Diabetic Neuropathy Is Defined Biology Essay

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The most common form of diabetic neuropathy is distal symmetric sensorimotor poly neuropathy occurring with a frequency of approximately 50. Of these, up to 50 patients are asymptomatic [5]; but they may have evidence of neuropathy on simple clinical tests.[6]

Early detection of neuropathy is very important in patients with diabetes because early intervention with tight, stable glycemic control provides symptomatic relief and slows progression of peripheral neuropathy. Moreover, early diagnosis can prevent possible late neuropathic complications like foot ulcers and infections and this can ultimately reduce the number of amputations. [10]

Epidemiology of Diabetic Neuropathy

The following observations illustrate the prevalence and incidence of diabetic poly neuropathy:

United States:

A large American study estimated that 47% of patients with diabetes have some peripheral neuropathy. [41] Neuropathy is estimated to be present in 7.5% of patients at the time of diabetes diagnosis. More than half of patients have distal symmetric poly neuropathy. Focal syndromes such as carpal tunnel syndrome (14-30%), radiculopathies/ plexopathies, and cranial neuropathies account for the rest. Solid prevalence data for the latter two less common syndromes is lacking.   

The wide variability in symmetric diabetic poly neuropathy prevalence data is due to lack of consistent criteria for diagnosis, variable methods of selecting patients for study, and differing assessment techniques. In addition, because many patients are initially asymptomatic, detection is extremely dependent on careful neurologic examination by the primary care clinician.


In a cohort of 4400 Belgian patients, Pirart et al found that 7.5% of patients already had neuropathy when diagnosed with diabetes. [41]After 25 years, the number with neuropathy rose to 45%. In the United Kingdom, the prevalence of diabetic neuropathy among the hospital clinic population was noted to be around 29%.[42]Using additional methods of detection, such as autonomic or quantitative sensory testing, the prevalence may be higher.

Gender Distribution of Diabetic Neuropathy

Males with type 2 diabetes may develop diabetic polyneuropathy earlier than female patients. [43]

Patho physiology of Diabetic Neuropathy

The factors leading to the development of peripheral neuropathy in diabetes are not understood completely, and multiple hypotheses have been advanced. It is generally accepted to be a multi factorial process. Important contributing biochemical mechanisms in the development of the more common symmetrical forms of diabetic poly neuropathy likely include the following:

I. Micro vascular disease:

Vascular and neural diseases are closely related and intertwined. Blood vessels depend on normal nerve function, and nerves depend on adequate blood flow. The first pathological change in the microvasculature is vasoconstriction.[44] As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Vasodilator agents (e.g., ACE inhibitors, α1-antagonists) can lead to substantial improvements in neuronal blood flow, with corresponding improvements in nerve conduction velocities. Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy .[45]

II. Polyol pathway:

Hyperglycemia causes increased levels of intracellular glucose in nerves, leading to saturation of the normal glycolytic pathway. Extra glucose is shunted into the polyol pathway and converted to sorbitol and fructose by the enzymes aldose reductase and sorbitol dehydrogenase. Accumulation of sorbitol and fructose lead to reduced nerve myoinositol, decreased membrane Na+/K+ ATPase activity, impaired axonal transport, and structural breakdown of nerves, causing abnormal action potential propagation. This is the rationale for the use of aldose reductase inhibitors to improve nerve conduction. [46-47]

III. Advanced glycation end products (AGE):

AGEs may be formed external to the body (exogenously) by heating (e.g., cooking); [48] or inside the body (endogenously) through normal metabolism and aging. Under certain pathologic conditions (e.g., oxidative stress due to hyperglycemia in patients with diabetes), AGE formation can be increased beyond normal levels. AGEs are now known to play a role as pro inflammatory mediators in gestational diabetes as well. [49]

The non enzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advance glycation end products that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport.[50]

AGE formation in diabetes

In the pathogenesis of diabetes related AGE formation, hyperglycemia results in higher cellular glucose levels in those cells unable to reduce glucose intake (e.g., endothelial cells).[51] This, in turn, results in increased levels of NADH and FADH, increasing the proton gradient beyond a particular threshold at which the complex III prevents further increase by stopping the electron transport chain.[52] This results in mitochondrial production of reactive oxygen species, activating PARP1 by damaging DNA. PARP1, in turn, induces ADP-ribosylation of GAPDH, a protein involved in glucose metabolism, leading to its inactivation and an accumulation of metabolites earlier in the metabolism pathway. These metabolites activate multiple pathogenic mechanisms, one of which includes increased production of AGEs.

Examples of AGE-modified sites are carboxymethyllysine (CML), carboxyethyllysine (CEL), and Argpyrimidine, which is the most common epitope.

AGE formation in other diseases

The formation and accumulation of advanced glycation endproducts (AGEs) has been implicated in the progression of age related diseases.[53] They are recognized as photo sensitizers in the crystalline lens through cross linking,[54] which has implications for cataract development.[55] AGEs have been implicated in Alzheimer's Disease, cardiovascular disease, and stroke.[56] The mechanism by which AGEs induce damage is through a process called cross linking that causes intracellular damage and apoptosis.[57] Reduced muscle function is also associated with AGEs.

IV. Oxidative stress:

The increased production of free radicals in diabetes may be detrimental via several mechanisms that are not fully understood. These include direct damage to blood vessels leading to nerve ischemia and facilitation of AGE reactions. Despite the incomplete understanding of these processes, use of the antioxidant alpha lipoic acid may hold promise for improving neuropathic symptoms. [58-59]

V. Protein kinase C:

Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in the concentration of diacyl glycerol or Ca2+. Hence PKC enzymes play important roles in several signal transduction cascades.

PKC is implicated in the pathology of diabetic neuropathy. [61] Increased levels of glucose cause an increase in intracellular diacyl glycerol, which activates PKC. PKC inhibitors in animal models will increase nerve conduction velocity by increasing neuronal blood flow.


Fig 1: Diagrammatic presentation of etiopathogenesis of diabetic poly neuropathy

VI. Other important biomarkers:

Decreased Nitiric Oxide production[44]

Impaired Na+/K+ ATP ase[45]

Related contributing factors:

Problems that are a consequence of or co-contributors to these disturbed biochemical processes include altered gene expression with altered cellular phenotypes, changes in cell physiology relating to endoskeletal structure or cellular transport, reduction in neurotropins, and nerve ischemia. Clinical trials of the best studied neurotropin, human recombinant nerve growth factor were disappointing. However, with future refinements, one or more of these mechanisms may provide reasonable targets for pharmacological intervention.

In the case of focal or asymmetrical diabetic neuropathy syndromes, vascular injury or autoimmunity may play more important roles.


Fig 2: Pathogenesis of diabetic neuropathies

Ab, antibody; AGE, advance glycation end products; C¢, complement; DAG, diacylglycerol; ET, endothelin; EDHF, endothelium-derived hyperpolarizing factor; GF, growth factor; IGF; insulin-like growth factor; NFkB, nuclear factor kB; NGF, nerve growth factor; NO, nitric oxide; NT3, neurotropin 3; PKC, protein kinase C; PGI2, prostaglandin I2; ROS, reactive oxygen species; TRK, tyrosine kinase .

Classification of Diabetic Neuropathy

Diabetic neuropathy is classified into several syndromes, each with a distinct pattern of involvement of peripheral nerves. It is a herterogeous disorder that includes mono and polenuropahties, plexopathies and radiculopahties. [61]

Neuropathies are classified as symmetrical or asymmetrical (focal or multifocal).The symmetrical form can be sensory, motor, or both, as well as affecting the individual cranial or peripheral nerves. Patients often have multiple or overlapping syndromes. The most frequently encountered neuropathies are shown in table on next page:

Table 2: Classification of diabetic neuropathies:

Rapidly reversible

Hyperglycemic neuropathy

Generalized symmetric poly neuropathy

Acute sensory neuropathy

Chronic sensori motor neuropathy or distal symmetric poly neuropathy (DPN)

Small-fiber neuropathy

Large-fiber neuropathy

Autonomic neuropathy

Focal and multifocal neuropathies

Focal-limb neuropathy

Cranial neuropathy

Proximal-motor neuropathy (amyotrophy)

Truncal radiculoneuropathy

Coexisting chronic inflammatory de myelinating neuropathy (CIDP)

An overview of these subtypes of diabetic poly neuropathy is being given below:


Hyperglycemic Neuropathy:

Reversible abnormalities of nerve function may occur in patients with recently diagnosed or poorly controlled diabetes. These are unlikely to be caused by structural abnormalities, as recovery soon follows restoration of euglycemia. It usually presents with distal sensory symptoms and, whether these abnormalities result in an increased risk of developing chronic neuropathies in the future remains unknown.[


Acute Sensory Neuropathy:

Acute sensory (painful) neuropathy is considered by some authors a distinctive variant of the distal symmetrical polyneuropathy. The syndrome is characterized by severe pain, cachexia, weight loss, depression and, in males, erectile dysfunction. It occurs predominantly in male patients and may appear at any time in the course of both type 1 and type 2 diabetes. It is self-limiting and invariably responds to simple symptomatic treatment. Conditions such as Fabry's disease, amyloidosis, HIV infection, heavy metal poisoning (such as arsenic) and excess alcohol consumption should be excluded. [62]

Chronic Sensorimotor Neuropathy or Distal Symmetric Polyneuropathy (DPN)

DPN is probably the most common form of the diabetic neuropathies. [63-64]]

It is seen in both type 1 and type 2 DM with similar frequency and it may be already present at the time of diagnosis of type 2 DM]. A population survey reported that 30% of type 1 and 36 to 40% of type 2 diabetic patients experienced neuropathic symptoms]. Several studies have also suggested that impaired glucose tolerance (IGT) may lead to polyneuropathy, reporting rates of IGT in patients with chronic idiopathic polyneuropathies between 30 and 50% [65-68]]. Studies using skin and nerve biopsies have shown progressive reduction in peripheral nerve fibers from the time of the diagnosis of diabetes or even in earlier pre-diabetic stages (IGT and metabolic syndrome)[69]]. Painful diabetic neuropathy (PDN) affects approximately 30% of diabetic patients with neuropathy. It is extremely distressing for the patient and poses significant management difficulties because no treatment provides total relief, and side effects of therapy are a major limiting factor for titrating therapy.

Sensory symptoms are more prominent than motor and usually involve the lower limbs. These include pain, paresthesiae, hyperesthesiae, deep aching, burning and sharp stabbing sensations; similar but less severe to those described in acute sensory neuropathy. In addition, patients may experience negative symptoms such as numbness in feet and legs leading in time to painless foot ulcers and subsequent amputations if the neuropathy is not promptly recognized and treated. Unsteadiness is also frequently seen due to abnormal propioception and muscle sensory function[]. Some patients may be completely asymptomatic and signs may be only discovered by a detailed neurological examination.

On physical examination a symmetrical stocking like distribution of sensory abnormalities in both lower limbs is usually seen. In more severe cases hands may be involved. All sensory modalities can be affected, particularly loss of vibration, touch and position perceptions (large Aα/β fiber damage); and pain with abnormal heat and cold temperature perception (small thinly myelinated Aδ and unmyelinated C fiber damage). Deep tendon reflexes may be absent or reduced specially on the lower extremities. Mild muscle wasting may be seen but severe weakness is rare and should raise the question of a possible non-diabetic etiology of the neuropathy]. DPN is frequently accompanied by autonomic neuropathy, which will be described in more detail below. It is important to remember that all patients with DPN are at increased risk of neuropathic complications such as foot ulceration and Charcot´s neuro arthropathy.



Fig 3: Clinical presentation of small and large fiber neuropathies.

Clinical manifestations of small fiber neuropathies:

Small thinly myelinated Aδ and unmyelinated C fibers are affected.

Prominent symptoms with burning, superficial or lancinating pain often accompanied by hyperalgesia, dysesthesia and allodynia (exaggerated response to non-noxious stimuli).

Progression to numbness and hypoalgesia (Disappearance of pain may not necessarily reflect nerve recovery but rather nerve death, and progression of neuropathy must be excluded by careful examination) [70].

Abnormal cold and warm thermal sensation.

Abnormal autonomic function with decreased sweating, dry skin, impaired vasomotion and skin blood flow with cold feet.

Intact motor strength and deep tendon reflexes.

Negative NCVs findings.

Loss of cutaneous nerve fibers on skin biopsies.

Can be diagnosed clinically by reduced sensitivity to 1.0g Semmes Weinstein monofilament and prickling pain perception using the Waardenberg wheel or similar instrument.

Patients at risk of foot ulceration and subsequent gangrene and amputations

Clinical manifestations of large fiber neuropathies

Large myelinated, rapidly conducting A α /β fibers are affected and may involve sensory and/or motor nerves.

Prominent signs with sensory ataxia (waddling like a duck), wasting of small intrinsic muscles of feet and hands with hammer toe deformities and weakness of hands and feet.

Abnormal deep tendon reflexes.

Impaired vibration perception (often the first objective evidence), light touch and joint position perception.

Shortening of the Achilles tendon with pes equinus.

Symptoms may be minimal; sensation of walking on cotton, floors feeling "strange", inability to turn the pages of a book, or inability to discriminate among coins. In some patients with severe distal muscle weakness, there is inability to stand on the toes or heels.

Abnormal NCVs findings

Increased skin blood flow with hot feet.

Patients at higher risk of falls and fractures, and development of Charcot neuroarthropathy

Most patients with DPN, however, have a "mixed" variety of neuropathy with both large and small nerve fiber damages.

In the Rochester diabetic study, for example, approximately 50 percent of patients had distal symmetric polyneuropathy; about 14 percent had symptoms and a few percent had difficulty walking. Other neuropathies included median mononeuropathies (25 percent), autonomic neuropathy (7 percent), and other neuropathies, including thoracic and lumbar polyradiculopathy and cranial mononeuropathies (3 percent). [4]


Fig 4: A simplified view of the peripheral nervous system and description of the underlying causes of small- and large-fiber neuropathies.

A alpha fibers are large myelinated fibers, in charge of motor functions and muscle control. A alpha/beta fibers are large myelinated fibers too, with sensory functions such as perception to touch, vibration, and position. A delta fibers are small myelinated fibers, in charge of pain stimuli and cold perception. C fibers can be myelinated or unmyelinated and have both sensory (warm perception and pain) and autonomic functions (blood pressure, heart rate regulation, sweating, etc.). GIT =gastrointestinal tract; GUT =genitourinary tract.

Pathophysiology of Neuropathic Pain in Diabetic


The pathophysiology of neuropathic pain in diabetic neuropathy is complex and not well understood. The literature focusing on specific mechanisms relating to PDN is limited when compared with data available on the molecular processes leading to nerve damage in diabetes mellitus.

The International Association for the Study of Pain defined neuropathic pain as "pain initiated or caused by a primary lesion or dysfunction in the nervous system". Therefore, any lesion in the peripheral and/ or central nervous system can potentially cause pain.

With regard to the central and peripheral mechanisms leading to neuropathic pain, many of the postulated abnormalities are derived principally from models of non diabetic painful neuropathy and very few have been confirmed in diabetic patients. Thus, it is known that pain transmission in peripheral nerves occurs via the small A-δ and C-nerve fibers, but the source of pain may be central and/ or peripheral because diabetes affects all levels of the nervous system, from the peripheral nerves to the brain.

Peripheral mechanisms: The temporal course of nerve damage has been delineated from cross-sectional studies in which degeneration and demyelination are balanced in the early stages of neuropathy by axonal regeneration and remyelination. It has been suggested that degenerating nerve fibers and those that exhibit impaired regeneration may generate inappropriate excitation impulses, which are perceived as pain and paresthesia. With disease progression and a reduction in regenerative capacity, nerve fiber loss predominates, leading to sensory loss. Progressive nerve fiber loss has been attributed to a reduction in vascular endothelial growth factor expression in the foot skin of diabetic patients with increasing neuropathic severity. It has been demonstrated that patients with painful neuropathy show a decreased threshold for a cold stimulus and no difference for a heat pain stimulus compared with those without pain, which suggests that A-δ myelinated nerve fibers rather than C fibers may be important in the genesis of pain. In one skin biopsy study, significant intra epidermal nerve fiber (IENF; C-fiber) loss occurred in patients with PDN, yet in another study, diabetic patients with and without PDN showed no difference in IENF density.

Acute sensory neuropathy is usually associated with poor glycemic control but may also appear after sudden improvement of glycemia and has been associated with the onset of insulin therapy, being termed "insulin neuritis" on occasions. [71] [] Although the pathologic basis has not been determined, one hypothesis suggests that changes in blood glucose flux produces alterations in epineurial blood flow, leading to ischemia. A study, using in vivo epineurial vessel photography and fluorescein angiography, demonstrated abnormalities of epineurial vessels in patients with acute sensory neuropathy, with arteriovenous shunting and proliferating new vessels.[72] [{}]Other authors relate this syndrome to diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and propose an immune mediated mechanism.[73]]

Autonomic Neuropathy:

Diabetic autonomic neuropathy is a common complication of diabetes. It is a diagnosis of exclusion and may be unnoticed because of multi organ involvement and insidious onset. It can, however, cause severe dysfunction of a single organ. Among the problems that can occur are postural hypotension, gastro paresis, and enteropathy with constipation or diarrhea.

The mortality for diabetic autonomic neuropathy has been estimated to be 44% within 2.5 years of diagnosing symptomatic autonomic neuropathy [74]. In a meta analysis, the Mantel-Haenszel estimates for the pooled prevalence rate risk for silent myocardial ischemia was 1.96, with 95% confidence interval of 1.53 to 2.51 (p<0.001; n = 1,468 total subjects).]

Focal and Multifocal Neuropathies

Focal limb neuropathies :

These are usually due to entrapment and mononeuropathies must be distinguished from entrapment syndromes. [75-76] Entrapment syndromes start slowly, progress and persist without intervention. Carpal tunnel syndrome occurs three times as frequently in diabetics compared with healthy populations [77]] and is found in up to one-third of patients with diabetes. Its' increased prevalence in diabetes may be related to repeated undetected trauma, metabolic changes, or accumulation of fluid or edema within the confined space of the carpal tunnel[].[[

Mononeuropathies often occur in the older population with an acute onset, associated with pain, and a self-limiting course, resolving in 6-8 weeks. These can involve the median (5.8% of all diabetic neuropathies), ulnar (2.1%), radial (0.6%), and common peroneal nerves [78]. The most common peripheral mononeuropathy in diabetic patients is median mononeuropathy at the wrist. While estimates vary, it is likely that at least one-quarter to one-third of patients develop either symptomatic or asymptomatic median mononeuropathy. [79] Ulnar mononeuropathy, either at the elbow or, less commonly, at the wrist can also occur

In the lower extremities, peroneal mononeuropathies with compression at the fibula are a well recognized complication of diabetes. Common peroneal palsy, for example, can result in foot drop. It is probable, however, that isolated femoral mononeuropathies are rare in diabetes; many of these patients, after careful clinical and electrodiagnostic examinations, are found to have a high lumbar radiculopathy. [80-81]

Mononeuropathy multiplex -  Multiple mononeuropathies in the same patient are known as mononeuropathy multiplex (or asymmetric polyneuropathy). The other major disorder that can produce this syndrome is vasculitis, which should also be considered in affected patients [80]

Cranial mononeuropathy :

Cranial neuropathies in diabetic patients are extremely rare (0.05%) and occur in older individuals with a long duration of diabetes]. The most common cranial mononeuropathies occur in those nerves which supply the extraocular muscles, especially cranial nerves III (oculomotor), VI (abducens), and IV (trochlear). Patients with diabetic ophthalmoplegia typically present with unilateral pain, ptosis, and diplopia, with sparing of pupillary function. [82]

Facial mononeuropathy (Bell's palsy) occurs more frequently in diabetic than in non-diabetic patients. This observation suggests that the disorder is due to diabetes in some patients. [83-84]

& 5. Proximal motor neuropathy (Diabetic amyotrophy) and chronic demyelinating neuropathies:

For many years proximal neuropathy has been considered a component of DN. Its pathogenesis was ill understood[], and its treatment was neglected with the anticipation that the patient would eventually recover, albeit over a period of some 1-2 years, suffering considerable pain, weakness and disability. The condition has a number of synonyms including diabetic amyotrophy, lumbar poly radiculopathy and femoral neuropathy and is the most common type of diabetic poly radiculopathies. Diabetic amyotrophy is not a pure lumbo sacral plexopathy because it also affects the lumbo sacral nerve roots and peripheral nerves. The etiology is debated, and several patho physiologic mechanisms (ischemic, metabolic, and/ or inflammatory) have been proposed as the cause. Of these, the most likely cause is ischemic injury from a non systemic micro vasculitis.

The traditional features of diabetic amyotrophy include the acute, asymmetric, focal onset of pain followed by weakness involving the proximal leg, with associated autonomic failure and weight loss. Progression occurs over months and is followed by partial recovery in most patients. The same process can occur in the contra lateral leg, immediately following (within days) or much later than (months to years) the initial attack. The diagnosis of diabetic amyotrophy is mainly based upon the presence of suggestive clinical features in a patient with known or newly diagnosed diabetes mellitus. Appropriate laboratory investigations, particularly electro diagnostic studies, and neuro imaging in select patients, are useful to exclude other peripheral and central nervous system etiologies as a cause of the neurologic symptoms and signs.

No treatments are proven to be effective for diabetic amyotrophy. There is limited and conflicting data regarding the benefit of immunosuppressive therapies including oral prednisone, intravenous methyl prednisolone, intravenous immune globulin, cyclophosphamide, and plasma exchange.

It can be clinically identified based on the occurrence of these common features:

primarily affects the elderly (50 to 60 years) with type 2 diabetes,

onset can be gradual or abrupt,

presents with severe pain in the thighs, hips and buttocks, followed by significant weakness of the proximal muscles of the lower limbs with inability to rise from the sitting position (positive Gower's maneuver).

can start unilaterally and then spread bilaterally,

often coexists with distal symmetric polyneuropathy, and

spontaneous muscle fasciculation, or provoked by percussion can be detected.

Pathogenesis is not yet clearly understood although immune-mediated epineurial microvasculitis has been demonstrated in some cases. Immunosuppressive therapy is recommended using high dose steroids or intravenous immunoglobulin. [85]] The condition is now recognized as being secondary to a variety of causes unrelated to diabetes, but which have a greater frequency in patients with diabetes than the general population. It includes patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy, circulating GM1 antibodies and inflammatory vasculitis.[86-87]] In the classic form of diabetic amyotrophy, axonal loss is the predominant process.[88[]] Electrophysiologic evaluation reveals lumbosacral plexopathy.[89][[]] Biopsy of the obturator nerve reveals deposition of immunoglobulin, demyelination and inflammatory cell infiltrate of the vasa nervorum.[90][] Cerebrospinal fluid (CSF) protein content is high and there is an increase in the lymphocyte count. Treatment options include: intravenous immunoglobulin for CIDP [91][{}], plasma exchange for MGUS, steroids and azathioprine for vasculitis and withdrawal from drugs or other agents that may have caused vasculitis. It is important to divide proximal syndromes into these two subcategories, because the CIDP variant responds dramatically to intervention], whereas amyotrophy runs its own course over months to years. Until more evidence is available, they should be considered as separate syndromes.

Diabetic truncal radiculoneuropathy :

Diabetic truncal radiculo neuropathy affects middle aged to elderly patients and has a predilection for male sex. Pain is the most important symptom and it occurs in a girdle-like distribution over the lower thoracic or abdominal wall. Can be uni or bilaterally distributed. Motor weakness is rare. Resolution generally occurs within 4-6 months.

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Fig 5: Areas of involvement in different neuropathies