New Modalities in Diabetes Diagnosis

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 ADA1: 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 & OGTT1 • ≥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. FPG1 • Studies have shown the FPG test has a specificity exceeding 96%, but it is only 50% sensitive.2

6. FPG & OGTT1 • 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.org3 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 • Diabetes complications1,4: • CVD** • PVD • Nephropathy • Retinopathy • Neuropathy • Peripheral and autonomic • Hearing loss • Stroke • HTN Image source: http://www.netheryeye.com/OurServices/DiabeticRetinopathy.aspx

9. Neuropathy1,4 • 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 • Excess sugars and proteins broken down by the Maillard reaction5: • Creates AGE’s • 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. 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 VeraLight8 Image source: http://www.veralight.com/SCOUT_Video.html

17. Scout DS by VeraLight8 Image source: http://www.veralight.com/SCOUT_Video.html

18. Scout DS by VeraLight8 ≥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. Aδcause 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. normal mild moderate severe 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

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

25. References American Diabetes Association. “Standards of Medical Care in Diabetes-2010.” Diabetes Care. 2010:33(supplement 1):511-561. Hull, E., et al. “Noninvasive, optical detection of diabetes: model studies with porcine skin.” Optics Express. 2004;12(19):4496-4509. Centers for Disease Control & Prevention. “Harmonizing Hemoglobin A1C Testing.” Accessed online July 12th, 2011. http://www.ngsp.org/bground.asp American Diabetes Association website. “Living with Diabetes: Complications.” Accessed online July 10, 2011. http://www.diabetes.org/living-with-diabetes/complications/ 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. Ediger, M.N., B. Olson, and J Maynard. “Noninvasive Optical Screening for Diabetes.” Journal of Diabetes Science & Technology. 2009;3(4):776-780. Maynard, J.D. et al. “Noninvasive Type 2 Diabetes Screening”. Diabetes Care. 2007;30(5):1120-1124. VeraLight Website. “The VeraLight Scout DS.” Accessed online July 10th, 2011. http://www.veralight.com/products.html Hossain, P., A. Sachdev, and R. Malik. “Early detection of diabetic peripheral neuropathy with corneal confocal microscopy.” The Lancet. 2005;366:1340-1342. 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. 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.