
Glucagon
GLP-1
GLP-1
Donath et al. CELL Metabolism 17:860-72; 2013
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