Diabetic Neuropathy :

Complications and Management

 Diabetic Neuropathy
 About 60-70% of people with
diabetes have mild to severe
forms of nervous system damage,
including:
 Impaired sensation or pain in the feet
or hands
 Slowed digestion of food in the
stomach
 Carpal tunnel syndrome
 Other nerve problems
 More than 60% of non-traumatic
lower-limb amputations in the
United States occur among people
with diabetes.
Diabetic Peripheral Nerve Damage
Myelinated Neuron
 Incidence of Diabetic Neuropathy
as a proportion of all diabetics 20 years after diagnosis

No
neuropathy
10%

Asymptomati
c 40%

Symptomatic
50%
 Risk Factors
• Glucose control
• Duration of diabetes
• Damage to blood vessels
• Mechanical injury to nerves
• Autoimmune factors
• Genetic susceptibility
• Lifestyle factors
– Smoking
– Diet
 Physical manifestations

• Nerve fibers degenerate

• Blood vessels supplying the nerves
are ‘grossly diseased’

Any theory needs to account for both

 Underlying Mechanisms

Agreement not yet reached on exact

causal relationship between insulin
imbalance and nerve damage.

The relative importance and inter-

relationship of the various mechanisms
is the subject of ongoing research and
debate.
 Pathways of action

• Polyol pathway
• Triose phosphate effects
• Failure of nerve growth & repair
mechanism
• Fatty acid metabolism
 1. Polyol Pathway
• Polyol = Polyhydroxy alcohols
• High blood glucose
– Nerve cell and capillary membranes
have insulin-independent glucose
transport.
– High intra-cellular glucose levels
– Conversion of glucose to sorbitol in
nerve cells by aldose reductase enzyme
– Sorbitol cannot cross membranes and
therefore accumulates
•
1. Polyol Pathway
Consequences of high sorbitol concentration:
– Osmotic damage to nerve cells
– reduction in nerve myoinositol
– Inhibition of nitric oxide (NO) production
• Aldose reductase competes for NADPH
• NO is vasodilator
– Increased production of free radicals
• Superoxide, hydrogen peroxide, hydroxyl
• Formed during mitochondrial respiration
• Increased oxidative stress (proteins, lipids, DNA)
 1. Polyol Pathway
• Treatment possibilities
– Aldose reductase inhibitors
– Supplemental myoinositol
– Nitric oxide stimulation/sensitisation
– Vasodilators
– Antioxidants
 2. Triose glucose
• High intracellular phosphates
leads to
increased production of triose
phosphates
– Activation of protein kinase C (PKC) via
DAG
• Damages capillaries (permeability, contractility)
• Damages nerve function
– Non-enzymic reaction with proteins & DNA
• Advanced Glycation End-products (AGEs)
• Damage to capillaries and nerve fibres
• Specific cellular AGE receptors
• Protein cross-linking
 4. Fatty acid metabolism
• Functions of DGLA and AA in nerves
– Incorporated into membranes
• required for normal nerve structure, which
is required for normal nerve conduction
– Required for regulation of nerve
conduction
• via inositol/calcium cycle and PGE1
– Required for microvascular system
• DLMG - Prostaglandin E1
• AA - Prostacyclin
 Pathogenesis of Diabetic
Neuropathy
• Metabolic factors
– High blood glucose
– Advanced glycation end products
– Sorbitol
– Abnormal blood fat levels
• Ischemia
• Nerve fiber repair mechanisms
Natural history of diabetic
neuropathy and clinical
signs and symptoms with
pathological background.

• With increasing stage of

neuropathy, there is a
progressive loss of nerve fibers
that convey sensation.
• When the fibers undergo
degeneration or impaired re-
myelination, they release
impulse of positive symptoms.
• With progression of disease,
negative symptoms of sensory
loss are increased
Multifactorial etiology of diabetic
neuropathy:
Hyperglycemia exerts increased
polyol pathway, enhanced AGE
formation, increased oxidative
stress as well as cytokine
release.
These factors are complicatedly
interactive or independently
operate for the cause and
development of diabetic
neuropathy directly affecting
nerve tissues or through nutrient
vascular tissues
Mechanisms of how polyol
pathway causes neuropathy:
Increased polyol pathway affects
differently nerve fibers and
supplying vascular tissues.
In nerve tissues, polyol
yperactivity causes suppression
of PKC activity by the inhibition
of membranous PKC-a
expression while it causes
increased PKC activity by
elevation of membranous PKC-b
expression in vascular wall.
These dichotomous processes
eventually elicit decreased Na,K-
ATPase activity of nerve tissues
and delay of nerve conduction
Pathological findings of sural
nerve obtained from diabetic
patients with clinically overt
neuropathy.

There is a marked loss of

myelinated nerve fibers of both
large and small caliber.
Endoneurial vessels show typical
microangiopathic changes
exemplified by thickened wall
(arrow) (A).

There is also a marked loss of

unmyelinated fibers at EM level
(B).
 Diagnostic Tests
• Assess symptoms - muscle weakness,
muscle cramps, prickling, numbness or
pain, vomiting, diarrhea, poor bladder
control and sexual dysfunction
• Comprehensive foot exam
– Skin sensation and skin integrity
– Quantitative Sensory Testing (QST)
– X-ray
• Nerve conduction studies
• Electromyographic examination (EMG)
• Ultrasound
 Classification of Diabetic
Neuropathy

• Symmetric polyneuropathy
• Autonomic neuropathy
• Polyradiculopathy
• Mononeuropathy
 Symmetric Polyneuropathy
• Most common form of diabetic
neuropathy
• Affects distal lower extremities and
hands (“stocking-glove” sensory
loss)
• Symptoms/Signs
– Pain
– Paresthesia / dysesthesia
– Loss of vibratory sensation
 Complications of Sensorimotor
neuropathy
• Ulceration (painless)
• Neuropathic edema
• Charcot arthropathy
• Callosities
 Treatment of Symmetric
Polyneuropathy

• Glucose control
• Pain control
– Tricyclic antidepressants
– Topical creams
– Anticonvulsants
• Foot care
 Essentials of Foot Care
• Examination
– Annually for all patients
– Patients with neuropathy - visual inspection of
feet at every visit with a health care professional
• Advise patients to:
– Use lotion to prevent dryness and cracking
– File calluses with a pumice stone
– Cut toenails weekly or as needed
– Always wear socks and well-fitting shoes
– Notify their health care provider immediately if
any foot problems occur
 Autonomic Neuropathy
Symptomatic Subclinical abnormalities
Postural hypotension Abnormal pupillary
Gastroparesis reflexes
Diabetic diarrhea Esophageal dysfunction
Neuropathic bladder Abnormal cardiovascular
Erectile dysfunction reflexes
Neuropathic edema Blunted counter-
regulatory responses to
Charcot arthropathy hypoglycemia
Gustatatory sweating Increased peripheral
blood flow
 Autonomic neuropathy
• Affects the autonomic nerves
controlling internal organs
– Peripheral
– Genitourinary
– Gastrointestinal
– Cardiovascular
• Is classified as clinical or subclinical
based on the presence or absence of
symptoms
 Peripheral Autonomic
Dysfunction
• Contributes to the following
symptoms/signs:
– Neuropathic arthropathy (Charcot foot)
– Aching, pulsation, tightness, cramping, dry skin,
pruritus, edema, sweating abnormalities
– Weakening of the bones in the foot leading to
fractures
• Testing
– Direct microelectrode recording of
postglanglionic C fibers
– Galvanic skin responses
– Measurement of vascular responses
 Peripheral Autonomic
Dysfunction, cont.
• Treatment
– Foot care/elevate feet when sitting
– Eliminate aggravating drugs
– Reduce edema
• midodrine
• diuretics
– Support stockings
– Screen for CVD
 Genitourinary Autonomic
Neuropathy
Sign/Symptom Treatment
Bladder dysfunction Voluntary urination;
catheterization

Retrograde ejaculation Antihistamine

Erectile dysfunction PDE-5 Inhibitors (i.e.

Levitra®/vardenafil)

Dyspareunia Lubricants; estrogen

creams
 Gastrointestinal Autonomic
Neuropathy
• Symptoms/Signs
– Gastroparesis resulting in anorexia, nausea,
vomiting, and early satiety
– Diabetic enteropathy resulting in diarrhea and
constipation
• Treatment
– Other causes of gastroparesis or enteropathy
should first be ruled out
– Gastroparesis - Small, frequent meals,
metoclopramide, erythromycin
– Enteropathy - loperamide, antibiotics, stool
softeners or dietary fiber
 Cardiovascular Autonomic
Neuropathy
• Symptoms/Signs
– Exercise intolerance
– Postural hypotension
• Treatment
– Discontinue aggravating drugs
– Change posture (make postural
changes slowly, elevate bed)
– Increase plasma volume
 Polyradiculopathy
• Lumbar polyradiculopathy (diabetic
amyotrophy)
– Thigh pain followed by muscle weakness
and atrophy
• Thoracic polyradiculopathy
– Severe pain on one or both sides of the
abdomen, possibly in a band-like pattern
• Diabetic neuropathic cachexia
– Polyradiculopathy + peripheral neuropathy
– Associated with weight loss and
depression
 Polyradiculopathy, cont.
• Polyradiculopathies are diagnosed
by electromyographic (EMG) studies
• Treatment
– Foot care
– Glucose control
– Pain control
 Mononeuropathy
• Peripheral mononeuropathy
– Single nerve damage due to compression
or ischemia
– Occurs in wrist (carpal tunnel syndrome),
elbow, or foot (unilateral foot drop)
– Symptoms/Signs
• numbness
• edema
• pain
• prickling
 Mononeuropathy, cont.
• Cranial mononeuropathy
– Affects the 12 pairs of nerves that are
connected with the brain and control sight,
eye movement, hearing, and taste
– Symptoms/Signs
• unilateral pain near the affected eye
• paralysis of the eye muscle
• double vision
• Mononeuropathy multiplex
 Mononeuropathy, cont.

• Treatment
– Foot care
– Glucose control
– Pain control
 Other Treatment Options

• Aldose reductase inhibitors

• ACE inhibitors
• Weight control
• Exercise
 Anticonvulsant Drugs for
Neuropathic Pain Disorders
• Postherpetic neuralgia • HIV-associated
– gabapentin* neuropathy
– pregabalin * – lamotrigine
• Diabetic neuropathy • Trigeminal neuralgia
– carbamazepine – carbamazepine*
– phenytoin – lamotrigine
– gabapentin – oxcarbazepine
– lamotrigine • Central post-stroke pain
– pregabalin * – lamotrigine

*Approved by FDA for this use.

HIV = human immunodeficiency virus.
 Tricyclic Antidepressants:
Adverse
• Commonly reported AEs
Effects
(generally anticholinergic): Fewest
– blurred vision AEs • Desipramine
– cognitive changes
– constipation • Nortriptyline
– dry mouth
– orthostatic hypotension • Imipramine
– sedation
• Doxepin
– sexual dysfunction
– tachycardia Most • Amitriptyline
– urinary retention AEs
AEs = adverse effects.
 Principles of Opioid Therapy
•
for Neuropathic Pain
Opioids should be titrated for therapeutic efficacy
versus AEs
• Fixed-dose regimens generally preferred over prn
regimens
• Document treatment plan and outcomes
• Consider use of opioid written care agreement
• Opioids can be effective in neuropathic pain
• Most opioid AEs controlled with appropriate specific
management (eg, prophylactic bowel regimen, use of
stimulants)
• Understand distinction between addiction, tolerance,
physical dependence, and pseudoaddiction
Diabetic Neuropathy &
Glycemic Control
 GLYCEMIC CONTROL AND
COMPLICATIONS
• The Diabetes Control and Complications
Trial (DCCT) provided definitive proof that
reduction in chronic hyperglycemia can
prevent many of the early complications of
type 1 DM.
• This large multicenter clinical trial
randomized over 1400 individuals with type
1 DM to either intensive or conventional
diabetes management, and then evaluated
the development of retinopathy,
nephropathy, and neuropathy
Benefits of Glycemic Control

• nonproliferative and proliferative

retinopathy (47% reduction),
• microalbuminuria (39% reduction),
• clinical nephropathy (54% reduction)
• neuropathy (60% reduction)
Intensive Diabetes Management

• group would experience 15.3 more years

of life without significant microvascular or
neurologic complications of DM as
compared to individuals who received
standard therapy.
 Pharmacological Therapy for
Diabetes Mellitus
• Oral Diabetic Medications:
– Sulfonylureas
– Biguanides
– Alpha-Glucosidase Inhibitor
– Nonsulfonylurea Secretagogues
• Meglitinide
• D-phenylalanine derivatives
– Thiazolidinediones (TZDs)
• Insulins
– Mealtime Insulins
• Rapid Acting and Short Acting
– Basal Insulins
• Intermediate Acting and Long Acting
– Premixed
 Sulfonylureas
• Act by stimulating the pancreatic
secretion of insulin
• Side Effects
– Weight gain
– Hypoglycemia
– GI disturbances
– Skin reactions
• Two Classes
– 1st Generation
– 2nd Generation
 Biguanides
• Method of Action
– Suppresses hepatic glucose production
– Increases peripheral glucose uptake
• Side Effects:
– GI disturbances – usually dose related
– Lactic Acidosis – creatinine clearance level must
be known prior to therapy
 Alpha-Glucosidase Inhibitor
• Delay absorption of glucose from GI tract by
slowing the breakdown of complex
carbohydrates
• No systemic absorption
• Must be taken at the beginning of the meal
• Side Effects
– GI disturbances
• Acarbose (Glucobay®):
– Optimal Dose: 3 x 100 mg
– Titrated dose only for sensitive patients:
• Increased as tolerance is developed starting with 50 mg QD and
increasing to 100mg TID
Non-sulfonylurea Secretagogues
• Stimulate pancreatic insulin secretion but uses a
fast action with short duration
• Must be taken at the beginning of each meal and
avoided if meal is missed
• Side Effects
– Hypoglycemia
– Weight gain
• 2 classes of drugs:
– Meglitinide Class
• Repaglinide
– D-phenylalanine Derivative Class
• Nateglinide
 Thiazolidinediones (TZD)
• Decreases peripheral insulin resistance and hepatic
glucose production
• Side Effects
– Peripheral Edema
– Weight gain
– Caution in use with patients in advanced CHF
– Caution with liver failure - monitoring liver function
imperative
• 2 types available
– Pioglitazone
– Rosiglitazone
 References
American Diabetes Association: Preventive Foot Care in Diabetes
(Position Statement). Diabetes Care 27 (Suppl.1): S63-S64, 2004

Feldman, EL: Classification of diabetic neuropathy. In UpToDate.

Wellesley, MA, UpToDate, 2003

National Diabetes Information Clearinghouse. Diabetic Neuropathies:

The Nerve Damage of Diabetes. Bethesda, MD: National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of
Health (NIH), DHHS; 2002

National Diabetes Information Clearinghouse. Prevent Diabetes

Problems: Keep Your Feet and Skin Healthy. Bethesda, MD: National
Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health (NIH), DHHS; 2003
 References, cont.
Feldman, EL: Pathogenesis and prevention of diabetic
polyneuropathy. In UpToDate. Wellesley, MA, UpToDate, 2003.

Feldman, EL, McCulloch, DK: Treatment of diabetic neuropathy. In

UpToDate. Wellesley, MA, UpToDate, 2003.

Stevens, MJ: Diabetic autonomic neuropathy. In UpToDate.

Wellesley, MA, UpToDate, 2003.

Feldman, EL: Clinical manifestations and diagnosis of diabetic

polyneuropathy. In UpToDate. Wellesley, MA, UpToDate, 2003.