Biomarkers in diabetes

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Novel Biomarkers in Diabetes - a framework for understanding them

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Biomarkers in diabetes

  1. 1. BIOMARKERS INDIABETES
  2. 2. AGENDAIntroductionBiomarkers for Pathogenesis Prediction Treatment guidanceBiomarkers- traditional vs novelConclusion
  3. 3. WHAT IS A BIOMARKER?Objectively measured indicators or normalor abnormal physiological processes of anorganism
  4. 4. WHAT SHOULD A BIOMARKERDO?Improve the understanding of a disease processPredict disease severity / complicationImprove treatment targetingMonitor treatment efficacy
  5. 5. BIOMARKERS &PATHOGENESIS
  6. 6. BIOMARKERS AND DIABETESPATHOGENESISBroadly reflect these putative mechanisms of diabetes developmentRole of hepatic fatInflammation and diabetesAssociation and causalityAdiponectinVitamin D
  7. 7. HEPATIC FAT AND DIABETES
  8. 8. HOW LIVER MOLECULES CANSERVE AS MARKER
  9. 9. LIVER FAT SURROGATESUSED AS MARKERSALT Men in the top quarter (> 29 U⁄ l) of baseline ALT vs.those in bottomquarter (< 17 U⁄ l) had anadjusted odds ratio of 2.04 (95% CI 1.16–3.58) for incident diabetes in the West of ScotlandCoronary Prevention Study (WOSCOPS)Sattar N e al. Diabetes 2004; 53: 2855–2860.
  10. 10. ALT & INCIDENT DIABETESNewdiabetes>29 U/l => double risk of diabetes< 17 U/l17-21 U/l22 – 28 U/l0%1%2%3%4%5%0 1 2 3 4 5YearsSattar et al, Diabetes Nov 2004
  11. 11. LIVER FAT SURROGATESUSED AS MARKERSGGTBilirubinPAI -1tPA All have been implicated as the prediction markersSHBGFerritinCRP
  12. 12. INFLAMMATIONThe causality is not clearIntervention studies will serve as the litmus testSeveral molecules like CRP IL-6Have been implicated in the pathogenesis
  13. 13. INFLAMMATIONAND DIABETESSattar N. Biomarkers for diabetes prediction, pathogenesis or pharmacotherapy guidance? Past, present and future possibilities. Diabet Med. 2012 Jan;29(1):5-13.
  14. 14. FACTORS IMPLICATED BYEPIDEMIOLOGYAdiponectin Endogenous insulin sensitizer Increased adiponectin – increased all cause mortality- The “adiponectinparadox” More data neededVitamin D Deficiency supposed to cause diabetes Data weak Controversial
  15. 15. ADIPONECTIN , VITAMIN DAND DIABETES
  16. 16. Pathway of putative riskmechanismBiomarkerInflammationIL-6, CRP, Fibrinogen, Myeloperoxidase, Neopterin,Osteopontin, MCP-1, ST-2, MMP-9Tissue damage/ ischaemia Hs Troponin I /T, NT-proBNPMetabolicInsulin, Proinsulin, NEFAs, Adiponectin, Leptin, HBA1c,glucose, GGT?Renal eGFR, Cystatin-CLipoproteinsApolipoproteins AI, B, LpPLA2, sPLA2, Paroxonase ,Lp(a)Nutritional Homocysteine, N-3 fatty acids, Vitamin DEndothelial ADMA, t-PA , CAMS, VWFThrombotic Fibrin D-dimer, Plasma viscosityOxidation Telomeres, oxLDL
  17. 17. BIOMARKERS FOR DIABETESPREDICTION
  18. 18. PRINCIPLES TO PONDERNo need of perfectionSimple risk scores can get us farNeed to combine CVD and diabetes risk screeningHbA1c enters the arena!
  19. 19. Simple risk score at booking:i.e. no bloods AUROC 82%HDL-c, t-PA added AUROC(86%) & IDIBUT CRP, adiponectin NOpredictive value
  20. 20. 29 RCTS DM PATIENTS: SIMPLE PREDICTORSOF RISKPREISS, SATTAR, MCMURRAY (AHJ 2010)Urine protein- “Deathmerchant”?
  21. 21. Combined Cardiovascular risk / Diabetes screening:Current cardiovascular risk assessment questions:Age, gender, prior CVD, family Hx CVD, smoking, ethnicity, social deprivation (post code)Simple measurements:Blood pressure, BMIADD HbA1c to non-fasting lipids, U&Es, LFTsLow risk:General adviceRescreen in 3 years ≥6.0 - 6.4%DiabetesHigh risk:Lifestyle advice, weight lossRescreen in 1 yearPreiss, Khunti, Sattar: (Diab Med Jan 2011)≥6.5%<6.0%
  22. 22. BIOMARKERS IN PREDICTIONOF INCIDENT DIABETESToo many to know!Salomaa V, Havulinna A, Saarela O, Zeller T, Jousilahti P, Jula A, Muenzel T, Aromaa A, Evans A, Kuulasmaa K, Blankenberg S.Thirty-one novel biomarkers as predictors for clinically incident diabetes. PLoS One. 2010 Apr 9;5(4):e10100.
  23. 23. BIOMARKERSOFCOMPLICATIONS OF DIABETES
  24. 24. BIOMARKERS – COMPLICATIONS /TREATMENT GUIDANCE?1. To better predict CVD & microvascular & other complications?2. Predict declining beta cell function/ progression to insulin?3. Help predict differential response to therapies?4. Combine with genetics to determine not only causal pathways (e.g. TGgenetics, and retinopathy risk) but also treatment responses(phenotype/genotype)
  25. 25. BIOMARKERSANDNEPHROPATHY
  26. 26. CANDIDATE PLASMABIOMARKERS – DN TYPE 1 DMFour discovered Transthyretin, Apolipoprotein A1, Apolipoprotein C1 Cystatin C.
  27. 27. INFLAMMATORYBIOMARKERS IN DN TYPE 1DMFive urinary inflammatory markers IL-6 IL-8 Monocyte chemoattractant protein-1 Interferon-gamma-inducible protein (IP-10) Macrophage inflammatory protein-1δ
  28. 28. TYPE 2 DM –DN-BIOMARKERSCompared to type 1 , not much studiesBest studied so farUbiquitinSs2 micro globulin
  29. 29. BIOMARKERS FOR DIABETICRETINOPATHY
  30. 30. NOVEL BIOMARKERSPlasmin-α2-antiplasmin complex (PAP)*Fibrinogen*ApoAI#Retinal arteriolar tortuosity#*Nguyen TT, Alibrahim E, Islam FM, Klein R, Klein BE, Cotch MF, Shea S, Wong TY. Inflammatory, hemostatic, andother novel biomarkers for diabetic retinopathy: the multi-ethnic study of atherosclerosis. Diabetes Care. 2009Sep;32(9):1704-9.#Sasongko MB, Wong TY, Nguyen TT, Shaw JE, Jenkins AJ, Wang JJ. Novel versus traditional risk markers fordiabetic retinopathy. Diabetologia. 2012 Mar;55(3):666-70
  31. 31. DIABETIC RETINOPATHY- DOWE NEED MARKERS?Old New
  32. 32. BIOMARKERSOF DIABETICNEUROPATHY
  33. 33. NEUROPATHY- BIOMARKERSErythrocytes glutathione (GSH) levelPlasma malondialdehyde (MDA)Nitrite/nitrate (NOx)Homocysteine (Hcy) levelsSerum ceruloplasmin (Cp)Total antioxidants (TAO)Endothelin-1 (ET-1) levelsEl Boghdady NA, Badr GA. Evaluation of oxidative stress markers and vascular risk factors inpatients with diabetic peripheral neuropathy. Cell Biochem Funct. 2012 Jun;30(4):328-34El Boghdady NA, Badr GA. Evaluation of oxidative stress markers and vascular risk factors in patients with diabetic peripheral neuropathy. Cell Biochem Funct. 2012 Jun;30(4):328-34
  34. 34. BIOMARKERS –TRADITIONALVS NOVEL
  35. 35. TRADITIONAL VS NOVELBIOMARKERS“Only 50 % of the identified biomarkers were regarded valid due tomodest methodological quality and frequent lack of adjustment fortraditional risk factors. More rigorous evaluation of novel biomarkersis advocated to assess clinical applicability.”Validity of Biomarkers Predicting the Onset and the Progression ofNephropathy in Patients with Type 2 Diabetes: A Systematic ReviewMerel E. Hellemons 1*, Julia Kerschbaum 2*, Stephan J.L. Bakker 1, HannesNeuwirt 2, Bernd Mayer 3, Gert Mayer 2, Dick de Zeeuw 1 Hiddo J. LambersHeerspink 1, Michael Rudnicki 2
  36. 36. Plasma hsCRP, E-selectin, TPA, vWF and triglyceridessignificantly predicted onset or progression of nephropathy instudies combining normoalbuminuric and microalbuminuricpatients.Validity of Biomarkers Predicting the Onset and the Progression ofNephropathy in Patients with Type 2 Diabetes: A Systematic ReviewMerel E. Hellemons 1*, Julia Kerschbaum 2*, Stephan J.L. Bakker 1,Hannes Neuwirt 2, Bernd Mayer 3, Gert Mayer 2, Dick de Zeeuw 1 HiddoJ. Lambers Heerspink 1, Michael Rudnicki 2
  37. 37. UNMET NEEDSBiomarkers to predict the progressionto insulin therapyBiomarkers to predict differentialresponse to theapy
  38. 38. WHAT THE FUTURE HOLDS
  39. 39. FINAL THOUGHTS…

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