1. Diagnosis and Management of Diabetic Neuropathies Part 5 Aaron I. Vinik, MD, PhD, FCP, MACP Professor of Medicine/Pathology/Neurobiology Director of Research and Neuroendocrine Unit Eastern Virginia Medical School Strelitz Diabetes Center for Endocrine and Metabolic Disorders Norfolk, Virginia

2. For all three trials (SP742, SP743 and SP768), end point was defined as the last 4 weeks of the 12-week maintenance phase, and a last-observation-carried-forward approach was used. The p-values reported are for the comparison to placebo. *Mean change values reported † Least square mean change values reported Lacosamide in Painful Diabetic Neuropathy Selectively enhances slow inactivation of voltage- gated Na+ channels Modulates collapsin-response mediator protein 2 From Expert Review of Neurotherapeutics (2008) 8(11), 1649-1660 with permission of Expert Reviews Ltd. TrialPlacebo Lacosamide 400 mg/dayP-value SP742*-1.8-2.50.0126 SP743*-1.5-1.90.1248 SP768*-1.8-2.50.0507 Meta-analysis † (SP742, SP743 and SP768) -1.57-2.140.0006

3. Acetyl-L-Carnitine in Diabetic Neuropathy Double-blind placebo- controlled RCT; n=333 1 g IM for 10 days; 2 g orally for 355 days Primary outcome measure: NCV (motor and sensory) and amplitude; secondary: pain At 6 and 12 mo: NCV increased in active group; decrease or no change in placebo 199 pts had pain at baseline; 39% decrease at 12 mo De Grandis D, Minardi C. Drugs R D. 2002;3:223. * ** VAS 0 10 20 30 40 50 60 70 80 90 100 Pre6 mo12 mo Acetyl-L-carnitine Placebo * P<0.05 acetyl-L-carnitine vs placebo **P<0.01 acetyl-L-carnitine vs placebo

4. Topiramate Stimulates Nerve Regeneration Before Topiramate After Topiramate

5. Lifestyle Intervention for Pre-Diabetic Neuropathy Smith and Singleton. The Neurologist 2008;14: 23–29)

6. Neurologic Examination Autonomic Nerve Study Nerve- Conduction Study Glycemic Control Prevents Neuropathy The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977. Copyright © 1993 Massachusetts Medical Society. All rights reserved. Patients (%) P<0.001 P=0.04 P<0.001 0 5 10 15 20 25 30 35 40 Intensive therapy Conventional therapy

7. Epidemiology of diabetes intervention and complications (EDIC) study Metabolic Memory Counts Martin et al, 2006 Leroith, Fonseca, Vinik, 2006 Conventional therapy Intensive therapy 8-year follow-up of polyneuropathy (MNSI >2) after DCCT completion (n=1398) % with MNSI >2 1 9.1%  8.3% 8.2% 7.9% HbA 1c 7.4%  7.9% 8.1% 8.0% HbA 1c RR (95% CI): 43% (33-52%) Type 1 diabetes 30 25 20 15 10 0 2345678 EDIC year 5 End of DCCT DCCT, diabetes control and complications trial MNSI, Michigan neuropathy screening instrument

8. Pathogenesis Oriented Treatment of Distal Symmetric Diabetic Neuropathy Hyperglycemia PARP AGE formation Endogenous scavengers Reactive Oxygen Species Nitrotyrosine Diabetes Polyol pathway flux DyslipidemiaEFA dysmetabolism NEUROPATHY DAG PKC AII ET NO PGI 2 EDHF Vascular dysfunction Nerve and ganglion blood flow Endoneurial hypoxia Ischemia/ reperfusion ONOO - PKC ß Inhibitor ARIs Antioxidants Nutrinerve Pioglitazone ONOO - Vinik, A., Diabetic Neuropathies: New Treatment Modalities, Diabetic Microvascular Complications Today, Vol. 3(3), 23-26, 2006 Statins Aces/ Arbs

9. Summary and Conclusions: Diabetic Neuropathies Diabetic neuropathies are a heterogeneous group of disorders that occur in about 50% of patients with diabetes. Approximately 40% are painful. Single nerves may be involved (mononeuritis) and up to one third of patients have some form of entrapment. A variety of conditions masquerade as neuropathy and must be distinguished to avoid erroneous diagnoses and treatments. Distal symmetric polyneuropathy is the most common form of neuropathy and is a mixed sensorimotor neuropathy involving small and large fibers, with each fiber having a different etiology and producing its own constellation of features. Metabolic ( glucose and lipids) control as well as treatment of macrovascular risk factors is key to prevention. There are promising agents in the wings that address the core pathogenetic mechanisms and are potential targets for therapy in the future.

10. Conclusions Diagnosis requires the presence or absence of symptoms accompanied by objective signs of neuropathy or histologic evidence of loss of IENF Electrophysiology or a quantitative function test can be used for confirmation, but may be negative in small-fiber neuropathies Misdiagnosis is common, whether by specialists or generalists. There is a great need to educate physicians and health care providers and to ultimately empower patients to do self-evaluations

11. Acknowledgments