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

Diabetic Neuropathy

• Evidence for halting progression, causing reversal and

• Strategies for limiting the impact

• Sanjeev Kelkar

Diabetes Care Program 2004

Diabetic Neuropathy

• Evidence for halting progression

and causing reversal will be

tackled together

Diabetic NeuropathyEvidence 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)


• 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!!!!!

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)


• 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)

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

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

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


• 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

Diabetic Neuropathy


• 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)

Diabetic Neuropathy


• 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

Diabetic Neuropathy


• 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

Diabetic Neuropathy


• 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)

Diabetic Neuropathy


• 7th hope –

• Vasodialation or preventing vasoconstriction by ET1 antagonist in STZ rats

(Cameroon and Cotter, 1996)

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)

Diabetic Neuropathy

Evidence for halting progression, causing reversal• 8th hope –• Chronic Intermittent Intravenous Insulin Therapy CIIITRationale: 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

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.

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


• 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


• 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


• 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

Diabetic Neuropathy


• 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?

Diabetic Neuropathy


Symptomatic relief

Preventing ulceration, gangrene and amputation

Diabetic Neuropathy


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

Prostanoid deficiency

Evening Primrose oil

(Gamma linolenic acid)

Vasoconstriction

VasodilatorsACE inhibitors£ - blockers

Non enzymaticglycosylation

AminoguanidineFree radicals

Anti oxidants

Growth &Regeneration

Nerve growth factor

Topical ISDN spray

(Not as vasodilator, a NO donor)

Spinal cord stimulation

(TENS, PENS, NMDA channel blockers)

Lancinating pain

Burning pain

Painful cramps

Restless legs

Quinine sulphate

Clonazepam

Carbamazepine

Gabapentin

Allodynia

Plastic film to legs

Local anesthetics

Lidocaine

Mexiletine

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

Reassurance

Pain relief

Psychological support

Physiotherapy

Self limiting?

Carpal tunnel

Surgical decompression

Mononeuropathies

Compression

Amyotrophy

Diabetic Neuropathy

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

Diabetic Neuropathy


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

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

Documents

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