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

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Presentation on theme: "Marc Y Donath Targeting inflammation in the treatment of type 2 diabetes Targeting inflammation in the treatment of type 2 diabetes."— Presentation transcript:

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

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3 Maedler et al. J Clin Invest 2002;110:851– IL-1  (pg/islet) D-glucose L-glucose (mM) * Glucose induces IL-1β release from human islets

4 Islet inflammation in type 2 diabetes Human pancreata Type 2 diabetes Control CD68 insulin J. Ehses et al. Diabetes 56:

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

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7 312 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 IL-1Ra in type 2 Diabetes

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9 Primary endpoint: change in HbA 1c at 13 weeks Placebo Anakinra 4 Week 13 –0.6 – Glycated hemoglobin (%) P=0.004P=0.03

10 –0.2 – –20 – –4 –3 –2 3 –1 –20 –15 – Change from baseline (nM x min) Change from baseline (nM x min) Change from baseline (nM x min) Placebo Anakinra P=0.005 P= P= – 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

11 –2 –1 0 1 Change from baseline (mg/liter) Placebo Anakinra P<0.001 C-Reactive proteinInterleukin-6 –3 –4 –5 –6 –2 –1 0 1 Change from baseline (mg/liter) –3 4 Week 134 Week 13 P<0.001P=0.002P=0.02

12 MechanismDrugdurationMain 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 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: ; 2011; IL-1β antagonsim anti-IL-1β antibody 13 weeks HbA1c , CRP  insulin secretion  High basal HbA1c. Strong effects on gylcaemia Diabetes Care. 35: ; 2012 IL-1β antagonsim anti-IL-1β antibody 4 weeks insulin secretion  CRP  Low basal HbA1c Diabetes, Obesity and Metabolism 14: 1088–1096; IL-1β antagonsim anti-IL-1β antibody 16 weeks CRP , HbA1c  insulin secretion  Underpowered for low basal HbA1c Diabetes Metab Dec;39(6): IL-1β antagonsim Anti-IL-1β antibody) 12 weeks and follow up for 24 weeks HbA1c , CRP  insulin secretion  Further improvement of HbA1c at week 24 Diabetes Care Aug;36(8): 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 weeksinsulin 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

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, : ) 1.Placebo-corrected decrease in HbA1c of -0.27, 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, 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 glucose 5.Enhanced insulin secretion 6.Reduction in CRP

14 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 …

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 Patient with Crohn Disease & Type 1 Diabetes Diabetes Care 36:e90–91, 2013 Calprotectin level (μg/g) Infliximab Normal range

19 Patient with Crohn Disease & Type 1 Diabetes Diabetes Care 36:e90–91, 2013 C-peptide Secretion index Infliximab Whole body sensitivity index Infliximab

20 Patient with Crohn Disease & Type 1 Diabetes Diabetes Care 36:e90–91, 2013 Plasma glucose level (mmol/L) Time (min) Mar Jun Oct Apr Infliximab

21 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

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

23 OBESITY EXERCISE IL-6

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

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

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

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

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

29 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

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

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

32 26-year-old Lean body mass index (21.5kg/m 2 ) Acute onset of hyperglycaemia Auto-antibodies to β-cell antigens Rapid insulin dependence Patient with Type 1 Diabetes Index patient CELL Metabolism 17:448–455, 2013

33 Patient with Type 1 Diabetes Glucose and insulin levels during OGTT CELL Metabolism 17:448–455, 2013

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

38 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 Mutation in a Family with Type 1 Diabetes

39 MY Donath

40 1. Histology : <10% infiltrated islets with 15 CD45 cells 2.Clinical studies 3.Genetic 4. Polyglandular autoimmune syndrome  Primary defect: secretory dysfunction? Virus ?

41 Release of GLP-1 from islets from hyperglycaemic animals on HED. Upregulation of α-cell GLP-1 in Psam. obesus A.M.K. Hansen et al. (Diabetologia 2011, 54:1379–1387)

42 Glucagon and GLP-1 secretion from non-diabetic and type 2diabetic islets A local GLP-1 system in human pancreatic islets P. Marchetti et al (Diabetologia 2012, 55:3262–3272) Glucagon GLP-1

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


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