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