Diabetic Neuropathy

1. Diabetic Neuropathy • Evidence for halting progression, causing reversal and • Strategies for limiting the impact • Sanjeev Kelkar Diabetes Care Program 2004

2. Diabetic Neuropathy • Evidence for halting progression and causing reversal will be tackled together

3. Diabetic Neuropathy Evidence for halting progression, causing reversal • Experience - inexorable progression of DPN once started, • Hyperglycemia the trigger, poorer the control worse is progression • Hyperglycemia not the only factor though • Tight control not always possible • Success with symptomatic treatment satisfactory • Progression though not halted – in fact disappearance of pain may indicate worsening and not success (Aron Vinik – Exp Clin Endocrinol Diabetes- 109 (2001) Suppl 2)

4. Diabetic Neuropathy Evidence for halting progression, causing reversal • Etiology – Multiple mechanisms suggested – so we do not really know • Data from animal experiments – does not translate to good outcomes in humans – ARIs a case in point • Type 1 and 2 have different pathological features, frequencies, mechanisms (Aron Vinik – Exp Clin Endocrinol Diabetes- 109 (2001) Suppl 2) • Light at the end of the tunnel? – Yes – not dazzling but hopeful!!!!!

5. Diabetic Neuropathy Evidence for halting progression, causing reversal • 1st hope – tight control of blood glucose • DCCT in 9 years with intensive back up • 50% reduction in intensive group • 3% of primary prevention group at the end showed minimal impairment versus 10% in conventional treatment group • Secondary prevention groups showed 56% reduction (DCCT Research group 1993)

6. Diabetic Neuropathy Evidence for halting progression, causing reversal • 2nd hope – • Pancreas transplantation with establishment of normoglycemia prevents progression • 115 transplants – motor & sensory NCV significantly increased - clinical signs and autonomic tests showed slight improvement • Transplant halts progression and improves function (Navarro et al 1997)

7. Greet Van Den Bergh • Critical illness polyneuropathy and insulin treatment – differences • Reduced length of stay in ICU in the intensive insulin group had less patients screened – 20.5% as against 26.3% • p = .007

8. Greet Van Den Bergh • Of the patients screened – • Intensive insulin treated group was less likely to develop critical illness polyneuropathy; • In those who developed it, it resolved quicker than the conventional group

9. Greet Van Den Bergh • In conventional group – linear correlation between blood glucose and neuropathy • In this study there is only one difference in the way the two groups are treated • Intensive against conventional insulin therapy

10. Diabetic Neuropathy Evidence for halting progression, causing reversal • 3rd hope – • Control of oxidative stress • Alpha lipoic acid – a thiol replenishing and redox modulating agent • Anti oxidant actions: Metal chelating activity ROS scavenging Regenerating endogenous antioxidants like glutathione, Vit C & E Repair of proteins, DNA and lipids

11. Diabetic Neuropathy Evidence for halting progression, causing reversal • 3rd hope – • Control of oxidative stress • Shown to be effective in ameliorating both somatic and autonomic neuropathy in diabetes in European trials • Stimulates skeletal muscle glucose uptake and changes NADH / NAD+ & GSH GSSG ratios • Currently large trial in USA (Ziegler et al, 1995, 1997, 1999, Roy et al, 1997)

12. Diabetic Neuropathy Evidence for halting progression, causing reversal • 4th hope – • Control of oxidative stress – gamma linolenic acid • Serves as an important constituent of neuronal membrane phospholipids • Serves as a substrate of PGE2 – PGE2 helps preserve blood flow to the nerves • Metabolism of GLA impaired in diabetes • Multi-center double blind placebo controlled trial by Keen et al, 1993, showed significant improvement in clinical and electrophysiologic testing

13. Diabetic Neuropathy Evidence for halting progression, causing reversal • 5th hope – • Control of oxidative stress – Vit E • Most efficient antioxidant in lipid phase - (Vinik ibid) • Pharmacologic doses of Vit E may improve defective motor nerve conduction in persons with diabetes (Tutuncu et al, 1998) • Reduces endoneurial lipid peroxidation that has a tendency to self perpetuate lipid peroxidation

14. Diabetic Neuropathy Evidence for halting progression, causing reversal • 6th hope – • Vasodialation: Cilostozol – Rat data impressive • Improves Na+ K+ ATPase channels activity • Improves structural myelin, ratio of endoneurial and vascular area ratios • Improves MNCV and cAMP activity • No human trials yet on neuropathy (Inada et al, 1996, Ushera et al, 1997, Suh et al, 1999)

15. Diabetic Neuropathy Evidence for halting progression, causing reversal • 7th hope – • Vasodialation or preventing vasoconstriction by ET1 antagonist in STZ rats (Cameroon and Cotter, 1996)

16. Diabetic Neuropathy Evidence for halting progression, causing reversal • 8th hope – • Chronic Intermittent Intravenous Insulin Therapy CIIIT (Thomas Oki, et al in Diabetes Technology and Therapeutics Vol 3, Number 1, 2001, Mary Ann Liebert)

17. Diabetic Neuropathy Evidence for halting progression, causing reversal • 8th hope – • Chronic Intermittent Intravenous Insulin Therapy CIIIT Rationale: Pulsatile insulin infusions trying to improve portal hepatic venous insulin levels, thereby normalizing Respiratory Quotient in persons with Diabetes using biostator Conceivably several days of hyperinsulinimic normoglycemic clamp could do the same

18. Diabetic Neuropathy Evidence for halting progression, causing reversal • 8th hope – • Chronic Intermittent Intravenous Insulin Therapy CIIIT • Best known effect on postural hypotension • Marked decrease in the intensity and frequency of postural dizziness in all subjects • Complete secession of postural dizziness in two months Other effects: Improved circadian BP rhythms with consequent possible effects on distensibility of the arterial tree and diabetic autonomic neuropathy also.

19. Diabetic Neuropathy Evidence for halting progression, causing reversal • 9th hope – Experimental - Nerve growth factors: Administration by injections, Selectivity of different NGFs for particular types Diabetes induced abnormalities in NGF receptors Gene therapy in rats have shown some promise • Alternative approach – Using small molecules of prosapsoin derivatives acting as ligands for NGF receptors stimulating growth are being tried (Calcutt, Tomlinson et al, Unpublished data) • TX14 a similar derivative has acute anti allodynic action in 30 minutes and 48 hours

20. Diabetic Neuropathy Evidence for halting progression, causing reversal • 10th hope – More than Experimental – C peptide seems pretty useful in halting / reversing T1 neuropathy Close to 100% Type 1 develop DPN • Totally deficient in C peptide • Not so in type 2 – has some C peptide • Decidedly different pathologic changes between T1 and T2

21. Diabetic Neuropathy Evidence for halting progression, causing reversal • 10th hope – C peptide seems pretty useful in halting / reversing T1 neuropathy • 3 hour IV infusion or 3 months of injections of C peptide improves autonomic nerve function (RR variations) Johansson BL, et al Diabetologia, 1996 • 3 months subgroup showed improved thermal discrimination threshold due to stimulation of Na-K-ATPase activity, better electrolyte balance, enzyme activity, endoneurial blood flow, NO release, • Insulin therapy alone did not achieve this Johansson BL, et al, 2000

22. Diabetic Neuropathy Evidence for halting progression, causing reversal • 10th hope – C peptide seems pretty useful in halting / reversing T1 neuropathy • Double blind placebo controlled study by Ekberg et al, 2003 showed significant improvement in Sural NCV (80%), and vibration perception threshold as compared to insulin only treated group More marked for greater deficits at baseline Peroneal motor nerve did not improve DRG rich in Insulin Receptors, secrets cytoskeletal proteins, that flow along the axons – hence improved? Sugimoto K 2002

23. Diabetic Neuropathy Evidence for halting progression, causing reversal • 11th hope – PKC inhibitors in STZ rats • 12th hope - Inhibiting accumulation of glycation products within the axon as it increases glycation of Axonal cytoskeletal proteins like tubulin, neurofilament and actin, contirbuting to axonal degeneration and slowing of axonal transport (Ryle C et al, 1997,) • Glycation of lamilin, a major constituent of Schwann cells and basal lamina, important in sprouting of nerves may cause impaired regeneration – Federoff et al, 1993 • Myelin basic and proteolipid proteins also glycate and are scavenged by macrophages via RAGE leading to segmental demyelination • Could we block RAGE?

24. Diabetic Neuropathy • Strategies for limiting the impact Symptomatic relief Preventing ulceration, gangrene and amputation

25. Diabetic Neuropathy • Strategies for limiting the impact Symptomatic relief of pain and dysesthesias NSAIDs, Amitryptiline, Carbamazepine, codeine etc Gabapentine 300 mg thrice Good glycemic control – insulin use if necessary Insulin well documented in Diabetic Amyotropy DA reversible in 18 months

26. Prostanoid deficiency Vasoconstriction Evening Primrose oil (Gamma linolenic acid) Vasodilators ACE inhibitors £ - blockers Non enzymatic glycosylation Aminoguanidine Growth & Regeneration Free radicals Anti oxidants Nerve growth factor

27. OTHER OPTIONS Topical ISDN spray (Not as vasodilator, a NO donor) Spinal cord stimulation (TENS, PENS, NMDA channel blockers)

28. SYMPTOMATIC TREATMENT Burning pain Lancinating pain Local anesthetics Lidocaine Mexiletine Carbamazepine Gabapentin Restless legs Clonazepam Painful cramps Quinine sulphate Allodynia Plastic film to legs

29. Diabetic Neuropathy • Painful neuropathies are associated with chronic fatigue due to sleep deprivation, depression and effects of drugging specially Carbamazepine, amytriptiline, etc • Patients need psychological support, many of the proximal truncal neuropathies are reversible, patients need that hope to be given to them, pain may stop on its own though damage may progress • Support and knowledge about what is happening or likely to happen - essential

30. Mononeuropathies • Compression • Amyotrophy Self limiting? • Reassurance • Pain relief • Psychological support • Physiotherapy Carpal tunnel Surgical decompression

31. Diabetic Neuropathy • Strategies for limiting the impact Preventing ulceration, gangrene and amputation • What to look for to act upon? • What action to take?

32. Diabetic Neuropathy • Strategies for limiting the impact Preventing ulceration, gangrene and amputation • What to look for to act upon? Vascular insufficiency – palpate, Doppler Corns, Calluses, pressure points – Inspection, Harris mat, Ink Pad, Mirror below the feet, Pedobarographs, Static Pressure images, Dynamic scans of variety of capabilities - Nails – Hypertrophied, angulated causing injury, ingrowing, - cut, trim, invert

33. Diabetic Neuropathy • Early cellulitis vis a vis Charcot’s • Deformities leading to pressure points – Corrective footwear, Inspect first the footwear in use, see if it is ok, where is it pinching? Does it follow the basic principles of footwear for anyone and for persons with diabetes? Change if necessary Web space and fungal infections; applications, baths, massages and fomentations Educate, educate, educate and educate