This document discusses biomarkers in diabetes, including: 1. Biomarkers can help improve understanding of disease processes, predict disease severity and complications, and monitor treatment efficacy. 2. Liver enzymes like ALT and GGT, inflammatory markers like CRP and IL-6, and adipokines like adiponectin have been implicated in diabetes pathogenesis. 3. Simple risk scores combining basic measures like HbA1c and lipids can effectively predict diabetes, though more research is still needed on novel biomarkers.

1. BIOMARKERS IN
DIABETES

2. AGENDA
Introduction
Biomarkers for
 Pathogenesis
 Prediction
 Treatment guidance
Biomarkers- traditional vs novel
Conclusion

3. WHAT IS A BIOMARKER?
Objectively measured indicators or normal
or abnormal physiological processes of an
organism

4. WHAT SHOULD A BIOMARKER
DO?
Improve the understanding of a disease process
Predict disease severity / complication
Improve treatment targeting
Monitor treatment efficacy

5. BIOMARKERS &
PATHOGENESIS

6. BIOMARKERS AND DIABETES
PATHOGENESIS
Broadly reflect these putative mechanisms of diabetes development
Role of hepatic fat
Inflammation and diabetes
Association and causality
Adiponectin
Vitamin D

7. HEPATIC FAT AND DIABETES

8. HOW LIVER MOLECULES CAN
SERVE AS MARKER

9. LIVER FAT SURROGATES
USED AS MARKERS
ALT
 Men in the top quarter (> 29 U⁄ l) of baseline ALT vs.those in bottomquarter (< 17 U⁄ l) had an
adjusted odds ratio of 2.04 (95% CI 1.16–3.58) for incident diabetes in the West of Scotland
Coronary Prevention Study (WOSCOPS)
Sattar N e al. Diabetes 2004; 53: 2855–2860.

10. ALT & INCIDENT DIABETESNewdiabetes
>29 U/l => double risk of diabetes
< 17 U/l
17-21 U/l
22 – 28 U/l
0%
1%
2%
3%
4%
5%
0 1 2 3 4 5
Years
Sattar et al, Diabetes Nov 2004

11. LIVER FAT SURROGATES
USED AS MARKERS
GGT
Bilirubin
PAI -1
tPA All have been implicated as the prediction markers
SHBG
Ferritin
CRP

12. INFLAMMATION
The causality is not clear
Intervention studies will serve as the litmus test
Several molecules like
 CRP
 IL-6
Have been implicated in the pathogenesis

13. INFLAMMATION
AND DIABETES
Sattar N. Biomarkers for diabetes prediction, pathogenesis or pharmacotherapy guidance? Past, present and future possibilities. Diabet Med. 2012 Jan;29(1):5-13.

14. FACTORS IMPLICATED BY
EPIDEMIOLOGY
Adiponectin
 Endogenous insulin sensitizer
 Increased adiponectin – increased all cause mortality- The “adiponectin
paradox”
 More data needed
Vitamin D
 Deficiency supposed to cause diabetes
 Data weak
 Controversial

15. ADIPONECTIN , VITAMIN D
AND DIABETES

16. Pathway of putative risk
mechanism
Biomarker
Inflammation
IL-6, CRP, Fibrinogen, Myeloperoxidase, Neopterin,
Osteopontin, MCP-1, ST-2, MMP-9
Tissue damage/ ischaemia Hs Troponin I /T, NT-proBNP
Metabolic
Insulin, Proinsulin, NEFAs, Adiponectin, Leptin, HBA1c,
glucose, GGT?
Renal eGFR, Cystatin-C
Lipoproteins
Apolipoproteins AI, B, LpPLA2, sPLA2, Paroxonase ,
Lp(a)
Nutritional Homocysteine, N-3 fatty acids, Vitamin D
Endothelial ADMA, t-PA , CAMS, VWF
Thrombotic Fibrin D-dimer, Plasma viscosity
Oxidation Telomeres, oxLDL

17. BIOMARKERS FOR DIABETES
PREDICTION

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. Simple risk score at booking:
i.e. no bloods AUROC 82%
HDL-c, t-PA added AUROC
(86%) & IDI
BUT CRP, adiponectin NO
predictive value

20. 29 RCTS DM PATIENTS: SIMPLE PREDICTORS
OF RISK
PREISS, SATTAR, MCMURRAY (AHJ 2010)
Urine protein- “Death
merchant”?

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, BMI
ADD HbA1c to non-fasting lipids, U&Es, LFTs
Low risk:
General advice
Rescreen in 3 years ≥6.0 - 6.4%
Diabetes
High risk:
Lifestyle advice, weight loss
Rescreen in 1 year
Preiss, Khunti, Sattar: (Diab Med Jan 2011)
≥6.5%<6.0%

22. BIOMARKERS IN PREDICTION
OF 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. BIOMARKERS
OF
COMPLICATION
S OF DIABETES

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. TG
genetics, and retinopathy risk) but also treatment responses
(phenotype/genotype)

25. BIOMARKERS
AND
NEPHROPATH
Y

26. CANDIDATE PLASMA
BIOMARKERS – DN TYPE 1 DM
Four discovered
 Transthyretin,
 Apolipoprotein A1,
 Apolipoprotein C1
 Cystatin C.

27. INFLAMMATORY
BIOMARKERS IN DN TYPE 1
DM
Five urinary inflammatory markers
 IL-6
 IL-8
 Monocyte chemoattractant protein-1
 Interferon-gamma-inducible protein (IP-10)
 Macrophage inflammatory protein-1δ

28. TYPE 2 DM –DN-
BIOMARKERS
Compared to type 1 , not much studies
Best studied so far
Ubiquitin
Ss2 micro globulin

29. BIOMARKERS FOR DIABETIC
RETINOPATHY

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, and
other novel biomarkers for diabetic retinopathy: the multi-ethnic study of atherosclerosis. Diabetes Care. 2009
Sep;32(9):1704-9.
#Sasongko MB, Wong TY, Nguyen TT, Shaw JE, Jenkins AJ, Wang JJ. Novel versus traditional risk markers for
diabetic retinopathy. Diabetologia. 2012 Mar;55(3):666-70

31. DIABETIC RETINOPATHY- DO
WE NEED MARKERS?
Old New

32. BIOMARKERS
OF DIABETIC
NEUROPATHY

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) levels
El 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
El 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. BIOMARKERS –TRADITIONAL
VS NOVEL

35. TRADITIONAL VS NOVEL
BIOMARKERS
“Only 50 % of the identified biomarkers were regarded valid due to
modest methodological quality and frequent lack of adjustment for
traditional risk factors. More rigorous evaluation of novel biomarkers
is advocated to assess clinical applicability.”
Validity of Biomarkers Predicting the Onset and the Progression of
Nephropathy 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 Hiddo J. Lambers
Heerspink 1, Michael Rudnicki 2

36. Plasma hsCRP, E-selectin, TPA, vWF and triglycerides
significantly predicted onset or progression of nephropathy in
studies combining normoalbuminuric and microalbuminuric
patients.
Validity of Biomarkers Predicting the Onset and the Progression of
Nephropathy 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 Hiddo
J. Lambers Heerspink 1, Michael Rudnicki 2

37. UNMET NEEDS
Biomarkers to predict the progression
to insulin therapy
Biomarkers to predict differential
response to theapy

38. WHAT THE FUTURE HOLDS

39. FINAL THOUGHTS…