Diabetes and Obesity as Inflammatory Diseases

Diabetes and Obesity as Inflammatory Diseases Jeremy Turner BHF Intermediate Fellow & Senior Lecturer, Imperial College Objectives: Obesity Inflammation Diabetes (T2DM) Atheroma • “Advances in Clinical Practice” • • • • • • Scale of the problem Background Clinical evidence of real effect Mechanisms Implications for clinical practice The future The Obesity Pandemic The Obesity Pandemic The Obesity Pandemic • • • • • • ~1 billion malnourished worldwide >1 billion overweight worldwide >350 million obese worldwide 2.5 million obesity-deaths annually 2000: 170 million diabetics worldwide 2020: Doubled Source: International obesity task force & WHO Background TNF and TNF Blockade Block TNF Reduced insulin resistance Conclusion: Inflammatory signals cause diabetes in obesity Clinical evidence of real effect Evidence for Inflammatory Activation in Obesity in Humans • Circulating marker association data • Expression profiling • Prospective studies – circulating markers and outcomes • Interventional studies Circulating Markers of Inflammation in Obesity & T2DM • • • • • • • • CRP (“hsCRP”) Fibrinogen TNF IL-6, IL-8, IL-18 MCP1 vWF ICAM PAI1 • Higher in obese vs lean • Higher in insulin resistant vs sensitive • Higher in T2DM vs normals Adipose Markers of Inflammation: CD68 Expression in Human Subcutaneous Adipose Tissue Weisberg, S. P. et al. J. Clin. Invest. 2003;112:1796-1808 Copyright ©2003 American Society for Clinical Investigation Is the “Inflammation” of Obesity More than an Epiphenomena? • Association is not causation • Other test of causation: – Temporal relationship – Dose dependency – Blocking the mediator blocks the outcome – Introducing the mediator recapitulates the phenotype Temporal Relationship Between Markers of Inflammation and Obesity Outcomes • Elevated IL-6 and hsCRP predict future risk of T2DM and MI • Independently of BMI Dose-dependency • Inflammatory markers correlate with BMI • IL-6 levels correlate with insulin resistance Blocking the Mediator: “REVERSAL” • • • • • Atorvastatin 80mg vs Pravastatin 40 mg Secondary prevention 502 patients End point = IVUS disease progression After correction for change in cholesterol, CRP reduction was an independent predictor of reduced atheroma progression. Rheumatoid Arthritis • Mortality rate due to IHD in RA 1.54 times control population. Wallburg-Johnsson et al. J Rheumatol. 1997 Mar;24(3) • Infliximab reduces IHD risk. Jacobsson et al.J Rheumatol. 2005 Jul;32(7) • Infliximab also improves insulin sensitivity Rheumatoid Arthritis • Mortality rate due to IHD in RA 1.54 times control population. Wallburg-Johnsson et al. J Rheumatol. 1997 Mar;24(3) • Infliximab reduces IHD risk. Jacobsson et al.J Rheumatol. 2005 Jul;32(7) • Infliximab also improves insulin sensitivity In-Vivo Experimental Evidence • TNF infusion increases insulin resistance in humans Is the “Inflammation” of Obesity More than an Epiphenomena? • Association is not causation • Other test of causation: – Temporal relationship – Dose dependency – Blocking the mediator blocks the outcome – Introducing the mediator recapitulates the phenotype – (biological plausability) Mechanisms Adipocytokines • “Inflammatory” – TNF – IL-6 • “Metabolic” – Leptin – Resistin – Adiponectin Macrophages in Adipose are a Source of Cytokin Implications for Clinical Practice • Lifestyle interventions • Pharmacological • Surgical Lifestyle • Dietary – Multiple studies show reduction of inflammatory markers in association with weight loss through dietary intervention. • Exercise – Mixed picture in the literature – Overall, associated with decrease in markers of inflammation – Not clear if this is over and above the effects of associated weight loss Surgery •Bariatric surgery •Proven to prevent diabetes •Weight loss ~ 30% •Several studies •Consistently reduces markers of inflammation Surgery •Bariatric surgery •Proven to prevent diabetes •Weight loss ~ 30% •Several studies •Consistently reduces markers of inflammation •Liposuction •Fewer reports •Even with 10 kg liposuction, no change in metabolic parameters and inflammatory markers eg. Klein et al, NEJM 2004 • • • • • Pharmacological Interventions that Reduce Markers of Inflammation Statins TZDs Orlistat Metformin Others Statins • REVERSAL study and CRP • Reduction of inflammatory markers in other situations eg sepsis TZDs • PROactive – Pioglitazone – 5238 T2DMs in RCT, secondary prevention – +ve 2 endpoints (†, MI & CVA), -ve 1 endpoints • Pioglitazone in T2DM with nephropathy – 21 days pioglitazone reduced CRP and IL-6 cf glipizide (non-RCT) – Agarwal Am J Physiol Renal Physiol. 2006 Mar;290(3) Orlistat • XENDOS study: Orlistat prevents T2DM • 36 obese individuals, 6 months orlistat – IL-6 and hsCRP at baseline, significantly higher in obese group cf. controls – 6.8 Kg weight loss, statistically significant CRP and IL-6 reductions – NOT an RCT Yesilbursa et al. Acta cardiol. 2005. 60 Metformin • DPP 3,234 adults with IGT, progression to T2DM: • Lifestyle • Metformin • Control • CRP reductions at 1 year: -29% -14% 0% Haffner et al. Diabetes. 2005 May;54(5) Others • ARBs • ACEIs • Fibrates • All reduce markers of inflammation and decrease cardiovascular mortality • HOPE: ACEI reduces onset of diabetes The Future • Rimonobant - CB1R antagonist • Glitazars - Combined PPAR  & agonists (Muraglitazar  excess CV mortality) • Oxyntomodulin - gut peptide with anorectic effects that also increases adiponectin levels • Others Conclusion Obesity Inflammation Diabetes (T2DM) Atheroma