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Diabetes Mellitus Complications  

Diabetes Mellitus  Complications                                                                                          REF: Larsen: Williams Textbook of Endocrinology, 10th ed. 2003, etc.           

See also  Diabetes Rx |  Diabetic Medications Protocol for acute Rx of hyperglycemia | Diabetic Ketoacidosis |  Perioperative Rx of DM  
Late Complication of Diabetes Mellitus:
  • Macro-vascular complications as:
    Atherosclerosis with MI, CVA, peripheral vascular disease

  • Micro-vascular complications as:
    Diabetic Retinopathy

    Diabetic Nephropathy
    Diabetic Neuropathy

  • Diabetic Gastroparesis  

* Diabetic Complications  can be prevented by meticulous Glucose Control Of Diabetes, Good Control of blood pressure & lipid, ACE-I Rx !



Diabetic retinopathy
Annual dilated funduscopic examinations are recommended; follow-up evaluation and treatment for abnormalities by ophthalmologists with specific expertise in fluorescein angiography and laser therapy can reduce visual loss. Cataract extraction in the setting of diabetic retinopathy can be associated with visual loss related to macular edema and requires special attention to avoid poor outcomes. Glaucoma seems to be more prevalent in people with diabetes. Expert eye care is essential for optimal outcomes in people with diabetes.

Diabetic retinopathy refers to progressive pathologic alterations in the retinal microvasculature, leading to areas of retinal nonperfusion, increased vascular permeability, and the pathologic proliferation of retinal vessels. In the United States, diabetes is the leading cause of blindness in persons aged 20 to 74 years. Retinopathy in patients with poorly controlled type 1 diabetes occurs in about 25% of patients 5 years after diagnosis, in 60% at 10 years, and in more than 95% at 15 years. Blindness occurs 25 times more frequently in diabetic patients than in control subjects and is seen most often after the disease has been present for at least 15 years, in the setting of advanced retinopathy. Approximately 10 to 15% of type 1 diabetic patients will become legally blind (visual acuity of 20/200 or worse in the better eye). In type 2 diabetes, though the incidence of blindness is lower, higher disease prevalence results in an even larger number of patients affected with severe visual loss.

Mild nonproliferative diabetic retinopathy (mild NPDR) is the earliest pathologic changes associated with retinopathy .
In type 1 patients, these changes generally begin 3 to 5 years after diagnosis. The first signs of mild NPDR are microaneurysms, which arise most often in areas of capillary occlusion. Subsequently, increasing vascular permeability leads to retinal blot hemorrhages (round, with blurred edges) and "hard" exudates (sharply defined and yellow). Infarctions of the nerve fiber layer, known as "soft" exudates or "cotton-wool spots," appear as white or gray, rounded swellings. At this early stage of retinopathy, visual acuity is generally unaffected, and the risk of progression to high-risk proliferative diabetic retinopathy (PDR) is about 15% at 5 years.
Moderate NPDR
is characterized by intraretinal microvascular abnormalities, including venous caliber changes, beading, and increased capillary dilatation and permeability. Later changes, termed severe or very severe NPDR, include progressive retinal capillary loss and ischemia, with further development of extensive hemorrhages, exudates, and microaneurysms. At 5 years, moderate and severe NPDR are associated with a 30% and 60% risk of progression to high-risk PDR, respectively.

Proliferative diabetic retinopathy (PDR) involves neovascularization, the growth of fine tufts of new blood vessels and fibrous tissue from the inner retinal surface or the optic head. Early proliferative changes are confined to the retina, but later invasion of the vitreous body constitutes high-risk PDR; during this end stage, fibrosis and contracture of the neovasculature results in retinal detachment and hemorrhage, the most important determinants of blindness. Occasionally, new vessels can invade the iris and anterior chamber, leading to sight-threatening closed-angle glaucoma.

Clinically significant macular edema (CSME) results from vascular leakage at the macula and can occur either with or without the stages of retinopathy described earlier. CSME is suggested by hard macular exudates on fundoscopic examination and can be confirmed with slit lamp biomicroscopy. In general, maculopathy is more common in type 2 patients, in whom it is an important contributor to the loss of visual acuity. As will be discussed, the treatment of CSME runs parallel to the treatment of other forms of diabetic retinopathy.

Duration of diabetes is closely associated with the onset and severity of diabetic retinopathy. Diabetic retinopathy is rare in prepubescent patients with type 1 diabetes, but nearly all patients with type 1 diabetes and more than 60% of patients with type 2 diabetes develop some degree of retinopathy after 20 years. In patients with type 2 diabetes, approximately 20% have retinopathy at the time of diabetes diagnosis and most have some degree of retinopathy over subsequent decades.
Diabetic retinopathy is the most frequent cause of new-onset blindness among American adults aged 20 to 74 years.
Lack of glycemic control is another significant risk factor for the onset and progression of diabetic retinopathy. The DCCT demonstrated a clear relationship between hyperglycemia and diabetic microvascular complications, including retinopathy in 1441 patients with type 1 diabetes.
In addition to the importance of intensive glycemic control in reducing the onset and progression of diabetic retinopathy as discussed earlier, it is critical for optimal ocular health of diabetic patients that several other systemic considerations (as hypertension, proteinuria, hyperlipidemia) be optimized.
Elevated BP exacerbates the development and progression of diabetic retinopathy.
Associations between renal and retinal angiopathy are numerous. Proteinuria or microalbuminuria is associated with retinopathy.  The presence and severity of diabetic retinopathy are indicators of the risk of gross proteinuria, and, conversely, proteinuria predicts PDR.
The effects of serum lipids on retinopathy and macular edema are less certain.
Smoking is a certain risk factor for CVD, progression of albuminuria to proteinuria, and nephropathy in both type 1 and 2 diabetic patients. However, the effects of smoking on diabetic retinopathy are unclear.

At present, medical management of diabetic retinopathy is aimed at controlling risk factors for progression as tight control of hyperglycemia, hypertension, hyperlipidemia, nephropathy, careful follow-up during pregnancy, and a good regular eye exam and follow up by an opthalmologist.



Diabetic nephropathy is the leading cause of end-stage renal disease requiring dialysis or transplantation. Early kidney disease is detectable as an increase in the microalbumin to creatinine ratio on a spot urine sample (>30 µg albumin per mg creatinine). This screening procedure should be performed annually. Patients exhibiting microalbuminuria should be treated with ACE inhibitors or ARBs, and their blood pressure treated to less than 130/80 mm Hg. If the creatinine is increased above normal or if the urinary sediment is active, consultation with a nephrologist or other provider with special expertise in the evaluation of kidney disease may be useful to direct overall treatment and to exclude other causes of kidney disease.

Diabetic nephropathy is clinically defined by persistent proteinuria greater than 500 mg/24 hours in a person with diabetic retinopathy without other renal disease. Listed as the chief cause of end-stage renal disease (ESRD) in North America, Japan, Korea, and most industrialized European nations, diabetic nephropathy in 1998 accounted for 44.5% of incident ESRD patients funded by Medicare.  Typically, diabetic ESRD patients have serious co-morbid conditions, especially heart, eye, and peripheral vascular diseases. It is not surprising, therefore, that caring for afflicted individuals imposes a major financial burden on family members and governments.

Both type 1 and type 2 diabetes cause renal disease. Compared to type 1, a slightly smaller and imperfectly defined proportion of type 2 patients progress to ESRD, but they represent more than 90% of those receiving renal replacement therapy with the diagnosis of diabetes.
Listed as the chief cause of end-stage renal disease (ESRD) in North America, Japan, Korea, and most industrialized European nations, diabetic nephropathy in 1998 accounted for 44.5% of incident ESRD patients funded by Medicare .  Typically, diabetic ESRD patients have serious co-morbid conditions, especially heart, eye, and peripheral vascular diseases.
Both type 1 and type 2 diabetes cause renal disease. Compared to type 1, a slightly smaller and imperfectly defined proportion of type 2 patients progress to ESRD, but they represent more than 90% of those receiving renal replacement therapy with the diagnosis of diabetes.
Kidney injury in diabetes is indistinguishable by diabetes type and affects glomeruli, arterioles, tubules, and interstitium.[415] [416] [417] Glomerular lesions include diffuse and nodular forms of intracapillary glomerulosclerosis.  


The natural history of diabetic nephropathy has been extensively studied in type 1 diabetes because it is usually possible to specify the exact time of onset. As first described by Mogensen, there are five distinct stages. The course of diabetic nephropathy can be followed by two main variables: proteinuria and GFR.

  1. Stage 1: Glomerular Hyperfiltration and Renal Enlargement  
    At onset of type 1 diabetes, approximately one third of individuals have an elevated GFR that is 20% to 40% higher than that of age-matched normal subjects.
  2. Stage 2: Early Glomerular Lesions or Silent Stage with Normal Albumin Excretion
    Those structural changes appear 18 to 36 months and may become prominent after 3.5 to 5 years after onset of type 1 diabetes..
  3. Stage 3: Incipient Diabetic Nephropathy or Microalbuminuric Stage
    The third stage, also called incipient diabetic nephropathy, is characterized by persistent and usually increasing microalbuminuria.   Hypertension may also be a feature of the microalbuminuric stage. Hyperfiltration and renal enlargement persist, though to a lesser degree. Microalbuminuria, defined as urinary AER greater than 30 mg/24 hours or 20 µg/minute and less than 300 mg/24 hours or 200 µg/minute, represents the first laboratory evidence of diabetic renal disease.  
    The prevalence of microalbuminuria varies from 25% to 40% in individuals with type 1 diabetes for 5 to 15 years.
    Persistent microalbuminuria rarely occurs during the first 5 years of type 1 diabetes or before puberty.
  4. Stage 4: Clinical or Overt Diabetic Nephropathy: Proteinuria and Falling Glomerular Filtration Rate  
    Albuminuria greater than 300 mg/24 hours, relentless decline of renal function, and hypertension define the fourth stage of diabetic nephropathy.  This stage, though variable, usually occurs 15 to 20 years after the onset of type 1 diabetes and after 5 or more years of diagnosed type 2 diabetes. The amount of urinary protein can be as little as 500 mg, but it can reach massive proportions, such as 20 to 40 g/24 hours. Continuing urinary protein loss of this magnitude is associated with increased glomerular pore size. There is a high mortality rate associated with proteinuria. Median survival is 10 years from the onset of proteinuria.
    Diagnoses other than diabetic nephropathy should be pursued whenever a nephrotic syndrome develops in a patient with short-term type 1 diabetes or in the absence of retinopathy.
    In subjects with type 1 diabetes, the prevalence of arterial hypertension ranges from 65% to 79% when macroalbuminuria is present.  Hypertension intensifies the rate of progression of established diabetic renal disease.
  5. Stage 5: End-Stage Renal Disease
    After 20 to 30 years of type 1 diabetes, about 30% to 40% of patients progress to ESRD. Recently, the interval between the onset of persistent proteinuria and the final stage of diabetic nephropathy has been lengthened by early and intensive treatment of hypertension and enhanced metabolic control of hyperglycemia.


Although renal structural changes and severity of target organ damage are similar in both types of diabetes, delayed diagnosis has complicated the construction of the natural history of diabetic renal disease in type 2 diabetes.
14-24% of newly diagnosed patients with type 2 diabetes have microalbuminuria, which is associated with hyperglycemia, elevated BP, smoking, and hyperlipidemia.
Microalbuminuria in type 2 diabetes is partially reversed by reduction of hyperglycemia and high BP.
Microalbuminuria raised the overall odds ratio for death to 2.4 and cardiovascular mortality to 2.0 over those without microalbuminuria.
Hypertension is highly characteristic of renal disease in type 2 diabetes, whether the individuals are normoalbuminuric, microalbuminuric, or macroalbuminuric.

Treatment of Diabetic Nephropathy:

  1. Strict glycemic control is of the utmost importance.
  2. Dietary protein restriction (i.e., 0.8 g/kg of body weight)
  3. ACE inhibitors and angiotensin II receptor blockers have consistently shown a delay in the progression of both proteinuria and declining GFR
  4. Good blood pressure control
  5. Good lipid control
  6. Hemodialysis or Peritoneal dialysis in ESRD (End Stage Renal Disease)
  7. Renal transplant



Early treatment of diabetic neuropathy should include tight glycemic control.

Diabetic neuropathy can be disabling as a consequence of autonomic dysfunction or discomfort. Symptomatic therapy of these various syndromes is beyond the scope of this chapter because there is no single agent that routinely works in even the most affected patients. The insensate foot is the strongest predictor of the risk for foot ulceration and amputation. Annual foot examinations focusing on skin integrity, structural abnormalities, adequacy of perfusion and neurologic function is essential. The Semmes-Weinstein 5.07- or 10-g filament is a particularly essential tool to use to evaluate sensory function, because most patients with insensate feet are unaware of their lack of sensation. People who cannot consistently feel the touch of the 10-g filament are at high risk of ulceration and should enter a comprehensive program of foot care, generally led by a podiatrist or other foot care specialist, including the use of emollients, special shoes, routine nail care, and careful daily self-examinations looking for early lesions.

Diabetic neuropathy (DN) is a common and troublesome complication of diabetes mellitus, leading to great morbidity and mortality and resulting in a huge economic burden for care of the patient with diabetes mellitus. It is the most common form of neuropathy in the developed countries of the world, accounts for more hospitalizations than all the other diabetic complications combined, and is responsible for 50% to 75% of nontraumatic amputations.
Diabetic neuropathy is a heterogeneous disorder that encompasses a wide range of abnormalities affecting proximal and distal peripheral sensory and motor nerves as well as the autonomic nervous system.
The major morbidity associated with somatic neuropathy is foot ulceration, the precursor of gangrene and limb loss.

Common types of diabetic neuropathies:

  1. Peripheral or Distal Symmetrical polyneuropathy - is the most common type.    Usually bilateral, the symptoms include numbness, paresthesias, severe hyperesthesias, and pain. The pain, which may be deep-seated and severe, is often worse at night. It is occasionally lancinating or lightning in type, resembling tabes dorsalis (pseudotabes). Fortunately, extreme pain syndromes are usually self-limited, lasting from a few months to a few years.
  2. Mononeuropathy , though less common than polyneuropathy, also may occur. Characteristically, there is a sudden wrist drop, foot drop, or paralysis of the third, fourth, or sixth cranial nerves. Other single nerves, including the recurrent laryngeal, have been reported to be involved. Mononeuropathy is characterized by a high degree of spontaneous reversibility, usually over a several-week period.
  3. Radiculopathy is a sensory syndrome in which pain occurs over the distribution of one or more spinal nerves, usually in the chest wall or abdomen. The severe pain may mimic herpes zoster or an acute surgical abdomen. Like mononeuropathy, the lesion is usually self-limited.
  4. Autonomic neuropathy may present in a variety of ways. The gastrointestinal tract is a prime target, and there may be esophageal dysfunction with difficulty in swallowing, delayed gastric emptying, constipation, or diarrhea. The latter symptom is often nocturnal. Incompetence of the internal anal sphincter may mimic diabetic diarrhea. Orthostatic hypotension and frank syncope may occur.
    Bladder dysfunction or paralysis is particularly distressing and often leads to the necessity of chronic catheter drainage. Impotence and retrograde ejaculation are additional manifestations in men. Erectile dysfunction is associated with a failure of nitric oxide generation in the penile vasculature.


DSPN (Distal Symmetrical Polyneuropathy) increases the risk of amputation 1.7-fold: 12-fold if there is deformity (itself a consequence of neuropathy) and 36-fold if there is a history of previous ulceration.
Once autonomic neuropathy sets in, life can become quite dismal, and the mortality rate approximates 25% to 50% within 5 to 10 years.
The natural history of diabetic neuropathy separates patients into two very distinctive entities:
(1) those who progress gradually with increasing duration of diabetes mellitus and
(2) those who have a relatively explosive onset and experience remission almost completely. Sensory and autonomic neuropathies generally progress, whereas mononeuropathies, radiculopathies, and acute painful neuropathies, although symptoms are severe, are short-lived and tend to recover.
Progression of DSPN  is related to glycemic control in both type 1 and type 2 diabetes mellitus. The most rapid deterioration of nerve function occurs soon after the onset of type 1 diabetes mellitus, and within 2 to 3 years there is a slowing of the progress with a shallower slope to the curve of dysfunction. In contrast, slowing of NCVs in type 2 diabetes mellitus may be one of the earliest neuropathic abnormalities and is often present at diagnosis.  After diagnosis, slowing of NCV generally progresses at a steady rate of approximately 1 m/second each year, and the level of impairment is positively correlated with duration of diabetes mellitus.
In a long-term follow-up study of patients with type 2 diabetes mellitus, electrophysiologic abnormalities in the lower limb increased from 8% at baseline to 42% after 10 years, and a decrease in sensory and motor amplitudes, indicating axonal destruction, was more pronounced than the slowing of the NCVs.

Diabetic neuropathy is not a single entity but a number of different syndromes, ranging from subclinical to clinical manifestations depending on the classes of nerve fibers involved.
The onset of neuropathy may be acute, with pain or, insidious, with chronic pain as well as clinical features of a mixed sensorimotor dysfunction.
According to the San Antonio Convention,
the main groups of neurologic disturbance in diabetes mellitus include the following:

  1. Subclinical neuropathy, determined by abnormalities in electrodiagnostic and quantitative sensory testing without concomitant clinical sign and symptoms.
    It is diagnosed on the basis of the following:
    • Abnormal electrodiagnostic tests with decreased NCV or decreased amplitudes;
    • Abnormal QST for vibration perception, light touch, thermal warming, and cooling thresholds;
    • QAFT revealing diminished heart rate variation with deep breathing, Valsalva maneuver, and postural testing.
  2. Focal neuropathies, which include mononeuropathies and entrapment syndromes.
    occur primarily in the older population, their onset is generally acute and associated with pain, and their course is self-limiting, resolving within 6 to 8 weeks. These are due to vascular obstruction after which adjacent neuronal fascicles take over the function of those infarcted by the clot.
    Treatment is predominantly symptomatic for pain. If there is weakness such as of the facial muscles, physical therapy and electrical stimulation may be necessary to prevent the weakness from becoming permanent.
    Entrapment syndromes
    that start slowly, progress, and persist without intervention must be distinguished from mononeuropathies. Common entrapment sites in diabetes mellitus patients involve median, ulnar, radial, femoral, and lateral cutaneous nerves of the thigh, peroneal nerves, and medial and lateral plantar nerves. Entrapment syndromes are found in one third of patients with diabetes. For example, carpal tunnel syndrome occurs twice as frequently in people with diabetes mellitus compared with a normal healthy population. It is important, therefore, to elicit a detailed history of the distribution of pain and weakness and to perform the equivalent of Tinel's test at various levels of entrapment. If recognized, the diagnosis can be confirmed by electrophysiologic studies.   There are nonsurgical and surgical treatment options.
  3. Diffuse clinical neuropathy, which may be
    proximal  motor neuropathy or distal symmetrical neuropathy and have
    large-fiber symmetrical sensorimotor
    small-fiber neuropathy and
    autonomic dysfunction.

Diffuse (Clinical) Neuropathies      
The condition is known by a number of synonyms: proximal neuropathy, femoral neuropathy, diabetic amyotrophy, and diabetic neuropathic cachexia.

Proximal motor neuropathy can be clinically identified based on recognition of the following common features:

  • Primarily affects the elderly.
  • Gradual or abrupt onset.
  • Begins with pain in the thighs and hips or 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).
  • Begins unilaterally and spreads bilaterally.
  • Coexists with DSPN.
  • Is characterized by spontaneous or percussion-provoked muscle fasciciulation.

Proximal motor neuropathy is now recognized as being secondary to a variety of causes unrelated to diabetes mellitus but that occur more frequently in patients with diabetes mellitus than in the general population. The condition includes patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy, circulating GM1 antibodies and antibodies to neuronal cells, and inflammatory vasculitis.  It was formerly thought to resolve spontaneously in 1.5 to 2 years, but now, if found to be immune-mediated, it can resolve within days of initiation of immunotherapy. The condition is readily recognizable clinically with prevailing weakness of the iliopsoas, obturator, and adductor muscles, together with relative preservation of the gluteus maximus and minimus and hamstrings.

Treatment options include intravenous immunoglobulin for CIDP, plasma exchange for monoclonal gammopathy of unknown significance, steroids and azathioprine for vasculitis, and withdrawal from drugs or other agents that may have caused a 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 separate syndromes.

Distal Symmetrical Polyneuropathy (DSPN)  
Distal symmetrical polyneuropathy (DSPN)
is the most common and widely recognized form of diabetic neuropathy. The onset is usually insidious but occasionally is acute, following stress or initiation of therapy for diabetes mellitus. DSPN may be either sensory or motor and involve small nerve fibers, large nerve fibers, or both. Small-fiber dysfunction usually occurs early and often is present without objective signs or electrophysiologic evidence of nerve damage.  It is manifested by early lower limb symptoms of pain and hyperalgesia in the lower limbs, followed by a loss of thermal sensitivity and reduced light touch and pinprick sensation.  
Most patients with DSPN, however, have a "mixed" variety of neuropathy, with both large-fiber and small-fiber damages. In the case of DSPN, a "glove-and-stocking" distribution of sensory loss is almost universal. Early in the course of the neuropathic process, multifocal sensory loss also might be found. In some patients, severe distal muscle weakness can accompany the sensory loss, resulting in an inability to stand on the toes or heels.

Small-Fiber Neuropathy
Clinical Manifestations of Small-Fiber Neuropathies

  1. Symptoms prominent. Pain is of the C-fiber type. It is burning and superficial and associated with allodynia, i.e., interpretation of all stimuli as painful (e.g., touch).
  2. Late in the condition, hypoalgesia.
  3. Defective warm thermal sensation.
  4. Defective autonomic function with decreased sweating, dry skin, impaired vasomotion and blood flow, and a cold foot.
  5. Remarkable intactness of reflexes, motor strength.
  6. Electrophysiologically silent.
  7. Loss of cutaneous nerve fibers using PGP 9.5 staining.
  8. Diagnosed clinically by reduced sensitivity to 1.0-g Semmes Weinstein monofilament and pricking sensation using the Waardenberg wheel or similar instrument.
  9. Abnormalities in thresholds for warm thermal perception, neuro-vascular function, pain, quantitative sudorimetry, and quantitative autonomic function tests.
  10. Risks are foot ulceration and subsequent gangrene.

At present, however, control of hyperglycemia and meticulous foot care are the mainstays of therapy.

Some of the suggested therapies for painful small-fiber neuropathy:

  • Capsaicin or lidocaine topically
  • Clonidine can be applied topically
  • Tramadol and Dextromethorphan
  • Antidepressants as Nortriptyline
  • Carbamazepine
  • Gabapentin
  • Transcutaneous Electrical Nerve Stimulation (TENS)
  • Analgesics
    are rarely of much benefit in the treatment of painful neuropathy, although they may be of some use on a short-term basis for some of the self-limited syndromes, such as painful diabetic third nerve palsy. Use of narcotics in the setting of chronic pain generally is avoided because of the risk of addiction.

Recommendatinos for First- and Second-Tiere Agents for Diabetic Peripheral Neuropathic Pain (DPNP) 2006

First tier Rx:

  • Duloxetine (Cymbalta), Oxycodone CR, Pregabalin (Lyrica), TCA (Tricyclic Antidepressants)

Second tier Rx:

  • Carbamazepine (Tegretol), Gabapentin (Neurontin), Lamotrigine (Lamictal), Tramadol (Ultram), Venlafaxine ER (Effexor ER)

Topical Rx:

  • Capsaicin, Lidocaine

Other Rx:

  • Bupropion, Citalopram, Metadone, Paroxetine, Phenytoin, Topiramate

RE: Mayo Clinic Proceedings Supplment April 2006, p: S22-23

Acute Painful Neuropathy
In some patients, a predominantly small-fiber neuropathy develops, manifested by pain and paresthesias early in the course of diabetes mellitus. It may be associated with the onset of insulin therapy and has been termed insulin neuritis.  By definition, it has been present for less than 6 months. Symptoms often are exacerbated at night and are manifested in the feet more than the hands. Spontaneous episodes of pain can be severely disabling. The pain varies in intensity and character. In some patients, the pain has been variably described as burning, lancinating, stabbing, or sharp. Paresthesias or episodes of distorted sensation, such as pins and needles, tingling, coldness, numbness, or burning, often accompany the pain. The lower legs may be exquisitely tender to touch, with any disturbance of the hair follicles resulting in excruciating pain. Because pain can be exacerbated by repeated contact of the lower limbs with foreign objects, even basic daily activities, such as sitting at a desk, may be disrupted. Pain often occurs at the onset of the disease and is often worsened by initiation of therapy with insulin or sulfonylureas.  
It may be associated with profound weight loss and severe depression, termed diabetic neuropathic cachexia.  This syndrome occurs predominantly in male patients and may occur at any time in the course of both type 1 and type 2 diabetes mellitus.
It is self-limiting and invariably responds to simple symptomatic treatment.

Chronic Painful Neuropathy
Another variety of painful polyneuropathy is characterized by an onset occurring later (often years) in the course of diabetes mellitus, in which the pain persists for longer than 6 months and becomes debilitating. This condition may result in tolerance to narcotics and analgesics and, finally, to addiction. It is extremely resistant to all forms of intervention and is most frustrating to both patient and physician.

Chronic Small-Fiber Neuropathy
Disappearance of these symptoms may not necessarily reflect nerve recovery but rather nerve death. When patients volunteer the "apparent improvement," progression of the neuropathy must be excluded by careful examination. Pain, however, may persist even with dead nerves. The objective physical features include loss of warm thermal perception, decreased heat pain, cold pain, loss of touch pressure perception, and impairment of blood flow. A foot with these findings is at risk for repeated minor trauma, foot ulceration, infection, and gangrene. Small-fiber neuropathies have profound effects on quality of life and mortality.

Large-Fiber Neuropathies
Large-fiber neuropathies may involve sensory nerves, motor nerves, or both .  These tend to be the neuropathies of signs rather than symptoms. Large fibers subserve motor function, vibration perception, position sense, and cold thermal perception.
Characteristic features are wasting of the interosseous muscles of the hands and feet, giving rise to the hammertoe deformities and pes equinus, and the loss of hand grip strength and the ability to tie knots and do buttons. There is a significant impact on activities of daily living.
Objective findings include loss of reflexes, decreased vibration perception, ataxic gait, and inability to perform a tandem stand or one-legged stand for longer than 30 seconds. There is no impairment of blood flow, the feet are often hot, and there is a susceptibility to osteopenia of the feet and a risk of Charcot's neuroarthropathy.
Clinical Presentation of Large-Fiber Neuropathies

  1. Impaired vibration perception (often the first objective evidence) and position sense.
  2. Depressed tendon reflexes.
  3. A delta type deep-seated gnawing, dull, like a toothache in the bones of the feet, or even crushing or cramp-like pain.
  4. Sensory ataxia (waddling like a duck).
  5. Wasting of small muscles of feet with hammertoes (intrinsic minus feet and hands) with weakness of hands and feet.
  6. Shortening of the Achilles tendon with pes equinus.
  7. Increased blood flow (hot foot).
  8. Risk is Charcot's neuroarthropathy.

Management of Large-Fiber Neuropathies

  1. Gait and strength training.
  2. Pain management as detailed in text.
  3. Orthotics should be fitted with proper shoes for the deformities.
  4. Tendon lengthening for Achilles tendon shortening.
  5. Bisphosphonates may be given for osteopenia.
  6. Surgical reconstruction and full-length casting as necessary.


Diabetic autonomic neuropathy may involve any system in the body. Involvement of the autonomic nervous system can occur as early as the first year after diagnosis, and major manifestations are cardiovascular, gastrointestinal, and genitourinary system dysfunction . Reduced exercise tolerance, edema, paradoxic supine or nocturnal hypertension, and intolerance to heat due to defective thermoregulation are a consequence of autonomic neuropathy.

Clinical Features of Autonomic Neuropathies

  • Cardiovascular
    • Resting tachycardia
    • Orthostatic hypotension
      - posture-related dizziness and syncope.
      RX: Volume expansion, Supportive Garments, Drug Therapy (9-fluorohydrocortisone, Metoclopramide, the a2 -antagonist yohimbine, small dose clonidine, a1-adrenergic agonist midodrine) 
    • Silent myocardial infarction, congestive heart failure, and sudden death
  • Gastrointestinal
    • Gastroparesis
      Rx: multiple small feedings, Metoclopramide, Erythromycin given as either a liquid or a suppository,jejunostomy placement
    • Diarrhea, constipation
      For Stasis of bowel contents with bacterial overgrowth -Treatment with broad-spectrum antibiotics is the mainstay of therapy, including tetracycline or trimethoprim and sulfamethoxazole.  Metronidazole appears to be the most effective and should be continued for at least 3 weeks.
      Retention of bile may occur and can be highly irritating to the gut. Chelation of bile salts with cholestyramine 4 g three times daily mixed with fluid may offer relief of symptoms.
      Diphenoxylate plus atropine
      may help control diarrhea; toxic megacolon can occur, however, and extreme care should be used.
      In refractory cases, small doses of octreotide can be helpful in controlling diarrhea.
  • Genitourinary
    • Bladder dysfunction
      doxazosin, self-catheterization
    • Erectile dysfunction
      Sildenafil (Viagra) 50-100 mg
  • Peripheral
    • Gustatory sweating
      Topically applied glycopyrrolate, an antimuscarinic compound, is effective treatment in reducing both the severity and frequency of sweating of the head and neck region while eating food that triggers this reflex.
    • Pupillary abnormalities
    • Disturbed neurovascular flow
    • Edema
  • Metabolic
    • Hypoglycemia unawareness, hypoglycemia unresponsiveness


Correlation of HgA1c to Average Blood Glucose
  •  6% - 135 mg/dL |  7% - 170 mg/dL  |   8% - 205 mg/dL  |   9% - 240 mg/dL  |  10% - 275 mg/dL  |  11% - 310 mg/dL  | 12% - 345 mg/dL
    Each 1% above 6% add 35 mg/dl to the base 135 mg/dL.

* Try to keep HgbA1c < 6-7% with good glycemic control !!!