Inflammation & Type 2 Diabetes Prof. Marc Y. Donath

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1 Inflammation & Type 2 Diabetes 1, MD Chief Endocrinology, Diabetes & Metabolism University Hospital Basel Petersgraben 4 CH-431 Basel, Switzerland MDonath@uhbs.ch Innate immunity as a sensor of metabolic disturbance DANGER! 2 Glucose induces b-cell apoptosis in P. obesus Glucose (mm): Diabetes 48:

2 Glucose induces IL-1b release from human islets IL-1b (pg/islet) D-glucose (mm) L-glucose (mm) Maedler et al., J Clin Invest 22; 11: 81 6 Hyperglycemia induced b-cell production of IL-1b Type 2 diabetes Insulin IL-1b Psammomys obesus Insulin IL-1b Control Low-energy Diabetes High-energy High-energy & Phlorizin Maedler et al., J Clin Invest 22; 11: 81 6 Endogenous production of interleukin-1 receptor antagonist (IL-1Ra) Human islets IL-1Ra Insulin Control Diabetes 6 PNAS 11: 8138; 24 2

3 Islet cells express IL-1 receptor at far higher levels than other tissues 7 Böni-Schnetzler et al., Endocrinology 1: , 29 Decreased functional b-cell mass in type 2 diabetes One Tough Puzzle Inflammation Leptin, IL-6 TNFa, IL-1b NF-kB 8 Glucose FFA, LDL IL-8 Pander Immune cell infiltration The missing piece 9 3

4 Islet inflammation in type 2 diabetes Human pancreata Control Type 2 diabetes 1 Insulin CD68 J. Ehses et al., Diabetes 6: weeks 8 weeks 16 weeks Mice on Chow Diet Mice on High Fat Diet 11 J. Ehses et al., Diabetes 6: IL-1Ra reduces islet inflammation in the GK rat 12 J.A Ehses et al., PNAS 16: 13998, 29 4

5 IL-1Ra reduces islet immune cell infiltration in the GK rat Macrophage staining Control IL-1Ra 13 J. A Ehses et al., PNAS 16: Islet inflammation in type 2 diabetes CD68: Type 2 Diabetic TUNEL: Type 2 Diabetic CD68: Type 2 Diabetic 14 J. Ehses et al., Diabetes 6: Donath & Shoelson Nat. Rev. Immun. 211; 11: 98-17

6 16 Primary endpoint: change in HbA1c at 13 weeks Placebo Anakinra.3 P=.4 P=.3 1. Glycated hemoglobin (%) Week 13 Fasting plasma glucose (mm) Week P<.1 P<. 17 Ratio of proinsulin to insulin AUC for C-peptide after oral glucose Change from baseline P=. Change from baseline (nm x min) 2 P= Change from baseline (nm x min) AUC for C-peptide after IV glucose P=.8 Change from baseline (nm x min) AUC for C-peptide after oral and IV glucose combined P=. 18 Placebo Anakinra 6

7 C-Reactive protein Interleukin-6 (IL-6) 1 P=.2 P=.2 1 P<.1 P<.1 Change from baseline (mg/liter) Change from baseline (mg/liter) Week Week 19 Placebo Anakinra IL-1 inhibition provides durable improvement in b-cell function and inflammatory status 2. Diabetes Care 32: ; IL-1 antagonism in type 2 diabetes 1) Interleukin-1-receptor antagonist in type 2 diabetes mellitus; N Engl J Med. 27; 36: ) Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes; Diabetes Care 29 32: ) Treatment with anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study; J Clin Endocrinol Metab. 211; 96: ) IL-1β antibody improves insulin secretion rates in subjects with impaired glucose tolerance and type 2 diabetes; ADA Meeting 211; 36-LB ) Safety and efficacy of monthly s.c. canakinumab administration for the treatment of hyperglycaemia in metformin monotherapy-treated type 2 diabetic patients; EASD Meeting 211; P89 6) Pharmacokinetic and pharmacodynamic modelling of subcutaneous LY218912, a neutralising IL-1β antibody, in patients with type 2 diabetes mellitus; EASD Meeting 211; P897 7) Safety, tolerability and efficacy of subcutaneous LY218912, a neutralising IL-1b antibody, in patients with type 2 diabetes; EASD Meeting 211; P898 8) Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes mellitus; Diabetes Care, 3(8): , 212 7

8 J Clin Endocrinol Metab 96: , 211 Anakinra treatment showed decrease in systemic inflammation as a decrease of C-reactive protein and leukocytes Anakinra treatment showed an increase in the disposition index measurements which shows improved insulin secretion 22 American Diabetes Association, 71 st scientific sessions June 24-28, 211 San Diego, CA 23 IL-1b antibody (canakinumab) improves insulin secretion rates in subjects with impaired glucose tolerance (IGT) and type 2 diabetes (T2DM); Rissanen A, Howard C, Botha J and Thuren T; 36-LB Safety, tolerability and efficacy of subcutaneous (SC) LY (LY), a neutralizing IL-1b antibody, in patients (Pts) with type 2 diabetes (T2DM) Sloan-Lancaster J, Abu-Raddad E, Polzer J, Miller J. W, Scherer J. C, Berg J. K., Landschulz W. H; 47-LB; (Published online as: Double-Blind, Randomized Study Evaluating the Glycemic and Anti-inflammatory Effects of Subcutaneous LY218912, a Neutralizing IL-1β Antibody, in Patients With Type 2 Diabetes, Diabetes Care, 213 Online Ahead of Print, doi:1.2337/dc ) Monthly s.c. canakinumab administration in type 2 diabetic patients Baseline HbA1c th EASD Annual Meeting, Hensen, J. et al., Abst 89 8

9 Double-Blind, Randomized Study Evaluating the Glycemic and Anti-inflammatory Effects of Subcutaneous LY218912, a Neutralizing IL-1β Antibody, in Patients With Type 2 Diabetes Diabetes Care, 213 Online Ahead of Print, doi:1.2337/dc Placebo-corrected decrease in HbA1c of -.27, -.38 and -.2% for.6, 18 and 18 mg by end of treatment (week 12) 2. Placebo-corrected decrease in HbA1c of -.18, -.9 and -.43% for.6, 18 and 18 mg by end of follow up (week 24; sustained effect for 12 weeks) 3. Patients achieving HbA1c < 7% 2.4, 31.3, and 26.3% for.6, 18, and 18 mg 4. Decreased postprandial glucose. Enhanced insulin secretion 6. Reduction in CRP 2 Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes mellitus Diabetes Care, 3(8): , 212 Single doses of.3 and.1 mg/kg: Placebo-corrected decrease in HbA1c.8% after 3 months single injection Enhanced C-peptide secretion Reduction in CRP Reduction in spontaneous and inducible cytokines Improvement in fatigue Diabetes Care (1): e18 26 The IL-1 system & insulin resistance The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity Cell metabolism 21; 12(6): 93-6 The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance Nature medicine 211; 17(2): Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling Nat Immunol 211; 13(): Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1beta transcription in human adipose tissue Diabetes 211 Feb; 6(2):

10 Canakinumab (Anti-IL-1b) anti-inflammatory thrombosis outcomes study (CANTOS) CANTOS sub-study on long-term effect of canakinumab on insulin secretion rate and other glucose control parameters following an oral glucose tolerance test in type 2 diabetics 17,2 participants over 4 years!!! Primary endpoint: CV Secondary endpoints: New onset diabetes Diabetes specific sub-study 28 Exercise IL-6 Obesity 29 Exercise-induced GLP-1 is IL-6 dependent IL-6 (pg/ml) Active GLP-1 (pmol/l) 1 1 Resting Running Exercise 9 WT IL-6 KO Active GLP-1 (pmol/l) 12 1 Resting Running Active GLP-1 (pmol/l) Exercise Isotype IL-6 AB 9 Ellingsgaard et al., Nat Med 211; 17:

11 IL-6 improves oral glucose tolerance 31 Blood glucose (mmol/l) ipgtt Insulin (ug/l) Ctrl IL-6 inj Blood glucose (mmol/l) OGTT: chow OGTT Chow Ctrl Chow IL-6inj Ellingsgaard et al., Nat Med 211; 17: Ctrl IL-6 inj Skeletal Muscle IL-6 Intestine GLP-1 32 Pancreatic Islet b b b a a a b a b b b a β b b a a a b a b b IL-6 improves b-cell function in obese mice Insulin (ug\l) Insulin (ug\l) HF ctrl HF IL6inj OGTT: HF OGTT: db/db db/db Ctrl db/db IL6inj Blood glucose (mmol/l) Blood glucose (mmol/l) HF ctrl HF IL6inj db/db Ctrl db/db IL6inj Insulin (ug\l) Insulin (ug\l) OGTT: ob/ob ob/ob Ctrl ob/ob IL6inj OGTT: HF-STZ 1 3 HF-STZ ctrl HF-STZ IL6inj Blood glucose (mmol/l) Blood glucose (mmol/l) ob/ob Ctrl ob/ob IL6inj HF-STZ ctrl HF-STZ IL6inj 11

12 Intermittently elevated IL-6 improves glucose homeostasis 34 Ellingsgaard et al., Nat Med 211; 17: Intermittently elevated IL-6 increases GLP-1 synthesis in intestine and pancreas Intestine Pancreas 3 Ellingsgaard et al., Nat Med 211; 17: Proglucagon processing Proglucagon GaRPP Glucagon IP1 GLP-1 IP2 GLP-2 L cell Prohormoneconvertase 1/3 (PC1/3) GRPP Glucagon IP1 GLP-1 IP2 a cell Prohormoneconvertase 2 (PC2) GRPP Glucagon IP1 36 GLP-2 GLP-1 IP2 GLP-2 12

13 IL-6 increases GLP-1 in human a-cells 37 Ellingsgaard et al., Nat Med 211; 17: HF diet increases GLP-1 synthesis and PC1/3 expression in a-cells PC1/3 Glucagon Overlay IL-6 KO Chow Wild type HF diet Chow 38 HF diet Summary Adipose Tissue Skeletal Muscle IL-6 39 Intestine GLP-1 Brain Hypothalamus Satiety Pancreatic Islet PC1/3 b b b a a GLP-1 b b a b a a b β b b a a a b a b b b-cell function and survival 13

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