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

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

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: 2356-2370

Donath & Shoelson | 2011;11:98-107

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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

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 * **

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

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

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. 356:1517-26; 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. 96:2119-26; 2011; IL-1β antagonsim anti-IL-1β antibody HbA1c, CRP High basal HbA1c. Strong effects on gylcaemia Diabetes Care. 35:1654-62; 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. 2013 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. 2013 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

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) 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) 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… 14

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

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 ?????

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

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

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

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

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

EXERCISE OBESITY IL-6 23

Exercise-induced GLP-1 is IL-6 dependent Ellingsgaard et al. Nat Med 2011; 17:1481-9. 24

Intermittently elevated IL-6 increases GLP-1 synthesis in intestine and pancreas INTESTINE PANCREAS Ellingsgaard et al. Nat Med 2011; 17:1481-9. 25

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

IL-6 increases GLP-1 in human α cells Ellingsgaard et al. Nat Med 2011; 17:1481-9. 27

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; 17:1481-9. 28

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 α β GLP-1 INTESTINE ISLET Insulin secretion M. Y. Donath & R. Burcelin, Diabetes Care 2013 36 Suppl 2:S145-8. 30

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 2013 36 Suppl 2:S145-8. 31

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

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

T to C exchange in exon 1 of SIRT1 leads to a Leucine to Proline mutation at residue 107 (L107P) E1 (1-430) E3 (4161-4402) E5 (22068-22215) E7 (24534-24719) E9 (31542-33661) E2 (2696-2812) E4 (6681-6833) E6 (23324-23403) E8 (27751-28308) Untranslated region c.[320T>C] p.Leu107Pro N C Deacetylase Domain 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 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

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

Histology : <10% infiltrated islets with 15 CD45 cells Clinical studies Genetic 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