1. Targeting inflammation in the treatment of
type 2 diabetes
Marc Y Donath

3. Glucose induces IL-1β release from human islets
0.8 *
0.6
IL-1 (pg/islet)
0.4
0.2
D-glucose
5.5
11.1
33.3
5.5
L-glucose (mM)
27.8
Maedler et al. J Clin Invest 2002;110:851–60

4. Islet inflammation in type 2 diabetes
Human pancreata
Control
Type 2 diabetes
DIRE QUE AMYLOID DONC TYPE 2
Dire que aussi CD163
insulin
CD68
J. Ehses et al. Diabetes 56:

5. Donath & Shoelson |
2011;11:98-107

6. 6

7. IL-1Ra in type 2 Diabetes 312 patients contacted 124 screened
70 randomized
188 no response, or
disinterest, 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

9. Primary endpoint: change in HbA1c at 13 weeks
Placebo
Anakinra 4
Week 13
–0.6
–0.3
0.0
0.3
hemoglobin (%)
Glycated
P=0.004
P=0.03 3
Week
–2.0
–1.0
0.0
1.0 6 8 12
Fasting plasma
glucose (mM)
*P<0.01
**P<0.05 * **

10. AUC for C-peptide after oral and IV glucose combined
Ratio of proinsulin
to insulin
AUC for C-peptide
after oral glucose
Placebo
Anakinra
0.1 20
P=0.05
P=0.005 10
0.0
Change from baseline
(nM x min)
Change from baseline
–0.1
–10
–0.2
–20
AUC for C-peptide
after IV glucose
AUC for C-peptide after oral
and IV glucose combined 25 3 20 2 15 1 10
Change from baseline
(nM x min)
Change from baseline
(nM x min) 5 –1
P=0.08
P=0.05 –5 –2
–10 –3
–15 –4
–20

11. Change from baseline (mg/liter) Change from baseline (mg/liter)
Placebo
Anakinra
C-Reactive protein
Interleukin-6 1
P=0.02
P=0.002 1
P<0.001
P<0.001 –1 –2
Change from baseline (mg/liter)
Change from baseline (mg/liter) –1 –3 –4 –2 –5 –6 –3 4 13 4 13
Week
Week

12. Clinical studies using IL-1 antagonism to treat patients with type 2 diabetes
Mechanism
Drug
duration
Main findings*
Remarks/Limits
Source
IL-1 receptor blockade
Anakinra
(Kineret)
13 weeks
HbA1c, leukocyte, CRP
insulin secretion
Dose not adapted to body weight
N Engl J Med. 356: ; 2007
Follow up for 39 weeks
Sustained CRP, insulin secretion, insulin requirement
Follow up study of the one above
Diabetes Care. 32:1663-8; 2009
4 weeks
Prediabetic patients
J Clin Endocrinol Metab. 96: ; 2011;
IL-1β antagonsim
anti-IL-1β antibody
HbA1c, CRP
High basal HbA1c. Strong effects on gylcaemia
Diabetes Care. 35: ; 2012
insulin secretionCRP
Low basal HbA1c
Diabetes, Obesity and Metabolism 14: 1088–1096; 2012.
16 weeks
CRP, HbA1c
Underpowered for low basal HbA1c
Diabetes Metab Dec;39(6):524-31
Anti-IL-1β antibody)
12 weeks and follow up for 24 weeks
Further improvement of HbA1c at week 24
Diabetes Care Aug;36(8):2239-4
1 week and follow up for 4 weeks
insulin sensitivity
T1D and IR
EASD Meeting 2012, Abstract 560
insulin secretion (1st phase insulin secretion improved)
Subjects with impaired glucose tolerance
EASD Meeting 2013, Abstract 739

13. Double-Blind, Randomized Study Evaluating the Glycemic and Anti-inflammatory Effects of Subcutaneous LY , a Neutralizing IL-1β Antibody, in Patients With Type 2 Diabetes (Diabetes Care, : )
Placebo-corrected decrease in HbA1c of -0.27, and -0.25% for 0.6, 18 and 180 mg by end of treatment (week 12)
Placebo-corrected decrease in HbA1c of -0.18, 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

14. 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… 14

15. Donath et al. CELL Metabolism 17:860-72; 2013

16. 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

17. 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 ?????

18. Crohn Disease & Type 1 Diabetes
Patient with
Crohn Disease & Type 1 Diabetes
Calprotectin level
(μg/g)
Infliximab
Normal
range
On the following slides, I present you the case of a 26-year-old Ashkenazy Jewish male who was diagnosed with Type 1 diabetes on the basis of the following characteristics:
- He had a lean body mass index of 21.5 kg/m2,
- Hyperglycaemia, with acute onset
- auto-antibodies to glutamic acid decarboxylase (1150 U/L) and islet-cell autoantibody -2 (3.0 U/L) and finally rapid insulin dependence.
Diabetes Care 36:e90–91, 2013

19. Crohn Disease & Type 1 Diabetes
Patient with
Crohn Disease & Type 1 Diabetes
Infliximab
Infliximab
Secretion index
C-peptide
sensitivity index
Whole body
On the following slides, I present you the case of a 26-year-old Ashkenazy Jewish male who was diagnosed with Type 1 diabetes on the basis of the following characteristics:
- He had a lean body mass index of 21.5 kg/m2,
- Hyperglycaemia, with acute onset
- auto-antibodies to glutamic acid decarboxylase (1150 U/L) and islet-cell autoantibody -2 (3.0 U/L) and finally rapid insulin dependence.
Diabetes Care 36:e90–91, 2013

20. Crohn Disease & Type 1 Diabetes
Patient with
Crohn Disease & Type 1 Diabetes
Mar. 2011
Plasma glucose level
(mmol/L)
Jun. 2011
Oct. 2011
Apr. 2012
Infliximab
On the following slides, I present you the case of a 26-year-old Ashkenazy Jewish male who was diagnosed with Type 1 diabetes on the basis of the following characteristics:
- He had a lean body mass index of 21.5 kg/m2,
- Hyperglycaemia, with acute onset
- auto-antibodies to glutamic acid decarboxylase (1150 U/L) and islet-cell autoantibody -2 (3.0 U/L) and finally rapid insulin dependence.
Time (min)
Diabetes Care 36:e90–91, 2013

21. Thank you Boston D. Sinclair J. Gromada Cambridge F. Gribble Denmark
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
Karlsen
Denver
C. Dinarello
Geneva
P. A. Halban
K. Bouzakri
Seattle
S. E. Kahn
Toronto
D. J. Drucker
Zurich
A. Lauber
D. Konrad
Thank you

22. Hyperglycemia induced -cell production of IL-1
Type 2 diabetes
Psammomys obesus
Insulin
IL-1b
Insulin
IL-1b
Low- energy
Control
Diabetes
High-
energy
High-energy
& phlorizin
J Clin Invest 2002;110:851–60

23. EXERCISE
OBESITY
IL-6 23

24. Exercise-induced GLP-1 is IL-6 dependent
Ellingsgaard et al. Nat Med 2011; 17: 24

25. Intermittently elevated IL-6 increases
GLP-1 synthesis in intestine and pancreas
INTESTINE
PANCREAS
Ellingsgaard et al. Nat Med 2011; 17: 25

26. Proglucagon processing
GRPP
Glucagon
IP1
GLP-1
IP2
GLP-2
L cell
α cell
Prohormoneconvertase 1/3 (PC1/3)
Prohormoneconvertase 2 (PC2)
GRPP
Glucagon
IP1
GRPP
GLP-1
Glucagon
IP2
IP1
GLP-2
GLP-1
IP2
GLP-2 26

27. IL-6 increases GLP-1 in human α cells
Ellingsgaard et al. Nat Med 2011; 17: 27

28. IL-6 PC1/3 GLP-1 GLP-1 β cell function and survival Satiety α β
ADIPOSE TISSUE
SKELETAL MUSCLE
IL-6
GLP-1
GLP-1
PC1/3
INTESTINE
PANCREATIC ISLET α β
β cell function and survival
Satiety
Ellingsgaard et al. Nat Med 2011; 17: 28

29. 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)

30. Acute GLP-1 effects on β-cells
Food α β
GLP-1
INTESTINE
ISLET
Insulin secretion
M. Y. Donath & R. Burcelin, Diabetes Care Suppl 2:S145-8. 30

31. IL-6 IL-6 IL-6 Chronic GLP-1 effects on β-cells PC1/3 GLP-1 Glucagon
ADIPOSE TISSUE
IL-6
GLucose
SKELETAL MUSCLE
IL-6
IL-6
Inflammation
PC1/3 α β
GLP-1
Glucagon
ISLET
Insulin production
β cell survival
GLP-1
M. Y. Donath & R. Burcelin, Diabetes Care Suppl 2:S145-8. 31

32. 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
On the following slides, I present you the case of a 26-year-old Ashkenazy Jewish male who was diagnosed with Type 1 diabetes on the basis of the following characteristics:
- He had a lean body mass index of 21.5 kg/m2,
- Hyperglycaemia, with acute onset
- auto-antibodies to glutamic acid decarboxylase (1150 U/L) and islet-cell autoantibody -2 (3.0 U/L) and finally rapid insulin dependence.
CELL Metabolism 17:448–455, 2013

33. Patient with Type 1 Diabetes
Glucose and insulin levels during OGTT
To further characterize the pathology of the this patient, we performed an oral glucose-tolerance test, which is shown on this slide.
As expected, -cell function was severely impaired with almost no increase in insulin secretion after oral glucose stimulation in our diabetic patient, in red, compared to a healthy familiy member, shown in green.
The most strikingly point was, that, for a Type 1 diabetic patient, basal insulin levels were very high, even when compared to the control
CELL Metabolism 17:448–455, 2013

34. T to C exchange in exon 1 of SIRT1
leads to a Leucine to Proline mutation at residue 107 (L107P)
E1 (1-430)
E3 ( )
E5 ( )
E7 ( )
E9 ( )
E2 ( )
E4 ( )
E6 ( )
E8 ( )
Untranslated region
c.[320T>C]
p.Leu107Pro
N C
Deacetylase Domain
Regions necessary for SIRT1 activation
CELL Metabolism 17:448–455, 2013

35. Histone deacetylase Sirt1
Regulation of lifespan / Protecting against age-related diseases
Adaptation of metabolism to calorie intake
Activated by Reseveratrol

36. Mutation of SIRT1 in Familial Type 1 Diabetes
CELL Metabolism 17:448–455, 2013

37. Mutation of SIRT1 in Familial Type 1 Diabetes
Stimulation with IL-1β
Stimulation with IL-1β and INFγ
Stimulation with IL-1β and INFγ
Stimulation with IL-1β
Stimulation with IL-1β
CELL Metabolism 17:448–455, 2013

38. 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

39. MY Donath

40. Histology : <10% infiltrated islets with 15 CD45 cells
Clinical studies
Genetic
Polyglandular autoimmune syndrome
Primary defect: secretory dysfunction? Virus ?

41. 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.

42. 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

43. Donath et al. CELL Metabolism 17:860-72; 2013