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Marc Y Donath

Targeting inflammation in the treatment of type 2 diabetes. Marc Y Donath. Glucose induces IL-1 β release from human islets. 0.8. *. 0.6. IL-1  (pg/islet). 0.4. 0.2. 0. 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.

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Marc Y Donath

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

  2. Glucose induces IL-1β release from human islets 0.8 * 0.6 IL-1 (pg/islet) 0.4 0.2 0 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

  3. Islet inflammation in type 2 diabetes Human pancreata Control Type 2 diabetes CD68 insulin J. Ehses et al. Diabetes 56: 2356-2370

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

  5. 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 35 assigned to placebo • 2 withdrew • 1 had an infected foot ulcer with phlegmone • 1 unblinded himself by analyzing study drug 34 completed the study 33 completed the study NEJM 356: 1517

  6. Placebo Anakinra 0.3 1.0 0.0 0.0 Glycated hemoglobin (%) Fasting plasma glucose (mM) –0.3 –1.0 * * *P<0.01 **P<0.05 ** ** P=0.004 P=0.03 –0.6 –2.0 4 13 0 3 6 8 12 Week Week Primary endpoint: change in HbA1c at 13 weeks

  7. Ratio of proinsulin to insulin AUC for C-peptide after oral glucose Placebo Anakinra 0.1 20 P=0.05 10 P=0.005 0.0 Change from baseline (nM x min) Change from baseline 0 –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 0 0 P=0.08 –1 P=0.05 –5 –2 –10 –3 –15 –4 –20

  8. Placebo Anakinra C-Reactive protein Interleukin-6 1 1 P=0.02 P=0.002 P<0.001 P<0.001 0 0 –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

  9. Clinical studies using IL-1 antagonism to treat patients with type 2 diabetes

  10. 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

  11. 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…

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

  13. The Inflacomb StudyMarc Donath, Gökhan Hotamisligil, Steven ShoelsonSteven Kahn, Herbert Tilg, Stefano Del Prato, Thomas Mandrup-Poulsen, Cees Tack, Gerit-Holger Schernthaner, Thomas Stulnig, Michaela Diamant, Nicolas Paquot

  14. 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 ?????

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

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

  17. Patient with Crohn Disease & Type 1 Diabetes Jun. 2011 Mar. 2011 Oct. 2011 Apr. 2012 Plasma glucose level (mmol/L) Infliximab Time (min) Diabetes Care 36:e90–91, 2013

  18. 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

  19. 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

  20. OBESITY EXERCISE IL-6

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

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

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

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

  25. ADIPOSE TISSUE GLP-1 β cell function and survival Satiety SKELETAL MUSCLE α α α α α α α α α α β β β β β β β β β β β β β β β β IL-6 INTESTINE PANCREATIC ISLET PC1/3 GLP-1 Ellingsgaard et al. Nat Med 2011; 17:1481-9.

  26. 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)

  27. Insulin secretion Acute GLP-1 effects on β-cells α α α α α α α α α α Food β β β β β β β β β β β β β β β β GLP-1 INTESTINE ISLET M. Y. Donath & R. Burcelin, Diabetes Care 2013 36 Suppl 2:S145-8.

  28. Insulin production β cell survival Chronic GLP-1 effects on β-cells α α α α α α α α α α β β β β β β β β β β β β β β β β ADIPOSE TISSUE IL-6 GLucose SKELETAL MUSCLE Glucagon PC1/3 GLP-1 IL-6 IL-6 Inflammation ISLET GLP-1 M. Y. Donath & R. Burcelin, Diabetes Care 2013 36 Suppl 2:S145-8.

  29. 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

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

  31. T to C exchange in exon 1 of SIRT1 leads to a Leucine to Proline mutation at residue 107 (L107P) E1 (1-430) E5 (22068-22215) E7 (24534-24719) E9 (31542-33661) E3 (4161-4402) E2 (2696-2812) E4 (6681-6833) Untranslated region E6 (23324-23403) E8 (27751-28308) c.[320T>C] p.Leu107Pro N C Regions necessary for SIRT1 activation CELL Metabolism 17:448–455, 2013

  32. Histone deacetylaseSirt1 • Regulation of lifespan / Protecting against age-related diseases • Adaptation of metabolism to calorie intake • Activated by Reseveratrol

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

  34. 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

  35. 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

  36. MY Donath

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

  38. 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.

  39. 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

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

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