neuropathy reversal and limiting impact skke

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– PGE2helps 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
Evening Primrose oil
(Gamma linolenic acid)
Vasoconstriction
Vasodilators
ACE inhibitors
£ - blockers
Non enzymatic
glycosylation
Aminoguanidine
Free radicals
Anti oxidants
Growth &
Regeneration
Nerve growth factor

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

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

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

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