DIABETIC NEUROPATHY
´Diabetic neuropathic pain is one of the biggest
complications of diabetes which has equal incidence in both type1 and type 2
diabetes.
´Neuropathic pain is one of the most frequent
complications (1.6% patients Worldwide).
´It can occur
as a co-morbidity of diseases like diabetes, side effects of treatment,
injury, chemotherapeutic drugs or as a
disease itself.
´DN
is clinical and sub clinical syndrome condition that accompanies diabetes with
the burning, tingling, prickly, and shooting pain in hands, feet, and legs.
´The
most studied mechanisms are
•increased
polyol pathway,
•activation
of PKC pathway,
•increased
oxidative stress,
•increased
Advanced Glycation Endproduct (AGE) formation and action
Diabetes
mellitus (DM) is one of the major health problem around the world, with many
medical and financial burdens, a micro vascular complication associated with
diabetes, is one of the most common forms of neuropathy , which is affecting
more than 60% of the all diabetic patients during disease course (Hosseini et al., 2013). The persistent level of hyperglycemia
in diabetic patients is associated with, glycosylation and oxidative damage to
important fats, proteins and nucleic acids resulting into structural and functional
damage of nerve fibers, with the development of diabetic neuropathy (Albers et al., 2014). DN development and
progression may be immunologically mediated through the activation of
inflammatory cascades through augmentation of glucose hexosamine pathway influx,
stimulation of receptor for advanced glycation end products (AGEs), activation
of nuclear factor kappaB (NFκB) and enhancement of inflammatory cytokine releases,
such as TNF-α and IL-6. (Goldberg et al.,
2009).
Figure-1 Pathway of neuropathic
pain
The diabetic dyslipidemia is involved in diabetic neuropathy development as the increased free fatty acids directly damaging Schwann cells, meanwhile the increased oxidation of cholesterol to oxysterols inducing apoptosis, as well the raised level of LDL, which reformed in DM by either oxidation or glycation induce apoptosis, and also causes reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation (Padilla et al., 2011; Jang et al., 2011). And also the loss of the neurotropic function of insulin, through either a deficiency in type-1 DM or resistance and a relative deficiency in type-2 DM, enhance the development of diabetic neuropathy via neuronal mitochondrial dysfunction, apoptosis and oxidative damage (Kim et al.,2012). These previous changes involved in the pathogenesis of microvascular dysfunction, with subsequent stimulation of the macrophage recruitmentand thus the additional enhancement of inflammatory reactions, thereby, making a vicious circle that disturbed the nerve function and ends eventually in neuronal death that manifested clinically as DN (Tesch 2007).
Figure-2 STZ-mechanism of action
CAUSES OF DIABETIC NEUROPATHY
Damage to nerves and blood vessels
The exact cause likely differs for each type of neuropathy. Researchers think that over time, uncontrolled high blood sugar damages nerves and interferes with their ability to send signals, leading to diabetic neuropathy. High blood sugar also weakens the walls of the small blood vessels (capillaries) that supply the nerves with oxygen and nutrients.Inflammation in the nerves caused by an autoimmune response. The immune system mistakes nerves as foreign and attacks them.But also hereditary disposition, toxic inhibition or paraneoplastic development can cause polyneuropathy.
SIGNS AND SYMPTOMSDiabetic Neuropathy means the affection of many nerves due to very different reasons and it can therefore develop many different symptoms. Most frequent are paraesthesia such as prickling, numbness, burning of the feet, but also palsies, disorders of speech and failure of cerebral nerves.
DIAGNOSIS
TREATMENT
Diabetic neuropathy has no known cure. The goals of treatment are to:
- Slow progression of the disease
- Relieve pain
- Manage complications and restore function
Slowing progression of the disease
Consistently keeping your blood sugar within your target range is the key to preventing or delaying nerve damage. Doing so may even improve some of your current symptoms. Your doctor will determine the best target range for you based on several factors, such as your age, how long you've had diabetes and your overall health.For many people who have diabetes, the American Diabetes Association generally recommends the following target blood sugar levels:
- Between 80 and 130 mg/dL (4.4 and 7.2 mmol/L) before meals
- Less than 180 mg/dL (10.0 mmol/L) two hours after meals
For many people who have diabetes, Mayo Clinic generally recommends the following target blood sugar levels before meals:
- Between 80 and 120 mg/dL (4.4 and 6.7 mmol/L) for people age 59 and younger who have no other medical conditions
- Between 100 and 140 mg/dL (5.6 and 7.8 mmol/L) for people age 60 and older, or for those who have other medical conditions, including heart, lung or kidney disease
Relieving painMany prescription medications are available for diabetes-related nerve pain, but they don't work for everyone. Side effects are always possible. When considering any medication, talk to your doctor about the benefits and drawbacks to determine what might work best for you.Pain-relieving prescription treatments may include:
- Anti-seizure drugs. Some medications used to treat seizure disorders (epilepsy) are also used to ease nerve pain. The American Diabetes Association recommends starting with pregabalin (Lyrica). Others that have been used to treat neuropathy are gabapentin and carbamazepine
- Antidepressants. Some antidepressants disrupt the chemical processes in the brain that make you feel pain. You don't need to have depression for these medicines to ease nerve pain. Two classes of antidepressants have been used for neuropathy treatment. Tricyclics, including amitriptyline, desipramine and imipramin.Serotonin and norepinephrine reuptake inhibitors (SNRIs) may ease pain with fewer side effects. The American Diabetes Association recommends duloxetine as a first treatment. Another that may be used is venlafaxine
Managing complications and restoring functionYour diabetes health care team will likely include different specialists, such as doctor that treats urinary tract problems (urologist) and a heart doctor (cardiologist), who can help prevent or treat complications.
Treatment depends on the neuropathy-related complication you have:
- Urinary tract problems. Some medications can interfere with bladder function. Your doctor may recommend stopping or changing medications. A strict urination schedule or urinating every few hours (timed urination) while applying gentle pressure to the bladder area (below your bellybutton) is recommended. Other methods, including self-catheterization, may be needed to remove urine from a nerve-damaged bladder.
- Digestive problems. To relieve mild signs and symptoms of gastroparesis — indigestion, belching, nausea or vomiting — doctors suggest eating smaller, more-frequent meals, reducing fiber and fat in the diet, and, for many people, eating soups and pureed foods. Diet changes and medications may help relieve diarrhea, constipation and nausea.
- Low blood pressure on standing (orthostatic hypotension). Treatment starts with simple lifestyle changes, such as avoiding alcohol, drinking plenty of water, and sitting or standing slowly. Sleeping with the head of the bed raised 6 to 10 inches helps prevent swings in blood pressure. Your doctor may also recommend compression stockings and similar compression support for your abdomen (abdominal binder). Several medications, either alone or together, may be used to treat orthostatic hypotension.
- Sexual dysfunction. Medications taken by mouth or injection may improve sexual function in some men, but they aren't safe and effective for everyone. Mechanical vacuum devices may increase blood flow to the penis. Women may find relief with vaginal lubricants.
Pregabalin (PGB) is a well-recognized central nervous system depressant. It is a structural analog of gamma-amino butyric acid. It is a non-opioid drug and is a α2-δ ligand that modulates the activity of voltage-gated calcium channels. It was introduced by US Food and Drug Administration (FDA) in December 2004. It was first discovered for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and post-herpetic neuralgia (PHN)
MECHANISM OF ACTION - PGB is an antagonist of voltage-gated calcium channels. It crosses the blood brain barrier and binds potently to α2-δ subunit, an auxiliary protein associated with voltage gated calcium channels. The drug binds to this channel thereby diminishing calcium entrance at hyper excitable nerve terminals. This results in a decreased level of the excitatory neurotransmitters glutamate, norepinephrine, and substance P (Taghdiri et al., 2015). PGB reduces synaptic release of neurotransmitters in selected regions of the central nervous system including cortex, olfactory bulb, hypothalamus, amygdala, hippocampus, cerebellum, and dorsal horn of the spinal cord. This is achieved by binding of the drug to the α2-δ Type 1 protein of the P/Q type voltage-gated calcium channels thereby reducing the availability of calcium ions required for membrane fusion and exocytosis of neurotransmitters. This mechanism is responsible for the anxiolytic, anticonvulsant, and analgesic activity of PGB (Mico et al., 2012).
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