Prevention, Diagnosis, and Treatment of Microvascular ComplicationsPart 1 / Diabetic Neuropathy

Prevention, Diagnosis, and Treatment of Microvascular Complications
Part 1 / Diabetic Neuropathy

Bill Polonsky

News flash: Well-managed diabetes is the leading cause of …NOTHING.

—Bill Polonsky, PhD, CDE. Director, Diabetes Behavioral Institute, San Diego, CA

Historical Perspective

When insulin was discovered in 1922 by Fredrick Banting and Charles Best, only 2% of the population of industrialized countries had diabetes. Patients managing to survive the effects of severe calorie-restricted diets prescribed as the only means of treatment for diabetes often suffered from cataracts, blindness, severe foot and leg infections, sterility, boils, and tuberculosis. Infectious diseases that could be managed successfully in nonimmune compromised patients proved fatal to diabetics. Patients with gangrene or postoperative infections would often be left to linger until death because little could be done to promote acceptable wound healing or reduce their emotionally charged neuropathic pain. Women who were able to conceive rarely were able to carry the fetus to term. Diabetes became a death sentence to those afflicted by the disease. The life expectancy of patients with T1DM diabetes was between 6 and 12 months from the time of diagnosis. Most patients died in hospital wards where medical personnel offered only starvation as a therapeutic option to those who were already emaciated and dehydrated from acute diabetic ketoacidosis.

Death from diabetic ketoacidosis in 1900 overstimulated the senses of patients and health-care providers alike as described in “The History of Insulin” by Michael Bliss.¹

“When the doctors found an abundance of ketones in the urine, they knew the diabetes was entering the final states. They could smell it, too, for some ketone bodies were also volatile and were breathed out. It was a sickish-sweet smell, like rotten apples, that sometimes pervaded whole rooms or hospital wards.”

There is little doubt that the discovery of insulin has had the most significant effect on global health than any other drug in history. For the first time, physicians had a truly effective and powerful weapon against a mortal disease. Yet insulin was not a “cure” for diabetes. Following the awarding of the Nobel Prize in medicine (1923) to the discoverers of insulin, Dr. Elliott Joslin predicted that the era of the coma as the central problem of diabetes would give way to the era of complications.¹ The miracle of insulin has been to multiply the life expectancy of patients with diabetes 25-fold. No longer are patients dying of diabetic ketoacidosis but of the complications related to chronic exposure to hyperglycemia.

Historians view the success of insulin with stunning irony. Insulin has allowed patients with diabetes to live longer and to propagate. The number of people worldwide with diabetes began and is continuing to rise. Many patients with diabetes who are not aggressively managed, especially from the onset of their disease, develop complications that are costly to themselves as well as to society. Although so many people worldwide were celebrating the discovery of insulin, others were prophesying that the introduction of insulin as a life-saving treatment for diabetes would cause society to bear a financial burden for patients who become long-term survivors. In 1923, Dr. Otto Leyton of London urged that insulin “be given free to poor diabetics only on the condition that they have no progeny.”²

The prediction in the 1920s that prolonging the lives of patients with diabetes would result in economic hardship has certainly become a modern reality. Thus, with the discovery of insulin, the true complexity of the diabetic state was beginning to unfold. The era of death from coma was transformed into an era of death from complications. When Banting received his standing ovation upon being presented with his Nobel Prize for medicine in 1923, the attendees at the ceremony honestly believed that the mystery of diabetes had been solved. Little did they know that the true complexity of diabetes would become apparent only when patients lifespans approached those of euglycemic individuals.

As patients diagnosed with diabetes are living years longer than those diagnosed only 10 to 20 years ago, exposure to “cumulative glycemic burden” favors the activation of microvascular and macrovascular complications pathways.³,⁴ Prior to 2004, the American Diabetes Association (ADA) recommended that the A1C not be allowed to exceed 8% and that patients be treated to a goal of 7%.⁵ By dropping the 8% “action threshold” in favor of a general recommendation to treat “most patients” to less than 7% in 2004, the ADA for the first time acknowledged the importance of reducing one’s exposure to chronic hyperglycemia.⁶ Yet not all patients with excessive glycemic burdens will develop complications while others with minimal exposure to hyperglycemia may lose their vision. Thus, physicians who manage patients with diabetes must be fully aware of one’s customized metabolic targets, family history, environmental factors, which may trigger complication pathways (obesity, smoking, alcohol use, physical inactivity) and duration of disease in order to minimize one’s complication risk. Compassionate care for primary care providers is defined by one’s ability to assist patients navigate safely through a “minefield laden with complication pathway triggers” while balancing one’s quest to achieve metabolic normalcy.

Risk Factors for Developing Microvascular Disease Extend beyond Glycemic Control

The basic tenet that targeted glycemic control minimizes one’s risk of developing long-term complications appears to be well established based on epidemiologic observations and prospective clinical trials. Published standards of care suggest maintaining A1C levels as close to normal as possible.⁷ Unfortunately, some patients with well-managed diabetes may still develop long-term complications, while others with poor control appear to be immune from any ill effects of chronic hyperglycemia.⁸ How can this inequity of diabetes-related complications be explained to patients who are doing all they can to minimize risk as well as to those who are nonadherent to all therapeutic interventions?

The Joslin Gold Medalists comprise 351 U.S. residents who have survived with T1DM for greater than 50 years.⁹ A high proportion of Medalists remain free from proliferative diabetic retinopathy (42.6%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%).
Why would patients who for so long were using only one to two injections of insulin per day who had no access to intensive glucose monitoring, blood pressure (BP) or lipid management have exceeded all expectations by minimizing their prevalence of complications? Other patients with T1DM develop proliferative retinopathy and chronic kidney disease despite remaining vigilant in maintaining their prescribed A1C levels. Clearly, factors other than simple glycemic control factor into long-term outcomes for all patients with diabetes.

One of the most important contributors to diabetes complications are the accumulation of advanced glycation end products (AGEs). AGEs develop as a result of nonenzymatic, irreversible glycation of proteins, lipids, and nucleic acids.¹⁰ Chronic hyperglycemia, glycemic variability, and oxidative stress drive the formation of AGEs, which bind to receptors (RAGE) on endothelial cells. Once receptor bound, AGEs contribute to vascular injury by increasing procoagulant activity, adhesion molecule expression, monocyte influx, altered endothelial cell signaling, vascular stiffness, and oxidative stress.¹⁰

In the Joslin Gold Medalist population, AGE levels had an inverse relationship to microvascular complication rate. Could these unique individuals have a genetically expressed self-defense mechanism, which protected them against long-term microvascular events? After all, AGEs are not “user friendly” and tend to upregulate complications.¹¹ As shown in Figure 5-1, the binding of AGEs to AGE receptors would normally upregulate the expression of multiple complication pathways.¹² The
more AGEs become receptor bound, the greater the likelihood of developing a complication over time. However, patients, such as the Joslin Gold Medalists, appear to have been provided with a truly unique gift from their parents known as a “soluble” AGE. As the AGE binds to the RAGE, a small protein ligand breaks free of the receptor effectively “blocking” the complication pathway from progressing forward. Patients who can produce the “soluble RAGE” are likely to be symptom free, whereas those patients who lack the soluble component are prone to develop the complications.

Figure 5-1 • Protective Mechanism of the Advanced Glycation End Product (AGE) Pathway.

AGEs form via nonenzymatic glycation of proteins, lipids, and nucleic acids. Once formed, AGEs promote vascular stiffness and alter cellular receptor signaling by binding with AGE receptors (RAGE). The greater the number of AGEs bound to RAGE, the more enhanced oxidative stress becomes resulting in a downstream cascade of events, which, over a number of years, will often result in a number of microvascular complications. However, in patients who “escape” microvascular disease despite having a history of prolonged hyperglycemia and elevated AGEs, binding of AGEs to RAGE induces the release of a soluble receptor ligand known as sRAGE. sRAGE competitively reduces activation of AGE complication pathways, thereby blocking the downstream cascade mechanism which would otherwise induce microvascular complications. Patients who are genetically prone to producing the sRAGE ligand may be spared complications. Those who cannot produce the sRAGE ligand may be at higher risk of developing microvascular disease. (Adapted from Yan SF, Ramasamy R, Schmidt AM. The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res. 2010:106:842-853.)

From a clinical perspective, the lessons learned from the Joslin Gold Medalist suggest that patients who demonstrate few if any microvascular and macrovascular complications 15 to 20 years after being diagnosed with diabetes may be at lower risk of complications. Targeting an A1C of 6% to 7% in these individuals may not be necessary and could increase the likelihood of developing hypoglycemia. However, patients who develop complications within 5 to 10 years of being diagnosed with diabetes may not have protective mechanisms to minimize the progression of retinopathy, neuropathy, and nephropathy. These patients should be identified and treated ambitiously, making certain that they achieve all of their metabolic targets. In addition, such individuals should be screened for macrovascular complications. Lifestyle interventions, such as weight loss, smoking and alcohol cessation, exercise, and self-blood glucose monitoring should be emphasized.

Although HEDIS Quality Assurance programs stress the importance of treating patients’ A1Cs to target, scientific evidence suggest that glycemic control may play only a minor role in the progression of some complications.¹³ Hirsch and Brownlee have suggested that the A1C and the duration of diabetes explained only 11% of the variation in retinopathy risk for the entire Diabetes Control and Complication Trial (DCCT) study population.¹⁴ The remaining 89% of the risk should be attributed to environmental factors, lipids, BP, glycemic variability, and genetics. Much remains to be explored to help clinicians and patients minimize their long-term complication risks.

Primary care physicians face a daunting task striving to reverse modifiable risk factors, which have been implicated in promoting complications. The percentage of U.S. adults who report themselves as being smokers, inactive, obese, overweight, and having hypertension or elevated cholesterol is shown in Figure 5-2.¹⁵ Fortunately, the percentage of patients with diabetes who smoke has
declined from 21.7% in 1994 to 20% in 2007. All other risk factor trends have been increasing during this same reporting period.¹⁵ Duration of diabetes and exposure to glycemic burden also impact the risk of complications.¹⁶

Figure 5-2 • Risk Factors for Complications Among Adults with Diabetes in the United States—2007. According to the CDC, 15.1% of U.S. adults with diabetes smoked, 38.2% reported being physically inactive, 83.5% were overweight or obese, 51.1% were obese based on self-reported height and weight, 67% had hypertension, and 62.6% said that they were diagnosed with high cholesterol. Centers for Disease Control and Prevention Data and Trends. http://www.cdc.gov/diabetes/statistics/comp/fig10.htm. Accessed December 12, 2011.

Biochemical and Molecular Pathways That Trigger Diabetes-related Complications

The sequelae of chronic hyperglycemia in diabetes of all phenotypes are divided into microvascular and macrovascular complications. The consequences of microvascular disease include loss of vision, renal insufficiency, and neuropathy (distal sensory neuropathy and diabetic autonomic neuropathy [DAN]). Macrovascular complications include myocardial infarction (MI), stroke, and peripheral arterial disease (PAD). The link between glycemic burden and induction of disease-specific complication pathways has been established by four independent biochemical abnormalities: increased polyol pathway flux, increased formation of AGEs, activation of protein kinase C (PKC), and increased hexosamine pathway flux. These seemingly unrelated pathways have an underlying common denominator: an increase in oxidative stress caused by the overproduction of superoxide by the mitochondrial electron transport chain.

• Oxidative Stress

The microvascular and macrovascular complications of diabetes are believed to be caused by oxidative stress. Intracellular oxidative stress occurs when the production of reactive oxygen species (by-products of normal metabolism) exceeds the capacity of the cells’ antioxidants to neutralize them, resulting in cellular dysfunction and damage.¹⁷ Oxidative stress may be minimized by maintaining optimal control of metabolic parameters such as glucose, lipids, and BP. Endothelial cells chronically exposed to oxidative stress activate multiple complication pathways (Fig. 5-3).

Figure 5-3 • The “Downstream Effects” of Oxidative Stress-Induced Diabetes Complication Pathways. Postprandial and fasting hyperglycemia and glycemic variability result in the production of superoxide within the mitochondria of endothelial cells. NO regulates vascular tone and minimizes adhesion molecule penetration of the vascular walls. When superoxide interacts with peroxynitrate, the endothelial cell’s mitochondrial electron transport system becomes impaired, resulting in endothelial dysfunction. Transcription of endothelial-derived cytokines induces pathways known to activate microvascular complications. Peroxynitrate also favors lipid oxidation leading to atherosclerosis and macrovascular disease. NF-kβ, nuclear factor kappa B. (Adapted from Unger J. Reducing oxidative stress in patients with type 2 diabetes mellitus: a primary care call to action. Insulin. 2008;3:176-184.)

Endothelial cells maintain the barrier between the blood and the vascular wall. Nitric oxide (NO), which is produced within the endothelial cell, regulates vascular tone, while keeping the vessel walls smooth and free of adhesion molecules. Peroxynitrite (PN) (an NO derivative) is formed when NO interacts with superoxide produced within the mitochondria of oxidatively stressed endothelial cells. PN inhibits the endothelial cell’s mitochondrial electron transport system, induces endothelial dysfunction, and activates the expression of endothelial-derived cytokines. These cytokines act like a fuse on a stick of dynamite igniting a series of pathways that, over time will promote the development of microvascular and macrovascular disease.¹⁷,¹⁸

Oxidative stress is triggered more powerfully by postprandial glucose fluctuations than by sustained hyperglycemia.¹⁹ The effects of oxidative stress on long-term diabetes outcomes have important implications in clinical practice. Why do some patients who have “normal” “A1C” levels lower than 6% develop retinopathy, whereas others who have “poorly controlled diabetes” (A1C greater than 9%) remain retinopathy-free their entire lives?

In the DCCT, the diabetic retinopathy (DR) risk at identical sustained levels of A1C was significantly reduced by intensive treatment.²⁰ For example, in the group of patients who had a sustained A1C of 9% for the entire study duration, the risk of retinopathy was reduced by more than 50% in the intensive control group, even though both the conventional and intensively treated patients had identical A1C levels. Intensively managed patients had less DR due to improved daily glycemic variability when compared with glucose profiles of the conventionally treated patients. This study demonstrates the importance of hyperglycemia, hypoglycemia, and “malglycemia” in promoting complications. Figure 5-4A,B show a patient with chronic kidney disease and retinopathy whose initial “malglycemia” improved with the addition of a GLP-1 analogue.

Figure 5-4 • Improvement in Glycemic Variability. A 52-year-old school teacher with stage 4 chronic kidney disease and nonproliferative retinopathy. Despite being on an insulin pump, the patient’s self-blood glucose monitoring suggests wide glycemic variability as shown in panel A. (Each + symbol represents a glucose value obtained during that time over a 2-week interval.) The square represents the average fasting and postprandial glucose values over 2 weeks. After the patient was placed on liraglutide (off label with concurrent use of insulin), his glycemic control and variability were significantly improved. Although this case is suggestive of glycemic variability, MAGE as determined by continuous glucose sensing is the most appropriate model for measuring daily variability as shown in panel B. (Case courtesy of Jeff Unger, MD.)

Acute glucose fluctuations and hyperglycemia both at fasting and during the postprandial periods result in accelerated advanced glycation and the generation of oxidative stress. Chronic hyperglycemia is best assessed by measuring A1C, whereas acute fluctuations (also known as MAGE—mean amplitude of glycemic excursions) may be determined mathematically by continuous glucose monitoring.¹⁹ Thus, both acute glycemic variability and measures of chronic hyperglycemia (A1C) are important factors in upregulating oxidative stress (Fig. 5-5). Some experts believe that glucose variability (MAGE) greater than 40 mg per dL, as measured by continuous glucose sensors, should be targeted for intensive intervention to minimize oxidative stress.²¹ One should note that oxidative stress is considered the unifying mechanism, which drives all complication pathways related to diabetes.²²

Hyperglycemia, whether acute (postprandial) or chronic, has tissue-damaging effects on cell types such as capillary endothelial cells of the retina, mesangial cells in the renal glomerulus, and peripheral neurons. Why are some cells prone to develop complications, whereas others appear to be immune to the effects of similar exposure to chronic hyperglycemia? The answer lies in a cell’s ability to assimilate the amount of glucose required as an energy source before transporting nonessential glucose out of the cell. Cells (such as neurons and nephrons) that are inefficient interstitial transporters of glucose undergo oxidative stress, which induces endothelial dysfunction, vascular inflammation, and activation of pathways that trigger complications.¹⁷ Other cells [such as those in the gastrointestinal (GI) tract] are more efficient at transporting excessive glucose from inside the cell externally, thereby minimizing the risk of oxidative stress.

Vascular endothelial cells form physical and biologic barriers between the vessel wall and the circulating blood cells, with the endothelium playing an important role in the maintenance of vascular homeostasis. Central to this role is the endothelial production of NO, which is synthesized by the constitutively expressed endothelial isoform of NO synthase. Vascular diseases, including hypertension, diabetes, and atherosclerosis are characterized by impaired endothelium-derived NO bioactivity that may contribute to clinical cardiovascular events. Endothelial cells exposed to oxidative stress generate high levels of reactive oxygen species via their mitochondrial electrontransport chain. Susceptible cells will activate biochemical pathways likely to progress toward longterm microvascular and macrovascular complications unless metabolic stability is restored.

Endothelial dysfunction drives atherosclerosis. Endothelial cell protective mechanisms (e.g., NO and prostacyclin), which are derived vasodilators, favor antiatherogenic mechanisms within the vasculature. Expression of endothelium-derived vasoconstrictors (e.g., endothelin-1 and thromboxane) has been associated with proatherosclerotic events.²³,²⁴

Just as a town’s department of public works is responsible for repairing potholes that plague city streets, the body has the capacity to form a cellular “patch” over a site of acute endothelial injury. Derived from bone marrow, endothelial progenitor cells (EPCs) are mobilized to the peripheral
circulation in response to tissue ischemia through the release of growth factors and cytokines. The EPCs hone into the ischemic or damaged tissue and stimulate endothelial repair. In addition to traditional cardiovascular risk factors, oxidative stress has been associated with reduction in the number and function of circulating EPCs, whereas an expanded EPC pool decreases cardiovascular mortality.²⁵

Figure 5-5 • Relationship between Hyperglycemia Markers and Microvascular Complication Risk. Fasting hyperglycemia and postprandial hyperglycemia both contribute to excessive glycation, resulting in a rise in A1C. Acute fluctuations in daily glycemia, as measured by continuous glucose sensors, like A1C will result in a rise in oxidative stress. Complication pathways are activated in response to oxidative stress. Therefore both chronic and acute hyperglycemic abnormalities should be targeted and controlled in order to minimize one’s risk for developing long-term complications. (Adapted from Monnier L, Colette C. Glycemic variability. Should we and can we prevent it? Diabetes Care. 2008;(Suppl 2):S150-S154.)

Oxidative stress may even be induced in individuals without diabetes. Using a hyperglycemic clamp, euglycemic subjects exposed to ambient glucose levels greater than 200 mg per dL for just 2 hours were found to have increased levels of urinary F2 isoprostanes (a surrogate marker of oxidative stress).²⁶ Exposure to blood glucose levels greater than 180 mg per dL results in prolonged endothelial cell dysfunction and vascular inflammation, which persist for 7 days, even once the acute episode of hyperglycemia is reversed.⁴ Thus, patients with both acute and chronic hyperglycemia live in a constant state of oxidative stress, a metabolic status that favors progression toward microvascular and macrovascular endpoints. From a clinical perspective, a patient who records a fasting blood glucose of 200 mg per dL has likely been exposed to activated oxidative stress-related metabolic pathways during their entire resting hours. Failure to recognize and reverse this glycemic burden will put patients at risk for complications that can have a profound effect on their longevity and quality of life.

Table 5-1 lists therapeutic approaches a patient may employ to reduce oxidative stress.

• Advanced Glycosylation

Nonenzymatic glycosylation and oxidation of proteins are natural phenomena of aging that occur very slowly. As glucose becomes incorporated into proteins, AGEs are formed in an irreversible chemical reaction. During this process, reactive oxygen species, such as superoxide and hydrogen peroxide, are also produced. When ambient glucose levels are elevated, the extent of glycosylation increases as sugars become attached to free amino groups on proteins, lipids, and nucleic acids, thereby altering the function and metabolism of these macromolecules. AGE receptors (RAGEs) on macrophages induce monocytes and endothelial cells to increase the production of inflammatory cytokines and adhesion molecules²⁷ (Fig. 5-6). The resulting basement membrane thickening can cause symptoms such as joint stiffness and diffuse pain in response to light touch. AGEs can also bind to AGE receptor sites on endothelial cell surfaces, leading to increased inflammatory responses, vascular permeability, and procoagulant activity. The ability to form and detoxify AGE by-products may be genetically predetermined, explaining why some patients who have poor glycemic control
are fortunate to experience no diabetes-related complications, whereas those less fortunate with prediabetes may develop retinopathy or painful diabetic neuropathy (Fig. 5-1).

TABLE 5-1. Practical Approaches to Reducing Oxidative Stress

1. Use insulin analogues preferentially over human insulin because their pharmacokinetic profiles mimic physiologic pharmacokinetic profiles more closely.

2. Advise patients to inject prandial rapid-acting insulin analogues 15 min prior to meals if their baseline glucose levels are >80 mg/dL. This will allow the absorption of insulin to match up more precisely with the onset of carbohydrate absorption from the gut

3. Reducing carbohydrate intake will lessen postprandial glucose excursions

4. Exercising will improve peripheral insulin resistance and help reduce postprandial hyperglycemia

5. Use incretin therapies such as GLP-1 analogues or DPP-4 inhibitors where appropriate. These drugs work to reduce postprandial excursions.

6. Pramlintide, a synthetic analogue of human amylin, has been shown in clinical trials to reduce surrogate markers of oxidative stress

Adapted from Unger J. Reducing oxidative stress in patients with type 2 diabetes mellitus: a primary care call to action. Insulin. 2008;3:176-184.

Figure 5-6 • Pathway Linking Advanced Glycation to Diabetes Complications. (See text for explanation of pathway.)

• Activation of the Polyol Pathway

During hyperglycemia, glucose levels rapidly increase in tissues, such as the kidneys, nerves and retina that are insulin-independent for glucose uptake. Excess glucose enters the polyol pathway activating aldose reductase, which increases intracellular levels of fructose and sorbitol in these complication prone target sites.²² (Fig. 5-7). The resulting alteration in osmotic gradient favors penetration of water, protein precipitation, and cataract formation within ocular lenses. In peripheral nerves, elevated sorbitol levels leads to axonal edema, altered neurologic function and neuropathic pain. The effects of polyol pathway activation within the kidneys are debated, but may ultimately result in dysfunction of the proximal tubules.

• Activation of the Protein Kinase C Pathway

Hyperglycemia activates production of diacylglycerol (DAG), a second messenger protein that relays signals from receptors on the cell surface to target molecules within the cell (Fig. 5-8). Second messengers not only alter the normal activity of a cell, but amplify the signal, which induces the change. Among the signals induced by second messaging, DAG’s primary role is activation of the PKC pathway. PKC production initiates a complex intracellular signaling cascade, affecting gene expression in many organs and tissues throughout the body.²⁸ The effects of the PKC enzyme within plasma membranes are cell specific. In patients with diabetes, PKC activation has been linked with retinopathy and nephropathy.

• Hexosamine Pathway

Hyperglycemia results in a diversion of glucose metabolism from glycolysis to the pathologic hexosamine pathway. The shift in normal metabolism causes a change in gene transcription within affected cells favoring the production of inflammatory cytokines as shown in Figure 5-9. Rising plasma concentrations of transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor type-1 (PAI-1) adversely affect the kidneys and the vasculature.²²

Figure 5-7 • Relationship of the polyol pathway to activation of diabetic neuropathy hyperglycemia results in an increased accumulation of sorbitol and fructose in cells such as neurons and retina tissue, which are unable to eliminate the excess sugars. This changes the osmotic gradient within these susceptible cells, resulting in neuronal dysfunction.

Figure 5-8 • Activation of the PKC Pathway. Chronic hyperglycemia induces the activation of the PKC pathway, which, when combined with increasing oxidative stress and inflammatory cytokine production, results in thickening of the renal arteriolar walls, glomerular basement membrane, and tubular basement membrane. Retinal vessels are also affected by an increase in hyperglycemia-induced PKC signaling.

Figure 5-9 • Hexosamine Pathway and Hexosamine Complications Pathway. The normal route of glucose metabolism is through glycolysis. During hyperglycemia, glucose is diverted into the hexosamine pathway in which an enzyme called GFAT (glutamine fructose-6 phosphate amidotransferase) converts the fructose-6 phosphate into glucosamine-6 phosphate. This results in pathologic changes in gene expression within the cell nucleus. Inflammatory cytokines, PAI-1 and TGF-β1 are produced by the cells resulting in vascular disease affecting the kidneys and arteries. (From Schleichler ED, Weigert C. Role of hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int. 2000;58(Suppl 77):S13-S18.)

• Neuroinflammation

Autoimmune mechanisms may play a role in both the initiation and rate of deterioration of neuropathy. The production of free radicals and superoxide can disrupt the normal neuroprotection achieved by the neurovascular unit.²⁹ The neurovascular unit consists of a neuron surrounded by astrocytes and microglial cells (Fig. 5-10A). Astrocytes maintain extracellular ion homeostasis within neurons.³⁰

Microglial cells (Fig. 5-10A) are the resident macrophages of the central nervous system.³¹ As biologic sensors, these cells continually survey the neurons, making certain that normal neurophysiologic protective mechanisms are active. Microglial cells are capable of mounting both an inflammatory and reparative response when they become “activated.” Once the microglial cells become activated, through physical stress or pharmacologic interference with their protective mechanisms, they produce inflammatory cytokines [interleukin-6 (IL-6)], damage neuronal segments, and alter neurologic activity (Fig. 5-10B).³¹ Opioid use has been found to activate microglial cells, causing them to produce inflammatory cytokines, which result in chronic, disabling pain.³²

Figure 5-10 • Neuroinflammation. A. Anatomy of the neurovascular unit. B. Microglial cell activation. The neurovascular unit consists of astrocytes, which are modulators of ions and glutamate within neurons and microglial cells. Microglial cells are living sensors, which protect a given neuronal segment. Stable microglial cells (pictured on the left of B) produce a cytokine IL-10, which protect the neuron from inflammation. Microglial cell activation will occur when patients are exposed to physical or emotional stress. Certain medications, such as opioids, will also trigger microglial cell activation (shown on the right of B). Once activated, the microglial cells shift cytokine production to IL-6 and glutamine, both of which are inflammatory and injurious to the neuron. (Adapted from Unger J. Diabetic neuropathy: early clues, effective management. Appl Neurol. 2005:23-30.)

Diabetic Neuropathy

This chapter will discuss screening, diagnosis, and management of diabetic neuropathy. Microvascular disorders related to chronic kidney disease and retinopathy will be presented in Chapter 6.

• Introduction to Neuropathic Disease

The neuropathies are among the most common of the long-term complications of diabetes, affecting up to 50% of patients.³³ The clinical features of diabetic neuropathy vary immensely. Patients may present to a wide spectrum of specialists including dermatology, podiatry, urology, cardiology, psychiatry, gynecology, cardiology, family medicine, rheumatology, pain management, orthopedics, ophthalmology, audiology, ENT, and gastroenterology. Neuropathies are characterized by a progressive loss of nerve fibers and nerve fiber density, resulting in altered nerve conduction velocity. There is increasing evidence that measures of neuropathy, such as electrophysiology and quantitative tests, are predictors of not only endpoints, including foot ulceration, but also mortality.³⁴ Screening, diagnosing, and managing patients for both sensory and autonomic neuropathies are well within the realm of primary care. Recognizing that patients have cardiac autonomic dysfunction warrants specialty referral.

An expert panel has defined diabetic neuropathy as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.”³⁵ Neuropathy cannot be diagnosed without an appropriate neurologic examination. Because up to 75% of patients may be asymptomatic, all patients with diabetes must be screened frequently to determine the presence of signs suggestive of diabetic peripheral and autonomic neuropathies.

Neuropathy is one of the most common complications of diabetes, with a lifetime prevalence between 25% and 50% in persons with diabetes.³⁶ In developed countries, diabetic neuropathy accounts for 50% to 75% of nontraumatic amputations.³⁷ Mortality in patients with autonomic neuropathy is 25% to 50% within 10 years of the onset of symptoms.³⁸

Approximately 50% of patients with diabetes experience symptomatic diabetic peripheral neuropathy (DPN), yet only 15% to 25% have symptoms severe enough to warrant treatment.³⁹ Estimates of the number of people in the United States with diabetic peripheral neuropathic pain (DPNP) range from 600,000 to 3.6 million.⁴⁰

Diabetic neuropathy can be identified in patients with prediabetes and impaired glucose tolerance (IGT). A study evaluating 77 patients with idiopathic peripheral neuropathy found that 33% were diagnosed with IGT and 19% had clinical diabetes.⁴¹ Up to 35% of patients with IGT (prediabetes) have painful neuropathy.⁴²

Perkins et al. demonstrated a 30% reduction in sural nerve fiber density in patients with diabetic neuropathy in comparison to nondiabetic individuals.⁴³ Prolonged hyperglycemia (A1C greater than 9%) not only reduces nerve fiber density but also results in delayed nerve conduction velocity.⁴⁴ Alterations in normal nerve conduction velocity will be perceived as neuropathic pain and may contribute to autonomic dysfunction.

• Risk Factors for Developing Diabetic Neuropathy

Of the 1,172 patients with T1DM who participated in the DCCT, neuropathy developed in 23% who had no evidence of neuropathic disease at baseline.⁴⁵ The highest rates of neuropathy in patients with T2DM occur in those who have had hyperglycemia for more than 25 years. Factors other than glycemic control appear to be influential in determining risk for developing neuropathy. Elucidating the risk factors for neuropathy is important, given the association between the risk factors and increased diabetes-related morbidity and mortality. Mortality in patients with neuropathy is high, and the cause of death is often coronary heart disease.⁴⁶ Risk factors for the development of neuropathy may be categorized as modifiable and nonmodifiable (see Table 5-2).

• Definition and Classification

The typical DPN is a chronic, symmetrical, length-dependent sensorimotor polyneuropathy. DPN develops in association with a background of chronic hyperglycemia and comorbid metabolic
derangements related to hypertension and hyperlipidemia. DPN is statistically associated with other microvascular complications such as DR and diabetic neuropathy.⁴⁶

TABLE 5-2. Risk Factors for Diabetic Neuropathy

Neuropathy Modifiable Risk Factors	Neuropathy Nonmodifiable Risk Factors
• Obesity	• Family history
• Hypertriglyceridemia	• Advancing age
• Cigarette smoking	• Duration of diabetes
• Hypertension
• Glycemic variability
• A1C
Adapted from Tesfaye S, Chaturvedi N, Eaton SEM. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352:341-350.

Many proposed classifications for diabetic neuropathy have been published. For point of discussion, Table 5-3 lists a means by which the neuropathy may be localized as well as categorized. Figure 5-11 shows the pain distribution common to the sensorimotor neuropathies.

Sensorimotor Neuropathies

Diabetic amyotrophy typically occurs in patients aged 50 to 60 years who have T2DM. Presenting symptoms include severe pain and unilateral or bilateral muscle weakness associated with atrophy of the proximal thigh muscles. The cause, although unknown, may be related to infarctions in the lumbosacral plexus. Diabetic amyotrophy results in severe and debilitating pain. Patients experience difficulty in climbing stairs or simply getting up from seated positions.

TABLE 5-3. Classification of Diabetic Neuropathy

Sensorimotor Neuropathies
Examples Based Upon “Disease Localization”	Sensorimotor (Disease Location/Description)
Mononeuropathy (confined to a single nerve)	• Carpal tunnel syndrome • Tarsal tunnel syndrome • Ulnar neuropathy • Peroneal nerve entrapment syndrome • Lateral femoral cutaneous nerve entrapment syndrome
Mononeuritis multiplex (may involve the distribution of severa peripheral nerves)	• Painful, simultaneous, or sequential involvement of individua nerve trunks • Evolves over days or years • Presents with acute or subacute loss of sensory and motor function of individual nerves • Pattern is initially asymmetric. • Over time symptoms may become symmetrical. • Common locations are in the low back, hip, and leg.
Plexopathy	• Diabetic amyotrophy • Diabetic truncal radiculoneuropathy
Distal sensory symmetric polyneuropathy	• Bilateral, symmetrical painful paresthesias, worse at rest and improves with activity. Most often starting in feet, then progressing to hands
Focal neuropathy	• Confined to the distribution of a single cranial or peripheral nerve
Hypoglycemia awareness autonomic failure	• Loss of hypoglycemia counterregulation • May result in immediate loss of consciousness without warning that blood glucose levels are falling • Frequent episodes of hypoglycemia including exercise-induced, nocturnal and recurrent mild events occurring within the same 24-h period
Cardiac autonomic neuropathy	• Impaired autonomic control of the cardiovascular system • Associated with high risk of all-cause mortality, silent ischemia, coronary artery disease, stroke, diabetic nephropathy, and perioperative morbidity • Orthostatic hypotension common • Have abnormalities in BP regulation
Diabetic gastropathy	• Results in disordered gut motility in patients with T1DM primarily • Patients may experience impaired oral drug absorption, erratic glycemic control due to mismatch between normal absorption of insulin and delayed nutrient absorption from the gut. • Abdominal bloating, early satiety, fecal incontinence, nocturnal diarrhea, and constipation are common features. • Poor postprandial regulation of BP. Patients experience postprandial hypoglycemia • Patients express poor quality of life.
Sexual dysfunction	• Men experience loss of erectile function and loss of libido. • ED is a predictor of silent MI for patients with T2DM. • ED prevalence varies between 35% and 90% within males having diabetes. • Women have vaginal dryness and dyspareunia.
Diabetic uropathy	• Secondary to alteration of the detrusor smooth muscle, neuronal dysfunction, and urothelial dysfunction • Affects 43%-87% of patients with T1DM and 25% of T2DM • Difficulty with delayed and complete bladder emptying • Frequent urinary tract infections • Nocturia
Sudomotor dysfunction	• Sweat glands are innervated by unmyelinated cholinergic sympathetic C-fibers, which become dysfunctional in some patients with diabetes. • May result in dryness of the skin in the feet increasing one’s risk of foot ulceration and infections • Loss of sweating may impair exercise function, resulting in dehydration on hot days. • High risk for Charcot arthropathy • Patients with severe sudomotor dysfunction sweat only from the neck down, not on the forehead. • Some patients may experience hyperhidrosis or gustatory sweating timed to occur within minutes of eating.

Figure 5-11 • Pain Distribution Associated with Sensorimotor Neuropathies. (Modified from presentation by Charles Argoff at American Conference on Pain Medicine, New York. June 16, 2007.)

Mononeuropathies

Focal and multifocal neuropathies are confined to the distribution of a single peripheral nerve (mononeuropathy) or multiple peripheral nerves (mononeuropathy multiplex). Mononeuropathies are caused by vasculitis, ischemia of the capillaries supplying the neurons, or nerve infarcts.⁴⁷ Cranial neuropathy in diabetic patients is rare, typically affecting older persons with a long history of diabetes.⁴⁸ Cranial nerves III, IV, or VI may be involved (Fig. 5-12). The classic presentation of a cranial neuropathy is acute-onset diplopia with ptosis and papillary sparing associated with ipsilateral headache. Neurologic deficits resolve on average within 21/2 months. Recurrence rates are 25% in patients with diabetes. Advise patients with a cranial neuropathy to wear a patch over the affected eye and to adhere to strategies that improve glycemic control.
Nerve entrapment syndromes begin gradually and may become disabling over time without intervention. Most often, the median, ulnar, peroneal, lateral femoral cutaneous, or tibial nerve within the tarsal tunnel is involved. Entrapment syndromes affect up to 30% of patients with diabetes and should be evaluated carefully in all those with signs and symptoms of neuropathy.⁴⁹
Carpal tunnel syndrome (median neuropathy) is a clinically relevant problem in 6% of patients with diabetes.⁵⁰ Painful paresthesias of the fingers may progress to a deep-seated ache, which radiates proximally through the forearm. Symptoms are worse at night. Motor weakness can become progressive, and thenar wasting occurs over time.

Figure 5-12 • Left VI Nerve Palsy. Left-sided cranial nerve VI palsy in a patient with poorly controlled T1DM (A1C = 9.6%) who recovered spontaneously within 12 weeks after the onset of her symptoms of dyplopia and unilateral headaches. (Photo courtesy of Jeff Unger, MD.)

Figure 5-13 • Demonstrates Distribution of Paresthesias in a Patient with a Positive Phalen Test. A. The Phalen test—forearms held vertically and hands held in complete flexion for 1 minute—is positive if paresthesia develops in the median nerve. B. Distribution within 30 seconds. C. The Tinel sign—percussion over the median nerve that induces paresthesia over the distribution of the nerve—is suggestive of carpal tunnel syndrome.

Two clinical tests (Phalen and Tinel signs) may be used to screen for carpal tunnel syndrome as shown in Figure 5-13. The Phalen test—forearms held vertically and hands held in complete flexion for 1 minute—is positive if paresthesia develops in the median nerve distribution within 30 seconds. The Tinel sign—percussion over the median nerve that induces paresthesia over the distribution of the nerve—is suggestive of carpal tunnel syndrome. However, nerve conduction studies are required to confirm the diagnosis. Treatment options include wrist splints for nocturnal symptoms. Cortisone injections in the carpal tunnel may provide symptomatic relief; however, they often need to be repeated. Surgical intervention is required for pain relief and to prevent the acceleration of muscle wasting.

Ulnar neuropathy occurs in 2% of diabetic patients as a result of nerve compression immediately distal to the ulnar groove beneath the edge of the flexor carpi ulnaris aponeurosis in the cubital tunnel. Alcoholism is a risk factor. Typical symptoms include painful paresthesias in the fourth and fifth digits associated with hypothenar and interosseous muscle wasting. Treatment is conservative. Patients with motor loss and muscle wasting may require surgical intervention.
Compression of the lateral femoral cutaneous nerve (meralgia paresthetica), although uncommon in diabetes, can result in pain, paresthesias, and sensory loss over the lateral aspect of the thigh. Most cases resolve spontaneously. In cases associated with severe pain, allodynia, and disability, corticosteroid injections using focal nerve blocks at the inguinal ligament or surgical decompression may be required.
Tarsal tunnel syndrome is a painful lower limb entrapment syndrome that involves the tibial nerve, as it traverses the tarsal tunnel. The tibial nerve innervates only the muscles of the soles. Walking or standing triggers severe burning pain over the plantar aspect of the foot. A positive Tinel sign on the underside of the medial malleolus with atrophy of the sole muscles are typical
clinical observations. Sensation over the dorsum of the foot is normal. Ankle reflexes are maintained. Nerve conduction studies demonstrate asymmetry compared with the normal leg.

Treatment options include nighttime splinting in a neutral position and targeted injections of local anesthetics and corticosteroids into the tarsal tunnel. Surgical decompression remains a controversial option in patients with diabetes who have severe pain and abnormal nerve conduction studies.⁴⁹

Diabetic truncal radiculoneuropathy affects middle-aged and elderly men. The primary feature is pain of acute onset that resolves spontaneously within 4 to 6 months. The pain— which is worse at night—is described as an aching or burning sensation with superimposed lancinating stabs. Patients describe the location of pain as being in a girdle-like distribution along the lower thoracic or abdominal wall. The pain may be unilateral or bilateral. Patients may experience profound weight loss associated with the onset of their symptoms. Clinical findings range from no abnormalities to sensory loss and painful hyperesthesia in a complete dermatomal pattern.

Diabetic truncal radiculoneuropathy shares many features with diabetic amyotrophy, except the latter is more painful and occurs in patients whose glycemic control is much worse.

Sensorimotor Neuropathy

Only gold members can continue reading. Log In or Register to continue