Diabetic Polyneuropathy

The presence of symptoms and/ or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes

  • est. 20.8 million people with DM in the US (2005)
  • 6th leading cause of death
  • 25% of diabetics develop foot complications at some point
  • > 1/2 of lower extremity amputations (86,000/year)
  • 80% after foot ulcer or injury

DiabetesMellitus is the most common cause of peripheral neuropathy in the developed world

  • 50% experience painful symptoms
  • 20% seek treatment
  • Affects 50-90% of patients with Diabetes Mellituts

Average yearly cost of pain meds: $1600

Incidence depends on Diabetes Mellitus duration and glycemic control.


  • calluses
  • skin changes
  • vascular problems
  • infections
  • joint abnormalities
  • charcot
  • ulcerations
  • amputation
  • 50-75% of nontramatic amputation (Duby et al)
  • Emotional reactions
  • Energy
  • Pain
  • Physical mobility
  • sleep
  • employment
  • recreation
  • social interactions
  • Poor Glycemic control
  • Cigarette smoking
  • HTN
  • Height
  • hypercholesterolemia


Pain and paresthesia

  • Burning pain
  • knife like
  • electrical sensation
  • constricting
  • hurting
  • freezing
  • throbbing
  • allodynia
  • Sensory Loss
  • More prevalent than positive
  • Asleep
  • “Dead”
  • Numbness
  • Tingling
  • Prickling

10% of Neuropathy in Diabetes Mellitus are not caused by Diabetes Mellitus


  • Monoclonal Gammopathy
  • Multiple Myeloma
  • Sjogren’s Syndrome

Genetic Disease
  • Hereditary motor and sensory neuropathy
  • Hereditary motor and autoimmune neuropathy
  • Fabry’s Disease

Infectious Disease
  • HIV
  • Hepatitis Virus
  • Leprosy
  • Tabes Dorsalis
  • Lyme Disease

Inflammatory Causes
  • Chronic Inflammatory Demyelinating Polyneuropathy
  • Paraneiplastic Neuropathy

Metabolic Disease
  • Uremia (including renal Failure)
  • Hypothyroidism

Nutritional Deficiencies
  • Alcoholism
  • Vitamin B deficiencies

Toxic Causes
  • Heavy metal poisoning
  • Drugs (paclitaxel, metronidazole, amiodarone, dapsone, nitrofurantoin, linezolid)

  • Polyarthritis nodosa (including Churg-Strauss variant)
  • Wegner’s Granulomatosis


Charcot Marie Tooth
– lead, arsenic
Vitamin B deficiency
Chronic alcoholism (nutritional deficiency)
Amyloid neuropathy
Guillian-Barre Syndrome
– cholchicine, hydralazine
Renal Insufficiency
Malabsorption disease

  • Semmes-Weinstein monofilament
  • 128hz tuning fork
  • Sharp/ dull
  • light touch
  • Warm cold
  • Distribution
    – mononeuropathy – focal lesion of a single nerve
    – polyneuropathy
  • Duration
  • Demyelinating Vs. Axonal
    – Electrodiagnosis studies
  • Course

Laboratory Investigation


CBC, ESR, CRP, Vit B-12, folate


Biochemical and endocrine
comprehensive metabolic panel (fasting blood glucose, renal function, liver function), glycosylated Hb (HbA1C), thyroid function test, serum protein electrophoresis.


Specialized test for specific diseases
connective tissue disease, vasculitis, nerve biopsy etc.



Quantitative Sensory Testing

  • Computer-based, nonivasive, psychophysical, semiobjective measure
  • Measure thermal and vibration sensations and cold-or-heat evoked pain threshold
  • Not specific to peripheral nerve function


Depressed nerve conduction velocity velocity usually indicates demyelination


Nerve Conduction velocity diminishes gradually DPN

  • Changes in nerve conduction velocity does not correlate with onset or severity of DPN pain or other clinical symptoms
  • Insensitive to pathological changes associated with DPN pain

Figure 1 Algorithm showing a stepwise approach to the assessment and investigation of a possible neuropathy. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CMT, Charcot-Marie-Tooth; EMG, electromyography; GBS, Guillain-Barre syndrome; HNPP, hereditary neuropathy with liability to pressure palsies; NCS, nerve conduction studies.



Classification: Clinical Patterns



  • Diabetic Poplyneuropathy
  • Diabetic autonomic neuropathy
  • “diabetic cachexia” Painful distal neuropathy associated with weight loss
  • Insulin neuritis
  • Hypoglycemic neuropathy



  • Diabetic radiculoplexus neuropathies
  • Lumbosacral
  • Thoracic
  • Cervical



  • Median neuropathy at the wrist
  • Ulnar neuropathy at the elbow
  • Peroneal neuropathies at the Fibular head


Cranial neuropathy

  • oculomotor palsy
  • abducens palsy



Why Distal & symmetrical?

Pathologically and electrophysiologically all nerves are affected in DPN
– large sensory or autonomic fibers predominate

Chronic DPN usually reveals a symmetrical sensory loss to all modalities in a stocking distribution
– Nerve fibers are affected in a length dependent fashion
* greater distance from the parent body

Small less myelinated fibers are affected first, Sensory rather motor

  • Focal Fiber Loss
  • Ischemic neuropathy
    – multiple regenerating fascicles, replace areas devoid of myelinated fibers
  • Decreased VEGF(A)

2 mechanisms

direct hyperglycemia-induced damage to nerve paremchyma

  • alteration in key enzymes (reduction in Na+/K+ ATP activity)
  • Reduction of neurotrophic factors, apoptosis, neuron loss

neuronal ischemia brought about indirectly by hyperglycemia induced blood flood

  • endoneuronial edema, increased endoneurial pressure, Capillary closure, schemia
  • Reduction in a NO, decreased vasorelaxation

Microvascular Disease

Blood flow decreased by 50% to peripheral nerves (Packer)

Vascular changes precede the development of DPN

Direct correlation between vessel damage and severity of DPN

Small blood vessels changes

  • thickening of the basement membranes of endoneurial capillaries
    – ischemic nerve injury
  • endothelial cell activation and proliferation
  • Pericyte degeneration
  • Monocyte adhesion

Histopathological Characteristics DPN

  • Characterized by a loss of myelinated and unmyelinated fibers observed in transverse nerve sections
  • thickening of axons- Increase in intracellular fluid

decrease in monofilaments
  • Capillary narrowing involving small myelinated or non-myelinated c-fibers

Mechanisms of hyperglycemia-induced vascular damage

  • In general, the adverse effects of hyperglycemia can cause vascular dysfunction by:
    – generating toxic and reactive metabolites
    – alternating intracellular signaling pathways
  • Aldose Reductase (Polyol Pathway) Theory
  • Advanced Glycation Endproduct Theory
  • Reactive Oxygen Intermediate Theory
  • Protein Kinase C Theory

Aldose Reductase Pathway

  • In Lab animals, osmotic imbalance that produces (edema) generative Schwaan cell changes
  • Some prevention of the pathological changes in rodent models of diabetic neuropathy, retinopathy, and nephropathy
  • Increased levels of AR in the lens–> cataract

Increased NADH/NAD+ ratio, alter gene expression, complications

Decline in NADPH, decrease generation of NO in endothelial cells



  • a mediator of cell-to-cell communication and potent vasodilator
  • Macrophages use as a cytotoxic agent
  • Impaired neuronal NO generation induces hyperalgesia

AGE Evidence

  • Aminoguanidine has been shown to block the development of microvascular complications of diabetes in animal models
  • Direct relationship between AGE levels and endothelium-dependent and independent vasodilation
  • Decreased endothelium prostacyclin (PGI2) production
  • Increased endothelial permeability to macromolecules

AGE Overview

Hyperglycemia, natural aging process

Maillard Reaction
  • irreversible binding of sugar to protein
  • nonenzymatic glycation

  • damage cells by impairing the function of a wide range of proteins (i.e. basic fibroblast growth factor), hormones, cytokines
  • Binding of AGE to RAGE produces a cascade of cellular signaling event
  • Modifications of extracellular structural proteins such as collagen and intracellular proteins
  • Inhibits production of NO
  • decreases the bioavailability and activity of endothelium derived NO NO
  • inhibits many mechanisms the contribute to the artherosclerosis
    – leukocyte adhesion
    – vascular smooth muscle cell growth
    – platelet adhesion

One of the oldest theories of Diabetic Complications

  • Decreased levels of antioxidants such as reduced Glutathione, NADPH Vitamin C, and Vitamin E in patients with diabetes
  • Increased levels of makers of Oxidative stress (oxidized LDLP and urinary isoprostanes)

Decreases equivalents used to drive the synthesis of ATP


increased oxidant levels stress reduces NO levels
– altered vasoregulation
– less detoxification of ROS

damages cellular proteins
– Vit E and Lipoic acid have improved early hemodynamic changes in the kidney, retina,and peripheral nervespromotes leukocyte adhesion to the endothelium while inhibiting its barrier function

Protein Kinase C Theory

intracellular signaling molecule, regulates many vascular functions permeability

  • vasodilator release
  • endothelial activation
  • growth factor signaling

Increased levels in various tissues of animals w/ diabetes

Inhibitors have been shown to block may abnormalities in endothelial cells

Activation of Protein Kinase C in the blood vessels of the retina, kidney, and nerves can produce

  • increased permeability
  • NO dysregulation
  • increased leukocyte adhesion
  • alterations in blood flow

PKC inhibitors- reversed


Tight glycemic control
  • emphasis of management
  • DCCTS (Diabetes Control and Complications Trail)
    – Intensive therapy of Type I diabetes reduces the frequency of appearance of neuropathy by 60% over a 5 year period in patients who did not have neuropathy at the onset of the study
  • UK Prospective Diabetes Study, Steno Study Rochester




  • Capsaicin– depletes tissues of substance P and reduces chemically induced pain
  • Topical Nitrate


Physical Therapy

  • percutanous nerve stimulation, static magnetic field therapy, low intensity laser therapy, monochromatic infrared light



Surgical Decompression

  • Neurolysis of the common peroneal nerve at the fibular neck, and deep peroneal at the dorsum of the foot
  • release of the 4 medial ankle tunnel – tarsal, medial and lateral plantar, calcaneal
  • Internal neurolysis of the tibial nerve
  • Prospective study 60 DM; 40 of unknown eitology

  • Non-traditional agents
  • Most effective in elderly (more tolerated)
  • Tramadol- opiod-like centrally acting synthetic narcotic analgesic effects on presynaptic Cl channels
  • Oxycodone controlled release
  • Addiction!
  • Possible add on therapy?


  • mainstay in many centers
  • Use is restricted due to frequency and severity of S.E.
  • Attempts to target mainly NE and 5HT
  • Reason for SE: affects many types of receptors such as muscurinic, histamine, dopamine, NMDA and alpha one receptors
  • Cymbalta (Duloxetine) equal affinity for 5HT and NE
    – primarily related to Anti-ACh actions: dry mouth blurred vision, cardiac arrhythmias, sedation, urinary retention, conatipation,and postural hypertention
    – Caution with: Monoamine oxidase inhibitor, those with uncontrolled narrow-angle glucoma, pts taking thioridazine


Anticonvulsants (Pregablin)


  • NA channel blockade
  • Potentiation of GABA activity
  • Ca+2 channel blockade
  • NMDA anatagonist

Derivative of GABA.

  • Attaches to overfiring nerve cellsbonds to Ca2+ channelmodualtes influx of Ca2+ in the hyperexcited neuronDecreases the flow of Ca2+ into the axon during depolarization or firing of the neuron decreasing the neurotransmitter release from the neuron
    � – Decreases in excitatory neurotransmitter (glutamate, NE, Substance P and Calcitonin gene- related peptide
Treatment: Future

VEFG (vacular endothelial growth factor)

– gene transfer in DM rats: restored NCV, nerve blood flow, nerve vessel numbers to normal


Identify the common pathway used by glucose to exert their effects
– New therapies against Protein Kinase C


Neutralization of specific glucotoxins such as ROS and AGE
– inhibitors of AR, AGE inhibitors, antioxidants, and anti-inflammatory agents
– Lack of efficacy due to dose limiting S.E. and inability to achieve adequate drug tissue levels

Treatment: Alpha Lipoic Acid
  • Free radical scavenger – acts as an antioxidant in preventing the oxidative stress associated w/ DPN
  • Germany > 30 years
  • Replenishes Glutathione


  • Diabetic neuropathy is a frequent complication of DM
  • Hyperglycemia and it’s metabolites can cause bewildering array of biomechanical and biological changes in vascular and peripheral neuronal tissues
  • The multiplicity of pathways by which hyperglycemia can generate toxic metabolites likely explains the general lack of efficacy of intervention targeted to a specific glucotoxin


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Vinik, Aron. Clinical Review: Use of Antiepileptic Drugs in the Treatment of Chronic Painful Diabetic Neuropathy. The Journal of Clinical Endocrinolgy 2005. 90:4936-4945
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