Diabetic neuropathy is a family of nerve disorders

Diabetic
neuropathy is a family of nerve disorders caused as a result of diabetes
mellitus. Diabetes mellitus is a chronic metabolic disorder that affects the
bod’s ability to turn glucose into energy needed to carry out various bodily
functions. Diabetes is a Greek originated word meaning siphon (to pass
through), mellitus is derived form Latin, and translates to sweet or honeyed.

This is because in those who have diabetes mellitus, a high concentration of
glucose (sugar) is found in the bloodstream as well as urine (https://health.howstuffworks.com/diabetes).

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When people eat carbohydrates, the intestines break down the carbohydrates into
glucose. After this is done, there is an elevation of glucose in the
bloodstream. The insulin producing beta cells in the pancreas are signaled to
produce and secrete insulin. Insulin is a hormone that attaches and signals to
cells to absorb the glucose from the blood steam in order to use it for energy
(https://www.endocrineweb.com).

However, in individuals suffering from diabetes, they are unable to produce
insulin, or are able to produce insulin, but for various reasons their body is
unable to properly utilize it.

There are various forms of diabetes such
as: gestational, LADA, MODY, cystic fibrosis induced, juvenile onset, but these
subsets are generally categorized into Type One diabetes (insulin deficient),
and Type Two diabetes (insulin resistance). Nonetheless, both categories lead
to elevated glucose. Prolonged elevated blood glucose leads to complications
such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy (http://www.diabetes.org/diabetes-basics).

Earlier studies of diabetes, excluded nervous system pathologies that arose as
a result of diabetes. But, around the nineteenth century, Pavy del Calvi, a
medical doctor and researcher, was the first to note a linkage between diabetes
and diabetic neuropathies. In 1921, Frederick Banting, a Canadian doctor,
alongside Charles Best, an American biomedical scientist jointly discovered insulin.

It was this discovery that gave rise to interest in research of diabetes
complications. Not too long after the invention of insulin used to treat
diabetes, Fagerberger noticed that most diabetes complications were due to
micro vascular damage (https://patient.info/doctor/diabetic-neuropathy).

Epidemiology and Etiology

Diabetic neuropathy affects sixty to
seventy percent of all patients diagnosed with any form of diabetes. Diabetic
neuropathy is generally more common among males than females, with a ratio of
roughly two to one. In regards to onset of diabetic neuropathy, type one
diabetics usually develops DN ten years or more after initial diagnosis of type
one diabetes. On the contrary, type two diabetics are commonly diagnosed with
DN at the same time of their diabetes diagnosis. In type one diabetes, symptoms
of the disease tend to abruptly develop, and progress quite rapidly. But, in
type two diabetes symptom progression tends to be on the slower side, and in
many instances takes years to become clinically noticeable. A hemoglobin A1c
(Hb A1c) is a test that measures the concentration of glucose on red blood
cells over the last three moths. Typically high glucose concentration on red
blood cells is indicative of poor glycemic control. Type two diabetics tend to
have higher A1c levels at diagnosis than type one diabetics. It is believed
that the difference in the aggressive progression of type one diabetes and the
often slow diagnosis of type two diabetes account for the difference in onset
of neuropathy in type one and type two diabetics. Type two diabetics are more
likely to develop DN, even with good glycemic control. This may be due to the
different pathways involved in DN for type one and type two diabetics (Luo, et
al, 2017). There are several established risk factors associated with diabetic neuropathy.

These risk factors are: gender, a history of poor glycemic control (Hg A1c of
7.0 and above), increased duration of diabetes (the longer one has diabetes
more likely he/she is to develop DN), heart disease, smoking, a history of
diabetic retinopathy and or diabetic nephropathy, and hypertension (Jaiswal et
al 2017).  

When nerve fibers and blood vessels are
exposed to high blood glucose, capillaries that provide nutrients and oxygen to
nerves are damaged and destroyed. This damage is what leads to diabetic
neuropathy. In type one diabetics it is believed that gylcotoxicity is the
cause of DN, while in type two diabetics it is believed that lipotoxicity is
what leads to DN. Painful neuropathy is due to: expansion of receptive fields,
reduction in threshold to activate neurons, and lastly, exaggerated response to
synaptic inputs (Feldman, et al, 2017). Pain is caused in DN when there is an
expansion in the effective stimulation in the range of sensitive locations,
such as fingers and toes. In normal neurons, the threshold needed for
depolarization is around -55mV to -65mV. However in painful DN, there is a
reduction of this threshold that leads to pain (Luo, et al, 2017). There are
four major types of DN, they are: chronic peripheral neuropathy, and acute
peripheral neuritis, which both affect sensory nerves, autonomic neuropathy
which affects nerves involving involuntary bodily functions, and proximal motor
neuropathy, which is the only DN that affects motor neurons (https://patient.info/doctor/diabetic-neuropathy).

Signs and Symptoms

Presentation of DN is dependent on the
type of neuropathy involved. Chronic peripheral neuropathy has equal prevalence
among type one and type two diabetics. The symptoms of CPN include: reduced
sensitivity to touch such as hot and cold temperatures, as well as sensations
to pain. Pain hypersensitivity, as well as burning, stinging, and deep aching
pains are all symptoms of chronic peripheral neuropathy. In acute peripheral
neuritis, onset is usually abrupt, and is associated with sudden glycemic
control after long term uncontrolled diabetes. It is unrelated to diabetes
duration, almost always reversible, and ordinarily involves burning foot pain
that tends to worsen at night. In autonomic neuropathy, cardiac, genitourinary,
gastrointestinal, and proximal motor systems are commonly afflicted. Symptoms
of cardiac autonomic neuropathy are: resting tachycardia, exercise intolerance,
congestive heart failure, and postal hypertension. Symptoms of genitourinary
autonomic neuropathy include impotence, urinary hesitancy, and overflow
incontinence. Gastrointestinal neuropathy indications entail: abdominal
dissention, nausea and vomiting, diarrhea, and dysphasia. Dysphasia caused by
DN may or may not become cancerous cells. Lastly, with proximal motor
neuropathy, patients ordinarily experience weakness and muscle atrophy of the
thigh and pelvic muscles, and severe pain in their upper legs (https://patient.info/doctor/diabetic-neuropathy).

Mechanisms

Most DN research is focused on DN linked
pathways related to redox and the metabolic state of dorsal root ganglion and
schwann cells. Researchers have discovered three metabolic mechanisms that
result in DN. The polyol pathway is activated only when there is a high
concentration of glucose in the bloodstream. It is a two-step metabolic pathway
in which glucose is reduced to sorbitol, which is then converted into fructose,
using the enzyme aldose reductase. However, aldose reductase requires
nicotinamide adenine dinucleotide phosphate (NADPH). NADPH, then proceeds to
oxidize NADP+, which allows sorbitol to be converted into fructose using the
enzyme sorbitol dehydrogenase (Feldman, et al, 2017). When excess glucose from
the bloodstream is converted into sorbitol with the help of aldose reductase,
cells experience osmotic imbalance caused by increased sorbitol. The body
compensates for the imbalance by having an efflux of myoinositol and taurine,
which regulates glucose metabolism and signals to cells when glucose uptake is
needed. It is the loss of myoinositol that impairs normal nerve physiology,
resulting in DN (Feldman, et al, 2017).

The second step of the polyol pathway
that leads to DN occurs when aldose reductase depletes cellular stores of
NADPH. NADPH is required for nitric oxide (NO) generation of the essential
antioxidant glutathione. As a result of this depletion, cytoplasmic reactive
oxygen species (ROS) is created, which leads to ROS-mediated intracellular
injury and dysfunction. ROS is a natural byproduct of normal metabolism of
oxygen and is responsible for cell signaling and homeostasis. Yet, during
cellular environmental stress increased ROS levels result in significant damage
to cell structures (Feldman, et al, 2017).

The Protein
kinase C (PKC) pathway regulates numerous cellular responses including gene
expression, protein secretion, cell proliferation, and the inflammatory
response. Toxicity of this pathway
due to excess glucose in the bloodstream is most commonly associated with Type
one diabetic neuropathy (glycotoxicity). In this pathway, glycolysis is
increased as a response to excess glucose found in the blood stream. It is this
increase that leads to neuronal damage. Glycolysis converts glucose into
pyruvate, needed for the Krebs cycle. Increased glycolysis causes accumulation
of dihydroxy-acetone phosphate, which is then converted into diaclyglyceral
(DAG). Increased DAG activates the PKC pathway. The activation of this pathway
leads to metabolic impairment such as insulin resistance, which activates the
polyol pathway and leads to neuronal damage (Feldman, et al, 2017).  The mechanism that causes DN most associated
with Type two diabetics is inflammation due to lipototoxicity. As most type two
diabetics are over weight or suffer from obesity, they often have an
accumulation of lipid-intermediates from their diets found in non adipose
tissue. These lipids upregulate proinflammatory cytokines. The combination of
hyperglycemia and hyperlipidemia leads to oxidative stress, which triggers
inflammatory signaling cascades, causing activation of proinflammatory
cytokines, instigating inflammation, and ultimately neuronal dysfunction and
death (Luo, et al, 2017).

Diagnoses & Tests and Current
Treatments

Diabetic neuropathy is usually diagnosed
based on a patient’s symptoms, physical exam, and medical history. However,
there are a few tests that help aide health care providers in concluding on a
DN diagnosis. Nerve conduction tests measure how fast impulses move through
one’s nerve. A portable monofilament test may be used in assessing the loss of
protective sensations in fingers and toes. Electromyography (EMG) measures the
health of muscles and nerve cells that control motor neurons. This test’s
purpose is to identify proximal motor neuropathy. Autonomic testing is used to
diagnosed painful small fiber neuropathy, and quantitative sensory testing uses
thermal (warm/cold), as well as vibratory stimulator technology to diagnose
peripheral diabetic neuropathy (Jaiswal, et al 2017).

As of now there are no drugs that specifically
target the various mechanisms of DN. Those who suffer from symptoms, therapies
are aimed at alleviating the symptoms and improving one’s quality of life. Current
therapies include: bed foot cradles and contact dressing for feet pain at night.

Tramadol and opioids, another class of drugs are used for pain. But, opioids
are reserved for patients who have extreme DN pain, as opioids have been proven
to have addictive effects. Erythromycin and botox are often used for gastrointestinal
DN related symptoms. ACE inhibitors, beta-blockers, and digoxin all aide in
alleviating cardiac autonomic neuropathy symptoms. Cialis and Viagra are drugs
given to help men suffering from impotence due to DN. Physical therapy is
frequently recommended by health care providers to help strengthen muscles
affected by motor neuronal injury. Lastly, counseling is often a psychological
form of therapy for patients who are having trouble coping with their DN
diagnosis and life style changes that are needed as a result of a DN diagnosis (Jaiswal,
et al 2017).

Emerging Therapy

A promising therapy that combats diabetic
neuropathy is mesenchymal stem cell (MSC) transplant. This is a particular
interest to researchers for several reasons. One such reason is, MSCs has the
capacity for self-renewal and the potential to differentiate into multiple cell
types. MSCs can also derive from many different sources, these cells are found
in bone marrow, adipose tissue, nervous tissue, amniotic fluid, umbilical cord,
placenta, menstrual blood, and dental pulps (Zhou, Zhang, & Quian, 2016). MSCs
secretion of neurotrophic factor provides neuroprotective and
neuro-regenerative effects.

In a review that looked at six hundred
twelve MSC transplant studies, one particular study revealed that type one
diabetes induced mice showed improved glycemic control, renal function, and
regeneration of normal pancreatic beta cells. Another study showed improved
cardiac neuropathy in type one diabetes induced mice (Zhou, Zhang, & Quian, 2016). As with any new treatments, there
are obstacles that need to be addressed before MSC stem cell transplant becomes
a routine therapy for DN. In many studies increased tumor formation was
observed in induced type one diabetes mice transplanted with blood marrow MSC.

Route of transplantation also needs further exploration. Studies have shown a
barrier of systematic delivery such as, more required cells needed for
injection due to passive entrapment with non-specific cell tissue. Another
barrier of systematic delivery is getting MSC stem cells to tissue of interest
with clinically high efficiency. Researchers are still working on establishing
the optimal dose and frequency of MSC stem cell transplant, as many studies
show MSC stem cell survival rate of less the five percent when injected.  It is important to note that the duration of
beneficial effects are still unknown. Lastly, rejection is a major area of
concern. Several studies have shown a high rejection rate of MSC stem cell
transplant (Zhou, Zhang, & Quian, 2016).

Conclusion

Diabetic neuropathy is a group of nerve disease that occurs in
insulin deficient and insulin resistant diabetics.  There are three main mechanisms that have been
linked to DN, which are: polyol pathway, affecting both type one and type two
diabetics, PKC pathway, affecting type one diabetics, and an inflammatory
response due to dietary lipids affecting type two diabetics. Prognosis of DN is
partly dependent on how well diabetes is managed. With proper care of diabetes
and good glycemic control, progression of DN can be slowed and in some cases
even reversed. Autonomic neuropathy is associated high mortality because those
presenting with autonomic neuropathy often also suffer from diabetic
retinopathy, and diabetic nephropathy. Peripheral neuropathy increases the risk
of burns, injuries, foot ulcerations, and ultimately amputation. Current
therapies focus on symptoms rather than combating specific mechanisms of DN.

However, with continued research of MSC stem cell transplantation, there may
possibly be a cure for DN all together.