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Diabetic neuropathy

Diabetic neuropathy is a heterogeneous disorder that encompasses a wide range of

abnormalities affecting both proximal and distal peripheral sensory and motor nerves, as
well as the autonomic nervous system (ANS)
Multiple etiologies of diabetic neuropathy include a metabolic insult to nerve fibers,
neurovascular insufficiency, autoimmune damage, and neurohormonal growth factor
deficiency. Hyperglycemic activation of the polyol pathway leading to accumulation of
sorbitol and potential changes in the NAD:NADH ratio may cause direct neuronal
damage and/or decreased nerve blood flow. Activation of protein kinase C induces
vasoconstriction and reduces neuronal blood flow. Increased oxidative stress with
increased free radical production causes vascular endothelium damage and reduces
nitric oxide bioavailability. Excess nitric oxide production may result in formation of
peroxynitrite and damage endothelium and neurons, a process referred to as nitrosative
a) Cardiovascular autonomic neuropathy:
Cardiovascular autonomic neuropathy occurs in ~17% of patients with type 1 diabetes
and 22% of those with type 2. It is characterised by abnormalities in heart rate control
and central and peripheral vascular dynamics.
Clinical features:
1. Orthostatic hypotension, usually due to damage to the efferent sympathetic
vasomotor fibers, particularly in the splanchnic vasculature. In addition, there is a
decrease in cutaneous, splanchnic and total vascular resistance that occurs in
the pathogenesis of this disorder. Patients with orthostatic hypotension typically
present with lightheadedness and presyncopal symptoms. Symptoms such as
dizziness, weakness, fatigue, visual blurring, and neck pain also may be due to
orthostatic hypotension.
2. Exercise intolerance due to impaired sympathetic and parasympathetic
responses that normally augment cardiac output and redirect peripheral blood
flow to skeletal muscles. Exercise tolerance is also reduced by a reduced ejection
fraction, systolic dysfunction, and decreased diastolic filling.
3. Enhanced intraoperative cardiovascular lability,
4. Increased incidence of asymptomatic ischemia, and myocardial infarction. These
patients have more chances of silent ischemia. Reduced appreciation for
ischemic pain can impair timely recognition of myocardial ischemia or infarction
and thereby delay appropriate therapy. The characteristic diurnal variation in the
onset of myocardial infarction is altered in diabetic patients, with a lower morning
peak and a higher percentage of infarction during evening hours. Mortality rates
after a myocardial infarction are also higher for diabetic patients than for
nondiabetic patients.
5. Increased heart rate followed by a decrease in heart rate and, ultimately, a fixed
heart rate due to progressive dysfunction of the cardiac sympathetic nervous
system. Heart rate variability is considered the earliest indicator and most

frequent finding in symptomatic cardiovascular autonomic dysfunction. Regional

myocardial autonomic denervation and altered vascular responsiveness in
diabetic autonomic neuropathy may predispose to malignant arrhythmogenesis
and sudden cardiac death.
Tests for diagnosing cardiac autonomic neuropathy:
Ewing et al proposed five simple non-invasive cardiovascular reflex tests
-1.Valsalva maneuver
2. Heart rate response to deep breathing,
3. Heart rate response to standing up,
4. Blood pressure response to standing up, and
5. Blood pressure response to sustained handgrip
Today, sensitive and early assessment of cardiovascular autonomic neuropathy is
possible by means of noninvasive autonomic function tests, including power
spectral analysis of a series of successive R-R intervals (frequency domain
Treatment :
1. Antioxidant alpha-lipoic acid slows the progression of neuropathy
2. Cardioselective beta blockers restores the parasympathetic sympathetic
imbalance by sympathetic inhibition and thus may be helpful in treating
orthostatic hypotension.
3. ACE inhibitors like quinapril improves heart rate variability but controversial
4. 9-alpha flurohydrocortisone may be helpful for treating orthostatic
hypotension. Treatment is initiated with a 0.1 mg tablet and can be increased
to 0.5 mg daily
5. The peripherally acting selective -agonist midodrine is the most widely used
of these pressors. Patient sensitivity to this agent varies and the dose should
be titrated from 2.5 mg to 10 mg three times a day.
b) Impaired microvascular skin blood flow:
In diabetes, the rhythmic contraction of arterioles and small arteries is disordered.
Defective blood flow in the small capillary circulation is found with decreased
responsiveness to mental arithmetic, cold pressor, handgrip, and heating.
Impaired microvascular skin blood flow causes:
1. Reduction in the amplitude of vasomotion
2. Premature aging
3. Dry skin, loss of sweating, and the development of fissures and cracks that
are portals of entry for microorganisms, leading to infectious ulcers and
ultimately gangrene.
4. Increased osteoclastic activity resulting in reduced bone density
c) Gastrointestinal autonomic neuropathy:
Esophageal dysfunction due to vagal neuropathy. Symptoms include heartburn
and dysphagia for solids. Diabetic autonomic neuropathy can impair both gastric
acid secretion and gastrointestinal motility, causing gastroparesis diabeticorum.
Major clinical features of this disorder are early satiety, anorexia, nausea,
vomiting, epigastric discomfort, and bloating. Patients with gastroparesis have
emesis of undigested food consumed many hours or even days previously. The
finding of retained food in the stomach after an 8- to 12-hour fast in the absence

of obstruction is diagnostic of gastroparesis. Gastroparesis is also associated

with the development of bezoars. Due to gastroparesis there is disruption
between glucose absorption and exogenous insulin administration. This can
result in wide swings of glucose levels and unexpected episodes of postprandial
hypoglycemia and apparent "brittle diabetes."
Diarrhea and other lower gastrointestinal tract symptoms may also occur.
Diabetic diarrhea manifests as a profuse, watery, typically nocturnal diarrhea,
which can last for hours or days and frequently alternates with constipation.
Fecal incontinence due to anal sphincter incompetence or reduced rectal
sensation is another manifestation of diabetic gastrointestinal neuropathy.
Tests to diagnose:
1. Esophageal dysmotility diagnosed by esophageal motility testing and
esophageal scintigraphy.
2. Gastroparesis can be diagnosed by visualising gastric emptying of
radionuclide labelled food by scintigraphic imaging.
1. Good diabetic control
2. Small frequent meals
3. Prokinetic agents used to treat diabetic gastropathy are metoclopramide,
domperidone, erythromycin, and levosulpiride
4. In case of diabetic diarrhea restriction of soluble fiber and regular effort to
move the bowels is indicated. In addition, trials of gluten-free diet, restriction
of lactose, cholestyramine, clonidine, somatostatin analog, pancreatic enzyme
supplements, and antibiotics such as metronidazole may be indicated.
d) Genitourinary autonomic dysfunction:
Charachterised by:
1. Erectile dysfunction
2. Retrograde ejaculation
3. Neurogenic bladder
Treatment includes psychological counseling, medical treatment, or surgery.
Medical treatment may include sildenafil taken at a dose of 50 mg. Sildenafil is a
guanine monophosphate type-5 phosphodiesterase inhibitor that enhances blood
flow to the corpora cavernosae with sexual stimulation. A lower dosage is needed
for individuals with renal failure or liver dysfunction. Tadalafil (20 mg) and
vardenafil (20 mg) are also effective in more than 60% of diabetic patients with
erectile dysfunction.
e) Sudomotor dysfunction:

Manifests as anhidrosis of the extremities, which may be accompanied by

hyperhidrosis in the trunk. Initially, patients display a loss of thermoregulatory
sweating in a glove and stocking distribution that, with progression of autonomic
neuropathy, extends from the lower to the upper extremities and to the anterior
abdomen, conforming to the length dependency of diabetic neuropathy.
f) Hypoglycemic autonomic failure:
The spectrum of reduced counterregulatory hormone responses (in particular
epinephrine) and decreased symptom perception of hypoglycemia due to
decreased ANS activation after recent antecedent hypoglycemia has been
termed "hypoglycemia-induced autonomic failure." 45 Hypoglycemia-induced
autonomic failure leads to a vicious cycle of hypoglycemia unawareness that
induces a further decrease in counterregulatory hormone responses to