Diabetic Microvascular Disease: An Endocrine Society Scientific Statement

Eugene J. Barrett; Zhenqi Liu; Mogher Khamaisi; George L. King; Ronald Klein; Barbara E. K. Klein; Timothy M. Hughes; Suzanne Craft; Barry I. Freedman; Donald W. Bowden; Aaron I. Vinik; Carolina M. Casellini

Disclosures

J Clin Endocrinol Metab. 2017;102(12):4343-4410. 

In This Article

The Microvasculature and Diabetic Neuropathy

Introduction

Diabetic neuropathies are very common and troublesome complications of diabetes that lead to morbidity and mortality and a huge economic burden for diabetes care.[618,619] Distal symmetric polyneuropathy (DSPN) is the most common form of neuropathy. It is responsible for 50% to 75% of nontraumatic amputations.[619,620] Diabetic neuropathy is a set of clinical syndromes that affect distinct regions of the nervous system, singly or combined. It may be silent and go undetected while exercising its ravages. Or, it may present with clinical symptoms and signs that, although nonspecific and insidious with slow progression, mimic those of other diseases. Clinicians, therefore, diagnose diabetic neuropathy by exclusion. Unfortunately, diabetic neuropathy is underdiagnosed. Even when symptomatic, less than one third of physicians recognize diabetic neuropathy or discuss it with their patients.[621]

Epidemiology

The epidemiology and natural history of diabetic neuropathy remain poorly defined. This is due, in part, to variable criteria for diagnosis, failure of many physicians to recognize and diagnose the disease, and lack of standardized methodologies for the evaluation of these patients.[622] It has nonetheless been estimated that 50% of patients with diabetes have diabetic neuropathy, and in the United States, 2.7 million have painful neuropathy. Of 25% of patients attending a diabetes clinic who volunteered symptoms, 50% tested positive for neuropathy after a simple clinical test (such as the ankle jerk or vibration perception test), and almost 90% tested positive to sophisticated tests of autonomic function or peripheral sensation.[623] Neurologic complications occur in both T1DM and T2DM and in various forms of acquired diabetes.[51] The major morbidity associated with DSPN is foot ulceration, a precursor to gangrene and limb loss. DSPN increases the risk of amputation 1.7-fold. However, that risk jumps to 12-fold if there are deformities (itself a consequence of neuropathy) and 36-fold if there is a history of previous ulceration.[624] Each year, 96,000 diabetic patients in the United States undergo amputations. It is estimated that up to 75% of these amputations are preventable.[620] Diabetic neuropathy also impacts QOL by causing pain, weakness, ataxia, and incoordination (predisposing to falls and fractures).[625] For patients over the age of 65, diabetes increases fall risk by 17-fold, leading to fractures and traumatic brain injury. Autonomic neuropathy likewise decreases QOL and is associated with mortality rates between 25% and 50% within 5 to 10 years.[626,627]

DSPN causes a variety of syndromes for which there is no universally accepted classification. Operationally, they are subdivided into focal/multifocal neuropathies, including diabetic amyotrophy and symmetric sensorimotor polyneuropathy. The latter is the most common type, affecting ~30% of diabetic patients in hospital care and 25% of those in the community.[628,629] DSPN is defined as a symmetrical, length-dependent, sensorimotor polyneuropathy attributable to metabolic and microvascular alterations resulting from chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates.[630] Its onset is generally insidious. Without treatment, the course is chronic and progressive. The loss of small-fiber–mediated sensation results in the loss of thermal and pain perception, whereas large-fiber impairment results in loss of touch and vibration perception. Sensory fiber involvement may also result in positive symptoms, such as paresthesias and pain. Nonetheless, up to 50% of neuropathic patients can be asymptomatic.

Diabetic autonomic neuropathy rarely causes severe symptoms.[622,631] However, in its cardiovascular form, it is definitely associated with at least a threefold increased risk for mortality.[632–634] More recently, studies have implicated diabetic autonomic neuropathy, or even autonomic imbalance between the sympathetic and the parasympathetic nervous systems, as predictors of cardiovascular risk.[633,634]

Neuropathic pain is defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system".[635] Diabetic neuropathy pain is a clinical problem that is difficult to manage. It is often associated with mood and sleep disturbances, and patients with diabetic neuropathy pain are more apt to seek medical attention than those with other types of diabetic neuropathy. Recognizing psychological problems early is critical to the management of pain, and physicians need to go beyond the management of pain if they are to achieve success. Patients may also complain of decreased physical activity and mobility, increased fatigue, and negative effects on their social lives. Providing significant pain relief markedly improves QOL measures.[636,637]

Classification of Diabetic Neuropathies

Figure 7 describes the classification Thomas proposed,[638] which was later modified.[628,639–641] It is important to note that different forms of diabetic neuropathy often coexist in the same patient (e.g., distal polyneuropathy and carpal tunnel syndrome).

Figure 7.

Modified diabetic neuropathy classification first proposed by Thomas. N, normal. Reference: Jirousek et al. (25).

Natural History of Diabetic Neuropathies

The natural history of diabetic neuropathies separates them into two very distinctive entities, namely those that progress gradually with increasing duration of diabetes, and those that remit usually completely. Sensory and autonomic neuropathies generally progress, whereas mononeuropathies, radiculopathies, and acute painful neuropathies (although manifesting severe symptoms) are short-lived and tend to recover.[642] The progression of diabetic neuropathy is related to glycemic control in both T1DM and T2DM.[1,643] It appears that the most rapid deterioration of nerve function occurs soon after the onset of T1DM. Within 2 to 3 years, there is a slowing of the progress with a shallower slope to the curve of dysfunction. In T2DM, slowing of NCVs may be one of the earliest neuropathic abnormalities and often is present even at diagnosis.[644] After diagnosis, slowing of NCV generally progresses at a steady rate of ~1 m/s/y, and the level of impairment is positively correlated with the duration of diabetes. Although most studies have documented that symptomatic patients are more likely to have slower NCVs than patients without symptoms, NCVs do not correlate with the severity of symptoms. In a long-term follow-up study of T2DM patients,[645] electrophysiologic abnormalities in the lower limb increased from 8% at baseline to 42% after 10 years. In particular, a decrease in sensory and motor amplitudes (indicating axonal destruction) was more pronounced than the slowing of NCVs. Using objective measures of sensory function, such as the vibration perception threshold test, researchers have reported a rate of decline of 1 to 2 vibration units/year. However, this rate of decline now appears to be less severe, most likely due to improvements in general health and nerve nutrition. This is particularly important when doing studies on the treatment of diabetic neuropathy, which have always relied on differences between drug treatment and placebo and have apparently been successful because of the decline in function occurring in placebo-treated patients.[646] Recent studies have pointed out the changing natural history of diabetic neuropathy with the advent of therapeutic lifestyle change and the use of statins and ACEi, which have slowed the progression of diabetic neuropathy and drastically changed the requirements for placebo-controlled studies.[62] It is also important to recognize that diabetic neuropathy is a disorder wherein the prevailing abnormality is loss of axons, which electrophysiologically translates to a reduction in amplitudes and not conduction velocities; therefore, changes in NCV may not be an appropriate means of monitoring progression or deterioration of nerve function. Small, unmyelinated nerve fibers are affected early in diabetes and are not reflected in NCV studies. Other methods of measuring diabetic neuropathy that do not depend on conduction velocities (such as quantitative sensory testing, autonomic function testing, or skin biopsy with quantification of intraepidermal nerve fibers) are necessary to identify diabetic neuropathy patients.[647–649]

Pathogenesis of Diabetic Neuropathies

Historically, there were two competing hypotheses regarding the origins of diabetic neuropathy. One school of thought held that this was largely secondary to metabolic abnormalities within the nerve and/or Schwann cells, whereas others held that diabetic neuropathy was another manifestation of diabetic microvascular disease. Increasingly, researchers believe that nerve and microvascular injury both contribute to nerve dysfunction. Some of the controversy arose because of the complexity of how diabetic neuropathy presents, as well as the limited ability to study the disease and its pathogenetic mechanisms, particularly early in its course. Research has clearly shown that with DSPN there is progressive axon degeneration of all fiber types, and this is accompanied by demyelination. However, microelectrode polarography has shown sural nerve hypoxemia accompanied by diminished endoneural blood flow,[650,651] indicating that these changes (which are the proximal cause for the nerve dysfunction) are accompanied by changes in the microvasculature.

Causative factors include persistent hyperglycemia, oxidative and nitrosative stress, inflammation, and autoimmune-mediated nerve destruction (see Biochemical Pathways of Microvascular Injury). These factors affect the microvasculature, Schwann cells, and the nerves themselves. However, diabetic neuropathy is a heterogeneous group of conditions with widely varying pathology, suggesting differences in pathogenic mechanisms for the different clinical syndromes. Recognizing the clinical homolog of these pathologic processes is the first step in achieving the appropriate form of intervention. It is also clear that structural changes in the microvasculature within peripheral nerves occur early in the course of diabetes. It has been known for many years that the vessel wall within peripheral nerves becomes thickened in individuals with DPN. This is attributed to increases in BM thickness, which is accompanied by pericyte degeneration and endothelial cell hyperplasia. These changes are, in many ways, similar to what we see within the microvasculature in other tissues. We also see these qualitative changes in individuals with diabetes without clinical peripheral neuropathy, although the changes are quantitatively less marked. These changes are typically more marked in endoneural than in epineurial vessels for reasons that are unclear.

Clinical Presentation of Diabetic Neuropathies

The spectrum of clinical neuropathic syndromes described in patients with diabetes includes dysfunction of almost every segment of the somatic peripheral and autonomic nervous system.[38] We can distinguish each syndrome by its pathophysiologic, therapeutic, and prognostic features.

Focal and multifocal neuropathies. Focal neuropathies comprise focal-limb neuropathies and cranial neuropathies. Focal limb neuropathies are usually due to entrapment, and we must distinguish mononeuropathies from these entrapment syndromes (Table 5).[640] Mononeuropathies often occur in the older population; they have an acute onset, are associated with pain, and have a self-limiting course resolving in 6 to 8 weeks. Mononeuropathies can involve the median (5.8% of all diabetic neuropathies), ulnar (2.1%), radial (0.6%), and common peroneal nerves.[652] Cranial neuropathies in diabetic patients are extremely rare (0.05%) and occur in older individuals with a long duration of diabetes.[653] Entrapment syndromes start slowly, and will progress and persist without intervention. Carpal tunnel syndrome occurs 3 times as frequently in patients with diabetes compared with healthy populations[654] 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, and/or the accumulation of fluid or edema within the confined space of the carpal tunnel.[640]

Proximal motor neuropathy (diabetic amyotrophy) and chronic demyelinating neuropathies. For many years, clinicians thought that proximal neuropathy was a component of diabetic neuropathy. There was a poor understanding of its pathogenesis.[655] As a result, clinicians often left the condition untreated with the anticipation that the patient would eventually recover, albeit over a period of some 1 to 2 years and after suffering considerable pain, weakness, and disability. Proximal neuropathy has a number of synonyms, including diabetic amyotrophy and femoral neuropathy. Its common features include the following: (1) it primarily affects elderly patients (50 to 60 years old) with T2DM; (2) the onset can be gradual or abrupt; (3) it presents with severe pain in the thighs, hips, and buttocks, followed by significant weakness of the proximal muscles of the lower limbs and an inability to rise from the sitting position; (4) it can start unilaterally and then spread bilaterally; (5) it often coexists with DSPN; and (6) it is characterized by muscle fasciculation, either spontaneous or provoked by percussion. Its pathogenesis is not yet clearly understood, although immune-mediated epineurial microvasculitis occurs in some cases. Clinicians generally prescribe immunosuppressive therapy using highdose steroids or intravenousimmunoglobulin.[656] Proximal neuropathy can occur secondary to a variety of conditions unrelated to diabetes. However, these unrelated conditions have a greater frequency in patients with diabetes than the general population and include chronic inflammatory demyelinating polyneuropathy, monoclonal gammopathy, circulating GM1 antibodies, and inflammatory vasculitis.[653,654,657,658]

In the classic form of diabetic amyotrophy, axonal loss is the predominant process[659] and electrophysiologic evaluation reveals lumbosacral plexopathy.[660] In contrast, if demyelination predominates and the motor deficit affects proximal and distal muscle groups, clinicians should consider the diagnoses of chronic inflammatory demyelinating polyneuropathy, monoclonal gammopathy of unknown significance, and vasculitis.[661,662] Clinicians often overlook these demyelinating conditions. However, recognition is very important; unlike diabetic neuropathy, they are sometimes treatable. Furthermore, they occur 11 times more frequently in diabetic than nondiabetic patients.[663,664] A biopsy of the obturator nerve reveals deposits of immunoglobulin, demyelination, and inflammatory cell infiltrate around the vasa nervorum.[657,665] Cerebrospinal fluid protein content is high, and there is an increase in the lymphocyte count. Treatment options include intravenous immunoglobulin for chronic inflammatory demyelinating polyneuropathy,[666] plasma exchange for monoclonal gammopathy of unknown significance, steroids and azathioprine for vasculitis, and withdrawal of other drugs or agents that may have caused vasculitis. It is important to divide proximal syndromes into these two subcategories, because the chronic inflammatory demyelinating polyneuropathy variant responds dramatically to intervention,[661,667] whereas proximal neuropathy amyotrophy runs its own course over months to years. Until more evidence is available, clinicians should consider these as separate syndromes.

Diabetic truncal radiculoneuropathy. Diabetic truncal radiculoneuropathy affects middleaged to elderly patients and has a predilection for the male sex. Pain is the most important symptom, and it occurs in a girdle-like distribution over the lower thoracic or abdominal wall. It can be unilaterally or bilaterally distributed. Motor weakness is rare. Resolution generally occurs within 4 to 6 months.

Generalized symmetric polyneuropathy.Acute sensory neuropathy: Some consider acute sensory (painful) neuropathy a distinctive variant of 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 T1DM and T2DM. 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.[638]

Acute sensory neuropathy is usually associated with poor glycemic control but may also appear after a sudden improvement in glycemic control and has been associated with the onset of insulin therapy (occasionally referred to as insulin neuritis).[668] Although the pathologic basis has not been determined, one hypothesis suggests that changes in blood glucose flux produce alterations in epineurial blood flow, leading to ischemia. A study using in vivo epineurial vessel photography and fluorescein angiography demonstrated abnormalities in epineurial vessels, including arteriovenous shunting and new-vessel proliferation in patients with acute sensory neuropathy.[669] Some relate this syndrome to diabetic lumbosacral radiculoplexus neuropathy and suggest a possible immunemediated mechanism.[649]

Chronic sensorimotor neuropathy or distal symmetric polyneuropathy. DSPN is seen in both T1DM and T2DM with similar frequency, and it may be already present at the time of T2DM diagnosis.[644] A population survey reported that 30% of T1DM and 36% to 40% of T2DM patients experienced neuropathic symptoms.[59] Several studies have also suggested that impaired glucose tolerance may lead to polyneuropathy. The studies reported rates of impaired glucose tolerance between 30% and 50% in patients with chronic idiopathic polyneuropathies.[670–674] Studies using skin and nerve biopsies have shown a progressive reduction in peripheral nerve fibers from the time of the diagnosis of diabetes or even from earlier prediabetic stages (impaired glucose tolerance and metabolic syndrome).[648,675,676] Sensory symptoms are more prominent than motor symptoms and usually involve the lower limbs.

Mild muscle wasting may occur, but severe weakness is rare, which should raise the question of a possible nondiabetic etiology of the neuropathy.[51,622,630,649]

Clinical manifestations of small-fiber neuropathies. Clinical manifestations of small-fiber neuropathies (Figure 7) include symptoms of burning, superficial, or lancinating pain often accompanied by hyperalgesia, dysesthesia, and allodynia; disruption of small thinly myelinated Aδ and unmyelinated C fibers; a progression to numbness; abnormal cold and warm thermal sensations; abnormal autonomic function with decreased sweating, dry skin, cold feet, and impaired vasomotion and skin blood flow; intact motor strength and deep tendon reflexes; negative NCV findings; loss of cutaneous nerve fibers on skin biopsies; and clinical diagnosis by reduced sensitivity to 1.0 g Semmes Weinstein monofilament and prickling pain perception using the Wartenberg wheel or similar instrument.

Clinical manifestations of large-fiber neuropathies. Clinical manifestations of large-fiber neuropathies (Figure 7) include the following: disruption of large myelinated, rapidly conducting Aα/β fibers, which may involve sensory and/or motor nerves; prominent signs with sensory ataxia (waddling like a duck) and the wasting of small intrinsic muscles of feet and hands with hammertoe deformities and weakness of hands and feet; abnormal deep tendon reflexes; impaired vibration, light touch, and joint position perception; abnormal NCV findings; increased skin blood flow with hot feet; higher risk of falls, fractures, and the development of Charcot neuroarthropathy; and minimal symptoms, which may include a sensation of walking on cotton, floors feeling strange, inability to turn the pages of a book, inability to discriminate among coins, and (in some patients with severe distal muscle weakness) inability to stand on the toes or heels.

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

Diagnosing Diabetic Peripheral Neuropathy

In 2010, The Toronto Expert Panel on Diabetic Neuropathy Classification redefined the minimal criteria for the diagnosis of typical DPN.[630]

The diagnosis of DPN should rest on the findings from a clinical and neurologic examination. These include the presence of positive and negative neuropathic symptoms and signs (either sensory or motor), such as sensory deficits, allodynia, hyperalgesia, motor weakness, or absence of reflexes.[677]

When making a diagnosis of DPN, clinicians should assess both symptoms and signs based on the following guidelines:

  1. Symptoms alone have poor diagnostic accuracy in predicting the presence of polyneuropathy.

  2. Signs are better predictors than symptoms.

  3. Multiple signs are better predictors than a single sign.

  4. Relatively simple examinations are as accurate as complex scoring systems.

Conditions mimicking diabetic neuropathy. Conditions that mimic diabetic neuropathy include neuropathies caused by alcohol abuse, uremia, hypothyroidism, vitamin B12 deficiency, peripheral arterial disease, cancer, inflammatory and infectious diseases, and neurotoxic drugs.[70] An atypical pattern of the presentation of symptoms or signs (i.e., the presence of relevant motor deficits, an asymmetrical or proximal distribution, or rapid progression) always requires referral for electrodiagnostic testing.

Clinical assessment tools for diabetic neuropathy. Clinical assessment should be standardized using validated scores for both symptom severity and the degree of reproducible neuropathic deficits. These would include the Michigan Neuropathy Screening Instrument,[678] the Neuropathy Symptom Score for neuropathic symptoms, and the Neuropathy Disability Score or the Neuropathy Impairment Score for neuropathic deficits.[679]

Objective diagnosis of diabetic neuropathy. The neurologic examination should focus on the lower extremities and include foot inspection for deformities, ulcers, fungal infection, muscle wasting, hair distribution or loss, and the presence or absence of pulses. Clinicians should assess sensory modalities using simple handheld devices (touch by cotton wool or soft brush; vibration by 128 Hz tuning fork; pressure by the Semmes-Weinstein 1 g and 10 g monofilament; pinprick by Wartenberg wheel, Neurotip, or a pin; and temperature by cold and warm objects).[680] Finally, clinicians should test the Achilles reflexes[639,681] (Table 6).

Nerve conduction studies. We recommend using electrophysiologic measures for both clinical practice and multicenter clinical trials.[682,683] In a long-term follow-up study of T2DM patients,[645] NCV abnormalities in the lower limbs increased from 8% at baseline to 42% after 10 years of disease. The Diabetes Control and Complication trial reported a slow progression of NCV abnormalities. The sural and peroneal NCVs diminished by 2.8 and 2.7 m/s, respectively, over a 5-year period.[643] Furthermore, in the same study, patients who were free of neuropathy at baseline had a 40% incidence of abnormal NCV in the conventionally treated group vs 16% in the intensive therapy-treated group after 5 years. However, the neurophysiologic findings vary widely depending on the population tested and the type and distribution of the neuropathy. Patients with painful, predominantly small-fiber neuropathy have normal test results. There is consistent evidence that small, unmyelinated fibers are affected early in diabetes, and routine NCV tests do not diagnose these alterations. Therefore, other methods, such as quantitative sensory testing or skin biopsy with quantification of intraepidermal nerve fibers, are needed to detect these patients.[647–649] Nevertheless, electrophysiological testing plays a key role in ruling out other causes of neuropathy and is essential for the identification of focal and multifocal neuropathies.[622,639]

Summary of diagnosis of diabetic polyneuropathies. Adetailed clinical examination is the key to diagnosing diabetic polyneuropathies. The last position statement of the American Diabetes Association recommends that clinicians should screen all patients with diabetes for diabetic neuropathies at diagnosis in T2DM and 5 years after diagnosis in T1DM. These screenings should occur annually and must include sensory examinations of feet and ankle reflexes.[639]

The diagnosis of diabetic polyneuropathies is mainly clinical and involves specific tests according to the type and severity of the neuropathy. However, depending on the clinical findings, other nondiabetic causes of neuropathy must always be excluded.

Treatment of diabetic polyneuropathies

Diabetic polyneuropathy treatment should target different aspects of the disease in the following order: first, underlying pathogenic mechanisms; second, symptoms and improvement in QOL; and third, the complications of neuropathy and their progression.[83] We will review very briefly in this work only those issues related to treating the underlying pathogenetic mechanisms. A more complete approach to clinical management of the consequences of diabetic polyneuropathies is beyond the scope of this review and can be found in other texts.

Treatment of specific underlying pathogenic mechanisms.Glycemic and metabolic control: Several long-term prospective studies have assessed the effects of intensive diabetes therapy on the prevention and progression of chronic diabetic complications.[1,197] In the DCCT and UKPDS studies, only a minority of subjects had symptomatic DSPN at entry. In the DCCT study, intensive diabetes therapy slowed but did not completely prevent the development of DSPN in T1DM patients. In the DCCT/EDIC cohort, the benefits of former intensive insulin treatment persisted for 13 to 14 years in T1DM patients after DCCT closeout. These included a durable beneficial effect on polyneuropathy and cardiac autonomic neuropathy (hyperglycemic memory).[684,685]

Conversely, in T2DM patients, the results were largely negative. The UKPDS showed a lower rate of impaired vibration perception thresholds (vibration perception thresholds >25 V) after 15 years for intensive therapy vs conventional therapy (31% vs 52%, respectively). However, the only additional time point at which vibration perception thresholds reached a significant difference was the 9-year follow-up, whereas the rates after 3, 6, and 12 years did not differ between the groups. Likewise, the rates of absent knee and ankle reflexes, as well as the heart rate responses to deep breathing, did not differ between the groups.[197] In the ADVANCE study (which included 11,140 patients with T2DM randomly assigned to either standard glucose control or intensive glucose control), the relative risk reduction (95% CI) for new or worsening neuropathy for intensive vs standard glucose control after a median of 5 years of follow-up was −4 (−10 to 2), without a significant difference between groups.[604] Likewise, in the Veterans Affairs Diabetes trial [including 1791 military veterans (mean age, 60.4 years) with a suboptimal response to therapy for T2DM], there were no differences between the intensive or standard glucose control groups for DSPN or microvascular complications after a median follow-up of 5.6 years.[88] The ACCORD trial[196] halted intensive therapy aimed at HbA1c <6.0% before the study ended (because of a higher mortality in that group) and transitioned patients to standard therapy after 3.7 years, on average. At transition, sensation to light touch was significantly improved on intensive vs standard diabetes therapy. After 5 years (end of study), patients on intensive therapy had a better Michigan Neuropathy Screening Instrument Score and significant improvements in sensation to vibration and light touch vs patients on standard diabetes therapy. However, because of the premature study termination and the aggressive HbA1c goal, the neuropathy outcome in the ACCORD trial is difficult to interpret.

In the Steno 2 study,[686] intensified multifactorial risk intervention (including intensive diabetes treatment, ACE inhibitors, antioxidants, statins, aspirin, and smoking cessation) in patients with microalbuminuria showed no effect on DSPN after 7.8 years (range: 6.9 to 8.8) and 13.3 years (patients were subsequently followed for a mean of 5.5 years). However, the progression of cardiac autonomic neuropathywas reduced by 57%. Thus, there is no evidence that intensive diabetes therapy or a target-driven intensified intervention aimed at multiple risk factors favorably influences the development or progression of DSPN, as opposed to cardiac autonomic neuropathy in T2DM patients. However, the Steno study used only vibration detection, which exclusively measures the changes in large-fiber function.

Oxidative stress: A number of studies have shown that hyperglycemia causes oxidative stress in tissues that are susceptible to diabetes complications, including the microvasculature and peripheral nerves. Therapies that are under investigation include AR inhibitors, ALA, γ-linolenic acid, benfotiamine, Metanx, and PKC inhibitors.

As discussed elsewhere in this review, excess glucose in diabetic patients accelerates AGE generation, which leads to intra- and extracellular protein cross-linking and protein aggregation. RAGE activation alters intracellular signaling and gene expression, releases proinflammatory molecules, and results in an increased production of ROS that contributes to diabetic microvascular complications. Aminoguanidine, an inhibitor of AGE formation, showed good results in animal studies, but trials in humans have been discontinued because of toxicity.[687] Benfotiamine is a transketolase activator that reduces tissue AGEs. Several independent pilot studies have demonstrated its effectiveness in diabetic polyneuropathy. In a 3-week placebo-controlled study, subjective improvements in neuropathy scores were seen in the group that received 200 mg daily of benfotiamine tablets, with a pronounced decrease in reported pain levels.[688] In a 12-week study, the use of benfotiamine plus vitamin B6/B12 significantly improved NCV in the peroneal nerve along with appreciable improvements in vibratory perception. An alternate combination of benfotiamine (100 mg) and pyridoxine (100mg) has improved diabetic polyneuropathy in a small number of diabetic patients.[689]

Metanx is a natural food product for managing endothelial dysfunction. It contains L-methyl-folate, pyridoxal 5′-phosphate, and methylcobalamin. Metanx counteracts endothelial NOS uncoupling and oxidative stress in vascular endothelium and peripheral nerves. A 24-week, double-blinded, placebo-controlled multisite study concluded that, although there was no significant change in vibration perception threshold, there were significant improvements in both neuropathic symptoms and mental health.[690] Metanx significantly improved the Neuropathy Total Symptoms Score-6 (which includes numbness, tingling, aching, burning, lancinating pain, and allodynia) at week 16 (P = 0.013) and week 24 (P = 0.033) vs placebo. Moreover, there were significant improvements on the Mental Health Component of the Short Form-36 Health Survey. In this study, metformin use was a major predictor of a beneficial response. Metformin can cause vitamin B12 deficiency and neuropathy.[691] In particular, previously established normal values have grossly underestimated the level at which the peripheral nervous system is at risk[692,693] (levels >400 pg/mL are required for neuronal integrity). These findings support the use of Metanx as a safe approach for short-term alleviation of diabetic neuropathy symptoms, although we need future studies to further define these effects and their impact on long-term outcomes.

AR inhibitors reduce the flux of glucose through the polyol pathway, inhibiting tissue accumulation of sorbitol and fructose. A 12-month study of zenarestat reported a dose-dependent improvement in nerve-fiber density.[694] A 1-year trial of fidarestat in Japanese patients with diabetes reported an improvement of symptoms,[695] and a 3-year study of epalrestat showed improved NCV and vibration perception.[100] Studies are currently exploring newer ARIs, and some positive results have emerged.[696,697] However, it is becoming clear that these newer ARIs alone may not be sufficient, and combinations of treatments may be needed.[640]

Patients have used ALA or thioctic acid, which have antioxidant and thiol-replenishing redox-modulating properties. A number of studies show a favorable influence of these agents on microcirculation and on the reversal of symptoms of neuropathy.[698–700] A metaanalysis including 1258 patients from four RCTs concluded that 600 mg intravenous ALA daily significantly reduced symptoms of neuropathy and improved neuropathic deficits.[701] The SYDNEY 2 trial showed significant improvement in neuropathic symptoms and neurologic deficits in 181 diabetic patients with three different doses of ALA compared with placebo over a 5-week period.[702] The NATHAN 1 trial examined the long-term efficacy and safety of ALA. The trial randomly assigned diabetic patients (n = 460) with mild-tomoderate DSPN to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. The primary end point was a composite score (NIS-LL and 7 neurophysiologic tests). The study showed that 4-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point. However, ALA did result in a clinically meaningful improvement and prevention of progression of neuropathic impairments, and it was well tolerated. The primary reason the composite score did not improve was that nerve conduction deficits in the placebo-treated group did not progress. Thus, the study was unable to show secondary prevention of progression of the composite end point by treatment with ALA.[703]

We need further investigation to clarify ALA's effect on neuropathic deficits vs nerve conduction parameters and/or quantitative sensory tests. Additionally, we need to address cost-benefit analyses, optimal treatment duration, and delineation of patients with disease characteristics most likely to benefit from ALA supplementation.[704]

PKCactivation is a critical step in the pathway to diabetic microvascular complications. Both hyperglycemia and disordered FA metabolism activate PKC, resulting in the increased production of vasoconstrictive, angiogenic, and chemotactic cytokines (including TGF-β, VEGF, ET-1, and intercellular adhesion molecules). A multinational, randomized, phase-2, double-blind, placebo-controlled trial with RBX (a PKCβ inhibitor) failed to achieve the primary endpoints, although it reported significant changes in a number of domains.[61] Nevertheless, there was a statistically significant improvement in symptoms and vibratory detection thresholds in RBX- vs placebo-treated subjects in a subgroup of patients with clinically significant symptoms but less severe diabetic neuropathy at baseline (sural nerve action potential >0.5 μV).[705] A recent, smaller, single-center study showed improvements in symptom scores, endothelium-dependent skin blood flow measurements, and QOL scores in the RBX-treated group.[646] These studies and the NATHAN studies point to a change in the natural history of diabetic neuropathy due to the advent of therapeutic lifestyle change, statins, and ACEi. These factors have slowed the progression of diabetic neuropathy and drastically altered the requirements for placebo-controlled studies.

Growth factors: There is increasing evidence that there is a deficiency of nerve growth factor in diabetes, as well as a deficiency of dependent neuropeptides substance P and calcitonin gene-related peptide, and that this contributes to the clinical perturbations in small-fiber function.[706] Clinical trials with nerve growth factor have not been successful and are subject to certain caveats with regard to design. Nevertheless, nerve growth factor still holds promise for sensory and autonomic neuropathies.[623] The pathogenesis of diabetic neuropathy includes loss of vasa nervorum, so it is likely that the appropriate application of VEGF would reverse the dysfunction. Introducing the VEGF gene into the muscle of diabetic animal models improved nerve function.[707] There are ongoing VEGF gene studies involving the transfection of the gene into human muscle.

Immune therapy. Several autoantibodies have been found in human sera that are both associated with diabetic neuropathy and can react with epitopes in neuronal cells. One study reported that in patients with diabetes there was a 12% incidence of an association between a predominantly motor form of neuropathy and monosialoganglioside antibodies (anti-GM1 antibodies).[665] Perhaps the clearest link between autoimmunity and neuropathy is the 11-fold increased likelihood of chronic inflammatory demyelinating polyneuropathy, multiple motor polyneuropathy, vasculitis, and monoclonal gammopathies in diabetes.[663] New data, however, support a predictive role of the presence of antineuronal antibodies on the later development of neuropathy, suggesting that these antibodies may not be innocent bystanders but neurotoxins.[625,708] There may be selected cases (particularly those with autonomic neuropathy, evidence of antineuronal autoimmunity, and chronic inflammatory demyelinating polyneuropathy) that may benefit from intravenous immunoglobulin or largedose steroids.[661]

Summary

Diabetic neuropathies are some of the most common complications of diabetes that lead to significant morbidity and mortality and higher health care costs. The spectrum of clinical neuropathic syndromes described in patients with diabetes includes dysfunction of almost every segment of the somatic, peripheral, and autonomic nervous system. Focal neuropathies include focal-limb neuropathies due to entrapment syndromes and cranial neuropathies. Proximal muscle weakness from amyotrophy and chronic demyelinating neuropathies both occur with increased frequency in the diabetic population, but require different treatments. Distal neuropathies include DSPN and a distinctive variant known as acute sensory neuropathy, which are diagnosed by history and clinical examination. Specific diagnostic testing (e.g., quantitative sensory testing, skin biopsy and intraepidermal nerve-fiber density analysis, contact heat-evoked potentials, sudomotor function testing, and nerve conduction studies) can aid in the diagnosis and treatment.

Intensive glycemic and metabolic control can significantly influence the development or progression of DSPN, but not reverse established neuropathy. Therapies, including benfotiamine, AR inhibitors, Metanyx, and ALA, to reduce oxidative and nitrosative stress have shown encouraging results.

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