1. New Modalities in Diabetes Diagnosis Presented By: Kristin J. Brown, MSIV Dr. William M. Scholl College of Podiatric Medicine July 2011 Image source: http://www.nsinc.org/what-we-treat.php

2. Who Should Be Tested? According to the ADA 1 : Overweight/obese adults BMI >25 Who have one or more additional risk factors At age 45 years Repeat testing every 3 yrs If pre-diabetic, test every year.

3. Methods of Diagnosis  Source: ADA’s “Standards of Medical Care” 1

4. HbA1c vs. FPG & OGTT 1  ≥6.5 diagnose DM  Disadvantages  Higher in cost  Limited availability for testing.  Can be altered in patients with anemia and hemoglobinopathies.  Benefits  Fasting not required  Greater pre-analytical stability than FPG  Less vulnerable to alterations than FPG during stress & illness.

5. FPG 1  Studies have shown the FPG test has a specificity exceeding 96%, but it is only 50% sensitive. 2

6. FPG & OGTT 1  OGTT has been shown to have a sensitivity of 73% and specificity of 80%. 2  Both FPG and OGTT are invasive, fasting exams that suffer from poor reproducibility. 2

7. www.ngsp.org 3 HbA1c Assay Interferences “If your diabetes patient has a hemoglobin variant, your lab should use one of the methods that does not show interference from the variant, thus producing an accurate A1C result.”

8. Complications DDiabetes complications 1,4 : CCVD** PPVD NNephropathy RRetinopathy NNeuropathy PPeripheral and autonomic HHearing loss SStroke HHTN Image source: http://www.netheryeye.com/OurServices/DiabeticRetinopathy.aspx

9. Neuropathy 1,4  One of the most common late complications of DM.  Leading cause of non-traumatic amputations in the US.  Has a role in other late complications of diabetes.   Neuropathic ulcerations!  Increases risk of mortality.

10. Neuropathy Etiology  AGE’s (Advanced Glycation End products) 5  Increased in hyperglycemia & oxidative stress  Sugars cross-link with other proteins  Contribute to segmental demyelination and interact with nitric oxide  neronal apoptosis.  Excess sugars and proteins broken down by the Maillard reaction 5 :  Creates AGE’s Image source: http://www.artistaday.com/?p=5717/

11. AGE’s  Increased in skin collagen in those with neuropathy. 5  Especially pentosidine and cross-lines  These when excited with near-UV and blue light. fluoresce Image source: http://thegist.dermagist.com/how-to-increase-collagen-and-elastin-production

12. AGE’s  First screened via punch biopsy that often times required a suture for closure. 2  Now studies using near infrared (NIR) technologies. 2  Non-invasive  Portable & immediate results  Readings corrected for intrinsic fluorescence parameters. (dark vs. light skin, etc.) Image source: http://www.punchbiopsycpt.com/what-is-a-punch-biopsy

13. Studies  M.N. Ediger, B. Olson, and J Maynard. “Noninvasive Optical Screening for Diabetes.” Journal of Diabetes Science & Technology. 2009;3(4):776-780. 6  Retrospective cohort of 2,793 subjects  All identified as naïve & at risk based on the ADA’s Standard of Care Guidelines.  Compared FPG, HbA1c, and OGTT to SIF.  OGTT at 2hr 75g was considered the baseline.  Results

14. Studies  J.D. Maynard et al. “Noninvasive Type 2 Diabetes Screening”. Diabetes Care. 2007;30(5):1120-1124. 7  351 subjects with one or more DM risk factors.  Ages 21-86 years  Compared HbA1c, FGT, SIF vs. OGTT  84 pts had AGT (OGTT >140 mg/dL)  Results

15. Studies  B.N. Conway et al. “Skin Intrinsic Fluorescence Correlates with Autonomic and Distal Symmetrical Polyneuropathy in Individuals with Type 1 Diabetes.” Diabetes Care. 2011;34:1000-1005. 5  111 people with DM1  Mean age 49 years  Determined if CDSP and autonomic neuropathy associated with SIF vs. HbA1c.  Results

16. Scout DS by VeraLight 8 Image source: http://www.veralight.com/SCOUT_Video.html

17. Scout DS by VeraLight 8 Image source: http://www.veralight.com/SCOUT_Video.html

18. Scout DS by VeraLight 8 ≥50 =diabetic <50 =normal Image source: http://www.veralight.com/SCOUT_Video.html

19. Corneal Confocal Microscopy  “A rapid, non-invasive technique that enables a prospective and reiterative evaluation of the human cornea at high magnification [1-2 µm resolution].” 9  Utilizes confocal optics, which allows examination of a focused point. 9  Coronal sections of the cornea.  Can visualize corneal epithelium, Bowman’s membrane (nerve-complex), stroma, and endothelium.  Even better than histopathological exams! 9  Fun fact: The cornea is the most densely innervated part of the human body! 9

20. Corneal Confocal Microscopy Cont…  The cornea contains C and Aδ fibers. 9  Reminder: C fibers are large, unmyelinated fibers responsible for slow, aching pain. Aδ cause fast, sharp pain.  Those fibers account for the majority of symptoms in diabetic neuropathy, and have been shown to be damaged first. 9

21. Study  M. Tavakoli, et al. “Corneal Confocal Microscopy: A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy.” Diabetes Care. 2010;33(8):1792-1797. 10  110 DM and 17 healthy pts.  Assessed on NDS, QST, NCV (sural & peroneal), NCCA, CCM.  Results

22. Image source: M. Tavakoli, et al. “Corneal Confocal Microscopy: A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy.” Diabetes Care. 2010;33(8):1792-1797. O5 normal moderate mild severe

23. Conclusion  Skin Intrinsic Fluorescence and Corneal Confocal Microscopy are two technologies at the forefront of diabetic and diabetic neuropathy diagnosis.  They are non-invasive techniques that give immediate results, and have been shown by multiple studies to be superior to other techniques.  While they aren’t seen widely now, you will probably see them soon…

24. Image source: http://www.nsinc.org/what-we-treat.php Thank you. Questions?

25. References 1. American Diabetes Association. “Standards of Medical Care in Diabetes-2010.” Diabetes Care. 2010:33(supplement 1):511-561. 2. Hull, E., et al. “Noninvasive, optical detection of diabetes: model studies with porcine skin.” Optics Express. 2004;12(19):4496-4509. 3. Centers for Disease Control & Prevention. “Harmonizing Hemoglobin A1C Testing.” Accessed online July 12 th, 2011. http://www.ngsp.org/bground.asphttp://www.ngsp.org/bground.asp 4. American Diabetes Association website. “Living with Diabetes: Complications.” Accessed online July 10, 2011. http://www.diabetes.org/living-with- diabetes/complications/http://www.diabetes.org/living-with- diabetes/complications/ 5. Conway, B.N. et al. “Skin Intrinsic Fluorescence Correlates with Autonomic and Distal Symmetrical Polyneuropathy in Individuals with Type 1 Diabetes.” Diabetes Care. 2011;34:1000-1005. 6. Ediger, M.N., B. Olson, and J Maynard. “Noninvasive Optical Screening for Diabetes.” Journal of Diabetes Science & Technology. 2009;3(4):776-780. 7. Maynard, J.D. et al. “Noninvasive Type 2 Diabetes Screening”. Diabetes Care. 2007;30(5):1120-1124. 8. VeraLight Website. “The VeraLight Scout DS.” Accessed online July 10 th, 2011. http://www.veralight.com/products.html http://www.veralight.com/products.html 9. Hossain, P., A. Sachdev, and R. Malik. “Early detection of diabetic peripheral neuropathy with corneal confocal microscopy.” The Lancet. 2005;366:1340-1342. 10. Tavakoli, M. et al. “Corneal Confocal Microscopy: A novel and noninvasive test to diagnose and stratify the severity of human diabetic neuropathy.” Diabetes Care. 2010;33(8):1792-1797. 11. Malik, R.A. et al. “Corneal Confocal Microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients.” Diabetologia. 2003;46:683-688.